Sensorimotor Behavior in

Children Born Preterm and

Adolescents with Cerebral Palsy
Side preference, movement organization, and training

Anna-Maria Johansson

Department of Psychology
Umeå 2012
This work is protected by the Swedish Copyright Legislation (Act 1960:729)
ISBN: 978-91-7459-510-9
Cover design by Henrik Johansson
Electronic version available at http://umu.diva-portal.org/
Printed by: Print & Media
Umeå, Sweden 2012
To my loved ones ♥

i
ACKNOWLEDGEMENTS
The past few years have been an inspiring and exciting time where I have
had the opportunity to work and develop in a stimulating research
environment. There are several people and instances that have enabled the
making of this thesis and contributed to making these years such a special
time.

I would firstly like to thank all the families, children and adolescents for
partaking in the studies. Without you there would be no thesis.

My supervisors Louise Rönnqvist and Erik Domellöf, thank you for your
excellent advisory skills involving lots of encouragement and support. I
greatly value your openness, good humor, go-for-it attitude, and your
willingness to share your experience and expert knowledge. You make a
great team!

Without funding, of course, there would be few opportunities to endeavor

into a research career. I would like to thank the Norrbacka-Eugenia
Foundation for funding my Ph.D. studies and the Swedish Research Council
for their contribution to the projects.

Special thanks to Aijaz Farooqi and Magnus Domellöf for your advice and
collaboration in the data collection. I would also like to thank Jennie, Johan,
Henrik, Kalle, and Helena for your assistance in the projects.

I am also very grateful for the invaluable comments and suggestions for
improvements on earlier work and drafts of this thesis from Gustaf
Gredebäck, Anna-Sara Claeson, Anna Stigsdotter-Neely, Linus Andersson,
och Kerstin Rosander.

During my time as a Ph.D. student I have been at the MRI clinic at the
Norrlands’ University Hospital collecting data for the projects involved.
Although these results did not make it into the thesis I am nevertheless
grateful to the staff at the clinic for your kind assistance. A special thanks to
our collaborators in the research focused on imaging; Katrine Åhlström
Riklund, Richard Birgander, Thomas Lindqvist and Niklas Lenfeldt.

I have also made many friends at the Department of Psychology. Carola,

Petra (who among many other things happens to be the best roomie ever!),
Camilla, Daniel, Inga, Eva, Helene, Mikael S, Esther, Olympia, Susanne and

ii
Linus. Thank you all for the good times. You are an important reason for why
these years have been so much fun!

I would like to thank my family and friends for your love, support, and
patience with my, at many times, both physical and mental absence. A very
special thank you to Henrik for designing the cover of the thesis, producing
the included photographs, great work with movement data processing, pizza
evenings with you and your girls, and of course for being a great brother.
Darling Ella, thank you for lending us a hand with the cover and for letting
me use your photographs. To Lars, the co-founder of project JJ, thank you
for blessing my life with your presence!

Umeå, October 2012

iii
TABLE OF CONTENTS

ACKNOWLEDGEMENTS ii
TABLE OF CONTENTS iv
ABSTRACT vii
SAMMANFATTNING PÅ SVENSKA ix
ABBREVIATIONS xiii
LIST OF PAPERS xiv
INTRODUCTION 1
Preterm birth and CP 1
Demographics 1
The vulnerable preterm brain 3
Maturational aspects 3
Biological mechanisms 3
Lesion types and their effect on brain development 4
Genetic factors 6
Sensorimotor and intellectual function in children born preterm 7
General motor functions and the relation to risk factors 7
Intellectual function in children born preterm 9
Relations between motor function and cognition in children born preterm 11
Upper-limb goal-directed movements in children born preterm 12
Handedness and movement performance in children born preterm 13
Cerebral Palsy 15
Functional impairments in children with CP 15
Risk factors for the development of CP 17
Brain lesions in CP 17
Goal-directed upper-limb movements in CP 18
The malleable brain 19
Plastic changes in development 19
Plasticity and interventions 19
OBJECTIVES 21
METHODS 22
Systematic review and meta-analysis (study I) 22
Study design and inclusion criteria 22
Quality assessment 22
Statistical methods 23
Empirical studies (studies II-IV) 25
Study designs 25
Handedness, movement performance, and intellectual function in children born
preterm (studies II and III) 25
Short- and long-term effects of timing and rhythmicity training on upper-limb
movements in children with cerebral palsy (study IV) 25

iv
 Participant description and recruitment process (study II-IV) 26
Studies II-III 26
Study IV 28
Methods of assessment 29
Frequency assessment of hand dominance (studies II and III) 29
3-dimensional motion analyses (studies II-IV) 30
Interactive Metronome (study IV) 35
Gross Motor Function Classification System (Study IV) 38
Manual Ability Classification System (Study IV) 38
Arm/hand function questionnaire (study IV) 39
Socioeconomic information (studies II-III) 40
Wechsler’s Intelligence Scale for Children (study III) 40
Journal background/ medical birth history (studies II-IV) 40
Statistical methods 41
Study II 41
Study III 42
Study IV 42
Ethical considerations 42
SUMMARY OF RESULTS AND BRIEF DISCUSSION OF FINDINGS 43
UStudy I 43
Study II 46
Study III 50
Study IV 52
GENERAL DISCUSSION, FUTURE PROSPECTS AND CONCLUSIONS 56
Differences between the groups of children born preterm and fullterm 56
Hand preference 56
Movement organization 57
Intellectual function 58
The influence of age, GA, and sex 59
Handedness: a dichotomy between preference and performance? 60
Training of sensorimotor functions 61
Timing training and constraints 61
Feedback in sensorimotor learning 62
Motor planning or biomechanical constraints? 62
Methodological considerations 63
Future prospects and conclusions 64
The role of intellectual function in movement organization 64
The role of sensory and proprioceptive information in movement organization 65
The role of larger study populations 66
The advancement of synchronized metronome training studies 66
REFERENCES 67

v
vi
ABSTRACT
Preterm birth (< 37 complete gestation weeks, GWs) is the single most
prominent risk factor for the development of cerebral palsy (CP). This is due
to the immature physiological state of the preterm born infant which
increases the risk of brain lesions. In CP, prominent sensorimotor, cognitive,
and perceptual deviations are manifested with varying degrees of functional
impairment. Although the majority of children born preterm (PT) do not
develop CP, sensorimotor and cognitive deficits are frequently reported in
the absence of major disability. To date, few studies have focused on detailed
kinematic analysis of upper-body goal-directed movements and how aspects
of movement organization and control are related to hand preference,
intellectual function, gestational age, and sex within groups of prematurely
born children. Further, studies evaluating effects of sensorimotor training in
persons with CP is needed and of importance as positive effects on
movement performance may increase individual autonomy as a
consequence.

To investigate the prevalence of non-right hand preference within children

born PT in comparison to children born fullterm (FT), a meta-analysis and
literature review were performed (study I). It was shown that children born
PT had increased rates of non-right handedness (NRH) corresponding to
22% compared to 12% in the FT group (odds ratio 2.12). In study II, hand
preference and side specific movement performance in children born PT (≤
35 GWs) compared to an age matched group of children born FT were
investigated. All included participants were 4-8 years of age without major
disability. Movement performance was studied through detailed kinematic
registrations of the head, arm, and hand during a goal-directed task and
hand preference through observations of the hand used when manipulating
different objects. On a group level, the children born PT, specifically those
born < 33 GWs, showed an increased rate of NRH, weaker strength of hand
preference, and a lack of side specificity in terms of movement kinematics. In
general, the children born < 33 GWs also displayed poorer movement
organization and control as expressed by longer durations, less smooth and
longer distances of the movement trajectories. These findings imply that
preterm birth has long term effects on sensorimoror organization and
function, possibly reflecting a developmental delay and/or a persistent effect
that may be associated with the increased risk of deviations in brain
development.

In study III, associations between movement performance, assessed with the

same task as in study II, and intellectual function (Wechsler Intelligence

vii
Scale for Children, 4th ed; WISC-IV) were studied. This study included a
subsample of the children from study II at 6-8 years of age. The results
showed a link between movement organization and general intellectual
functioning (IQ), when controlling for effects of GA and sex, for the PT born
but not the FT born children. These findings suggest shared neural
underpinnings and interrelated development of motor and intellectual
functions.

In study IV, kinematic analysis of upper-body movements and subjective

experience of change in upper-body function were applied before and after a
period of synchronized metronome training (SMT) in adolescents with
varying degree of CP to study the effects of this type of training. The SMT
method applied entailed elements of movement timing and rhythmic
activation coupled with feedback and was hypothesized to train sensorimotor
integration. It was found that SMT did improve, to varying degrees, the
organization and control of movements in adolescents with CP. The
participants with more severe forms of CP reported substantial effects in
daily living activities. The observed effects of SMT warrant further study of
specific effects on movement planning, biomechanical constraints, and
attention.

The relation between hand preference and movement performance,

movement performance and intellectual function, and aspects related to the
SMT method applied in study IV are considered. Specifically, the lack of side
specific movement organization within the group of children born PT is
discussed from perspectives of motor learning, plasticity, and genetics.
Further, the relations between movement performance and intellectual
functions are considered and suggestions for how this association could be
tested are given. With relation to study IV, the functions trained by the
specific SMT method applied and the accessibility of individuals with
different degree of CP is discussed. Methodological considerations,
suggestions for methodological refinements and the development of research
paradigms aimed at the investigation of proposed new lines of enquiry are
presented

viii
SAMMANFATTNING PÅ SVENSKA
Varje år föds det drygt 100 000 barn i Sverige. Cirka 5% av dessa barn föds
för tidigt, det vill säga före 37 kompletta graviditetsveckor. Av de barn som
föds för tidigt har majoriteten en gestationsålder (antalet graviditetsveckor)
över 33 veckor (Medicinska födelseregistret, 2009). Omkring 8% av barn
som föds för tidigt diagnosticeras senare med cerebral pares (CP) (Ancel, et
al., 2006) och omkring hälften av personer med diagnosen CP har en för
tidig födelsehistorik (Beaino et al., 2010). CP är ett paraplybegrepp som
innefattar ett flertal icke-progressiva motoriska utvecklingsavvikelser av
olika karaktär och funktionsnedsättningsgrad, orsakade av hjärnskador som
inträffar under fosterlivet eller vid förlossningen. Vanligtvis så påverkas även
sensorik, perception, kognition, och beteende negativt (Rosenbaum, Paneth,
Leviton, Goldstein, & Bax, 2008). En prematur födsel utgör den största
riskfaktorn för utvecklingen av CP där risken är störst för de barn som föds
allra tidigast (Murphy, Sellers, MacKenzie, Yudkin, & Johnson, 1995). De
allra flesta barn som föds för tidigt drabbas dock inte av grav sensomotorisk
funktionsnedsättning som till exempel CP trots att det finns en ökad risk för
hjärnskador hos denna grupp. Ett flertal studier har ändå visat att barn som
fötts för tidigt och ej diagnosticerats med CP i högre grad än fullgångna barn
generellt har både motoriska (e.g., Williams et al., 2010) och kognitiva (e.g.,
Bhutta, 2002) funktionsnedsättningar.

I dagsläget så har endast ett fåtal studier fokuserat på att i detalj studera
organiseringen av målinriktade hand-armrörelser hos barn som fötts för
tidigt. Av dessa har merparten fokuserat på spädbarn i syfte att finna tidiga
markörer för sensomotoriska avvikelser. Då de sensomotoriska problemen
hos för tidigt födda barn kvarstår i skolåldern och i vissa fall är så diskreta
att de upptäcks först när barnet börjar skolan så kan rörelseanalys vara en
metod som kan bidra till ökad förståelse och kunskap om hur den
sensomotoriska påverkan uttrycks hos äldre barn. Ett av syftena med denna
avhandling var således att noggrant studera organiseringen av huvud-, arm-,
och handrörelser under en målinriktad handling hos barn som fötts för tidigt
jämfört med en grupp barn i samma åldrar (4-8 år) som fötts efter
fullgången graviditet. Av intresse är att studera relationen mellan aspekter
associerade med rörelseorganisation och handpreferens, intellektuell
förmåga, gestationsålder, samt kön. Då barn och ungdomar med CP utgör
den största diagnosgruppen som behandlas inom barn- och
ungdomshabiliteringar (Odding, Roebroeck, & Stam, 2006) finns det ett
stort behov av att utvärdera effekten av redan existerande träningsmetoder.
Ett ytterligare syfte med detta avhandlingsarbete var att utvärdera både kort-
och långtidseffekter av en etablerad träningsmetod (synchronized

ix
metronome training; SMT) som antas främja den sensomotoriska
integreringen hos ungdomar (12-17 år) med diagnosen CP. Effekterna av
denna träningsmetod utvärderades med hjälp av detaljerad rörelseanalys
samt ett frågeformulär gällande individens upplevelse av förändring.

Då barn som fötts för tidigt i vissa studier har visat sig ha en ökad prevalens
av icke-högerhänthet, det vill säga fler som är vänsterhänta eller tvåhänta
(ambidextra), så utfördes en systematisk litteraturgenomgång och en
metaanalys för att undersöka detta fenomen närmare (studie I). I denna
studie visade det sig att barn som fötts för tidigt i större utsträckning var
icke-högerhänta jämfört med barn som fötts efter en fullgången graviditet
(odds ratio 2.12). Hos de för tidigt födda barnen var 22% icke högerhänta
jämfört med 12% av de som fötts efter fullgången graviditet. Dock säger
handpreferensstudier inget om hur kvaliteten på rörelser utförda med den
föredragna eller icke-föredragna handen ser ut. För att undersöka
sambandet mellan handpreferens och kvalitet på rörelser kopplade till den
föredragna och icke-föredragna handen hos barn som fötts för tidigt, jämfört
med fullgångna åldersmatchade kontroller, utfördes kinematiska
rörelseanalyser samt ett testbatteri som undersöker handpreferens (studie
II). Barnen utförde målinriktade rörelser, med en hand i taget, i en uppgift
som ställer höga krav på öga-hand-koordination och precision. Uppgiften
bestod i att plocka upp och trä så många pärlor som möjligt på en smal pinne
under 30 sekunder. Denna studie visade att barnen med en för tidig
födelsehistorik, speciellt de mycket för tidigt födda (före graviditetsvecka
33), i större utsträckning var klassificerade som icke-högerhänta och hade en
svagare handpreferens i jämförelse med barnen som inte fötts för tidigt. De
mycket för tidigt födda barnen visade även, som grupp, en sämre
organisering av huvud-, arm-, och handrörelser vilket manifesterades i en
ökad längd, tidsåtgång och ojämnhet av rörelsebanorna. Oavsett
gestationsålder så visade den för tidigt födda gruppen barn inga
sidoskillnader i kvaliteten på rörelserna vilket däremot var tydligt hos
gruppen barn som fötts vid fullgången graviditet. Dock så skiljde sig gruppen
barn som fötts moderat för tidigt (mellan graviditetsvecka 33 och 35) inte
statistiskt signifikant åt från barnen i den fullgånget födda gruppen. Dessa
resultat indikerar en långvarig effekt av för tidig födsel på sensomotorisk
funktion. Den markanta påverkan som barnen som fötts före
graviditetsvecka 33 uppvisade, kan tolkas som en effekt av den ökade risken
för avvikelser i hjärnans utveckling.

I studie III undersöktes sambanden mellan intellektuell förmåga och

organiseringen av rörelser hos barn som fötts för tidigt samt hos barn som
fötts efter en fullgången graviditet i 6-8 års ålder (en subgrupp ur studie II).
Den intellektuella förmågan undersöktes med hjälp av Wechsler Intelligence

x
Scale for Children, 4:e upplagan, och den kinematiska uppgiften var den
samma som beskrivits ovan. Denna studie visade på skillnader i intellektuell
förmåga, specifikt gällande generell intelligens samt verbal och perceptuell
förmåga, där de för tidigt födda barnen hade lägre poäng än de fullgångna
barnen. Viktigt att poängtera är dock att medelvärdena för gruppen för tidigt
födda barn låg inom det normala spannet. Vidare så visade sig
gestationsålder och generell intellektuell förmåga ha betydelse för det
motoriska utförandet hos de för tidigt födda barnen, speciellt på den
föredragna sidan. Kön bidrog inte till att förklara skillnader i organiseringen
av rörelser. Intellektuell förmåga hade ingen relation till den sensomotoriska
funktionen hos gruppen barn som fötts efter en fullgången graviditet. Detta
belyser vikten av att studera kognitiva aspekter av motorisk funktion för att
bättre förstå de skillnader eller avvikelser som ofta påvisas hos barn med en
för tidig födelsehistorik. Dessutom skulle en sådan ansats öka kunskapen om
den interrelaterade utvecklingen av motorisk och intellektuell förmåga, både
ur ett beteendeperspektiv och ur ett hjärnutvecklingsperspektiv.

Kinematisk rörelseanalys användes även i studie IV för att beskriva

eventuella förändringar i rörelseorganisation efter SMT-träning hos
ungdomar med olika typer av CP och varierande grad av
funktionsnedsättning (studie IV). Ungdomarna utförde en målinriktad
uppgift som bestod i att tända små lampor i sekventiell ordning. Testerna
genomfördes vid tre tillfällen, före, i anslutning till avslutad SMT-träning
samt 6 månader efter avslutad SMT-träning. Träningsperioden varade i 4
veckor och innefattade 12 individanpassade SMT-sessioner. Den typ av SMT-
träning som användes i denna studie antas främja sensomotorisk integrering
genom rytmisk aktivering och timing av rörelser mot en auditiv och visuell
signal. Feedback på avvikelsen i synkronisering, och en instruktion om hur
deltagaren skall uppnå bättre rörelsetiming, ges direkt både auditivt och
visuellt. Denna studie visade på förändringar i rörelseorganisation och
motorisk kontroll hos flertalet av deltagarna. Dessa effekter kvarstod till viss
del vid uppföljningen efter 6 månader. Deltagarna med gravare
funktionsnedsättning rapporterade substantiella förändringar i förmågan att
delta i dagliga aktiviteter både direkt efter avslutad träning samt 6 månader
senare. De rapporterade effekterna gällde ökad snabbhet, minskad
muskeltonus, bättre arm-, hand- och fingerkontroll, samt ökad motivation
att använda armen och handen både i träning och vardagliga aktiviteter.
Dessa subjektivt upplevda förändringar tillsammans med de vi observerat i
de kinematiska parametrarna utgör en grund för fortsatta studier av effekter
av SMT hos denna grupp ungdomar och även hos andra grupper barn och
ungdomar med motoriska problem. En ansats där effekter av SMT-metoder
studeras utifrån rörelseplanering, biomekaniska restriktioner, samt
uppmärksamhet skulle vara av betydelse.

xi
I avhandlingen diskuteras även relationen mellan handpreferens och kvalitet
på rörelser i relation till den föredragna och icke-föredragna handen,
samband mellan organisering av rörelser och intellektuell förmåga, samt
aspekter relaterade till SMT metoden som applicerats i studie IV. Specifikt
diskuteras avsaknaden av en sidospecifik rörelseorganisering hos gruppen
barn som fötts för tidigt i relation till motorisk inlärning och hjärnans
förmåga att förändra sig. Relationen mellan organisering av rörelser och
intellektuell förmåga tas i beaktande och förslag på hur detta samband kan
undersökas i kommande studier ges. Vidare så diskuteras vilka funktioner
som SMT-metoden tränar samt dess tillgänglighet för barn och ungdomar
med olika grad av funktionsnedsättning relaterad till typ av CP diagnos.
Metodologiska överväganden och idéer för framtida forskningsansatser inom
dessa områden presenteras.

xii
ABBREVIATIONS

ANCOVA Analysis of covariance

BW Birth weight
CP Cerebral palsy
CS Corticospinal
ELBW Extremely low birth weight, < 1000 gram
E-PT Extremely preterm (< 28 GWs)
FT Fullterm
GA Gestational age, used interchangeably with GW
GM Gray matter
GMFCS Gross Motor Function Classification System
GW Gestational week, used interchangeably with GA
IVH Intraventricular hemorrhage
IQ Intelligence Quotient
MACS Manual Ability Classification System
M-PT Moderately preterm (33-35 GW)
MU Movement unit
MANCOVA Multivariate analysis of covariance
OR Odds ratio
PAM Pacemaker-accumulator model
PVL Periventricular leukomalacia
ROP Retinopathy of prematurity
SGA Small for gestational age
SMT Synchronized metronome training
SVZ Subventricular zone
VIQ Verbal IQ
V-PT Very preterm (29-32+6 GW)
WISC-IV Wechsler’s Intelligence Scale for Children, 4th edition
WM White matter

xiii
LIST OF PAPERS

I. Domellöf, E., Johansson, A.-M., & Rönnqvist, L. (2011). Handedness

in preterm born children: a systematic review and a meta-analysis.
Neuropsychologia, 49(9), 2299–310.
doi:10.1016/j.neuropsychologia.2011.04.033

II. Johansson, A.-M., Domellöf, E., & Rönnqvist, L. (2012). Hand

preference and side specificity in goal-directed movement
performance in children born preterm. (Under revision).

