REVIEW

The Anatomical Basis of Dystonia: Current View Using Neuroimaging

ricy, MD, PhD,1,2,3* Marina A.J. Tijssen, MD, PhD,4 Marie Vidailhet, MD,2 Ryuji Kaji, MD,5 Sabine Meunier, MD, PhD2
phane Lehe
Ste

1
Institut du Cerveau et de la Moelle (ICM) epiniere, Centre de NeuroImagerie de Recherche (CENIR), Paris, France
2
Universite Pierre et Marie Curie-Paris 6, Centre de Recherche de l’ICM epiniere, UMR-S975, INSERM, U975, CNRS, UMR 7225, Paris, France
3
Service de Neuroradiologie, Groupe Hospitalier Pitie-Salpetriere, Paris, France
4
Movement Disorders, Department of Neurology AB 51, University Medical Centre Groningen (UMCG), Groningen, the Netherlands
5
Department of Neurology, Institute of Health Bioscience, Tokushima University, Graduate School of Medicine, Tokushima, Japan

ABSTRACT: This review will consider the knowl-
edge that neuroimaging studies have provided to the
understanding of the anatomy of dystonia. Major advances
have occurred in the use of neuroimaging for dystonia in
the past 2 decades. At present, the most developed imag-
ing approaches include whole-brain or region-specific
studies of structural or diffusion changes, functional imag-
ing using fMRI or positron emission tomography (PET), and
metabolic imaging using fluorodeoxyglucose PET. These
techniques have provided evidence that regions other than
the basal ganglia are involved in dystonia. In particular,
there is increasing evidence that primary dystonia can be
viewed as a circuit disorder, involving the basal ganglia-
thalamo-cortical and cerebello-thalamo-cortical pathways.
This suggests that a better understanding of the dysfunc-
tion in each region in the network and their interactions are
important topics to address. Current views of interpretation
of imaging data as cause or consequence of dystonia, and
the postmortem correlates of imaging data are presented.
The application of imaging as a tool to monitor therapy
and its use as an outcome measure will be discussed.
C 2013 Movement Disorder Society
V
K e y W o r d s : MRI; PET; basal ganglia; cerebellum;
dystonia; diffusion imaging

Dystonia is characterized by involuntary sustained
muscle contractions causing twisting and repetitive
movements or abnormal postures.1 Dystonia is
observed in a wide range of clinical entities. Various
classifications of dystonia have been proposed. Dysto-
nia can be classified according to the parts of the body
that are affected; ie, focal dystonias of isolated body
region (torticollis, blepharospasm, spasmodic dyspho-
nia, and writer’s cramp), segmental dystonias involving
2 or more contiguous body regions, and multifocal and
generalized dystonias.1–3 Dystonia can also be classified
according to etiology, with primary dystonia, dystonia-
plus syndromes, and secondary dystonia.4–6 Primary
dystonias include disorders with no lesions using con-
ventional imaging. Primary dystonias may be idiopathic
or from genetic origin with some 30 genes or loci iden-
tified so far.7 Secondary dystonias result from specific
------------------------------------------------------------
*Correspondence to: Dr. Ste phane Lehe ricy, Service de neuroradiologie,
Groupe Hospitalier Pitie-Salpetriere, 47 Bd de l’Hopital, 75651 Paris Cedex
13, France; stephane.lehericy@psl.aphp.fr
Relevant conflicts of interest/financial disclosures: Nothing to report.
Received: 8 December 2012; Revised: 6 April 2013; Accepted: 2 May
2013
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/mds.25527
causes, such as stroke or traumatic brain injury, or may
be induced by treatments. Given the heterogeneity of
etiology of dystonia it is likely that the different forms
of dystonia have different neuroanatomical origin
although they probably share a common substrate.8,9
This review focuses on how neuroimaging and neu-
roanatomic studies have contributed to the under-
standing of the anatomical basis of dystonia. We
specifically address new, current, important issues by
asking 4 key questions. First, what are the respective
roles of the basal ganglia and the cerebellar networks
in dystonia? While there is a large body of literature
pointing toward a major role of the basal ganglia in
dystonia, more recent findings also point to the role of
other regions, in particular the cerebellum, and envis-
age dystonia as a network disorder involving both the
basal ganglia–thalamo-cortical and the cerebello-
thalamo-cortical networks. The second key issue is the
question of cause or consequence when interpreting
the changes observed using imaging findings in dysto-
nia. Although it is tempting to interpret imaging find-
ings as revealing abnormal brain structure and
function associated with the pathological process, it is
now clear that experience and practice can result in
changes in brain structure and connectivity. In