III. Domellöf, E., Johansson, A.-M., Farooqi, A., Domellöf, M., &
Rönnqvist, L. (2012). Relations between upper-limb movement
organization and IQ in children born preterm at school age.
(Submitted)

IV. Johansson, A.-M., Domellöf, E., & Rönnqvist, L. (2012). Short- and
long-term effects of synchronized metronome training in children
with hemiplegic cerebral palsy: a two case study. Developmental
neurorehabilitation, 15(2), 160–9.
doi:10.3109/17518423.2011.635608

Papers I and IV have been reprinted with the permission of the copyright
holders.

xiv
INTRODUCTION
The main objectives of this thesis were to study sensorimotor behaviors in
children born preterm and in adolescents with cerebral palsy (CP). The
studies within the thesis are focused on the investigation of hand preference,
side specific and general movement performance in children born preterm.
An important aim was also to study effects of synchronized metronome
training (SMT) on movement performance in adolescents with CP.
Movement performance was studied by detailed kinematic analyses of
upper-body (head, arm, and hand) goal-directed movements. Further,
associations between movement organization, gestational age (GA), sex and
intellectual function were studied in the children born preterm. Detailed
measures and analyses of movement organization were undertaken in this
endeavour.

The introduction to the thesis will provide a background to this area of

research. Firstly, the associations between preterm birth and CP are
presented from a demographic perspective. This is followed by a brief
description of the neurobiological and maturational aspects that render the
preterm born infant especially prone to brain lesions associated with CP.
This section also provides neurobiological explanations for why children
born preterm, without major disability, often show mild to moderate motor,
cognitive, and behavioral impairments. A theoretical account of hand
preference and a brief review of handedness within this group of children is
also given. Secondly, a background to sensorimotor and intellectual
functions and their relation in children born preterm without major
disability is presented. Thirdly, a description is given of the functional motor
impairments in CP and different CP diagnoses, associated brain lesions, and
effects of interventions.

Preterm birth and CP

Demographics

Every year, just over 100,000 children are born in Sweden. Of these,
approximately 5% are of preterm status (< 37 gestation weeks; GWs) where
the majority (≈4%) of children are born after GW 33 (The Swedish Medical
Birth Register, 2009). Over the past three decades, due to advancements in
obstetric and neonatal intensive care, there has been considerable
improvement in the survival rates of infants born preterm and/or with a low
(< 2500 grams) birth weight (BW). The main rise in survival rates can be

1
observed in infants born < 26 complete GWs or at extremely low BWs (<
1000 grams, ELBW) (e.g., Colvin, McGuire, & Fowlie, 2004). The immature
physiological state of the preterm born infant is associated with increased
risk of disruption or lesions to the developing central nervous system.
Preterm birth is the most prominent risk factor for the development of
cerebral palsy (Murphy, Sellers, MacKenzie, Yudkin, & Johnson, 1995),
which is a non-progressive disorder with persistent sensorimotor limitations
and frequent deviances in cognition, perception, and behaviour caused by
pre- or perinatal brain lesions (Rosenbaum, Paneth, Leviton, Goldstein, &
Bax, 2008). Children with CP constitute the largest diagnostic group treated
within pediatric rehabilitation services (Odding, Roebroeck, & Stam, 2006),
thus, research approaches aimed at the development, evaluation, and
improvement of training methods are necessary.

The prevalence of CP has been shown to be 1.5-2.5/1,000 live births (e.g.,

Cans et al., 2007; Himmelmann, Hagberg, & Uvebrant, 2010; Nordmark,
Hägglund, & Lagergren, 2001). Although rates of premature birth are
increasing in most countries (Blencowe et al., 2012), the incidence and
severity of CP in preterm born populations have been shown to be decreasing
(van Haastert et al., 2011). Within the population with CP in Sweden, 5.5%
were born < 28 GWs, 4.4% between GW 28-31, and 0.15% were born > 36
GWs (Himmelmann et al., 2010). Within populations born preterm, the
prevalence of CP has been estimated at approximately 0.7% at 34 GWs
(Marret et al., 2007), gradually increasing with lowering of GA to 4% in GW
32, and at approximately 20% at 24-26 GWs (Ancel et al., 2006). This is to
be compared to the prevalence of CP in the fullterm born population which
has been estimated to 0.9 to 1.43/1,000 live births (Ancel et al., 2006;
Himmelmann et al., 2010; Marret et al., 2007).

As shown, a relation between preterm birth and CP in terms of increased

prevalence of CP in preterm born populations is clearly evident. It is also
clear that the majority of children born preterm do not develop CP. However,
school-aged children born preterm without major disability have been shown
to have considerable cognitive, behavioral, motor, and neuromotor deficits
(Edwards et al., 2011; Ment, Hirtz, & Hüppi, 2009; Williams, Lee, &
Anderson, 2010; de Kieviet, Piek, Aarnoudse-Moens, & Oosterlaan, 2009). It
has been argued that neuromotor abnormalities are the most common
hidden disability among preterm children as they usually go undetected until
school age (Bracewell & Marlow, 2002).

2
The vulnerable preterm brain

It is well known that the developing brain has different susceptibility to

injury at different times in development, resulting in neuronal
developmental disruption and/or necrosis that is dependent on the type of
injury, time of occurrence in development, localization, and the extent of the
insult (e.g., Ferriero, 2004; Johnston & Hoon, 2006; Rees & Inder, 2005;
Volpe, 1998, 2009). The risk of such events occurring gradually increases
with lowering of GA, which puts the infant born preterm at increased risk of
suffering brain lesions (Volpe, 2008, 2009). At times the insult is so timed
and of such magnitude that it results in more severe sensorimotor deviations
as those seen in CP (Glinianaia, Rankin, & Colver, 2011).

Maturational aspects

The infant born preterm is specifically vulnerable to brain lesions due to an

interaction between the pathological effects of neuro-destructive events and
the developmental state of the infant. The lesions that occur in response to
the neuro-destructive events are primarily located in the cerebral white
matter (WM) as the vascular support of this area is underdeveloped and
vulnerable. The immaturity of the cerebral vascular system increases the risk
of oxygen deprivation and irregularities in perfusion pressure (Soul et al.,
2007; Volpe, 1998, 2008). Further, the infant born preterm has a respiratory
system that is underdeveloped, which adds to the risk of low oxygen
saturation (Volpe, 2001). From the 24th GW the arteries in the WM undergo
rapid development, where vascular interconnections are formed and as a
result of this development the infant born preterm is less susceptible to more
severe forms of WM insults after the 32nd GW (Johnston & Hoon, 2006).
However, aspects of the cerebral vascular system are still immature at 40
GW and falls in perfusion pressure may therefore still cause WM injury in
the moderately preterm and fullterm born child (Volpe, 2001). In terms of
brain development, the period of 24-40 GW is a time of important
developmental, often overlapping processes. Events resulting in brain insults
during this period affect several neuronal elements that have far-reaching
primary and secondary effects in terms of brain volume, and neuronal
organization and function (Myers & Ment, 2009; Volpe, 2009; de Kieviet,
Zoetebier, van Elburg, Vermeulen, & Oosterlaan, 2012).

Biological mechanisms

The brain lesions that infants born preterm have increased risk of are caused
by inflammation and/or infection, and/or oxygen deprivation, and/or
intracranial hemorrhages (Volpe, 2008). The infection/inflammation route

3
to brain lesions include maternal, placental, and infant
infections/inflammations and the hypoxic/ischemic route involves the
immature respiratory and vascular system of the infant born preterm. These
events result in the activation of destructive mechanisms within the central
nervous system. The activation of these mechanisms coincides with several
maturational factors that interact and lead to brain injury (Burd,
Balakrishnan, & Kannan, 2012; Ferriero & Miller, 2010; Volpe, 2009).

These destructive mechanisms (activation of microglia) are specifically

detrimental to the immature oligodendrocyte, which later develop into
myelin producing oligodendrocytes (Volpe, 2008, 2009). Other neuronal
elements associated with the establishment of thalamo-cortical connections
and proliferation of interneurons and glial cells have also been implicated
(Bystron, Blakemore, & Rakic, 2008; Ferriero & Miller, 2010; McQuillen &
Ferriero, 2005; Volpe, 2009). A sequela of microglial activation during the
latter half of pregnancy has been shown to lead to reduced cerebral WM
volumes (hypomyelination) due to the adverse effects on the immature
oligodendrocyte (Volpe, 2008). Further, during the third trimester
important organization of the cortex occurs when thalamic, association, and
commissural projections enter the cortical plate. Synapses are formed and
dendritic differentiation occurs. This is also a period of rapid development of
the cerebellum (Volpe, 2009). The establishment of these neural connections
(synapses) and the neural organization of the cortex have been shown to be
important for many higher cognitive functions (Volpe, 2009).

Lesion types and their effect on brain development

The most frequently occurring insult in the infant born preterm is related to
hypoxic-ischemic events and infection-inflammation. Far less common are
intraventricular hemorrhagic infarction (IVH) and periventricular
hemorrhagic infarction (Volpe, 2009). The most common lesion in the infant
born preterm is periventricular leukomalacia (PVL) which is believed to be
primarily caused by hypoxia-ischemia. PVL can also occur in the term infant
with cardio-respiratory disturbance and in infants that have been exposed to
maternal placental/fetal infection and inflammation (Volpe, 2008). PVL
lesions have been shown to be present in 50% of preterm born infants with a
birth weight of < 1500gram (Volpe, 2008) and in 80% of cases with CP,
especially prominent in those with spastic diplegia (Johnston & Hoon,
2006). A systematic review of neuroimaging studies in CP has shown that
83% of individuals with CP have neuropathology, where WM abnormalities
are the most frequently reported abnormality. The combination of WM and
gray matter (GM) abnormalities is more common in persons with hemiplegic
CP as this type of lesion usually occurs in fullterm births (Korzeniewski,

4
Birbeck, DeLano, Potchen, & Paneth, 2008). Hemiplegic CP is commonly
caused by IVH (Nelson & Lynch, 2004) and intracranial hemorrhagic lesions
occur in 25% of cases with PVL but are relatively rare in isolation (Volpe,
2008).

PVL has a focal and a diffuse component. In the focal component, all cellular
elements are affected and the lesion can cause cyst and cavity formation in
the periventricular WM or, more commonly, causes microscopic glial scars
that are generally undetectable by neuroimaging. The diffuse component is
more widespread in the WM and the immature oligodendrocytes are
selectively affected (Volpe, 2008, 2009). The focal component is located in
the deep WM at the end and border zones of the long penetrating arteries
whilst the diffuse form is located in the area surrounding the short
penetrators. One outcome of the diffuse form of PVL is hypomyelination
which can be observed as an enlargement of the lateral ventricles as a result
of the reduction of myelin (Volpe, 2008, 2009). Volpe (2009) suggests that
the diffuse microscopic form of PVL may account for the cognitive and
behavioral problems observed in preterm born children without major
disability, whereas the macroscopic forms account for the motor deviations
observed in cases with CP.

When the insult to the developing brain is severe, as often in IVH infarcts,
similar effects on brain development to those described above are observed
as part of the mechanism is the same. However, the site of hemorrhage is
usually in close proximity to the descending corticospinal system (CS) and
IVH usually destroys at least part of these fibers. The site of hemorrhage is
also a region where neurons are proliferated, resulting in neuronal loss and
migratory disturbance (Volpe, 2008). Much focus has been placed on the
development of the CS system in relation to pre- and perinatal brain injury
and CP. The CS system involves the corticospinal tract and the sensorimotor,
premotor, and primary motor cortices from which it originates (Pitcher,
Schneider, Drysdale, Ridding, & Owens, 2011). The CS system supports most
skillful behaviors involving the forearm, hand and fingers. It is the last motor
system to mature and its refinement is activity-dependent. It has been
argued that the protracted activity dependency of CS system development
makes is especially vulnerable to effects of pre-perinatal brain injuries. These
lesions may sever the axonal connections between the brainstem and the
cortex and as a result the CS system may be less able to establish synapses
that lead to reduced hand function (Martin, 2005). These lesions to the CS
system can lead to re-organization of motor control over the hands and arms
to one hemisphere with retained and improved ipsilateral connectivity as
observed in some individuals with hemiplegic CP (Staudt et al., 2002;
Staudt, 2007).

5
However, in children born preterm with CP, the thalamo-cortical pathways
have been shown to be more affected than the CS tract (Hoon et al., 2002,
2009). Further, a recent study in preterm born infants with no apparent
cerebral lesions has shown that a reduced thalamic volume predicts a
decreased cortical volume, lower volumes of the frontal and temporal lobes,
including the hippocampus, and reduced integrity of the CS tract. These
results were more prominent in lower GAs. The authors suggest that preterm
birth has specific effect on the thalamo-cortical system that has secondary
effects on related structures such as the CS system (Ball et al., 2012). These
findings are in accordance with the vulnerable state of the neurons
implicated in thalamo-cortical connectivity and the late migrating thalamic
neurons during the latter half of pregnancy (Volpe, 2009). Taken together,
these outcomes suggest that although motor impairments may be prominent
(as seen in the studies by Hoon et al., 2002, 2009), the sensory system may
be even more affected by WM lesions or developmental disruptions
associated with a preterm birth. A sensory system that is readily implicated
in WM lesions and disruptions in children born preterm is the cortical visual
system. Specifically, the dorsal cortical visual stream which underpins visuo-
spatial awareness, depth and motion perception has been implicated
(Atkinson & Braddick, 2007; Taylor, Jakobson, Maurer, & Lewis, 2009).
However, the involvement of the sensory systems does not exclude the
importance of an intact CS system for sufficient upper-limb function but
suggests more widespread effects on the brain than just the motor system.
This is in accordance with the disruptions caused by microglial activation as
previously described. Accordingly, a recent meta-analysis has shown
comparable volumetric reductions of the whole brain, WM, GM,
hippocampus, corpus callosum, and cerebellum in children born very
preterm (< 33 GW) (de Kieviet et al., 2012).

Genetic factors

Both CP and preterm birth have been shown to be associated with genetic
factors. In CP, several genetic mutations have been identified and the
disorder has been shown to be heritable to some extent (Moreno-De-Luca,
Ledbetter, & Martin, 2012). Costeff (2004) suggests that the brain lesions in
CP are caused by genetics in about 40% of cases and by pre- and perinatal
biological disturbances in 60% of cases. Further, it has been suggested that
risk factors associated with CP, including a preterm birth, also have genetic
underpinnings (Moreno-De-Luca et al., 2012). However, there are a limited
number of studies that have investigated the genetics associated with a
preterm birth but patterns of heritability and single gene mutations have
been identified. For example, a twin study have shown that gestational
length and birth weight are heritable to some extent (Clausson, Lichtenstein,

6
& Cnattingius, 2000). Risk factors associated with a preterm birth including
inflammation, uterine contractions, and endocrines, to name a few, have
been shown to have genetic underpinnings (reviewed in Behrman & Butler,
2007).

As explained, several maturational factors and their interaction with

normally occurring developmental processes render the infant born preterm
especially prone to the development of cerebral lesions and/or neuronal
disturbances. These mechanisms do in some cases lead to the development
of CP but may also be involved in adverse behavioral outcomes shown in
children born preterm without diagnosed neurodevelopmental deviations
(Ment et al., 2009; Williams et al., 2010; de Kieviet et al., 2009). Although it
is likely that children born preterm and children with CP share much in
terms of etiology, the limitations in motor functions and cognition differ.
Hence, aspects related to the specific research questions regarding children
born preterm will be described separately from those pertaining to the
children with CP. Sensorimotor and intellectual function and hand-
preference in children born preterm without major disability will be
reviewed in the following section.

Sensorimotor and intellectual function in children

born preterm

General motor functions and the relation to risk factors

Impaired motor and cognitive development have been stated to be the two
major adverse sequelae of preterm birth (Pitcher et al., 2011). Indeed,
studies have frequently shown that children with a preterm birth history
without major disability have increased levels of motor impairment (Burns et
al., 2009; Cooke, 2005; Davis, Ford, Anderson, & Doyle, 2007; De Kleine,
Nijhuis-Van Der Sanden, & Lya Den Ouden, 2006; Edwards et al., 2011;
Evensen, Skranes, Brubakk, & Vik, 2009; Foulder-Hughes & Cooke, 2003;
Goyen & Lui, 2009; Hack et al., 2005; Holsti, Grunau, & Whitfield, 2002;
Jongmans, 1998; Leversen et al., 2011; Powls, Botting, Cooke, & Marlow,
1995; Rademaker, 2004; Schmidhauser, 2006; Skranes et al., 2008; Torrioli
et al., 2000; Whitaker et al., 2006; Wocadlo & Rieger, 2008). A systematic
review and meta-analysis of the literature reporting motor function
outcomes in school-aged children born preterm without the diagnosis of CP
showed a high prevalence of moderate (19/100) and mild-moderate
(40.5/100) motor impairment (Williams et al., 2010). Likewise, a meta-
analysis revealed significant and persistent general motor impairment in
children born ≤ 32 GWs or with a BW ≤ 1500 gram without congenital

7
abnormalities. Fine motor skills were shown to be more affected than gross
motor skills and of the subtests, balance and manual dexterity were shown to
be most severely affected. The motor impairment was further shown to be
greater in the preterm born children who had had perinatal complications
than in those who had not (de Kieviet et al., 2009). Original research has
shown that children born preterm have deficits in ball handling skills
(Jongmans, 1998, also shown in the meta-analysis by de Kieviet et al., 2009)
and handwriting (Feder et al., 2005). Further, a systematic review has shown
that infants born preterm had a slower rate or lack of motor (Jongbloed-
Pereboom, Janssen, Steenbergen, & Nijhuis-van der Sanden, 2012).

The motor problems observed in children born preterm without known

neuropathology have been described as developmental coordination disorder
(e.g Foulder-Hughes & Cooke, 2003). A recent meta-analysis showed that 5-
8 year old children born at < 33 GWs or with a BW of < 1500 grams that did
not have CP were 6 times (odds ratio, OR = 6) more likely to fulfill the
criteria for developmental coordination disorder than their fullterm peers.
When the analysis was done applying a more generous criterion of
developmental coordination disorder that included milder motor problems,
the OR increased to 8.7 (Edwards et al., 2011). Recently, a compelling
theoretical account for a continuum of impairment and shared causal
pathways between developmental coordination disorder and CP has been
postulated (Pearsall-Jones, Piek, & Levy, 2010). The idea of shared causal
mechanisms is appealing from a biological perspective as the lesions
observed in CP are usually the most profound, although with a wide range in
severity, with severe effect on sensorimotor function. It is plausible that less
severe lesions and/or disruptions in brain development may cause less
severe but persistent sensorimotor impairments in children born preterm
without major disability.

Other research groups have described the deviations observed in children

born preterm without major disability as minor neuromotor dysfunction.
Children with minor neuromotor dysfunction display neuromotor
abnormalities that are persistent but show only mild to moderate
impairment in motor function and may have mildly delayed motor
development (Behrman & Butler, 2007). Mild minor neuromotor
dysfunction has been shown to be highly prevalent in children born preterm
(44% in children born < 33 GWs and 31% in children born at 33 to 34 GW) at
5 years of age. Further, the presence of mild or minor neuromotor
dysfunction in children born very preterm (< 33 GWs) was shown to be
associated with cognitive impairment, learning difficulties, and behavioral
and emotional problems (Arnaud et al., 2007).

8
Efforts have also been made to identify specific factors that affect motor
functions. In a study where 8 year old children born preterm (< 29 GWs or
with a BW < 1000 grams), whereof 42% were classed as having motor
impairments, retinopathy of prematurity (ROP; abnormal vascularization of
the retina which may result in loss of vision and problems with acuity), and
prolonged rupture of membranes were independently associated with poorer
motor outcomes. Importantly, the children born preterm included in the
study all attended mainstream school, were free of disability, had no
neurological impairment or visual or hearing deficits, and had a full scale
intelligence quotient (IQ) of > 84 points (Goyen & Lui, 2009). Other studies
have shown associations between poor motor function and the degree of
neurological impairment (Schmidhauser, 2006), presence of cerebral insult
in the neonatal period (Davis et al., 2007; Schmidhauser, 2006; Whitaker et
al., 2006), lower GWs (Cooke, 2005; Foulder-Hughes & Cooke, 2003;
Leversen et al., 2011), lower BWs (Foulder-Hughes & Cooke, 2003), being
small for gestational age (SGA) (Leversen et al., 2011), male sex (Davis et al.,
2007; Leversen et al., 2011; Whitaker et al., 2006), female sex (Powls et al.,
1995), number of days in ventilation in the neonatal period (Whitaker et al.,
2006), lower general IQ (Foulder-Hughes & Cooke, 2003), problems with
literacy and/or numeracy (Wocadlo & Rieger, 2008), poor academic
achievement, behavioral problems, externalizing behaviors (Davis et al.,
2007), visual impairment (Evensen et al., 2009), diagnosis of ROP (Leversen
et al., 2011), and poor physical fitness (Burns et al., 2009). Further, a recent
meta-analysis showed that visuo-motor integration was negatively affected
in children born < 33 GWs or with a BW of < 1,500 grams. The impairment
in visuo-motor integration was worse for the children with male sex, low IQ,
and lower GAs (Geldof, van Wassenaer, de Kieviet, Kok, & Oosterlaan, 2012).

Intellectual function in children born preterm

Several studies have reported lower scores, albeit in the normal range, on
tests measuring cognition in children born preterm (e.g., Allin et al., 2001,
2011; Bhutta, 2002; Foulder-Hughes & Cooke, 2003; Kontis et al., 2009). In
the meta-analysis by Bhutta and colleagues (2002), the cognitive test scores
were directly related to GA and BW, where the children with the lowest GAs
and BWs had the lowest cognitive test scores. This finding is most likely
related to the increased level of physiological immaturity of the infant born
at very (28-32 GWs) or with extremely (< 28 GWs) low GAs and BWs as the
risk of neurological insults increases with decreasing GA and BW. Other
studies have not been able to show an association between GA and IQ,
possibly due to the small number of children born extremely preterm in the
study samples (Bos & Roze, 2011). Very preterm (< 33 GWs) born
adolescents with or without neonatal brain lesions that had comparable GAs

9
have been shown to have lower IQ than those born fullterm. Further, those
with neonatal brain lesions had significantly lower IQ scores than the
children born preterm without cerebral lesions and the children born
fullterm, respectively. It was also shown that IQ scores correlated with
volumes of the WM and corpus callosum and that these volumes explained
70% of the variance in IQ within the preterm born groups (lesion/no lesion).
The IQ scores also correlated positively with academic achievement in the
children born preterm (Northam, Liégeois, Chong, Wyatt, & Baldeweg,
2011). However, other studies have not been able to show a connection
between brain lesions and cognitive outcome in children born preterm, again
possibly due to small study samples (Bos & Roze, 2011). Other factors
associated with adverse cognitive development in children born preterm
have been identified. These factors include late-onset sepsis (van der Ree,
Tanis, Van Braeckel, Bos, & Roze, 2011), GA, patent ductus arteriosus, head
circumference at the age of 7 (Cooke, 2005), male sex, number of ventilation
days and white matter injury as detected by neonatal ultrasound (Whitaker
et al., 2006). Where standardized IQ tests have been used, a global lowering
of intellectual function is usually reported (e.g., Allin et al., 2001, 2011; Hoff
Esbjørn, Hansen, Greisen, & Mortensen, 2006; Kontis et al., 2009; Peterson
et al., 2003; Soria-Pastor et al., 2009).

There is a general consensus that intellectual abilities are underpinned by

higher cognitive or executive functions and processes. Studies aimed at
investigating the executive functions in children born preterm have shown
substantial impairments compared to children born fullterm (Aarnoudse-
Moens, Duivenvoorden, Weisglas-Kuperus, Van Goudoever, & Oosterlaan,
2012; Mulder, Pitchford, Hagger, & Marlow, 2009; Mulder, Pitchford, &
Marlow, 2010). Observed deficits in executive function in children born very
preterm include verbal fluency, cognitive flexibility, response inhibition,
planning, and verbal and spatial working memory (Aarnoudse-Moens et al.,
2012; Aarnoudse-Moens, Weisglas-Kuperus, van Goudoever, & Oosterlaan,
2009). Further, performance on tasks tapping executive function in children
born preterm has been shown to be negatively influenced by a history of ROP
and current visual impairment (Böhm, Smedler, & Forssberg, 2004)
suggesting functional interrelatedness. Despite an early visual advantage in
infancy (Hunnius, Geuze, & Zweens, 2008; Ricci et al., 2008), children born
preterm have readily been shown to have lower test scores than fullterm
born controls on tasks with high demands on visual function (e.g., Geldof et
al., 2012; Hoff Esbjørn et al., 2006). The visual deficits or delays shown are
not exclusively related to the functions of the eye but also to the function of
cortical visual systems. Children born preterm with PVL have readily shown
cortical visual impairment (Weinstein et al., 2012). Specifically, children and
infants born preterm have been shown to have visual deficits supported by

10
the functions of the dorsal visual stream, the where and how visual system
(Atkinson & Braddick, 2007; Weinstein et al., 2012). The dorsal stream is
involved in the processing of motion, spatial awareness, and depth
perception. It originates in the occipital lobe and terminates in the posterior
parietal cortex. It is a cortical visual system that provides a ‘coordination
system’ of the visual environment whereon our movements are organized.
The intactness of the dorsal visual stream is important for accurate motion
in three dimensional space and dysfunction of it can be manifested in
clumsiness and compensatory movements in order to improve end point
accuracy (Dutton, 2003). Thus, the dorsal cortical stream is an important
part of a visuo-motor system that is highly involved in the transformation of
visual information into action. In addition, poor visuo-motor performance
has been associated with poorer executive functions, specifically inattention
and hyperactivity in children born preterm (Böhm, Lundequist, & Smedler,
2010).

Relations between motor function and cognition in children born

preterm

Historically, cognitive and motor development has generally been regarded

as separate entities with largely independent developmental trajectories and
neurological underpinnings (Davis, Pitchford, & Limback, 2011). However,
this view is beginning to be increasingly challenged by findings of
interrelated cognitive and motor functions in both healthy and at-risk
children. Cognition and motor performance, specifically visual perception
and fine motor control have been shown to be highly interrelated in typically
developing children (Davis et al., 2011). A recent study has also shown strong
correlations between the volumes of the cortical GM, caudate, and
cerebellum and cognition in fullterm born typically developing children,
suggesting the importance of specific structures in cognitive functions.
However, although fine motor skill was strongly correlated to cognitive
outcomes, no correlation between brain volumes and motor performance
was found. These findings may reflect the dispersed neural networks
supporting motor functions and also implicating cognitive functions as an
important mediator of motor performance (Pangelinan et al., 2011).

Relatively few studies have focused on the investigation of the associations

between cognitive outcomes and motor function in prematurely born
populations. However, there is a growing body of evidence associating a
lower level of intellectual ability with motor skill impairments within groups
of children born preterm. Foulder-Hughes and Cooke (2003) found
significantly lower scores on the Wechsler’s Intelligence Scale for Children,
III edition in children born < 32 GWs compared to typically developing

11
children born at term. The cognitive outcomes were negatively correlated to
motor outcome measures. Similarly, connections between academic
underachievement and poor motor function have been shown in children
born preterm (< 30 GWs) where increasing severity of motor impairment
corresponded to higher degree of underachievement (Wocadlo & Rieger,
2008). Further, poorer motor skills, in particular fine motor skills, have been
associated to the occurrence of sepsis in children born preterm (van der Ree
et al., 2011). A recent meta-analysis showed deviations in visuo-motor
integration in children born preterm. Visuo-motor integration is reliant on
visuo-spatial ability, fine motor abilities, and motor planning. The results
from the meta-analysis showed that GA, male sex, and full scale IQ were
associated with visuo-motor integration outcome where lower GAs, boys,
and lower IQ were connected to poorer visuo-motor functioning (Geldof et
al., 2012). Further, evidence is emerging that connect the function of the
motor cortices to higher cognitive processing including auditory and visual
speech perception and comprehension (Pitcher et al., 2011). Thus, the study
of the connections between motor function and cognition in preterm born
children is an important area of research.

Upper-limb goal-directed movements in children born preterm

As has been reviewed in the text above, there is evidence that children born
preterm have higher levels of motor impairments, specifically prominent in
balance, manual dexterity and visou-motor function (Atkinson & Braddick
2007; Feder et al., 2005; Jongmans, 1998; Schmidhauser, 2006; de Kieviet
et al., 2009). Given the effect a preterm birth can infer on the development
of the CS and visual systems such deviations are plausible. The WM integrity
of the motor region (CS tract) has been shown to be related more to motor
skills than GA in healthy neurologically intact 11 year-old-children born
between GW 24-41 (see Pitcher et al., 2011). Reaching, grasping and
prehensile movements have been argued to be the most fundamental of
manual skills. Such movements place high demands on control over
shoulder, elbow, wrist and finger joints as well as posture and balance
(Michel, 1991). In the study by Schmidhauser (2006), fine motor skills were
shown to be particularly impaired in children born preterm. A handful of
studies exist that have focused primarily on the kinematics of reaching (and
grasping) like movements in infants (Fallang, Saugstad, Grøgaard, &
Hadders-Algra, 2003; Grönqvist, Strand Brodd, & von Hofsten, 2011; Toledo
& Tudella, 2008) and children born prematurely (Sagnol, Debillon, & Debû,
2007), often from a perspective of early identification of neuromotor
deviations. Less optimal reaching and catching has been shown in 8-month-
old infants born very preterm as expressed by a bimanual catching strategy
and less energy-efficient movement paths (Grönqvist et al., 2011). Similarly,

12
less optimal reaching behavior in infants born preterm deemed to have a
high risk of neurodevelopmental deviation was evident at 6 months
corrected age (Fallang et al., 2003). In a follow up study of the same infants
at 6 years of age the inability to successfully reach and grasp at 4 months and
less optimal reaching and grasping at 6 months of age was related to a
complex form of neuromotor dysfunction at school age. Further, problems
with postural control in infancy were associated with a simpler form of
minor neurological dysfunction at 6 years of age (Fallang et al., 2005).
Visuo-motor control, in terms of error rates, movement segmentation, and
movement duration, have also been shown to be negatively affected by a very
preterm birth in 3.5 and 5 year old children (Sagnol et al., 2007).

Handedness and movement performance in children born

preterm

An important aspect of manual control is hand dominance where studies

have shown that the preferred hand manipulates objects and the non-
preferred hand acts as a stabilizer (MacNeilage, 1987). If the action is
bimanual with equal force constraints for both hands, the preferred and non-
preferred hand are used interchangeably as the acting hand depends on the
spatial location of the goal (Johansson et al., 2006). The expression of
handedness is the most striking observable form of human asymmetry and
its establishment is affected by genetic factors, environmental effects and
experiences during development, asymmetries in neurochemistry, and
disease (Toga & Thompson, 2003).

The origins of handedness is a long debated issue (see Hopkins & Rönnqvist,
1998 for a comprehensive theoretical account). A right sided preference for
the hand, foot, eye, and ear are usually found in the normally developing
population. About 90% of the population has been reported to have a right
hand preference (Porac & Coren, 1981). Although there is no question about
the dominance of a right-hand preference in the general population, lower
rates of right handedness have been reported (≈ 80%) (McManus, Rawles,
Moore, & Freegard, 2010). Further, males have been reported to have higher
frequencies of a non-right hand preference than females (e.g., Nicholls,
Johnston, & Shields, 2012). It is possible that the somewhat diverging results
from studies that report rates of hand preference could be a result of
differing assessment methods and population biases. Handedness has been
shown to be heritable, at least to some extent, and theories have been
developed based on genetic heritance principles (Annett, 1985). The right
shift theory suggests that the absence or presence of a single gene that codes
for cerebral asymmetry, primarily of language which usually is located in the
left hemisphere, increases or decreases the probability of subsequent right

13
handedness. Others have described all non-right handedness as having a
pathological origin stemming from pre- or perinatal neurological insult
(Bakan, 1971; Bakan, Dibb, & Reed, 1973). Further, the risk of birth stress
and thus a non-right hand preference has been suggested to be heritable
(Bakan, Dibb, & Reed, 1973). In these theories one does not inherit a hand
preference per se but the risk of birth stress that in turn cause a non right
hand preference. Other models suggests that there might be both heritable
natural and pathological origins of non-right handedness where early
neurological lesions constitute the pathological type in at risk populations,
such as premature birth (Bishop, 1990; Satz, 1972; Soper & Satz, 1984). The
occurrence of non-right handedness or less strong hand preference has been
implicated in a number of developmental disorders, often with genetic
associations, (e.g., Hauck & Dewey, 2001) and in children with prenatal
exposure to teratogenes (Domellöf, Rönnqvist, Titran, Esseily, & Fagard,
2009). Handedness is regarded as a reflection of the asymmetric
organization of the sensorimotor system and the expression of a non-right
hand preference may be a sign of disruption in the organization of the brain
(Sacco, Moutard & Fagard, 2006).

Although it has been suggested that motor performance and handedness are
different entities, studies have shown that motor performance is better with
the preferred hand in both right and left handers (Triggs et al., 2000; Triggs,
Calvanio, & Levine, 1997). Similarly, it has been shown that the distal
muscular control in the preferred hand is more refined than in the non-
preferred and that when using the non-preferred hand for a task demanding
highly skilled actions (handwriting) more proximal musculature is used
(Mack, Rothi, & Heilman, 1993). However, it was shown in the study by
Triggs and colleagues (2000), by use of regression analysis, that 90% of left-
handers and 93% of right-handers were categorized into the correct
handedness classification based on scores from motor performance tests
(finger tapping and pegboard) showing a less than perfect relationship
between performance and hand preference.

It is possible that the events associated with a preterm birth may affect the
development of brain organization through neuropathological and
environmental influences. To exemplify, an effect of such events on side
specificity may be seen in hemiplegic CP, where hemorrhage in primarily one
cerebral hemisphere results in extreme side specificity. There are some
studies that have investigated the occurrence of non-right handedness in
children born preterm (Marlow, Roberts, & Cooke, 1989; O’Callaghan, Burn,
Mohay, Rogers, & Tudehope, 1993; Powls et al., 1995; Ross, Lipper, & Auld,
1987, 1992; Saigal, Rosenbaum, Szatmari, & Hoult, 1992) showing a slight
increase in left and non-right handedness. However, few studies have related

14
hand preference to motor outcome in preterm born children (O’Callaghan et
al., 1993; Ross et al., 1992; Sagnol et al., 2007). O’Callaghan and colleagues
(1993) found that left handedness was associated with increased motor
difficulties, extreme preterm birth, increased cognitive problems, and
behavioral difficulties at 4-6 years of age. Further, cognitive and behavioral
deficits as well as poorer motor performance with the non-dominant hand
have been shown in left-handed children born preterm at 7-8 years of age
(Ross et al., 1992). In the study by Sagnol and colleagues (2007), the focus
was placed on investigation of side differences related to these kinematic
measures. It was found that the 3 year old children born preterm with very
low GAs expressed a delay in the expression of hand preference in terms of
movement duration where the age-matched control group born fullterm did
not. In the groups with older children, no difference was found in the
proportion of non-right handedness.

Cerebral Palsy

Functional impairments in children with CP

CP is the most common developmental disturbance causing lifelong physical

disability (Aisen et al., 2011; Krägeloh-Mann & Cans, 2009). The most recent
internationally accepted definition of CP reads:

“Cerebral palsy (CP) describes a group of permanent disorders of the

development of movement and posture, causing activity limitation, that are
attributed to non-progressive disturbances that occurred in the developing
fetal or infant brain. The motor disorders of cerebral palsy are often
accompanied by disturbances of sensation, perception, cognition,
communication, and behaviour, by epilepsy, and by secondary
musculoskeletal problems.”

(Rosenbaum, Paneth, Leviton, Goldstein, & Bax, 2008, p. 9)

The motor problems associated with CP form the basis for diagnosis of the
syndrome although severe sensory and cognitive deficits are common (Cans,
2007; Straub & Obrzut, 2009). Children with CP have deficiencies in the
control of muscle tone where it is either too high (hypertonia) or too low
(hypotonia) or a combination of the two. CP can be classified into three types
with different profiles of motor deviations. The first subtype is spastic CP
where at least two of the following symptoms must be present: Increased

15
tone, pathological reflexes, and an abnormal pattern of movement and/or
posture. The spasticity may be located to limbs on both sides of the body
(bilateral spastic CP) or one side (spastic unilateral CP) (Cans, 2007). The
unilateral subtype (hemiplegic CP) is the most commonly occurring subtype
accounting for 38% and the bilateral (diplegic CP/tetraplegic CP) form has a
prevalence of 39% (Himmelmann et al., 2010). The second type is ataxic CP
which is characterized by abnormal posture and/or movements and by
movements that are uncoordinated with too high or low force, abnormal
rhythm, and decreased accuracy (Cans, 2007). This is the rarest form,
present in 5% of cases with CP (Himmelmann et al., 2010). The third type is
dyskinetic CP where the motor profile contains movements that are
involuntary, uncontrolled, sometimes stereotyped, and recurring. Dyskinetic
CP may be dystonic, where movements are hypokinetic (stiff movements,
reduced activity) and hypertonic (unusually high tone) or choreo-atheotic,
where movements are hyperkinetic (stormy movements, increased activity)
with hypotonicity (unusually decreased tone). Dyskinetic CP has been shown
to be present in 17% of cases with CP (Himmelmann et al., 2010).