944 Movement Disorders, Vol. 28, No. 7, 2013


dystonia, over practice, abnormal sensorimotor inte-
gration and motor output may therefore explain at
least part of the changes that were reported. Several
studies that have tried to address this issue are pre-
sented in this work. A third question that is not solved
yet is to determine the cellular and molecular sub-
strates of imaging changes. This has important impli-
cations for guiding pathological studies to potential
cellular targets. Apart from some specific dystonic
conditions, such as X-linked dystonia, neuropathologi-
cal studies were frequently negative in sporadic dysto-
nia whereas imaging has detected mainly functional
but also structural abnormalities. Here, we present
potential cellular and molecular mechanisms that may
explain changes in brain structure evidenced using
magnetic resonance imaging (MRI). Last, we address
the question of whether imaging, together with a bet-
ter understanding of anatomical changes, may be used
as a tool to develop and evaluate treatments in
dystonia.
Is Dystonia Caused by Defects in
the Basal Ganglia, Cerebellum, or
Both?
There is extensive literature supporting the role of the ba-
sal ganglia in the pathophysiology of dystonia (Table 1).
The basal ganglia were first implicated in secondary dys-
tonia in neuropathological studies10,11 then in neuroi-
maging studies using computed tomography (CT)12–14
and MRI.15–18 Lesions were most frequently observed
in the basal ganglia (Fig. 1A)19 and the thala-
mus,15,16,18,20,21 but occasionally in other regions,
including the parietal cortex,22 the cerebellum,23–26 the
brainstem,17 and the upper spinal cord.27 The clinical
presentation varied depending on the site of the lesion,
suggesting that different forms of dystonias may have
different origins. For instance, basal ganglia lesions
most often resulted in hemidystonia; thalamic lesions
resulted in hand dystonia often associated with myoclo-
nus,15 tremor, and cerebellar syndrome; brainstem
lesions were associated with dystonia of the upper limb
and face with parkinsonism and tremor17; and spinal
cord lesion was associated with torticollis.27
In primary sporadic dystonia, on the other hand, con-
ventional imaging was normal until the advent of
voxel-based techniques such as voxel-based morphome-
try (VBM). Structural abnormalities were then reported
in the basal ganglia, the thalamus, the cerebellum, and
the cortex, especially in the sensorimotor and premotor
regions as recently reviewed (Fig. 1B).28–30 Gray matter
changes in the basal ganglia were observed in blepharo-
spasm,31,32 cervical dystonia in isolation32–34 or mixed
with upper limb dystonia,35,36 musician dystonia,37 and
writer’s cramp.38 Gray matter was most often
A N A T O M I C A L B A S I S O F D Y S T O N I A
increased, but decreases were also reported.34,38 The
explanation for this discrepancy is not known so far
but may be related to differences in the population
studied or in technical parameters that were used, as is
discussed further in the paragraph “Contrast and tech-
niques for structural imaging”. Improvement and stand-
ardization of quantitative MR techniques may help
solve this issue by allowing better comparison between
centers and studies. Changes were mainly located in the
putamen, but the caudate nucleus, the globus pallidus,
and the nucleus accumbens were also affected.35,36
Using diffusion imaging, changes in anisotropy, a
marker of the orientation of water diffusion in fiber
tracts, or diffusivity, an index of diffusion magnitude,
were shown in the basal ganglia in cervical dysto-
nia,32,39–41 and spasmodic dysphonia.42 No changes
were observed in blepharospasm.41 Anisotropy was
most often increased in the basal ganglia and sur-
rounding white matter.39,41,43,44 Diffusivity was either
decreased39,41 or increased.40,42 Changes were also
reported in other regions including the thalamus40,42
and its frontal connections,45 the corpus callosum,41
the white matter abutting the basal ganglia,43,44 basal
ganglia connections with the brainstem and the frontal
cortex,41,46 and the corticobulbar/corticospinal tract.42
Changes reported in the white matter surrounding the
basal ganglia may have been related to abnormalities
in neighboring fiber tracts, such as basal ganglia–thal-
amus, cortico–basal ganglia, or cortico-brainstem, and
corticospinal tracts, but this remains to be determined.
Specific investigation of these connections using high-
resolution tractography may help resolve this issue.47
Overall, the basal ganglia and their connections to the
cortex and the cerebellum were affected. Increased
fractional anisotropy (FA) in the basal ganglia was
attributed to increased cellular density and fiber coher-
ence, and more ordered tissue structure. Decreased FA
was attributed to a reduced number of connections.39,41
Abnormalities in regional glucose metabolism have
been evidenced in the basal ganglia of patients with pri-
mary sporadic dystonias using [18F]-fluorodeoxyglucose
positron-emission tomography (FDG-PET). Increase in
glucose metabolism was most frequently reported in
patients with cervical dystonia,48,49 blepharospasm,50
spasmodic torticollis,49 and mixed dystonias.51–53
Other regions such as the cerebellum, the frontal cor-
tex, the thalamus, and the pons showed more variable
increases or decreases (see Neychev et al.28 and Zoons
et al.29 for review). In sporadic dystonia and early-
onset primary dystonia (DYT1), an abnormal pattern
of metabolic activity characterized by increased metab-
olism was evidenced in a network including the poste-
rior lenticular nucleus, cerebellum, and supplementary
motor area (SMA).53–56 Abnormalities of dopaminergic
neurotransmission, with reduction in striatal D2 recep-
tor binding, have also been reported.57,58
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TABLE 1. Basal ganglia versus cerebellar involvement in dystonia in imaging studies