In a study by Himmelmann and colleagues (2006), the majority of children

with CP were shown to have mild to moderate gross (70%) and fine (75%)
motor impairments; a minority were thus shown to have severe limitations
(gross motor function -30%; fine motor function -25%). The severity of gross
motor impairment was further shown to increase as GA decreased. The
limitations in gross and fine motor function differed between the different
types of CP. Most (95%) of the children with spastic hemiplegic CP have
mild/moderate (Gross Motor Function Classification System; GMFCS; level
I-II) gross motor impairment and those with spastic diplegic CP were found
to have both mild/moderate (54%) and severe (GMFCS IV-V) (31%) gross
motor impairment. Most of the children with spastic tetraplegia (100%) and
dyskinetic CP (96%) had severe gross motor impairments whereas most of
the children with ataxia had mild/moderate impairments. In general, the
manual ability corresponded to that of the gross motor performance. The
same study showed high rates of learning disability (40%), epilepsy (33%),
and severe visual impairment (19%). Further, the number of accompanying
impairments also increased with the level of gross motor function. Children
with ataxia and hemiplegic CP had the lowest rates of accompanying
impairments and milder learning disability. Accompanying impairments
were most prevalent in tetraplegia and in those children born < 28 GWs
(Himmelmann, Beckung, Hagberg, & Uvebrant, 2006). It is apparent that
children with CP have functional difficulties in numerous domains. A
literature review has shown that; visuo-perceptual problems are highly
prevalent, verbal function is usually higher than non-verbal function (at least
for the less severe cases), learning problems occur in about half of the

16
children with CP, short-term memory is problematic, and that executive
functions are negatively affected (Straub & Obrzut, 2009).

Risk factors for the development of CP

Being born preterm is the single most important risk factor for later
development of CP and half of those diagnosed with CP have been born
prematurely (Beaino et al., 2010). Several different risk factors for the
development of CP have been identified. Being born before GW 28 has been
shown to be the single most important risk factor in one study (Sukhov, Wu,
Xing, Smith, & Gilbert, 2012) and for children born ≤ 32 GWs the presence
of cerebral lesions has been shown to be the best predictor (Beaino et al.,
2010). Other significant contributions to the development of CP are birth
asphyxia, respiratory distress syndrome, necrotizing enterocolitis,
intraventricular hemorrhage (Sukhov et al., 2012), male sex, preterm
premature rupture of membranes, spontaneous onset of labor before rupture
of membranes (Beaino et al., 2010), and genetic factors (Moreno-De-Luca e
al., 2012). Birth defects have been associated to increased risk of CP in both
preterm born and term born children (Sukhov et al., 2012). In preterm born
children, the risk of developing CP has been shown to increase with the
number of pre- and perinatal risk factors (Stoknes et al., 2012; Sukhov et al.,
2012). Of preterm born children with CP, 9% have been shown to have
preterm birth as a single risk factor (Stoknes et al., 2012).

Brain lesions in CP

70-80% of the lesions causing CP can be related to insults occurring

prenatally (Moreno-De-Luca et al., 2012). In a population-based study by
Himmelmann and colleagues (2010), it was found that 36% of lesions in
children with CP could be attributed to prenatal insults and 42% to the peri-
neonatal period whereas 21% remained unclassifiable. However,it is difficult
to determine the timing of the insult depending on the clinical expression of
CP as different etiologies at different times in development can result in the
same clinical expression and vice versa (Korzeniewski et al., 2008). Further,
the preciseness of the dating of lesions in CP imaging outcomes has also been
questioned as migrational processes have been shown to carry on later on in
early brain development than previously thought (Hüppi et al., 1998;
Lenroot & Giedd, 2006). With this in mind, there are indications that insults
in the first or early second trimester cause malformations due to
disturbances in migration processes (Krägeloh-Mann et al., 1995).
Malformations are more common in term infants and more prominently
found in hemiplegic CP than other types. Malformations have been found to
be prevalent in 10% of cases with CP (Korzeniewski et al., 2008). During the

17
latter parts of the second trimester and the third trimester, cerebral WM
insults (PVL) are prominent and occur primarily in the preterm born infant.
When there is WM injury in isolation, the result is often bilateral spasticity,
atheosis and ataxia. WM insult is the most common finding in CP (83%)
(Korzeniewski et al., 2008). PVL is also relatively common in fullterm born
infants although the distribution is then bilateral cortical-subcortical
(Johnston & Hoon, 2006). When the events leading to PVL are accompanied
by hemorrhages, the infarct is often unilateral and results in hemiplegic CP
(Candy, Hoon, Capute, & Bryan, 1993; Cioni et al., 1999). When insults occur
in the latter part of the third trimester, cortical and subcortical GM and the
periventricular WM are primarily affected (Candy et al., 1993; Korzeniewski
et al., 2008; Krägeloh-Mann et al., 1995). Absence of detectable adverse
neuroradiological findings has been reported in 17% of cases with CP,
(Korzeniewski et al., 2008).

Goal-directed upper-limb movements in CP

Several studies have investigated upper-limb function in children with CP

with focus on movement organization, control and planning. To study the
central aspects of the sensorimotor deviances in CP is of importance. Motor
planning impairment in CP has been argued to be just as disabling as the
functional impairments deriving from biomechanical constraints
(Steenbergen & Gordon, 2006). Studies have shown deficits in the planning
and timing of movements in hemiplegic CP where reaching trajectories have
been shown to more often consist of more than one movement
segmentation, have longer durations, and involve more proximal control
(Butler, Ladd, Louie, et al., 2010; Butler, Ladd, Lamont, & Rose, 2010;
Coluccini, Maini, Martelloni, Sgandurra, & Cioni, 2007; Domellöf, Rösblad,
& Rönnqvist, 2009; Hung et al., 2012; Jaspers et al., 2011; Kreulen,
Smeulders, Veeger, & Hage, 2007; Mackey, Walt, & Stott, 2006; Ricken,
Savelsbergh, & Bennett, 2006; Rönnqvist & Rösblad, 2007; Steenbergen,
Thiel, Hulstijn, & Meulenbroek, 2000; van der Heide, Fock, Otten,
Stremmelaar, & Hadders-Algra, 2006). These results have been interpreted
to reflect compensatory behavior in order to increase end-state control.
Kinematic analyses have also shown that the less-affected upper-limb in
hemiplegic CP has deviations in terms of increased postural involvement
(Domellöf, Rösblad, et al., 2009; Hung et al., 2012; Steenbergen &
Meulenbroek, 2006), longer movement durations, and later peak amplitudes
(Hung et al., 2012). Despite these studies and the importance of the arms
and hands in daily living, relatively little is known about the nature of the
deficits in goal-directed upper-body movements in CP. Increased knowledge
regarding these impairments could prove important in the development of
suitable intervention methods for this population.

18
The malleable brain

Plastic changes in development

Plasticity pertain to the altering of the functional organization of the brain in

response to experience, learning, and recovery from injury (Holt & Mikati,
2011; Johnston, 2009; Nudo, 2006). Plasticity processes have been studied
in children who have unilateral pre-perinatal brain injury in attempts to
understand how cortical organization processes are affected by such events
(Staudt, 2007, 2010) and to inform rehabilitative practice (Nudo, 2006). The
immature brain has greater vulnerability to brain insults (Volpe, 2009) and
at the same time increasing ability for neural plasticity (Staudt, 2007). Early
occurring insults may result in the reorganization of a function (i.e. language
being established in the contra-lesional right hemisphere) or the
maintenance and refinement of ipsilateral CS projections to the hand
affected by the insult (contralesional). Afferent aspects of language and
motor function (somatosensory processing and speech perception) have
been shown to remain in the lesioned hemisphere (Staudt, 2007). In hand
function, the ipsilateral connections have been shown to be functional in
fullterm and preterm born infants where trans-magnetic stimulation has
been shown to evoke bilateral activity in the upper limbs, with faster
latencies in the ipsilateral hemisphere (Eyre, Taylor, Villagra, Smith, &
Miller, 2001). The ipsilateral advantage was reduced during the first two
years of development whereas the contralateral projections became more
established. In infants with unilateral brain lesions, there was no down-
regulation of the function of the ipsilateral connections (Eyre et al., 2001).
These findings suggest activity dependence in the formation of the motor
system supporting manual dexterity (Eyre et al., 2001; Martin, 2005) and
the maintenance and establishment of ipsilateral connections should be
regarded as a sign of disturbance of developmental processes and not a
reparative function of the central nervous system (Eyre, 2007).

Plasticity and interventions

There has recently been a shift in the approach to the management of CP,
deriving from knowledge generated in the research field of neuronal
plasticity, where the central rather than the biomechanical impairments are
addressed (Schertz & Gordon, 2009; Wittenberg, 2009). Effects of early
interventions have been studied in preterm born infants. A meta-analysis
using studies with case-control design revealed that intervention programs
aimed at children born preterm that involve occupational therapy, physical
therapy, and neuro-psychological methods improved cognitive performance
in the short term (infancy and preschool ages) but no effect was observed on

19
motor function (Spittle, Orton, Doyle, & Boyd, 2007). Similar results were
presented by the same authors when only including randomized controlled
studies (Orton, Spittle, Doyle, Anderson, & Boyd, 2009). The results from
these meta-analyses might have been different if the sample had been
stratified by GA and/or presence of brain injury. A systematic review has
shown that increased brain growth and improved cognitive functions have
been shown to be the result of diets high in protein and exposure to rich
environments in infants with perinatal brain injury (Holt & Mikati, 2011).

In CP, most intervention methods are applied when the diagnosis is set,
which is usually late in terms of brain development. However, activity-
dependent plasticity appears across the lifespan, making therapies aimed at
improving function in older children and adults with CP feasible
(Wittenberg, 2009). Mechanisms behind activity-dependent plasticity not
only relate to the establishment and refinement of ipsilateral projections but
also to motor cortical organization. Studies of primarily monkeys have
shown that repeated activation alone is not sufficient to induce longstanding
and large functional changes. Such changes appear to be established by
movements with increasing demands on motor skills that involve multiple
joints in complex movement repertoires. Training such skills generates
motor cortical representations of multiple joint modules that, when
established, result in automatic co-activation of the joints represented in the
movement and the experience of a temporally timed execution. Further,
plasticity is best induced if feedback is given on performance and if the
degree of difficulty gradually increases (Nudo, 2006).

There is evidence supporting activity-based plasticity in hemiplegic CP in

response to constraint-induced movement therapy methods, with relatively
large and sustained improvements where the affected arm and hand are used
more frequently after the intervention (Huang, Fetters, Hale, & McBride,
2009). Further, action planning in terms of end-state comfort has been
shown to be positively affected after 8 weeks of intensive bimanual training
combined with constraint induced movement therapy in 3-6 year old
children with hemiplegic CP (Crajé, Aarts, Nijhuis-van der Sanden, &
Steenbergen, 2010).

20
OBJECTIVES
The main objectives of this thesis were to investigate sensorimotor behaviors
in children born preterm and in adolescents with CP. Hand preference, side
specific movement performance, and intellectual functioning are aspects that
have been shown to be affected by a preterm birth but few studies have
explored the relation between these. Studies I, II, and III are therefore
focused on the investigation of these aspects in children born prematurely,
without major disability, by employing both meta-analytical, frequency
based assessments, and kinematic movement analyses. Further, persons
with CP have a longstanding need of intervention methods that are aimed at
maintaining and improving functional capacity. Thus, investigations into the
effects of a sensorimotor training method on upper-body movement
performance in adolescents with CP were an important objective (study IV).

The following questions were posed:

Does a preterm birth affect the functional organization of the motor system
as expressed by increased rates of non-right handedness?

Do children born preterm without major disability have less well organized
upper-body movements during a goal-directed task with high demands on
precision compared to fullterm born children? Does GA affect these
outcomes?

Do children born preterm and their fullterm born peers express side
specialization in terms of more effective and well organized movements
with their preferred hand? Does GA influence the outcomes?

Is upper-body movement organization in fullterm born children associated

with intellectual function when controlling for the effects of GA and sex?

Does synchronized metronome training improve upper-body movement

organization, both in the short and long term, in adolescents with cerebral
palsy and will such changes have effect on activities in daily life?

21
METHODS
A number of different study designs, statistical methods, and assessment
methods are used in the studies in this thesis. In the following section the
details of the studies from a methodological perspective will be given,
starting with study design followed by descriptions of the participants and
how they were recruited, a detailed description of the assessment methods
including procedures, the statistical methods applied, and ethical
considerations. To improve associability of the text for the reader, the
methods related to the systematic review and meta-analysis (study I) will be
described first in a separate section, followed by a section with the methods
related to the empirical studies (studies II-IV).

Systematic review and meta-analysis (study I)

Study design and inclusion criteria

To explore the frequency of non-right handedness and its relation to

neurological and neuropsychological functions in children born preterm, a
meta-analysis and systematic literature review was performed. Suitable peer-
reviewed English language papers reporting hand dominance in children
born preterm were located by searching eight electronic databases using a
combination of the search terms "preterm", "prematurity", "premature",
"low birth weight" and "handedness", "hand preference", and "hand
dominance" and "children". The reference lists of the included publications
were also searched manually. The inclusion criteria stated that the children
born preterm had to be born < 37 GWs and be between 3- 18 years of age,
and the studies had to be of case-control design, where the participants were
comparable with regard to age and sex. The studies had to be published in
the 30 year period between September 1980 and September 2010. When
multiple publications derived from the same research team, efforts were
made to eliminate overlapping samples by contacting the authors of the
papers. Further, to maximize the number of cases included in the meta-
analysis, authors were contacted when sample integrity was unclear with
regard to GAs. Then unpublished data (participants included in studies II
and III) was also included in an attempt to combat the "file drawer problem".

Quality assessment

Independent quality assessments were made by two of the authors where the
included studies were rated on aspects of the characteristics of the study
population, comparability of cases and controls, representativeness of the

22
cases to the untested cases in the cohorts, the methodology applied in testing
handedness, and the relation between handedness and other outcomes. One
important reason for assessing the quality of the included studies was to test
whether sample heterogeneity was due to differing study characteristics.
Further, we assumed that studies with well described study samples and
more rigorous study designs would yield results where group differences
were more readily detected and thus results that were more accountable.

Statistical methods

The statistical analyses in study I was carried out in Comprehensive Meta-

Analysis 2.2 (BioStat Inc., Englewood, NJ, USA). As the samples were shown
to be heterogeneous an odds-ratio meta-analysis was chosen to investigate
the occurrence of non-right handedness in the prematurely and fullterm
born children. The confidence interval was set at 95% and the alpha value at
0.05. As meta-analyses by nature involve study samples recruited from
different populations that are assessed by means of different methods,
statistical homogeneity was assessed. Statistical homogeneity refers to the
approximated variance in study outcomes (point estimates) among studies
that are due to differences in study samples and methods and not chance
(Higgins, 2008). The homogeneity in the included studies was statistically
assessed using the I² method, where I² = [(Q − df)/Q] × 100% (Q = chi-
squared statistic, df = degrees of freedom), which results in a percentage
measure of the approximated heterogeneity. A heterogeneity value of < 40%
may be unimportant, 30-60% may reflect a moderate level, 50-90% may be
interpreted as a substantial level, and 75-100% may indicate a considerable
level. The magnitude of the heterogeneity was assessed by use of τ2 (tau
squared) statistics, which provides a point estimate of the amount of
variance across studies that is calculated on the actual effects (Higgins,
Thompson, & Spiegelhalter, 2009). Sources of heterogeneity should, if
possible, be investigated as results may otherwise be over-interpreted
(Thompson, 1994). Hence, the quality assessment scores were used as
sensitivity measures as they refer to some of the factors assumed to have
effect on among study variance.

As there in general is a risk that non-significant results are omitted from

publication, the so called "file drawer problem", it is important to perform
analyses that investigate the risk of publication bias. In the present study,
the risk of publication bias should be limited as only six of the included
studies had handedness as a principal research question (Ashton, 1982;
Ehrlichman, Zoccolotti, & Owen, 1982; O’Callaghan et al., 1993; Powls,
Botting, Cooke, & Marlow, 1996; Ross et al., 1987; Saigal et al., 1992), few of
the other studies tested handedness differences between study groups

23
statistically, and unpublished results were included (Rönnqvist et al.,
unpublished results). The occurrence of publication bias was assessed by
visual inspection of funnel plots where the standard error was plotted as a
function of study OR. Studies with large sample sizes will cluster close to the
combined point estimate near the top of the inverted funnel and studies with
smaller sample sizes will cluster closer to the bottom of the inverted funnel
with wider spread from the combined point estimate. If there are
discrepancies in which side of the combined point estimate the studies with
small samples occur, there may be publication bias in the dataset. If no
publication bias exists, the inverted funnel will be symmetrical (Higgins &
Green, 2011; Sterne & Egger, 2001). The tendency of smaller sample studies
to cluster on one side of the combined point estimate has also been termed
the "small study effect" (Sterne & Egger, 2001; Sterne, Gavaghan, & Egger,
2000), which is the tendency of smaller studies to show larger treatment
effects and to be omitted from publication if they show null effects to a
greater extent than studies with large sample sizes (Higgins & Green, 2011;
Littell, Corcoran, & Pillai, 2008). The occurrence of an apparent "small
study" effect may also indicate variations in the methods applied, differing
clinical samples, and heterogeneity effects thus caution is warranted when
investigating the funnel plot. Likewise, a non-significant result on tests of
publication bias does not guarantee that publication bias is non-existent
(Higgins & Green, 2011). In the present study, Egger's test of the intercept,
which is a linear regression model that tests for the "small study" effect, was
used when statistically testing publication bias (Egger, Davey Smith,
Schneider, & Minder, 1997). An inverse correlation is expected between
effect size and study size. The bias is quantified by regressing the
standardized effect on the inverse standard error. The slope is the size of the
treatment effect and the intercept and its significance level indicates
publication bias (Egger et al., 1997). Sensitivity analyses of the extent of
publication bias were conducted by means of Duval and Tweedie’s trim-and-
fill method (Duval & Tweedie, 2000; Littell et al., 2008). This method rests
on the assumption that point estimates of individual studies should appear
symmetrically around the combined point estimate in the funnel plot. If the
plot is asymmetrical, a number of studies are imputed to create an
apparently symmetrical plot and as a result of this the combined point
estimate is trimmed (Duval & Tweedie, 2000). If the asymmetry in the plot is
caused by the “small study” effect, the imputed studies will appear at the
bottom of the funnel plot (Littell et al., 2008).