Region affected Type of dystonia Primary measure Regions affected References

Basal ganglia
Lesions Secondary dystonia Location of lesion 12–14,16,18,19
VBM Blepharospasm Volume Pu 31,32
Cervical dystonia GP 32–35
Focal hand dystonia GP 36,37
Writer’s cramp 38
Generalized (idiopathic) GP 36
DYT1 dystonia Pu 33
DTI Cervical dystonia FA Pu 39,41
MD CN 40
Writer’s cramp FA 43,44
MD 42
FDG-PET Blepharospasm Metabolism CN 50
Cervical dystonia Pu 48,49
DOPA-responsive dystonia Pu 159
DYT1 dystonia Pu 54,132
DYT6 dystonia Pu 132
Mixed dystonias CN 51,53
Cerebellum
Lesions Secondary dystonia Location of lesion 23–26
VBM Blepharospasm Volume Hem 32
Cervical dystonia Floc 32,35
Writer’s cramp Hem 38
DTI Spasmodic dysphonia FA 42
DYT1 dystonia FA 95
DYT1 and DYT6 dystonias FA SCP 95
Tractography CRB-Thal 97
DYT11 dystonia FA, MD Brainstem 96
FDG-PET Blepharospasm Metabolism Verm 50,55
Cervical dystonia Hem 48
DOPA-responsive dystonia Verm 159
DYT1 dystonia Hem 54,132
Mixed dystonias Hem 51

VBM, voxel-based morphometry; Pu, putamen; GP, globus pallidus; DYT1, early-onset primary dystonia; DTI, diffusion tensor imaging; FA, fractional anisot-
ropy; MD, mean diffusivity; FDG-PET, [18F]-fluorodeoxyglucose positron-emission tomography; CN, caudate nucleus; Hem, hemisphere; Floc, flocculus; SCP,
superior cerebellar peduncle; CRB-Thal, cerebello-thalamic fasciculus; Verm, vermis.

Functional imaging with PET of functional MRI
(fMRI) has been extensively used to study dystonic
patients using various tasks that did or did not induce
dystonia. These studies have been extensively reviewed
elsewhere29 and only the main results are summarized
here. Changes in activation levels were in general
reported in a sensorimotor-related network that
included the primary sensorimotor cortex, medial and
lateral premotor areas, the parietal cortex, the basal
ganglia, the thalamus, and the cerebellum. In the basal
ganglia, studies reported either increased59–64 or nor-
mal activation65 during motor or sensory tasks,
although few studies reported reduced activation.66 It
is considered that tasks which induced dystonia were
likely to reflect dystonic activity in the motor cortex
and associated areas, whereas tasks that did not
induce dystonia were believed to reflect primary
changes in the brain or long-standing consequences of
dystonia. Some studies also reported abnormalities in
movement imagination67 and in the sensory represen-
tation in dystonias,62,68,69 supporting the view that
afferent inputs are inadequately processed at multiple
levels of the central nervous system. This is also sup-
ported by electrophysiological studies, which revealed
abnormalities of temporal and spatial discrimination
and integration of sensory signals, using vibration-
induced illusion or mental representation of
movement,70 or mapping of primary somatosensory
representations of the digits in patients with writer’s
cramp.71
There is also evidence coming from other sources to
support the role of the basal ganglia. Clinically, dys-
tonic movements and postures have been described as
part of levodopa-induced dyskinesia in Parkinson’s
disease with dysfunction of the nigrostriatal path-
ways.72 The efficacy of stereotactic neurosurgery of
the basal ganglia to improve generalized primary dys-
tonia either using lesioning73 or deep brain stimula-
tion74 of the internal segment of the globus pallidus
also points to a central role of the basal ganglia. Last,
several animal models point to dysfunction of the ba-
sal ganglia in dystonia.75,76 Dystonic movements were