24
Empirical studies (studies II-IV)

Study designs

Handedness, movement performance, and intellectual function in children

born preterm (studies II and III)

To assess handedness, movement performance in general and with the

preferred and non-preferred hand, and intellectual function in children born
preterm, a case-control study was performed. The study design enabled
comparison of the children born preterm with a group of fullterm born
children who were similar in age and sex. The groups involved children of 4
to 8 years of age and thus important information about age related changes
of the included children could be obtained. The assessment battery was
piloted on a number of typically developing children before the study
commenced.

Short- and long-term effects of timing and rhythmicity training on upper-

limb movements in children with cerebral palsy (study IV)

In study IV, the effects of the SMT method, the Interactive Metronome (IM),
on goal-directed upper-body movements in adolescents with differing
severity of CP were explored. Before the individually adjusted IM training
commenced, the participants completed a pre-test battery that included
kinematic movement registrations, measures of timing and rhythmic ability,
gross motor function and hand function. When the IM training had been
completed, a post-test battery was applied, where movement kinematics,
timing and rhythmic ability, and the subjective experience of possible
training effects were assessed. This battery was applied twice, immediately
after training completion (Post-test 1) and 6 months after training
completion (Post-test 2). The kinematic task was piloted on a typically
developing 13 year old child before the study was instigated. The study
design is summarized in figure 1.

25
 4 weeks 1-2 weeks 6 months

Individually adjusted
Pre-test Post-test 1 Post-test 2
IM training
12 sessions x 30 min

Timing/ rhythmic assessment (IM)*

Kinematic movement registration
Questionnaire
* Assessed at every training occasion

Figure 1: Schematic illustration of the study design and the included assessments at each time
point.

Participant description and recruitment process (study II-IV)

Studies II-III

Sixty-eight children born at < 35 GWs and cared for at the neonatal intensive
care unit at Norrland’s University Hospital, Umeå, Sweden between January
2000- June 2003 and January 2004- June 2005 were recruited. 376
children were identified from the birth records, where 225 could be localized
through the civil register. Of the initial 376, some could not be located, had
moved abroad or were deceased. Of the 225 that were located, 126 were
selected for invitation to the study. The selection criteria stated that the
families had to be able to travel to and from the university in one day. Of the
126 selected, 68 (54%) agreed to participate. Those who declined to
participate had slightly higher GAs (M GA= 32.8) than those who
participated (M GA= 31.3). 80 children of comparable age and sex were
recruited from birth records at the maternity ward of the same hospital. In
Table 1a-b, participant information with regard to age, sex, neonatal
characteristics, demographic information, and medical information from the
perinatal period for the children born preterm is presented. The children
ranged from 4 to 8 years of age when they participated and all children had
normal or corrected to normal vision. Three children in the prematurely
born group were diagnosed with CP and in the fullterm born group one child
had undergone brain surgery in infancy, one had childhood epilepsy, one
had the genetic syndrome NF1, and one did not manage to complete the test
battery due to excessive fussiness. These 7 children were not included in the
analyses of study II and III.

26
Table 1a: Age, sex, demographic, and pre-perinatal information of the
children born preterm.

Preterm born children (N=68) M SD Range

Age (years) 6.4 1.7 4.0-8.7
GA (weeks) 31.7 3.3 22.9-35.4
BW (grams) 1735 659 404-2962
BW standardized -1 1.4 -3.9-1.9
Birth length 41.2 5.2 27-49
Head circumference (cm) 29.6 3.8 20.4-35.5
Apgar 10 8.8 1 5-10
Mother's education (years) 14.3 2.7 7-21.5
Father's education (years) 13.6 3.0 5-21
n %
Female sex 30 44
SGA 14 21

RF pertaining to infection
Amnionitis 1 1.5
Infection 31 50
PPROM 11 16
RF pertaining to respiration
Preeclampsia/eclampsia 16 24
RDS 21 24
BPD 7 10
Respirator 13 19

PDA 12 18
NEC 2 3
ROP 16 24
GR I-II 13 19
GR III+ 3 4
Cerebral pathology in infancy 16 24
IVH GR I-II 9 13
IVH GR III+ 3 4
PVL 1 2
Mild abnormality non classified 3 5
Congenital malformations 10 15
Mild 8 12
Severe 2 3

Note: N = number; M = mean; SD = standard deviation; GA = gestational age; BW = birth

weight; SGA = small for gestational age (< 2 SD below the expected BW in relation to sex and
gestational age); RF = risk factor for brain injury; PPROM = preterm premature rupture of
membranes; RDS = respiratory distress syndrome; BPD = bronchopulmonary dysplasia; PDA =
patent ductus arteriosus; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity;
IVH = intraventricular hemorrhage; PVL = periventricular leukomalacia. Infection includes
both verified and non-verified cases and examinations of ROP and cerebral pathology is only
carried out in neonates born >33 gestational weeks as a standard medical procedure and the no
category thus contains children who have had this examination and were healthy and those who
had not received such examinations.

27
Table 1b: Age, sex, demographic, and neonatal information of the fullterm
born participants.

Fullterm born children (N= 80) M SD Range

A ge (y ears) 6.4 1 .8 3.7

GA (weeks) 40.3 1 .0 38-41 .9
BW (grams) 3691 41 3 291 0-47 90
BW standardized 0.06 0.7 9 -1 .68-2.1 2
A pgar 1 0 9.4 0.5 0 9-1 0

Mother's education (y ears) 1 4.7 2.6 9-25

Father's education (y ears) 1 4.0 3.1 9-20

n %
Female sex 36 45

Note: M = mean; SD = standard deviation; GA = gestational age; BW = birth weight.

Study IV

Five adolescents with varying severity of CP participated in study IV (3 male

and 2 female, age range 12-17 years), two with hemiplegic CP, and three with
diplegic CP. Two of the adolescents were included in the case study
presented in paper IV (cases I and II). The participants were locally recruited
through registration records at Kolbäcken Child Rehabilitation Centre in
Umeå, Sweden. Recruitment was based on willingness to participate in the
study and ability to follow instructions. Table 2 presents diagnosis, level of
gross motor function, and manual ability according to the GMFCS and
Manual Ability Classification System (MACS), together with additional
clinical background information regarding the participating adolescents.
Three participants (II, IV, and V) received upper-limb botulinum toxin
treatment during the overall study period, although none of them in close
conjunction with the individual training and testing period. One participant
(V) received post-surgery (lower-limb) physical therapy training in parallel
with participating in the present study.

28
Table 2: Age, diagnosis, functional severity of disability, and co-morbidities
of the adolescents with CP.

Case Age (years) Diagnosis MACS GMFCS Affected side/ limb Comorbidity
I 17 HCP II II Right side
II 13 HCP II I Left side Left sided hemianopsi
III 12 DCP II III Mainly legs Autism, ID
IV 16 DCP IV IV Legs and arms ID
V 13 DCP III IV Legs and arms ID, CVI
Note: HCP = hemiplegic cerebral palsy, DCP = diplegic cerebral palsy; MACS = Manual Ability
Classification System; GMFCS = Gross Motor Function Classification System; ID = Intellectual
disability; CVI = Cortical Visual Impairment

Methods of assessment

The included assessment methods in the empirical studies are listed in Table
3.

Table 3: Overview of the assessment methods and materials used for

classification of function, handedness, cognitive function, motor control and
coordination, timing training, behavior, changes in hand/arm function,
medical history, and parents’ educational background used in the empirical
studies.

Materials/Methods Study I Study II Study III Study IV

Birth records/ journal background x x x
Frequency based handedness assessment x x
Gross Motor Function Classification Sy stem x
Hand/arm function questionnaire x
Interactiv e metronome x
Kinematic mov ement analy sis x x x
Manual A bility Classification Sy stem x
Quality assessment x
Socio Ec onomic information x x
Weschlers Intelligence Scale for Children- IV x x

Frequency assessment of hand dominance (studies II and III)

Hand dominance was assessed by observing the children’s choice of hand

when interacting with a selection of objects. The assessment tool used is
based on the Edinburgh Handedness Inventory (Oldfield, 1971) and Coren
and Porac's (1980) laterality questionnaire. The children drew, cut with
scissors, hammered, opened lids on a set of boxes, and threw balls. Each
object was handed to the child at their midline when both their hands were
free and each action was repeated 3 or 5 times. A handedness index was
calculated by (R-L)/(R+L), which provides a value ranging from -1 to 1 where

29
negative values reflect a leftward bias and positive values a rightward bias.
Values between -.3 and .3 were regarded as mixed handedness.

3-dimensional motion analyses (studies II-IV)

To assess the spatio-temporal characteristics of upper-limb movements

(studies II-IV), optoelectronic recordings were made during goal-directed
actions. A six-camera optoelectronic recording system (ProReflex, Qualisys
Inc., Gothenburg, Sweden) was utilized. In the studies included in this thesis,
only passive semi-spherical markers were used. The sampling frequency was
120Hz for all studies. Simultaneous video recordings that were time-
synchronized with the optoelectronic systems were made. The information
derived from these was used for clarification purposes during data
processing. The 3D data was smoothed prior to the analyses with a 10 (study
IV) or 12Hz (studies II-III) Butterworth filter. All 3D co-ordinates were
analyzed by use of custom written software in Matlab (Mathworks Inc.,
Boston, MA).

Optoelectronic recording technique is one of the most precise methods

available for studying movements. It is non-invasive and accessible and
allows for quantification of the mechanisms of the musculo-skeletal
(Capozzo, Della Croce, Leardini & Chiari, 2005) and neural systems during
motion (Khutz-Buschbeck, Stolze, Jöhnk, Boczek-Funce & Illert, 1998). The
system is objective and reliable if measurements are recorded in a well
calibrated space and filtering and smoothing of data is applied to eliminate
random errors and at least two cameras are monitoring each marker at any
given time (Chiari, Della Croece, Leardini & Cappozzo, 2005). However, it is
not a method without limitations. It is most precise in smaller volumes as
the calibration of the space will be better: it is thus suitable for upper-
limb/body movements. Soft tissue artifacts where the skin slides on top of
the underlying bone are also an issue (Leardini, Chiari, Della Croce &
Cappozzo, 2005). Further, marker location must be well thought through as
it has been shown to affect reaching and grasping components of goal-
directed movements in 3 year olds. In this study, 7mm spherical markers
were attached to the distal phalanges of the index finger and thumb
(Domellöf, Hopkins, Francis & Rönnqvist, 2007). Thus, optoelectronic
recording methods provide a highly detailed picture of both the spatial and
temporal profile of movements with a measurement error of maximum 0.5
millimeter in the studies included in this thesis.

Kinematic movement registration of this type is a method that has been

applied to the study of sensorimotor development in healthy, normally
developing infants and children (e.g., Rönnqvist & Domellöf, 2006; von

30
Hofsten, 1991) and for assessment of motor function of the upper limbs in
children with CP (e.g., Chang, Wu, Wu, & Su, 2005; Domellöf, Rösblad, &
Rönnqvist, 2009; Mackey et al., 2006; Rönnqvist & Rösblad, 2007).
Optoelectronic methods have also been applied to the study of functional
asymmetries (e.g. Hopkins & Rönnqvist, 2002). It has also been shown that
movement patterns in infancy that are later associated with CP can be
identified using this type of method (e.g., Nakajima, Einspieler, Marschik,
Bos, & Prechtl, 2006). Hence, it is a suitable method for the objectives of this
thesis.

Bead threading task (studies II and III)

The children were seated comfortably in front of a testing table. The seat was
adjusted in height and distance from the table so that all children could
perform the task readily. Steady support for the feet was ensured. The
children were instructed to pick up small beads by use of a pincer grip and
thread them onto a rod sequentially. They were further instructed to try to
thread as many beads onto the rod as possible in 30 seconds picking only
one bead at a time. The beads were lined up in a row 36 centimeters either to
the right or the left of the rod depending on which hand was active (right
side in right hand condition and vice versa for left hand condition). The
distance between the beads and the rod infers midline crossings and a shift
of visual focus (See figure 2a-d for experimental task and marker
placement). The bead threading task was chosen for several reasons: 1) it is
both challenging and engaging for children; 2) it provides an optimal
experimental setup for kinematic registration of upper-body, arm and hand
movements; 3) the task has been found to demonstrate both gross
movement performance as well as more subtle information of
spatiotemporal performance (in children with fetal alcohol syndrome,
Domellöf, Fagard, Jacquet, & Rönnqvist, 2011; adolecents with Asperger’s
syndrome, intellectual dysfunction, and in children with posterior fossa
tumours, unpublished results). It is a unimanual task with high demands on
the coordination and control of head, arm and hand/finger movements. The
task involves transport (between the rod and row of beads), grip, and thread
phases (fine digit control). It is also highly demanding with regards to visuo-
motor integration as it involves head movement control as well as gaze
shifts. Accordingly, performances that are fast with high precision are
assumed to reflect successful movement planning and sensorimotor
integration resulting in a dynamic movement with few corrections.

The children were encouraged to perform the task 3 times with each hand,
where the order was counterbalanced and randomized. All children were

31
allowed to practice with a few beads with each hand before the recordings
commenced (the task is also described in Domellöf, Fagard, Jacquet, &
Rönnqvist, 2011). A total of 9 spherical markers were affixed with skin-
friendly adhesive tape to the right and left shoulders (29mm), elbows
(19mm), wrists (12mm), and index fingers (7mm). A marker was also affixed
to the forehead (12mm).

Figure 2a-d: Photographs and corresponding Qualisys Track Manager derived images of a 7
year old fullterm born child in (a-b) a pick phase and a (c-d) thread phase. Printed with parental
and child permission.

During the data handling process, unsuccessful trials were discarded to

ensure that only trials where the task was performed without errors were
subject to analysis. The onset and offset of each trial (pick-thread-to pick)
were defined as the frame where the tangential velocity of the wrist marker
was 60mm/s and decreasing when the active hand approached the line of
beads. The video recordings were used to verify the application of these
criteria. In the total prematurely born sample (study II), 2,960 (M = 46)
successful pick-thread-to pick cycles were performed and 146 (4.7%) cycles
were discarded due to either dropping of the bead or the child picking and
threading more than one bead at a time. In the fullterm born group, a total of
4,148 (M = 55) successful cycles were performed and 203 (4.7%) cycles were
discarded. When the kinematics of the preferred and non-preferred hand

32
were analyzed separately, the hand used for drawing was used as the
preferred hand for the children qualifying, according to the frequency
assessments, as mixed handed.

Extension-flexion adduction-abduction board (study IV)

To evaluate the effect of the IM intervention the participants performed a

goal-directed upper-limb task before the intervention commenced (Pre-test)
and at two time points after it concluded (Post-test 1 and Post-test 2). The
participants were seated in front of a custom-built platform that had 10 easy
to press button like light-switches (See figure 3 for task depiction and marker
placement). The participants were instructed to switch on the lights in a
sequential order determined by a contra-balanced block design. The goal was
that all participants should perform the task with their non-affected and
affected side (unimanual condition) and with both sides simultaneously
(bimanual condition). The children had to begin with their hands placed at a
marked starting point and press three light switches in a sequential order
starting either with the light switch located closest to the body and moving
forward (extension) or starting furthest away and moving back towards the
body (flexion) or starting at the center and moving horizontally (adduction)
or starting from the light switch furthest away in the horizontal direction and
moving towards the center (abduction). The experimental design resulted in
a 3 (non-affected/affected/bimanual) x 4 (extension/flexion/adduction/
abduction) protocol where each direction was to be performed 3 times,
resulting in a total of 36 trials for each testing occasion. The adolescents
were asked to perform the task with a clenched fist as differentiated finger
movements were strenuous for most of them. Two of the participants (case
IV and case V) could only perform the task with their least affected side and
by pushing the light switches with either the index finger (case V) or the
thumb (case IV). When the trial was unsuccessful, the participant was asked
to repeat the erroneous trial at the end of the related block.

For the data extraction process the velocity of the wrist marker was used.
The onset of the movement was defined as the frame when the wrist marker
had a velocity of 20mm/s that was increasing and the offset as the frame
when the wrist marker had a velocity of 100mm/s and was increasing after
the last successful light switch press. Video recordings were used as support
in the application of these criteria.

33
Figure 3a-b: a) Photograph and corresponding b) Qualisys Track Manager derived image of a
participant performing a bimanual abduction trial. Printed with permission.

Extracted kinematic parameters

Segmentation of the movement trajectory

Analysis of the segmentation of the movement trajectories was applied in
studies II-V as it has been shown to be a sensitive measure of the maturity
and integrity of the motor system (von Hofsten, 1991; Rönnqvist & Domellöf,
2006). Segmentations of the movement trajectory were calculated using an
algorithm developed by von Hofsten (1991) where each segmentation is
referred to as a movement unit (MU). An MU is defined as an acceleration
phase and a deceleration phase with an accumulated increase or decrease in
velocity of at least 20mm/s and an acceleration or deceleration exceeding
5mm/s2 (see figure 4b-c). This algorithm (or similar ones) has been applied
to several studies of development in reaching and grasping (Kuhtz-
Buschbeck, Stolze, Jöhnk, Boczek-Funcke, & Illert, 1998; von Hofsten, 1991);
arm movements in pre-reaching behavior (Bhat & Galloway, 2007; Bhat,
Lee, & Galloway, 2007); stepping response in the newborn infant (Rönnqvist
& Domellöf, 2006); arm movements in reaching and grasping in children
with hemiplegic CP (Rönnqvist & Rösblad, 2007); arm movements in
reaching in hemiplegic CP (Domellöf, Rösblad, & Rönnqvist, 2009; Mackey
et al., 2006; Schneiberg, McKinley, Gisel, Sveistrup, & Levin, 2010); and as a
stable test-retest measure of reaching in children with hemiplegic CP
(Schneiberg et al., 2010).

Cumulative distance

The 3-dimensional distance of each marker was extracted to gain insight into
the energy efficiency of the movement paths (see figure 4a). A shorter, more
direct, movement trajectory is usually a result of maturational processes
(e.g., van der Heide, Fock, Otten, Stremmelaar, & Hadders-Algra, 2005).

34
Figure 4a-c: a) illustration of the 3D motion of the wrist trajectory, b) and the velocity profile
of the same movement as in figure a where * indicate the onset and offset of the movement
units; o indicate the local minima; + indicate the local maxima, c) the relative size and the
number of MUs during the whole task (from onset to offset). Data derived from a right sided
(affected) bimanual abduction trial from study IV.

Movement duration

In studies II-IV, the actual movement time per pick-thread-to pick cycle or
light switch press was extracted from the preprocessing of the kinematic
data. This allowed for investigations into the movement time in relation to
the measures of coordination and control. The duration of goal-directed
upper limb movements has been shown to decrease as the child gets older
(e.g., van der Heide, Fock, Otten, Stremmelaar, & Hadders-Algra, 2005).

As the participants varied in the number of complete movement

cycles/phases they managed, all kinematic and duration data was made
relative before they were subjected to statistical analysis. The mean number
of MUs per complete pick-thread-to pick cycle (study II-III) and per
complete light-switch press (study IV) was calculated within and across
trials.

Interactive Metronome (study IV)

In study IV, a type of SMT method (Interactive Metronome, IM), developed

to assess and train timing, was used in the intervention. This method is
alleged to enhance motor functions in persons with a variety of

35
neurodevelopmental and neurodegenerative deviations. The method is
thought to improve motor timing by integration of sensorimotor modalities
through rythmic activation (Interactive Metronome INC, Weston, Florida,
USA). IM is based on synchronized rythmic activation of upper- and lower-
body extremities to a sensory signal (preset at 54 bpm but adjustable), where
timing of movements can be fine-tuned via the presentation of auditory and
visually presented timing error feedback. To date, few studies have
scientifically evaluated the effects of IM in children. Effects on reading
fluency have been found (Taub, McGrew, & Keith, 2007) and, although
mainly driven by a decrease in the control group, some improvement in
visual reaction time and visuo-motor control in a sample of children with
attention deficit hyperactivity disorder have been shown (Cosper, Lee,
Peters, & Bishop, 2009).

In study IV, the IM training regime was individually adjusted to suit the level
of skill of the participant with regard to the type of action being performed,
the type and amount of feedback provided, and the temporal interval of the
metronome. All cases participated in 4 weeks/12 sessions of individually
adjusted IM training. As the participants had different levels of ability, the
IM training regime was individually adjusted to suit each participant. This
resulted primarily in differences in the limbs involved and the total number
of rhythmic activations (number of beats the sensor was activated on). These
variations are presented in Table 4. At every training session and at the pre-
test and post-test occasions, each participant performed 2 minutes (108
repetitions, 54bpm) of handclapping (bilateral for cases I-III and V;
unilateral for case IV) without error feedback, and 2 minutes (108
repetitions, 54bpm) with error-feedback (all cases except case IV). This
procedure allowed for assessment of rhythmic ability (without error
feedback, self-phased timing) and the ability to use the error feedback
provided to adjust movement timing (with error feedback).

Table 4: Information of the individualized IM training.

Case IM training of: Total N rhy thmic activ ations

I arms/legs 1 6,600
II arms/legs 1 6,200
III arms 1 3,1 00
IV least affected arm 7 ,800
V arms/ least affected arm 6,7 00

36
What is trained in the IM paradigm?

Coordination both within and between limbs are required for fast, accurate
and energy-efficient movement execution. The timing of movements
between different limbs (e.g. head and hand) and within limbs (e.g. shoulder,
elbow, and wrist) is crucial for skilled performance in both single unit
actions and in actions requiring multiple units (Schmidt & Lee, 2005).

Theoretical support for why the IM would be beneficial for movement

coordination and timing stems from two sources: the pacemaker-
accumulator model (PAM) and the concept of emergent timing. The PAM
assumes that there is a centralized internal clock that sets a phase upon
which behavior can be organized. The ticks of the internal clock are
generated at a fixed frequency and they are detected by a counter. This
enables precise timing of motor sequences (Koomar et al., 1998; Taub et al.,
2007). Uncoordinated movements are in this theory believed to stem from a
faulty pacemaker as organization and sequencing may be intact (Koomar et
al., 1998). In accordance with the PAM, the timing of movements in IM is
event-related and thereby a clear goal (to synchronize) exists and in the IM
paradigms where no error feedback is provided one must have a temporal
representation of the interval between the events (metronome beats).
However, the execution of coordinated and timed movements is not just
internally driven by a pacemaker but is also dependent on information from
the environmental situation and the goal of the action. In IM training, most
movements are supposed to be of a circular fashion with movements that are
smooth and continuous (e.g., hand clapping with circular motions), which
relates to emergent timing rather than event timing. In emergent timing, the
ability to maintain a given interval is not dependent on or require explicit
awareness of the interval duration (Schmidt & Lee, 2005). Rather, it has
been hypothesized that timing under such conditions emerges from the
dynamics of trajectory control (Zelaznik, Spencer, & Ivry, 2002).

Another aspect of IM is the relatively slow phase (54 bpm) at which

rhythmicity and timing are usually trained. Research suggests that mental
interval timing consists of two sub-systems. The automatic timing system
processes discrete-event (discontinuous) timing in milliseconds and heavily
involves the cerebellum. The cognitively controlled timing system deals with
continuous-event timing (in seconds) that requires controlled attention and
working memory and primarily involves the basal ganglia and related
cortical structures (Lewis & Miall, 2006). Further, IM also entails a feedback
system used as a tool to improve timing skills against the metronome.
Feedback is crucial for learning a motor skill. Sources of feedback are
sensory information, the result of actions, as well as augmented stemming

37
from other sources than the individual. Some aspects of movements are
harder to evaluate using inherent (within the individual) feedback and
augmented feedback in terms of how to perform the movement is necessary
for improvement of skill. In IM, one can adjust the speed or trajectory of the
action in accordance with the augmented feedback provided by the system to
obtain a closer match to the metronome.

Gross Motor Function Classification System (Study IV)

The Gross Motor Function Classification System (GMFCS) (Palisano et al.,

2008) was used to provide a background description of the gross motor
abilities of the participants in the intervention study. In the GMFCS,
ambulatory ability is in focus. For 12-18 year old children the different levels
of the GMFCS refer to:

I. Walks without limitations indoor and outdoor and can climb stairs
without need of support. Can run and jump but balance and
coordination is impaired.
II. Can walk in most environments but usually assistance is required.
For longer distances a wheelchair may be needed. Can climb stairs
with assistance.
III. Can walk with hand-held mobility assistance and needs assistance
when moving from sitting to standing. Can use an electronic
wheelchair and climb stairs with assistance.
IV. Uses a wheelchair in most environments but can walk shorter
distances indoors with support. Can provide support with the legs
when being moved in standing position. Need of a wheelchair that
provides pelvic and upper body support. Uses an electrical
wheelchair but can sit in a manual for assisted transportation.
V. Is transported in all environments by use of a wheelchair. May
possibly be able to use an electronic wheelchair if it is well adjusted.
Has limited control of the head, upper body, legs and arms. Cannot
provide support with the legs when being moved.

Manual Ability Classification System (Study IV)

As with the GMFCS, the Manual Ability Classification System (MACS)

(Eliasson et al., 2006) was used as a background description of the children’s
functional ability of the hands. The GMFCS is a tool for judging how well the
child with hemiplegic CP can use their hands when handling objects
important in daily activities. It should be used to reflect self-initiated ability
and should measure normal functional level, not maximum performance. As
it has been developed for use with children with hemiplegic CP, bi-manual

38
ability is measured. In the present study, however, it was also applied to
children with diplegic CP.

The MACS classifies manual ability into the following 5 levels:

I. Handles objects with ease and with good results. Can have some
limitations in tasks that require speed and precision. Such
limitations does not limit the child’s independence in performing
daily activities and are limited to finger dexterity/ hand coordination
and control in the handling of heavy, fragile, new, or fine objects.
II. Handles most objects but with some limitation with regard to quality
and/or speed. Some activities may be avoided or may be performed
but with limitations. The limitations do usually not limit the child’s
ability to perform daily activities although some tasks may be
adjusted to ease performance. Can perform the same activities as in
level I but slower and with poorer quality. Usually uses
environmental support to ease performance (may for example use
surfaces as support) and differences between the hands in functional
level may limit the effectiveness in performance.
III. Has impairments in the handling of objects and require assistance in
preparation and/or adjustment of activities. The performance is slow
with limited success with regard to quality and quantity. Can
perform adjusted tasks independently.
IV. Can handle a limited number of objects in adjusted situations. Can
perform parts of activities with effort and limited success. Require
continuous support and help and/or adjusted equipment in order to
perform parts of activities.
V. Cannot handle objects and have severely limited ability to perform
simple actions. Is totally dependent on assistance. May be able to
participate in activities by means of for example, pushing buttons.

Arm/hand function questionnaire (study IV)

To acquire information about the subjective experience of change in tonus

and function of the affected (in cases I-III) and least affected (in cases IV-V),
arm/hand a questionnaire was devised. Questions probed experiences of
changes in muscle tone, ability to get dressed, ability to feed, and the ability
to use the arm/hand in daily activities and recreation. Questions about
changes in finger dexterity and in the functional level of the least
affected/affected arm/hand were also asked. The children and their parents
graded the changes as; (5) substantially positive change, (4) somewhat
positive change, (3) unchanged, (2) somewhat negative change, (1)
substantially negative change. Open questions were asked to gain

39
information about experiences of improved or worsened function, improved
or worsened function in the legs, and what effect (if any) was of most
importance. Finally, a question if the child had been involved in any other
type of training was asked, either during or after the IM training had
finished. The questionnaire was for the parents and the child to fill out
together and it was administered immediately after the IM training was
completed and 3 and 6 months after completion of training.

Socioeconomic information (studies II-III)

The parents of the children were asked a number of questions pertaining to

the socioeconomic status of the family. Questions about family structure (if
the parents were married, cohabitants or separated; mother as only
caregiver; father as only caregiver; other primary caregiver; other family
constellation; number of siblings), mother’s profession, father’s profession,
years of education of the mother and the father (starting from first grade).

Wechsler’s Intelligence Scale for Children (study III)

To assess the cognitive function of the fullterm and prematurely born

children in study III the Wechsler’s Intelligence Scale for Children, 4th
edition (WISC-IV) was administered. The tests included in the WISC-IV are
grouped into four cognitive domains: verbal comprehension (verbal
intelligence quotient, VIQ), perceptual reasoning (performance IQ), working
memory, and processing speed. These four domains together constitute the
full scale IQ which is an expression of general intelligence. The WISC-IV
assessment was made by professionals with previous experience of
administration of the test and other types of neuropsychological assessments
of children. The testing was carried out in a quiet room, free from possible
distracting materials. A shorter break was taken halfway through the testing
session to ensure the children’s sustained attention throughout all included
tests. The WISC-IV is a test that is extensively used for children between 6-16
ears-of-age in clinical practice and for research purposes.

Journal background/ medical birth history (studies II-IV)

In studies II-III, information from the children’s medical birth records was
extracted. This information was used both as background factors to describe
the children included in the studies and as factors included in the analyses of
the outcome data (see Tables 1a-b and 2 for background information). In
study IV, the journals from the associated rehabilitation center were used to
gain insight into the presence of any co-morbidities and results from the

40
children’s MRI scans, if they had received such. This information was solely
used to provide a more robust case description.

Statistical methods

All statistical analyses in studies II-IV were carried out using Statistica 9.
Table 5 is a summary of the statistical methods used in the empirical studies.

Table 5: Summary of the statistical methods applied in the empirical

studies.

Statistical methods Study II Study III Study IV

Wilcoxon matched pairs test x
T-test x
Pearson's χ2 x
Pearson's correlations x
Analysis of covariance x
Multiple hierarichal linear regression x
Multivariate analysis of covariance x
Effect sizes
Cohens d x
Pearson's correlations x
Partial Eta square, η 2 p x

Study II

In study II, the children born preterm were divided into three sub-groups
based on their GAs (moderately preterm; M-PT = 33-35, n = 35; very
preterm; V-PT = GW 29-32+6, n = 17; extremely preterm; E-PT = < 28 GWs,
n = 12). The outcomes were analyzed by means of analysis of covariance
(ANCOVAs), multivariate analysis of covariance (MANCOVAs), Pearson’s χ2,
and Pearson’s correlations. The kinematic outcomes were analyzed primarily
by MANCOVAs where side (preferred/non-preferred) and group (E-PT, V-
PT, M-PT, and fullterm; FT) were used as categorical predictors. Separate
ANCOVAs were performed on the kinematic outcomes to investigate side
effects within GA groupings. Age was used as a continuous covariate in these
analyses. Person’s correlations were used to further analyze the effect of age
within the sub-groupings. Significant effects were followed up by means of
‘unequal numbers honestly significant difference’ post-hoc analysis and
partial eta square (ηp2) was used as effect size estimate. Pearson’s χ2 was
used to test the difference in the frequency of non-right handedness between
the group of children born preterm and the FT born children. Significant
results are reported on the level of < .05, < .01 and, < .001.

41
Study III

Between group (prematurely vs. fullterm born) analyses of IQ were carried

out on the index values derived from the WISC-IV (verbal index,
performance index, working memory index, perceptual speed index, and full
scale IQ) by means of t-tests (two-tailed). The kinematic outcomes of interest
were also subjected to t-tests to establish presence of any group differences.
Cohens d was used as a measure of effect size on the outcomes from the t-
tests. Hierarchical multiple linear regressions within the prematurely and
fullterm born groups were conducted to explore the relationship between
movement kinematics and full scale IQ. GA (within the prematurely born
group only), sex and full scale IQ were used as predictors in the analyses. In
the prematurely born group GA was imputed in the first step, sex in the
second step, and IQ in the third. In the fullterm born group, sex was imputed
in the first step, followed by full scale IQ. The alpha level was set at p < .05 in
all analyses. Standardized Beta (β), R Square change (ΔR2), F change, and p
values are reported.

Study IV

In study IV, the kinematic outcome was analyzed on trial level where each
trial was paired with the corresponding trial at all three testing occasions.
Wilcoxon matched pairs tests were used as data was not normally
distributed. The alpha value was set at 0.025 (0.05/2) to correct for the
increased risk of type I errors as there were repeated analyses. Where
outcomes were statistically significant, Pearson’s correlation coefficient was
used to calculate an effect size. The uni- and bimanual conditions were
analyzed separately by side (affected/non-affected). Due to measurement
errors and premature onset of movement, 17 trials were discarded. A total of
105 trials for case I and a total of 104 for case II were subjected to statistical
analysis.

Ethical considerations

The children, adolescents and their parents were informed verbally and in
writing about the purposes and the contents of the studies. The parents of
the participating children gave informed consent in writing regarding study
participation and access to medical journals. All empirical studies were
approved by the Umeå Regional Ethical Board and were carried out in
accordance with the Declaration of Helsinki.

42
SUMMARY OF RESULTS AND BRIEF
DISCUSSION OF FINDINGS
Study I

The existence of increased rates of non-right handedness in children born

preterm is unclear as several studies, assessing handedness both directly or
indirectly as a background variable, have shown inconsistency in their
findings.

The research questions posed in study I were therefore:

i. Do children born preterm have higher occurrence of non-right

handedness than children born fullterm?

ii. Is non-right handedness associated with neurological deviations

and/or neuropsychological findings in children born preterm?

These questions were investigated through a systematic literature review and

a meta-analysis including 18 studies (1,947 cases, 8,170 controls). Odds ratio
(OR) calculations for dichotomous data revealed an OR of 2.12 (p. < 0001;
significant heterogeneity at 51%) in favor of non-right handedness in the
prematurely born populations included in the meta-analysis (see figure 3).
This corresponded to a percentage of non-right handedness of 22% in the
children born preterm and 12% in the control groups. Studies with higher
quality scores of how handedness was assessed and in the description of
their samples had higher cumulative ORs (2.45 and 2.55, respectively with
0% heterogeneity in both) than did those with low quality scores (1.70 and
1.52, respectively with significant heterogeneity at 74% for handedness
assessment alone). The lack of significant heterogeneity between the high
quality studies suggests that studies having less refined measures of hand
preference, less well defined study samples, and less well-matched control
groups, less information about participant background, demographics and
parental background, less rigorous study design, and less refined
recruitment processes had larger variations in study outcome than those
studies that had high levels of control and more refined assessment methods.

43
Figure 5: Random-effects odds ratio (OR) meta-analysis for non-right handedness in cases
and controls. The size of the study marker corresponds to study weight. 95% confidence interval
(CI) is represented by error bars. The weighted cumulative OR (open diamond) of non-right
handedness significantly favors cases. ¤ = unpublished data.

When assessing the occurrence of publication bias using Duval and

Tweedie’s trim-and-fill method (Duval & Tweedie, 2000). Seven studies
were imputed to the left (in favor of controls) of the cumulative point
estimate which was adjusted to 1.66. However, visual inspection of the
funnel plot indicates that no “small study” effect was apparent as the
imputed studies did not cluster at the bottom of the plot. As only six out of 18
of the included studies had a focus on studying handedness in children born
preterm and no apparent small study effect is present, the finding of an OR
of 2.12 in favor of cases may be regarded as a secure result.

In the literature review, it was revealed that 12 (Allin et al., 2006; Caldú et
al., 2006; Kesler et al., 2006; Lancefield et al., 2006; Marlow et al., 1989;
Nosarti et al., 2004; O’Callaghan et al., 1993; Powls et al., 1996; Ross et al.,
1987, 1992; Saigal et al., 1992; Zuazo, Garaizar, & Prats, 1999) of the
included studies attempted, either as a primary research question or as a
control measure, to relate handedness to neurological outcomes. This was
done with the rationale that non-right handedness may be related to early
occurring brain injury in the children born preterm. Of these, only two of the
studies were able to show such a connection (O’Callaghan et al., 1993; Saigal
et al., 1992). O’Callaghan and colleagues (1993) showed an association
between left handedness and the number of risk factors for brain injury and

44
in the study by Saigal and colleagues (1992) an association between non-
right handedness and neurological impairments was shown.

Based on the findings that preterm birth is associated with increased risk of
brain injury (Volpe, 2009) and the hypothesis that non-right handedness
may be caused by such insults (Bakan, 1971, 1977), the occurrence of non-
right handedness may also be related to neuropsychological functioning.
Increased rates of left hand preference has been shown to be related to lower
IQ scores, impaired motor abilities, and difficult temperament in 4 year old
children (O’Callaghan et al., 1993). Ross and colleagues similarly found
lower IQ scores and delayed language development in 4 year old prematurely
born non-right handed children (1987). The connection between lower IQ
scores and non-right handedness persisted at 7-8 years of age, where an
association between attention deficit hyperactivity disorder and non-right
handedness was shown (Ross et al., 1992). A linear relationship between
cognitive level and hand preference score, where increased level of non-right
handedness was related to lower cognitive scores, was found by Marlow and
colleagues (2007). However, several studies have not been able to show a
connection between non-right handedness and neuropsychological outcomes
(Luciana, Lindeke, Georgieff, Mills, & Nelson, 1999; Powls et al., 1996; Saigal
et al., 1992; Zuazo et al., 1999).

The findings from the meta-analysis suggest that preterm birth, at least in
some instances, is associated with disturbance of the typical development of
cerebral asymmetry related to hand preference. However, for most children
born preterm (78%) in this meta-analysis, a typical right handed preference
is established. It is possible that the differences in hand preference reported
in studies are related to sample heterogeneity as suggested by Bishop (1990).
It is, for example, possible that the expression of non-right handedness is
more prominent in children born most immaturely. Some of the studies
included in the meta-analysis that focused on children with an extremely
preterm birth or with an extremely low BW (< 27 GWs, < 1,000 grams) were
also able to show the highest incidences of non-right handedness (e.g.,
Marlow, Hennessy, Bracewell, & Wolke, 2007; Marlow et al., 1989). Less
skillful motor performance was shown by a few studies (O’Callaghan et al.,
1993; Ross et al., 1992). Children born with a BW of less than 1,500 gram
with a non-right hand preference have also been shown to have poorer
manual skills than right handed children born with a comparable BW (Powls
et al., 1996). Similarly, poorer writing skills were shown in children with low
gestational age (32-34 GA) and extremely low GA (< 27 GWs) even though
most of the children were right handed. Sagnol et al., (2007) showed a lack
of side differences in terms of movement time in 5 year old children born
preterm compared to controls. It is possible that the diminished frequency of

45
right handedness in children born preterm does not directly reflect a reverse
handedness pattern (i.e. left handedness) but rather a lack of specialization.
This could be due to the occurrence of brain injury and/or developmental
delay. At present, it appears that non-right handedness is more prevalent in
children born preterm but the underlying causes and mechanisms for this
phenomenon remain unclear.