946 Movement Disorders, Vol. 28, No. 7, 2013

 A N A T O M I C A L B A S I S O F D Y S T O N I A

FIG. 1. A: Localization of lesions resulting in secondary dystonia in 14 patients with basal ganglia infarct. Lesions were manually segmented on 3D
T1-weighted images. The area of overlap of all lesions was determined after normalization in the Montreal Neurological Institute (MNI) space. The
overlap area (in blue) is superimposed to the mean normalized anatomical images of the patients. The overlap was located in the posterior sensori-
motor part of the putamen (Delmaire C et al., unpublished data). Diffusion-based tractography using this overlap area as seed region showed that
this region was connected to the primary sensorimotor and premotor cortex. B: Statistical parametric maps demonstrating voxel-based morphome-
try (VBM) gray matter network changes in 30 patients with primary focal hand dystonia compared with 30 control subjects. Gray matter decrease
was observed in bilateral primary sensorimotor and premotor cortex, thalamus, cerebellum, and right putamen (P <.01 uncorrected, based on Delm-
aire et al.38).

observed after basal ganglia lesions in both
rodents77,78 and primates.79–83 In primates, lesions
inducing dystonia were located in the posterior senso-
rimotor putamen.84
Overall, the role of the basal ganglia in dystonia is
largely supported by convergent evidence from differ-
ent sources. However, a large majority of observations
have also shown that abnormalities associated with
dystonia are not limited to the basal ganglia but also
involve other brain regions, including the cerebral cor-
tex, the cerebellum, the thalamus, and the brainstem.
It is now clear these regions participate in dystonia.
There are several ways of interpreting their role in
dystonia.
Interpreting the Role of Other Regions in
Dystonia
The classical interpretation of changes outside the
basal ganglia is that they are consequences of basal
ganglia dysfunction. Several models of basal ganglia
dysfunction have been proposed to explain the occur-
rence of dystonia. Earlier models postulated that dys-
tonia results from (1) a failure of the filtering process
of the basal ganglia that facilitates voluntary move-
ments and suppresses competing ones which may
interfere with the selected movement,85 or (2) an
imbalance between the direct “excitatory” and indi-
rect “inhibitory” output pathways of the basal gan-
glia.86 Support for this latter model was recently
provided in a transgenic mouse model.87,88 In these
mice, selective blockade of fast-spiking inhibitory
interneurons, preferentially targeting neurons of the
direct pathway, produced symptoms that resembled
dystonia, suggesting that loss of local inhibition from
these interneurons created an imbalance between the
direct and indirect pathways.88 Another model was
derived from observations in patients with hereditary
dystonia DYT3 or X-linked recessive dystonia-parkin-
sonism (XDP), which is due to a mutation of the
TAF1 gene, a general transcription factor.89 These
patients have definite neuroanatomical and neurora-
diological lesions in the striatum (Fig. 2A,B).90,91 In
XDP, striosomal compartments are affected early in
the dystonic phase, suggesting imbalance between the
striosomal and matrix compartments as a cause of
dystonia.90 A similar interpretation was made for
DYT5 or dopa-responsive dystonia.92 According to
these models, abnormalities observed outside the basal
ganglia using neuroimaging may be secondary or com-
pensatory. Structural imaging modifications were
interpreted as plastic changes due to abnormal motor
output/sensory input from repetitive movements or
dystonic postures.

Movement Disorders, Vol. 28, No. 7, 2013 947

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FIG. 2. A: Coronal histological sections of the striatum stained using calcineurin in normal control and using calcineurin and calbindin in X-linked
recessive dystonia parkinsonism (XDP-DYT3) patients. The striatum of the control subject presented a strong labeling, diffusely distributed in the
caudate nucleus (CN), putamen (Pu), and nucleus accumbens (NA). In XDP patient, the neostriatum presented patches with high calcineurin labeling
and interpatch area with poor calcineurin labeling. Calcineurin-positive patches closely corresponded with calbindin-positive patches (indicated with
the asterisks). Scale bar 5 5 mm (adapted from Goto et al.90). B: T2-weighted axial magnetic resonance image showing bilateral striatal atrophy and
hyperintense rim around the lenticular nucleus (arrows).