Study II

The aim of study II was to investigate hand preference and side specific
specialization in terms of spatio-temporal organization of upper-body
movements in a group of children born preterm (≤35 GWs) at 4-8 years of
age. Four specific hypotheses and one exploratory research question were
posed. These were as follows:

The children born preterm compared to their fullterm born peers were
hypothesized to:

i. show less evident hand preference in terms of the frequency of hand

use when manipulating objects.

ii. have movement trajectories that are more segmented, longer in 3D

distance, and have longer durations.

iii. have less evident side specialization as expressed by less smooth and
coordinated hand/arm trajectories.

iv. have increased segmentation and movements of the head.

Of further interest was to explore if the results from the above stated
hypotheses were influenced by GA.

As a measure of control, the effect of sex on all kinematic outcomes were

analyzed by means of MANCOVAs where age at testing was used as a
continuous covariate and side (preferred/non-preferred) x sex (boy/girl) x
group (prematurely born/fullterm born). Sex was only significant as a main
effect on the number of MUs of the head (F(1. 265) = 20.59, p < .001, ηp2 =
0.03; girls, M = 256, SD = 108; boys, M = 313, SD = 120). Thus, due to the
general lack of overall effects of sex on the outcome variables and the limited
sample size as well as the unequal number of girls and boys in the groups
with the lowest GAs, sex was not included as a categorical predictor in the
analyses in study II.

46
Analyses of the frequency-based assessment of handedness showed that 85%
of the children born preterm and 93% of the fullterm born children were
right-handed. When the index values derived from the frequency-based
assessment were statistically tested, no significant results were noted (see
Table 6 for mean values, standard deviations, and p values) for any of the
groups or ages.

Table 6. Mean values and standard deviations of the laterality index and
category of hand preference presented by group.

Group Lat index- hand RH MH LH NRH

M SD n(%) n(%) n(%) n(%)
FT (n = 76) 0.76 0.35 71 (93) 3 (4) 2 (3) 5 (7)
M-PT (n = 35) 0.73 0.42 32 (91) 1 (3) 2 (6) 3 (9)
V-PT (n = 17) 0.50 0.60 12 (71) 2 (12) 3 (18) 5 (29)
E-PT (n = 13) 0.55 0.48 11 (85) 1 (8) 1 (8) 2 (15)
Overall PT (n =65) 0.63 0.49 55 (85) 4 (6) 6 (9) 10 (15)
Note: Lat. = laterality; M = Mean; SD = standard deviation; M-PT = moderately prematurely
(PT) born; V-PT = very PT born; E-PT = extremely PT born; FT- fullterm born.

It has been suggested that increased rates of non-right handedness, in terms

of the hand chosen when performing manual skillful tasks, may reflect early
occurring disruption of brain development (Bakan, 1971; Bishop, 1990; Satz,
1972; Soper & Satz, 1984), possibly caused by birth complications (Coren,
1995). Others have stressed that preterm birth itself is associated with
increased rates of non-right handedness (e.g., Marlow et al., 2007; Ross et
al., 1987). It is possible that events associated with preterm birth are related
to changes in atypical hemispheric organization. However, no significant
difference in hand preference was apparent in this study although the
children born < 33 GWs did have a lower mean value on the laterality index
of the hand. The frequency-based assessment of handedness showed that
85% of the children born preterm and 93% of the children born fullterm
were right-handed.

Regarding movement performance and side specificity, only the fullterm

born children expressed such a difference in movement duration and
movement segmentation of the head and wrist where the preferred side was
faster and smoother than the non-preferred side (see Table 7 for mean values
and standard deviations on the kinematic outcome parameters presented by
group. Outcomes are further presented by side and overall).

47
Table 7: Mean values and standard deviations of the kinematic outcomes by
group, overall and side.

Group Side 3D distance (mm) Movement Units (n ) Duration (s)

Wrist Head Wrist Head
M SD M SD M SD M SD M SD
FT (n = 76) Pref 862 252 272 96 10.9 4.6 14.1 7.9 2.9 0.7
N-pref 855 159 274 94 11.8 4.7 16.4 7.2 3.1 0.7
Overall 858 210 273 95 11.4 4.7 15.2 7.6 3.0 0.7
M-PT (n = 35) Pref 826 89 252 80 11.0 4.7 14.6 8.0 2.9 0.9
N-pref 819 89 266 86 11.1 3.4 15.7 6.6 3.0 0.7
Overall 822 88 259 83 11.0 4.1 15.1 7.3 3.0 0.8
V-PT (n = 17) Pref 945 185 337 143 15.7 9.0 18.6 10.0 3.7 1.6
N-pref 931 175 323 144 15.8 8.8 21.2 8.8 3.6 1.2
Overall 938 177 330 142 15.8 8.8 19.9 9.3 3.6 1.4
E-PT (n = 12) Pref 882 106 310 115 14.9 6.0 18.7 9.4 3.6 1.2
N-pref 880 114 320 117 13.7 4.6 18.8 6.6 3.5 1.0
Overall 881 108 315 114 14.3 5.3 18.8 7.9 3.6 1.1
Note: FT = fullterm born; PT = prematurely born; M-PT = moderatley PT; V-PT = very PT; E-PT
= extremely PT; mm = milimeter; s = seconds; Pref = preferred; N-pref = non-preferred

In terms of movement kinematics, as expected, the children born preterm

took longer time to complete a pick-thread-to pick cycle and had increased
segmentation of the movement trajectories of the wrists compared to their
fullterm born peers. The post-hoc analyses of these parameters showed that
the effect was located between the children born fullterm and moderately
prematurely and the children born very and extremely prematurely. The
latter two groups had more segmentations and longer durations than did the
groups with children born fullterm and moderately preterm. Similarly, the
children born preterm had more segmentations of the head and longer 3D
distances with the effect being located to the very prematurely born children,
possibly indicating increased looking and/or postural instability. Thus, the
increased segmentations and longer movement durations in the children
with lower GAs (< 33 GWs) possibly reflect developmental delay or deviation
in motor control. Similar associations between GA and motor skill have been
reported (O’Callaghan et al., 1993).

There were large age effects within all groups of children on all kinematic
outcome parameters, where the older children expressed faster, smoother,
and shorter movement paths (see figure 6a-d for examples of the association
between age and some kinematic outcomes). Such changes in movement
control with age are consistent with previous findings in 4 to 12 year old
children (Kuhtz-Buschbeck et al., 1998) and probably reflect improved

48
motor planning and increased maturation of the brain systems supporting
such actions.

Figure 6a-d: Correlations, regression line shown, between age at testing and mean number of
movement units and 3D distance of the wrist during performance with the preferred (a and c
respectively) and non-preferred (b and d respectively) side for the fullterm (FT), moderately
preterm (M-PT), very preterm (V-PT), and extremely preterm (E-PT) born children. The r value
(Pearson’s correlation coefficient) and its significance level are shown by group within each
graph. The x axis denotes age at testing in both graphs.

To summarize, the group differences observed between the children born

preterm and fullterm were located to the children born before GW 33. This
group of children had less well organized and controlled movements and had
lower laterality indexes as well as no clear side specificity in terms of
movement performance. The children born moderately preterm performed
equally well as the fullterm born children and had a pattern of side-specific
movement organization that was similar to that of the fullterm born
children. The observed findings may indicate that the children born very
preterm (< 33 GWs) who are more immature at birth have a higher risk of
adverse brain development resulting in more disorganized movements.
Further, it is possible that a developmental delay is more prominent in this
group of children.

49
Study III

The aim of study III was to investigate differences in intellectual function

and movement performance between children born preterm and children
born fullterm at 6-8 years of age. Further, the associations between general
intellectual function (full scale IQ) and kinematic outcomes when controlling
for GA and sex were of interest. The hypotheses were as follows:

i. There are significant differences in IQ scores and upper-body goal-

directed movement kinematics between the prematurely and
fullterm born children, where the children born preterm have lower
IQ scores and more disorganized movement trajectories.

ii. There is a relation between measures of general intellectual function

(full scale IQ) and the efficiency of upper-body movement
kinematics in the children born preterm after controlling for GA and
sex.

As hypothesized, the children born preterm had significantly lower IQ scores

than their fullterm peers. The children born preterm in this study had scores
that were in the normal range (M = 94.5), confirming previous findings (e.g,
Bhutta, 2002). No significant differences were found between the children
born preterm and the children born fullterm in any of the kinematic outcome
variables. Thus, the first hypothesis could only in part be supported.

In the hierarchal regression analyses of the children born preterm GA was

entered in the first step, sex in the second step and full scale IQ in the third
step. This allowed control for the effects of GA and sex in the examination of
the predictive capacity of IQ on the kinematic parameters. GA (entered in the
first step) was shown to be a significant predictor for the duration of the
preferred wrist (ΔR2 = 12.9%), 3D distance of the non-preferred wrist (ΔR2 =
16.6%), and MUs of the preferred wrist (ΔR2 = 15.8%). Full scale IQ (after
controlling for GA and sex) contributed a significant proportion of unique
variance to the prediction of the duration of the preferred wrist (ΔR2 =
11.8%) and MUs of the preferred wrist (ΔR2 = 17.7%). Note that the ΔR2 was
reduced from the first step to the third for duration on the preferred wrist
suggesting that GA alone was a better predictor for this kinematic outcome.
Within the group of children born preterm, sex did not contribute any
unique variance to any of the kinematic outcome parameters. Full scale IQ
only added unique variance to the predictions of the duration and
segmentation (MUs) of the movement trajectories on the preferred side (see

50
Table 8). Within the fullterm born group, a significant effect for sex was
revealed on the 3D distance of the head when the non-preferred side was
active.

Table 8: Multiple hierarchical linear regression analyses predicting

movement kinematics from IQ in the children born preterm.

Children born preterm

p value whole
2
Kinematic parameter Predictor β ∆R F change p value model

Duration (pref wrist) GA -0.238 0.129 4.442 0.044

Sex -0.037 0.000 0.006 0.939
FSIQ -0.365 0.118 4.390 0.045 0.044
Duration (non-pref wrist) GA -0.216 0.074 2.410 0.131
Sex -0.097 0.007 0.229 0.636
FSIQ -0.180 0.029 0.897 0.352 0.344
3D distance (pref wrist) GA -0.221 0.106 3.566 0.069
Sex 0.087 0.011 0.371 0.547
FSIQ -0.304 0.082 2.857 0.102 0.097
3D distance (non-pref wrist) GA -0.287 0.166 5.963 0.021
Sex 0.141 0.027 0.956 0.336
FSIQ -0.343 0.104 4.151 0.051 0.018
MUs (pref wrist) GA -0.250 0.158 5.640 0.024
Sex -0.041 0.000 0.005 0.943
FSIQ -0.447 0.177 7.435 0.011 0.009
MUs (non-prefwrist) GA -0.086 0.044 1.387 0.248
Sex -0.025 0.000 0.000 0.997
FSIQ -0.374 0.124 4.172 0.051 0.155
3D distance (head pref side) GA -0.232 0.105 3.504 0.071
Sex 0.277 0.086 3.066 0.091
FSIQ -0.245 0.053 1.962 0.172 0.047
3D distance (head non-pref side) GA -0.212 0.063 2.005 0.167
Sex 0.167 0.030 0.953 0.337
FSIQ -0.096 0.008 0.253 0.619 0.388
MUs (head pref side) GA -0.091 0.026 0.814 0.374
Sex 0.032 0.002 0.062 0.805
FSIQ -0.209 0.039 1.164 0.290 0.576
MUs (head non-pref side) GA -0.123 0.045 1.402 0.246
Sex 0.004 0.000 0.014 0.908
FSIQ -0.264 0.062 1.933 0.175 0.360
Note: FSIQ, full scale intelligence quotient from the Wechsler Intelligence Scale for Children 4th edition (WISC-IV); GA,
gestational age; MU, movement unit; pref= preferred. Duration is in seconds.

Hence, full scale IQ adds unique variance to the prediction of movement

kinematics within the group of children born preterm alone that is over and
above the variance explained by GA and sex. However, the amount of
variance explained is limited for both GA and full scale IQ (maximum
17.7%). In combination (the models with significant outcomes considered),
however, the variance explained from these three variables ranged from 13.9
to 33.5%. This suggests that there are several other sources where variance in
outcome may stem from, including natural differences in maturation.

51
In summary, the children born preterm show lower full scale IQ scores than
their fullterm born peers. The full scale IQ scores are associated with aspects
of movement performance even when the important influence of GA is
controlled for. No relations between IQ and movement organization were
evident in the fullterm born group. The associations between movement
kinematics and cognitive functions within the group of children born
preterm suggest shared neural underpinnings and interrelated development
of these functions.

Study IV

In study IV the aim was to explore possible short- and long-term effects of
the Interactive Metronome (IM) on aspects of spatio-temporal organization
of upper-body movements in CP.

We asked whether timing and rhythmicity training with the IM of

adolescents with hemiplegic CP would:

i. result in improved timing and rhythmic ability both with and

without error feedback.

ii. have effect on the spatio-temporal properties of goal-directed upper-

body movements.

iii. continue to have effects on timing/rhythmicity and/or spatio-

temporal properties of goal-directed upper-body movements at 6
months after completed training.

The focus in this section will be on the results from the outcomes of the
adolescents presented in paper IV (cases I and II) but data from the other
three participants will also be presented for comparative purposes.

Results of timing and rhythmic ability from the IM instrument showed that
cases I and II were both able to learn to adjust and synchronize their
movements to better match the metronome beat. Case I had improved
timing/rhythmic ability both when error feedback was given and when it was
not (see figure 7a). Case II showed a higher degree of reliance on error
feedback for closer synchronization and a lower degree of learning when no
error feedback was given (see figure 7b). The effects were maintained at the

52
Post-test 2 testing occasion for both cases. Learning was not shown by cases
III-V (see figure 7c-e).

Figure 7a-e: Outcomes from the IM training instrument at pre-test, post-test 1, and post-test
2- occasions.

Similar changes in timing and rhythmic ability as expressed by cases I and II

has also been shown in other studies (Shaffer et al., 2001; Sommer &
Rönnqvist, 2009; Taub et al., 2007). It is possible that the changes in timing
and rhythmic ability detected by the IM instrument relate to neuronal
plasticity mechanisms of the sensorimotor system (Nudo, 2006). Another
possibility is that such changes are related to improvements in the ability to

53
sustain attention as the IM training system incorporates such elements for
success.

Kinematic changes of the wrist were found on both the affected and the non-
affected side for case I and primarily on the non-affected side for case II. In
general, the effects were located on the non-affected side in the unimanual
condition and the affected side in the bimanual condition and were largely
maintained at Post-test 2 (see graphical representation of outcomes in figure
8 and 9 for MUS and duration respectively). Such changes lead to a more
energy-efficient movement trajectory. The changes in duration and
segmentation remained (or emerged) at post-test 2 for both participants. For
cases I, II, IV and V, movement segmentation and movement duration
decreased which can be interpreted as an indication of increased movement
control and/or reduced biomechanical constraint. Mean number of MUs and
mean duration by side and test occasion for each case is presented in figure 8
and 9 respectively. Case II had fewer noticeable changes in the kinematic
parameters included than did case I, which could possibly be explained by
the lower level of learning of timing/rhythmicity when no error signals were
provided. Case III showed no changes in terms of MUs or duration, possibly
related to a failure to learn the task and/or the co morbidity of autism and
intellectual dysfunction. In terms of 3D distance, some significant changes
were noted, where movement trajectories became longer (case V) and
shorter (cases II and III on the non-preferred/non-affected side).

Figure 8: Mean number of MUs presented by side for the Pre-test, Post-test 1, and Post-test 2
occasion for the cases in study IV. Note: * = p < .05; ** = p < .05; *** = p < .05

54
Figure 9: Mean duration presented by side for the Pre-test, Post-test 1, and Post-test 2
occasion for the cases in study IV. Note: * = p < .05; ** = p < .05; *** = p < .05.

In terms of the subjective experience of changes in arm and hand function,

cases IV and V reported substantial and somewhat substantial changes in
muscle tone, movement speed, and increased range of movements. With
regard to the open questions, both cases reported positive changes in
abilities associated with daily living (getting dressed, controlling the
electronic wheelchair, controlling the computer, etc.). These changes
remained, albeit somewhat reduced, at post-test2. As cases IV and V only
had some control over the movements of one arm, it is a possibility that they
experienced these changes as the trained arm was the arm used in activities.
In hemiplegic CP, the affected arm is usually not engaged in activities and is
usually the targeted arm/hand in constraint-induced movement therapies
(e.g., Crajé et al., 2010).

55
GENERAL DISCUSSION, FUTURE
PROSPECTS AND CONCLUSIONS
The main objectives of this thesis were to investigate hand preference,
general and side specific goal-directed upper-body movement performance
in terms of movement organization in children born prematurely compared
to children born fullterm. Further, the association between upper-body
movement performance and cognitive function, gestational age, and sex in
these groups of children were of interest. Another objective was to explore if
and how sensorimotor training affects the organization of upper-body
kinematics in adolescents with CP (study IV). The occurrence of non-right
handedness in children born preterm was investigated by means of an odds
ratio meta-analysis (study I), where case-control studies reporting the
frequency of handedness in their samples were included. Handedness, by
means of frequency observations of the hand selected in unimanual tasks,
and side specificity, in terms of movement kinematics during goal-directed
upper-body movements, was investigated (study II) in 4-8 year old children
born preterm and in an age-matched fullterm born comparison group. The
association between the kinematics of upper-body goal-directed movements
and intellectual function was explored in 6-8 year old prematurely and
fullterm born children (study III).

Differences between the groups of children born

preterm and fullterm

Hand preference

The findings presented in study I in this thesis show that the occurrence of
non-right handedness is doubled in populations of children born preterm.
This doubling corresponded to 22% occurrence of non-right handedness in
the prematurely born populations. Although the prevalence of a non-right
hand preference was shown to be heightened in children born preterm the
findings also implies that the majority of these children establish a right
hand preference. Results in line with this finding were shown in study II,
where the majority (85%) of the children born preterm expressed a right
hand preference. However, it appears that the groups with the lowest GAs (<
33 GWs) have higher rates of non-right handedness and the lowest
handedness index values. When statistically testing the frequency of
handedness category within the groups and when testing the index values,
only trends towards significance were shown (p = .08 and .09). It is possible

56
that we could not show a significant difference in hand preference as we had
a relatively small study sample, specifically in the lower GAs. The finding of
higher frequencies of non-right handedness in the lower GAs may be related
to the higher occurrence of risk factors associated with brain lesions in these
groups and/or maturational aspects of brain development (Volpe, 2008,
2009). This suggestion is in line with the theory proposed by Bakan (1971)
which suggests that early disruptions in brain development cause non-right
handedness. However, a recent study using a large sample (10.000 children
at the age of 10) could not establish a link between strength or direction of
hand preference (i.e., degree of right or left handedness) and the occurrence
of birth stressors including measures pertaining to respiration, circulation,
and signs of cerebral injury. What this study did show was that birth
stressors were associated with cognitive and behavioral problems (Nicholls
et al., 2012). These findings suggest that the theory proposed by Bakan
(1971) may be incorrect.

Others have proposed that genetic factors and early disruptions in brain
development may be underlying increased rates of non-right handedness in
prematurely born children (Annett, 1985; Bishop, 1990). In relation to the
findings of increased rates of non-right handedness and decreased strength
of hand preference reported in the thesis, a plausible explanation is, at least
in part, to be found in epigenetics. Both preterm birth and handedness have
been shown to be heritable to some degree (Annett, 1985; Clausson,
Lichtenstein, & Cnattingius, 2000) suggesting involvement of genetic
mechanisms. Another possible explanation, although speculative, is that
preterm birth affects the function of the neurons so that the brain becomes
less plastic, which has been shown by Pitcher and colleagues (2011), and a
result of this may be that a dominant and more specialized hand is harder to
establish. Such a mechanism could of course also be of genetic origin. It
would be interesting, in line with Bakan, Dibbs, and Reed (1973), to
investigate the possibility that families with an aggregated rate of non-right
handedness also have an aggregated rate of preterm births. Such an
endeavor requires a population based approach where a large number of
people with a non-right hand preference could be recruited.

Movement organization

Group differences between the children born < 33 GWs and the age-matched
fullterm born comparison groups at 4-8 years of age were found in
movement organization in terms of movement duration, 3D-distance, and
the number of segmentations of the movement trajectories (study II). The
children born moderately preterm performed as well as their fullterm born

57
peers. These findings suggest that the greater vulnerability of more
immature children in terms of the often increased occurrence of detrimental
medical complications and the less mature central nervous system, have
long-term consequences for sensorimotor development. The differences in
movement kinematics were found for both the wrist and head. Possible
explanations for these findings are: 1) a general developmental delay in
sensorimotor functions, 2) persistent sensorimotor control deficits, 3) visuo-
perceptual deviances related to the functions of specifically the dorsal visual
stream (Atkinson & Braddick, 2007; Dutton, 2003). Of course, only
developmental studies employing a longitudinal approach can uncover
whether the findings reflect a developmental delay or persistent deficit. It
would be interesting to include tests tapping into dorsal stream functions in
future studies of prematurely born children as this would further the
understanding of how sensorimotor control is affected by visuo-spatial and
motion perception. Of interest would also be to further study the kinematic
data used in studies II and III from a movement dynamics perspective where
head (eye) and hand coordination is explored. Such an approach would allow
disentangling the degree of visual guidance of the hand that is needed.

Intellectual function

In study III, children of 6-8 years of age from study II who had participated
in WISC-IV testing were included. It was shown that the groups differed on
the full scale IQ, verbal and, perceptual indices. The children born preterm,
as a group, had lower test scores in general compared to their fullterm peers.
The mean differences between the groups ranged from 5 to 7 points, which
can be regarded as functionally quite a small difference; however, the effect
sizes were moderate to large suggesting consistency within the groups. These
findings are in accordance with previously reported lower scores on IQ tests
(e.g., Allin et al., 2001, 2011; Bhutta, 2002; Hoff Esbjørn, Hansen, Greisen, &
Mortensen, 2006; Kontis et al., 2009; Peterson et al., 2003; Soria-Pastor et
al., 2009). Possible deviances underlying lowered IQ scores in children born
preterm have been suggested to be lesions of the type found in the diffuse
form of PVL, where myelination of the cerebral WM is affected (Volpe,
2009). Studies investigating the relationship between results from high
resolution magnetic resonance imaging and IQ measures are needed to
further the understanding of this relationship.

The largest difference between the children born preterm and the children
born fullterm was found on a test of auditory working memory (letter-
number sequencing). This test places high demands on attention, processing
speed, sequencing, and auditory short-term memory. Although the

58
prematurely and fullterm born groups did not differ on the working memory
index. The finding from the letter-number sequencing test warrant further
investigation of executive functions and processes and their relation to
aspects of sensorimotor performance, including action planning and motor
learning. Intellectual function (full scale IQ) was associated, when
controlling for the effect of GA and sex, with duration and segmentation of
the movement trajectories of the preferred wrist in the preterm born
children. No such relation was shown for the children born fullterm. This
suggests that approaches where cognitive aspects of movement coordination
and control are included may be shown to be an important line of enquiry
when studying sensorimotor function and its deviances in children born
preterm. Further, as IQ was shown to be a unique predictor of many of the
kinematic outcomes when controlling for GA and sex, further variance may
be explained if future research involves other measures known to have effect
on IQ, such as maternal education and other socio-economic variables.

The influence of age, GA, and sex

Age substantially influenced the kinematic outcomes in study II, where

movements became faster, smoother, and shorter with increasing age. This
effect was shown in all groups of children but the children born very and
extremely preterm had the steepest regression lines. Thus, in this data,
group differences in movement performance appear to be largest for the
youngest children, and gradually decreases with age to be non-significant at
the age of 7-8. Indeed, in study III, where an older (6-8) subsample of the
children in study II was included, no group differences were shown for any of
the kinematic outcomes. Possible explanations for this effect could be a
developmental delay that is most prominent in the youngest (4 years of age)
and most pretematurely born children. True developmental studies (i.e.,
longitudinal approaches) are needed to verify whether there is a differential
developmental effect within the groups. In terms of hand preference, age did
not influence the strength of the handedness index, indicating that the
children in general had an established side preference by the age of 4. This
finding is in accordance with results reported by Rönnqvist and Domellöf
(2006), where children of 3 years of age were shown to express a hand
preference in terms of the hand chosen when reaching and grasping.

Effects of GA were shown in both studies II and III. In study II, the children
born < 33 GWs exclusively explained group differences between the children
born preterm and fullterm. Thus, children born after 33 GWs performed
equally well, on a group level, as the fullterm born comparison children. GA
also influenced the movement kinematics in study III, where effects were

59
shown on the segmentation and duration of the movements, specifically on
the preferred wrist in the group of children born preterm. Thus, even though
no difference between the children born preterm and fullterm were shown in
movement kinematics in study III, the outcome in the prematurely born
group was clearly influenced by GA.

The influence of sex on kinematic outcomes was limited in study II and

controlled for in study III. In study III, it was shown that sex explained no
unique variance in movement performance within the group of prematurely
born children. However, this does not mean that sex may not influence the
kinematic outcome. Sex was imputed after GA in the models which
implicates that any shared variance of sex and GA may be “eaten up” by the
first imputed variable, thus allowing the first step to account for most
variance. Male sex has been shown to be a risk factor for CP (Beaino et al.,
2011), preterm birth (Di Renzo, Rosati, Sarti, Cruciani, & Cutuli, 2007), and
also for sensorimotor deviances in preterm born children (e.g., Whitaker et
al., 2006). Hence, investigations of the effect of sex or accounting for its
variance may prove important in future studies.

Handedness: a dichotomy between preference and

performance?

In study II, the only difference between the preferred and non-preferred side
in terms of movement performance was found in the fullterm born group on
measures of duration and segmentation of the movement trajectories. This
result is in line with findings reported by Triggs and colleagues (1997; 2000).
We found that when the preferred hand was performing the task, the
movements were faster, the wrist and head had less segmentation than when
the non-preferred hand carried out the task. Thus, kinematic information
related to the organization and proficiency of movements derived from
optoelectronic recordings is sensitive enough to detect subtle side
differences. Implicated in this finding is that handedness (preferred/non-
preferred) in terms of the frequency of hand use may not be a good indicator
of movement performance per se as most children in the prematurely born
group had an established right hand preference. As with the strength of the
indices derived from the handedness inventory and the increased rates of
non-right handedness in the groups with the lowest GAs (< 33 GWs),
interestingly, the differences found between the groups in movement
kinematics were located to these groups too. As previously discussed, it is
possible that larger sample sizes, specifically in the low GAs, would have
yielded a significant difference in the laterality index as well. The children

60
born < 28 GWs showed signs of reversed asymmetry in terms of movement
performance, where the preferred hand appeared to be more disorganized
than the non-preferred hand. There is a need for detailed studies aimed at
investigating the relation between side specificity and movement
performance from a developmental perspective. This would increase the
understanding of what role an established hand preference plays in fine and
skillful movement specialization. As the knowledge about the neural
mechanisms underlying the establishment of handedness is limited, such
studies would also benefit this research area.

Training of sensorimotor functions

Timing training and constraints

In study IV, the two participants with hemiplegic CP showed relatively good
initial timing ability as assessed by the IM instrument. They also showed
stable and evident improvement in timing and rhythmic ability over the
training period and their improved timing remained six months after
completed training. The adolescents with more severe diplegic CP (not
presented in the paper) showed no such improvements. A possible
explanation for this discrepancy is that 1) the efficiency and/or accessibility
of IM training may depend on the severity of a persons’s condition and
associated individual constraints, or that 2) the IM instrument is not suited
to detect such changes in persons with severe forms of movement
impairments. Reduced accessibility to the IM in persons with CP may derive
from deficits in the interpretation and amount of information available from
sensory systems as well as in proprioception and the control over muscle
groups needed for successful performance (e.g., Ricken et al., 2006). The
deviations in motor control may pose a specific problem with accessibility to
the IM as timing has been shown to emerge as a by-product of the dynamics
of trajectory control (Zelaznik, Spencer, & Ivry, 2002). As most movements
in the IM training method applied in the present study should be smooth,
continuous, and circular in fashion (e.g. hand clapping with circular
motions), the emergent timing properties deriving from the trajectory
control require the ability to perform such movements correctly. As such, an
inability to produce movements with emergent timing elements, due to the
internal and/or external constraints of the individual, may be a specific
limitation. Regarding the second point, the adolescents with hemiplegic CP
did show some short- and long-term improvements in movement kinematics
as did two of the adolescents with more severe forms of CP. This indicates
that there might be possible training effects of the IM that are not detected

61
by the instrument itself. However, it remains unclear if it is the timing
training properties or the repeated activation embedded in the IM training
or a combination of the two that have effects on movement activation and
control.

Feedback in sensorimotor learning

An element embedded in the IM training program that is important in motor

learning is feedback. In IM, feedback of movement performance is provided
visually and through audition where the magnitude and temporal direction
(early or late) of the error form the basis for movement correction. Hence,
the feedback system in IM provides the information required for error and
reinforcement motor learning (Wolpert, Diedrichsen, & Flanagan, 2011).
Effective and accurate sensory input and the processing of such are required
for skilled actions (Wolpert et al., 2011). Thus, the explicit form of
presentation of errors in IM may be particularly beneficial for persons with
CP as sensory information may, and/or the interpretation of such is often
impaired. The ability to learn motor skills through feedback in children with
hemiplegic CP has been shown to be governed by the same principles as in
the population without such impairments (Hemayattalab & Rostami, 2010).
How motor learning is modulated by feedback in more severe forms of CP
and the effect of co-morbidities is an understudied area of research.

Motor planning or biomechanical constraints?

Impairments in motor planning have been implicated in children with CP,

where kinematic analyses have shown deficits in end-state control (Crajé,
Aarts, Nijhuis-van der Sanden, & Steenbergen, 2010; Steenbergen & Gordon,
2006; Steenbergen, Verrel, & Gordon, 2007) and compensatory motor
actions (postural involvement, longer movement durations etc.) to increase
end-state control (Butler, Ladd, Louie, et al., 2010; Butler, Ladd, Lamont, &
Rose, 2010; Domellöf, Rösblad, & Rönnqvist, 2009; Mackey, Walt, & Stott,
2006; Rönnqvist & Rösblad, 2007). The kinematic data (movement
duration, MUs, and 3D distance) extracted from the 3D motion analyses in
study IV can collectively be used to analyze aspects of motor planning. The
reduction in segmentation, and in some instances 3D distance and
movement duration could be interpreted as improvements in planning
ability. However, other reasonable explanations are improved motor control
and release of biomechanical constraint. However, despite the origin of the
kinematic changes, more energy-efficient movements were observed.

62
Methodological considerations

Children born preterm have frequently been shown to have increased rates
of movement deviances as detected by standardized motor function test
batteries (e.g., Edwards et al., 2011; Williams et al., 2010; de Kieviet et al.,
2009). Optoelectronic recordings are reliable and sensitive to detect small
changes in motor control (as discussed in the methods section). The
application of this observational technique to the study of movements allows
for the extraction of detailed information pertaining to coordination and
control of movements. As the system is reliable under the correct conditions
and simply monitoring and recording marker placement over time, the
validity and reliability of studies utilizing it relate to the task that is used and
the information extracted. In the studies included in this thesis, care was
taken to have relatively constrained tasks in terms of how they were
performed to reduce within- and between-subject variability. In terms of
movement kinematics, group differences were detected in study II although
none of the children had diagnosed motor problems and in study IV,
kinematic changes after SMT training was detected. A step that is necessary
to take to further the understanding of the added value of kinematic
movement registrations is to include standardized motor function test
batteries to enable comparisons between the methods.

In terms of the kinematic information extracted, movement duration and

movement segmentation were measures where most group differences were
noted. It is possible that the 3D distance is more sensitive to choice of
strategy where movements with longer distances do not necessarily imply
that they are less well controlled and organized as has been suggested
(Rönnqvist & Domellöf, 2006; Schmidt & Lee, 2005). It is possible, although
speculative, that 3D distance becomes decoupled from other aspects of
movement control (MUs) with development, as the correlation between age
and 3D distance is lower than between age and MUs, specifically for the
wrist in the fullterm group in study II (see figure 6c-d). MUs are very
sensitive to on-line corrections (von Hofsten, 1991) and future research
involving children with CP should also include the relative size of the MUs as
the movement profile most likely involves several small corrections but also
larger jerk-type movements. Information about the size of the movement
may aid in the prospect of teasing apart biomechanical constraints from
aspects related to movement planning in children with CP, where larger
corrections possibly reflect the former and smaller corrections the latter.

A unifying issue embedded in all the kinematic studies included in this thesis
is the test-retest reliability of the tasks. This is specifically an issue within the
intervention study (study IV), where the evaluation of the SMT method

63
applied (IM) was primarily focused on changes of goal-directed upper-body
movement kinematics. Future studies must include a control group or
multiple pretests to ensure baseline stability. Despite the limitations with
kinematic movement registrations, the application of this method allows for
the extraction of more information than can be seen with the naked eye. It is
sensitive and reliable and has, as applied in this thesis, been shown to be
able to detect group and side differences as well as age effects.

Future prospects and conclusions

The findings presented in this thesis implicate long term effects of preterm
birth on movement organization and control, and intellectual function. In
general, the children born most prematurely were shown to have both lower
IQ and more disorganized movements compared to the prematurely born
children with higher GAs and the children born fullterm. Additionally the
children born at very low GAs also showed less side specific movement
performance and had higher rates of non-right handedness implicating
effects of preterm birth on cortical organization and/or sensorimotor
learning mechanisms. Several studies have shown that children born
prematurely, without major disability, have persistent and substantial
sensorimotor deviances (e.g., Edwards et al., 2011, de Kieviet at al., 2009)
and lower scores on cognitive tests (e.g., Bhutta, 2002). Of course, a lower
functional sensorimotor and cognitive level, even when only mild, can be a
barrier to both scholastic and personal achievements. Thus investigations
into the etiology and interrelatedness of these functions are an important
area of research. Further, applied research into the effects of sensorimotor
training on movement performance, executive function and aspects of
cognition in groups of children and adolescents where seemingly small
changes can be of relevance for individual autonomy is of importance. As
was shown in study IV, SMT resulted in improvements in movement
organization and, importantly, the subjective experience of change and
improvement was substantial for a number of the participants.

The findings presented in the thesis raise several important questions that
have implications for future research. These questions are primarily related
to study sample characteristics, study design, and the associations between
outcome measures. In the following sections, what I believe to be some of the
most central issues and the prospects that I would like to investigate in the
future are summarized.

64
The role of intellectual function in movement organization

As intellectual function (full scale IQ) was shown to be associated with

movement performance in the prematurely born population alone, it
important to further the study of this relationship within this group of
children. Of interest would be to investigate executive aspects of movement
performance i.e., movement planning, inhibition of a prepotent response,
motor learning, and on-line corrections in response to perturbations.
Further, investigations into how performances on tasks like these relate to
outcomes on standardized executive function tests would be of interest as it
would enable disentanglement of cognitive aspects from movement
performance. Cognition in action. Such an endeavor would benefit from
including the visuo-perceptual approach. Specifically dorsal stream
functions as it is highly involved in reach and grasp behaviors and has been
shown to be dysfunctional in children born very preterm (e,g., Atkinson &
Braddick, 2007). Further, the development of a side or hand preference and
how it is related to sensorimotor learning, and other types of learning, is of
interest. It is a possibility that deviances in neural plasticity mechanisms, as
shown by Pitcher and colleagues (2011), could at least in part offer an
explanation for the lack or reduction of side specificity in terms of hand
preference and movement organization as observed in studies I and II. Of
course, it would be specifically valuable if future studies were carried out
longitudinally. It is further of importance that future studies also aim at
improving control over possible confounding factors, specifically those
related to socio-economic variables and pre-perinatal risk factors. To enable
this level of control, larger study samples are needed or control can be
improved by using stratified samples that are comparable on possible
confounding factors.

The role of sensory and proprioceptive information in movement

organization

Movement performance relies not only on motor output but is tightly

coordinated and interrelated with vision, tactile input, and proprioception. It
is further influenced by the goal of the movement, task constraints, the
environment it occurs in and, as shown in study III, by intellectual function.
What happens if we occlude visual information? What is the effect if
proprioceptive information is altered? How important is the sensory
information for movement performance? What will the effect on movement
kinematics be if the cognitive, attentive, or inhibitory demand is higher?
What will the effect be if the task has high demands on sensorimotor
learning? It would be of interest to further develop the kinematic tasks used,

65
and to develop new sensitive out-of-the-laboratory sensorimotor tasks, to
try to tease these aspects apart.

The role of larger study populations

As evident from studies II and III, GA influences motor outcome

significantly, where the children born most prematurely (< 33 GWs) have the
poorest motor outcomes. To elucidate why this group appears to be most
negatively affected in terms of movement performance, attempts at
identifying specific factors associated with this group of children is of
importance. A promising place to start is to investigate the role of risk factors
that may be more prominent in this group of children. Larger samples than
those included here are needed for this endeavor. Further, a longitudinal
approach would be preferable as it would be possible to distinguish between
developmental delay and more permanent sensorimotor deviation. Further,
a population based study of non-right handed mothers would be relevant to
further the understanding of the underlying factors associated with the
apparent increased rate of non-right hand preference in the prematurely
born populations shown. This approach would allow for investigations of
whether this group of women has an increased risk of preterm labor and also
familial aspects of hand preference.

The advancement of synchronized metronome training studies

By including multiple pretests or a control group, the results from SMT

studies in children and adolescents with CP would be strengthened. Further,
the cognitive aspects of movement control should be distinguished from
biomechanical aspects within this group to increase understanding of the
effects of SMT. Functional magnetic resonance imaging could be applied in
the attempt to answer this question. As the IM training method places high
demands on attention and sensorimotor learning, tests related to these
functions should also be included. If, for example attention, is trained in
SMT it is important to find out whether training of this function is driving
the observed changes in motor performance. Further, it would be of interest
to apply the IM method on preterm born children with developmental
coordination disorder, and other groups that may benefit, as the task
constraints of IM (motions related to emergent timing) would be reduced for
this group compared to children and adolescents with CP.

66
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