More recent views point to dystonia as a network
disorder and try to accommodate evidence implicating
other brain regions.28,93 In network models, dystonia
may result from dysfunction or abnormal communica-
tion of any region in the network, alone or in combi-
nation.28 Among potential candidate regions, the
cerebellum and the cerebello-thalamo-cortical network
have received considerable attention (Table 1).28,93 In
addition to the frequent involvement of the cerebellum
in primary sporadic dystonia evidenced in imaging
studies, studies in DYT1 and DYT6 dystonia provided
further evidence that anatomical disruption of the cer-
ebellar outflow is an important factor determining the
occurrence of motor symptoms in these subjects. First,
microstructural abnormalities were reported in the vi-
cinity of the superior cerebellar peduncle in manifest-
ing and non-manifesting DYT1 and DYT6
carriers94,95 and DYT11 carriers.96 Second, diffusion
tractography showed reduced connectivity of the cere-
bellum with the thalamus in both clinically manifest-
ing and non-manifesting DYT1 and DYT6 mutation
carriers.97 Third, reductions in cerebello-thalamic con-
nectivity in DYT1 carriers correlated with motor acti-
vation responses as measured using regional cerebral
blood flow at rest and during movement.97 This corre-
lation was interpreted as loss of inhibition at the corti-
cal level consistent with a loss of cerebellar inhibitory
outflow.93,97 It is not known whether these findings
are specific to DYT1 and DYT6 dystonia or are also
present in sporadic cases. Together with the abnormal
metabolic activity pattern evidenced in the cerebello-
basal ganglia network,53,56,98 abnormalities point to
the cerebellum as playing a crucial role in the dis-
ease.93 In support of the role of the cerebellum in dys-
tonia, several animal models have implicated a
cerebellar dysfunction in dystonia. Although animal
models have several limitations, including their
debated relevance to human dystonia and the poor
characterization of dystonic symptoms, they provide
valuable direct information on the underlying anatom-
ical lesions. In the dystonic (dt) rat, which presents
abnormal movements resembling generalized dystonia,
surgical removal of the cerebellum eliminates dysto-
nia.99 In the tottering mutant mouse, which presents
abnormal movements resembling paroxysmal dystonia,
dystonic attacks were associated with early activation
of Purkinje cells and deep cerebellar neurons; selective
elimination of Purkinje cells eliminated dystonic
attacks.100 By using conditional genetics it was possi-
ble to obtain animals with gradients of cerebellar dys-
function. In these animals, abnormalities restricted to
Purkinje cells were sufficient to cause dystonia and the
extent of cerebellar dysfunction determined the extent
of abnormal movements.101 This suggests that focal
and generalized dystonia may arise through similar
cerebellar dysfunction of various extent.101
Another possibility is that the cerebellum interacts
with the basal ganglia to generate dystonia (Fig. 3).
There is evidence that the cerebello-thalamo-cortical
network may interfere with the basal ganglia–thalamo-
cortical network in both animals and humans. Ana-
tomically, the 2 networks are thought to communicate
in the motor cortex, where the final output coming
from distinct thalamic relays is organized.102 In addi-
tion, in macaques, a disynaptic pathway linking the
dentate nucleus and the striatum was evidenced using
histological tract tracing.103 A return pathway from
the basal ganglia to the cerebellum was also
reported.104 Physiologically, functional interactions
between the basal ganglia and the cerebellum were
recently demonstrated in mice, in which stimulation or
lesions of the cerebellum resulted in changes in striatal
dopamine levels.105 The same group has shown that in
mice models implicating the cerebellum, subclinical

948 Movement Disorders, Vol. 28, No. 7, 2013


FIG. 3. Schematic representation of basal ganglia and cerebellar net-
works and their possible interactions in dystonia. Ref indicates rele-
vant reference numbers. DN, dentate nucleus; GPe, external segment
of the globus pallidus; GPi, internal segment of the globus pallidus;
M1, primary motor cortex; PM, premotor cortex; STN, subthalamic
nucleus; SMA, supplementary motor area; VA, ventral anterior nucleus
of the thalamus; IL, intralaminar nuclei of the thalamus; VLp, ventral
lateral posterioir nucleus of the thalamus; SNr, substantia nigra pars
reticulata; CB ctx: cerebellar cortex.
basal ganglia lesions exaggerated dystonic movements.
In mice, an aberrant cerebellar output can have an
adverse effect to the basal ganglia and add dystonia to
parkinsonism.106 These findings implied that the basal
ganglia and the cerebellar networks interacted to gen-
erate abnormal movements.105
In humans, cerebellar outputs can modulate cortical
excitability and therefore interact with the basal gan-
glia–thalamo-cortical network at the cortical level.
This modulation was observed following repetitive
somatosensory stimulation,107–109 cerebellar degenera-
tion, or infarction.110
The cerebellum may play a role in the deficit in sen-
sorimotor integration observed in dystonia,70 as
shown using electrophysiological techniques. The cere-
bellum processes proprioceptive information, alters
somatosensory thresholds in the cortex, and plays a
key role in both temporal and spatial discrimina-
tion.111,112 Using dual-site and double-pulse transcra-
nial magnetic stimulation (TMS) in humans, it was
shown that cerebellar outputs modulated the excitabil-
ity of the primary motor cortex via their projections
to local GABAergic inhibitory interneurons.107,113 As
GABAergic inhibition in the primary motor cortex is
deficient in dystonia, this observation provides possi-
ble mechanisms by which the cerebello-thalamo-corti-
cal network may contribute to the loss of inhibitory
processes observed in dystonia.114,115 Last, abnormal
plasticity and learning processes are considered as im-
portant neurophysiological findings in dystonia.116–119
The cerebellum is also involved in saccadic adaptation
and eye-blink conditioning. Saccadic adaptation is
impaired in patients with myoclonus dystonia120 and
A N A T O M I C A L B A S I S O F D Y S T O N I A
eye-blink conditioning in patients with upper-limb
dystonia.121 These findings reinforce the view that
abnormal cerebellar functioning may support abnor-
mal adaptation in various forms of dystonia. Recently,
conditioning to the cerebellar cortex was shown to
prime ongoing sensorimotor plasticity in the motor
cortex.122,123 In healthy subjects, excitation of the cer-
ebellar cortex by anodal transcranial direct current
stimulation (tDCS) or intermittent theta burst repeti-
tive TMS (rTMS) prevented the development of paired
associative stimulation (PAS)-induced sensorimotor
plasticity in the motor cortex, whereas inhibition of
the cerebellum by continuous theta burst rTMS
enhanced and prolonged cortical plasticity.123
Whether abnormal responses of the motor cortex to
plasticity induction protocol (such as PAS) observed in
dystonia is related to abnormal cerebellar modulation
remains to be demonstrated.
Further evidence of abnormal interaction between
the basal ganglia and cerebellar networks in relation
with tremor and L-dopa–induced dyskinesias was
reported in Parkinson’s disease.124–126 Using concomi-
tant electromyographic recordings and functional con-
nectivity analysis with resting state fMRI, it was
found that tremor was related with pathological inter-
actions between the basal ganglia and cerebello-tha-
lamo-cortical circuits. It was proposed that the
cerebello-thalamic circuit, which controlled tremor
amplitude, was driven into tremor generation when
receiving transient signals from the dopamine-depleted
basal ganglia, which were transiently activated at the
onset of tremor episodes and presented increased func-
tional connectivity with the cerebello-thalamic circuit
through the motor cortex.126 A beneficial effect on L-
dopa–induced dyskinesias of repeated sessions of cere-
bellar inhibitory stimulation was demonstrated in
advanced parkinsonian patients,124,127 this effect was
paralleled by a decrease in [18F]-FDG uptake in
bilateral cerebellar hemispheres and dentate nucleus.
Both electrophysiological and imagery findings support
the hypothesis that the cerebello-thalamo-cortical
circuit is involved in the generation of L-dopa–induced
dyskinesia.128
In summary, although there is numerous and con-
verging evidence demonstrating the role of the basal
ganglia in the pathophysiology of dystonia, a number
of studies have also suggested a possible role of the
cerebello-thalamo-cortical pathway. However, as cere-
bellar lesions in humans most often result in ataxia,
the contribution of the cerebellum in dystonia remains
to be determined. One possibility is that dysfunction
more than destruction of the cerebellum results in dys-
tonia or that dystonia results from abnormal interac-
tions between the cerebellum and basal ganglia A
better understanding of cerebellar dysfunction and
interactions with the basal ganglia-thalamo-cortical
Movement Disorders, Vol. 28, No. 7, 2013 949
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L E H E E T A L .
network, at the basal ganglia or the cortical levels
using combined imaging and neurophysiological
approaches, will provide useful information to better
understand the contribution of the cerebellar network
in dystonia.
How Can We Distinguish Cause
from Consequence in Imaging
Studies?
Another important yet unsolved question is whether
observed changes reflect primary predispositions or are
secondary changes due to either differential environ-
mental conditions or to the involvement of regions
downstream from the primary site of dysfunction. Envi-
ronmental conditions in dystonia may include abnormal
sensory feedbacks to the brain resulting from move-
ment overflow, co-contractions and abnormal postures
in dystonic body parts, or recall of abnormal motor
programs. As prolonged changes in sensory feedback
induced by motor practice and training are known to
induce changes in brain structure, ie, in grey matter
volume or in fiber tracts and white matter, even among
normal subjects,129 such changes in dystonia may not
be a cause but a consequence of the dystonic move-
ments or traditionally of the dysfunction of the basal
ganglia. Cross-sectional studies can most often not dis-
tinguish whether the observed structural changes are
the cause or the consequence of the disease.
Solutions to this issue may come from studies in pre-
disposed patients, such as non-manifesting mutation
carriers, in patients with subclinical motor deficits or
physiological compensations that are not translated
into motor deficits, from longitudinal studies as well
as intervention studies. The use of endophenotypes is
thus one approach to this problem. Endophenotypes
have been defined as markers of subclinical gene car-
riage in unaffected relatives.130,131 Endophenotyping
looks for markers of altered gene expression in the
brain of non-manifesting gene carriers as exemplified
in the following paragraphs. Increased metabolic activ-
ity using FDG-PET was reported in a network includ-
ing the posterior lenticular nucleus, cerebellum, and
SMA in non-manifesting DYT1 gene carriers.54,55 This
abnormal metabolic pattern was unrelated to the pres-
ence of symptoms in DYT1 carriers as it was observed
in manifesting and non-manifesting carriers with a
similar expression.54,56 It differed from the one
observed in non-manifesting carriers of the DYT6
mutation because the metabolic abnormalities
involved the putamen, the cerebellum, the thalamus,
and the upper brainstem in these subjects.132 Reduc-
tion in striatal D2 receptor binding was reported in
manifesting as well as non-manifesting DYT1 car-
riers.133,134 Using diffusion imaging, reduced FA was
950 Movement Disorders, Vol. 28, No. 7, 2013
measured in the subgyral white matter adjacent to the
sensorimotor cortex94 and in the dorsal pons95 of
non-manifesting DYT1 carriers. More recently, using
tractography techniques, the same group showed
greater reduction in the integrity of thalamo-cortical
fiber tracts in non-manifesting DYT1 and DYT6
mutation carriers than in manifesting patients.97 Man-
ifesting and non-manifesting DYT1 mutation carriers
were also compared with idiopathic adult-onset pri-
mary dystonia (mostly cervical) and control subjects
using VBM. A genotype (DYT1 mutation status)–phe-
notype (dystonia) interaction was observed in the
putamen of these subjects.33 Asymptomatic DYT1 car-
riers had larger putamen than symptomatic DYT1
patients. Increased volume of the putamen in asymp-
tomatic DYT1 carriers was also evidenced in non-
DYT1 primary dystonia. In addition, symptom sever-
ity correlated negatively with putamen volume bilater-
ally in the DYT1 population. Functional imaging
studies also showed changes in non-manifesting sub-
jects. During performance of a finger-tapping task, in-
termediate activation levels were observed in non-
manifesting DYT11 mutation carriers.135 Non-mani-
festing DYT1 carriers showed impaired brain activa-
tion and performances during motor sequence
learning.136,137
Another group has investigated patients with adult-
onset primary torsion dystonia (AOPTD).131 They
used a sensitive endophenotype, the temporal discrimi-
nation threshold (TDT), as a marker of subclinical
gene carriage in unaffected relatives. The TDT is the
shortest time interval at which a subject can detect
that two stimuli are asynchronous. Patients with
AOPTD present sensory processing abnormalities in
tasks such as the TDT.138 Abnormal TDTs was found
in 86% of sporadic and familial AOPTD patients, and
one-half of the unaffected first-degree and second-
degree relatives of sporadic and familial AOPTD.
Bilateral increase in putaminal gray matter was found
in unaffected relatives with abnormal TDTs, which
suggested that structural changes in the putamen were
a primary phenomenon.131
In patients with writer’s cramp using magnetoence-
phalography (MEG), disorganized finger somatotopy
was reported in primary sensory regions.71 Abnormal-
ities were also observed in the nondominant hemi-
sphere coding the nondystonic limb representations,
which correlated with disease severity. As movements
of the nondystonic limb were normally executed,
abnormalities in the corresponding hemisphere were
unlikely to arise from abnormal peripheral inputs and
sensory afferent volleys and were interpreted as brain
initial dysfunction. Bilateral abnormalities in patients
affected unilaterally further support the notion that
both hemispheres are originally, possibly genetically,
affected by the disease and that imaging can detect
 A N A T O M I C A L B A S I S O F D Y S T O N I A

TABLE 2. Overview of the different imaging techniques

Method Techniques Primary measures Information

MRI techniques
Structural Region of interest Volume, shape, surface, thickness Morphometry
(T1-w, T2-w, IR)
Voxel-based techniques Concentration, density or volume of brain Morphometry; volume or signal changes
tissue
Cortical thickness; shape analysis Cortical thickness and shape Morphometry
Relaxometry Measurements of T1 and T2/T2* Relaxation times: T1/T2/T2*; relaxation Microscopic architecture of brain tissue;
rates: R1/R2/R2* brain iron (T2/T2*)
Magnetization Images with (MT) and without (M0) MT MT ratio (MTR 5 M0-MT/M0) Degree of myelination, axonal density
transfer pulse
Diffusion DWI, DTI, HARDI; tractography MD, RD, LD, FA, GFA; number of tracks, Diffusion of water in biological tissues;
probability of connection fiber tract-specific reconstructions
Functional Resting state fMRI BOLD signal fluctuations Functional connectivity within brain
networks
Activation fMRI BOLD signal fluctuations Activation levels and functional connec-
tivity during behavioral tasks
PET techniques
Metabolism [18F]-fluoro desoxyglucose ([18F]-FDG) Regional glucose metabolism Brain metabolism
Functional [15O]-H2O Regional cerebral blood flow (rCBF) Activation level during behavioral tasks
Neurotransmission Ligands for neuroreceptors Visualization of receptor pools Changes in receptor binding

MRI, magnetic resonance imaging; T1-w, T1-weighted; T2-w, T2-weighted; IR, inversion recovery; T1, T1 relaxation time; T2, T2 relaxation time; T2*, gradient
echo T2 relaxation time; R1, T1 relaxation rate; R2, T2 relaxation rate; R2*, T2* relaxation rate; MT, images with MT pulse; M0, images without MT pulse; MT,
magnetization transfer; MTR, magnetization transfer ratio; DWI, diffusion-weighted imaging; DTI, diffusion tensor imaging; HARDI, high angular resolution diffu-
sion imaging; MD, mean diffusivity; RD, radial diffusivity; LD, longitudinal diffusivity; FA, fractional anisotropy; GFA, generalized fractional anisotropy; fMRI,
functional MRI; BOLD, blood oxygen level dependent contrast; PET, positron emission tomography.

primary changes in dystonic patients. Impaired sensory
function and representation may thus be seen as sub-
clinical endophenotype trait of disease.130
Investigation of patients with subclinical motor defi-
cits also provided interesting information. An example
of this approach consisted of comparing patients
expressing or not expressing dystonic symptoms. For
instance, a whistling task allowed studying the oro-
mandibular motor system in clinically affected patients
with Meige’s syndrome (combining blepharospasm
and oromandibular dystonia) and unaffected patients
with isolated blepharospasm.139 During whistling,
patients with Meige’s syndrome showed deficient acti-
vation in the face primary motor and ventral premotor
cortex, whereas both forms of dystonia had increased
activation in bilateral somatosensory areas and caudal
SMA. This suggested that impaired motor activation
was specific to the clinically affected oromandibular
motor system in Meige’s syndrome whereas increased
somatosensory activation was independent of the
affected motor system.139 Task-independent altera-
tions within a writing-related parieto-premotor circuit
were also observed in writers’ cramp using resting
state fMRI.140
In summary, these data demonstrate that structural
changes can preexist the occurrence of symptoms in
dystonia in the basal ganglia and the cortex, and in
the cerebello-thalamo-cortical pathways. Presympto-
matic changes are markers of predisposition but may
not be sufficient to cause dystonia, as many at risk
subjects do not develop dystonia and other factors
such as overpractice are necessary. Data also showed
that changes can be modulated by the expression of
the disease. Differences between types of dystonia may
be relevant and point to differences in pathophysiol-
ogy, although this requires further investigation.
Why Have Pathological Studies
Failed to Reveal Abnormalities
Where Imaging Studies Point?
Another unsolved issue is to understand the discrep-
ancy between neuroimaging findings and the few his-
tological studies conducted so far, which showed only
limited morphological abnormalities.141 This question
is of importance, as a better understanding of the
changes depicted using neuroimaging may help guid-
ing future histological studies. Although modern neu-
roimaging methods have been used extensively to
study changes in brain structure of patients with dys-
tonia, the significance of the imaging changes remains
poorly understood. Speculation on the candidate
mechanisms that underlie neuroimaging changes can
help explain the neuroimaging observations (Table 2).
Contrast and Techniques for Structural
Imaging
VBM142 and cortical thickness types of analyses143
rely on the voxel-based comparison of T1-weighted

Movement Disorders, Vol. 28, No. 7, 2013 951

  R I C Y
L E H E E T A L .
signal intensities, which depend on T1 relaxation time.
T1 relaxation time reflects interactions between pro-
tons and their surroundings (called the lattice) and
depends mainly on the mobility of water within the
microenvironment.144 How this contrast relates to the
underlying cellular and tissue microstructure (neuronal
densities, cell size, myelination) is not known. As a
consequence, although VBM provides metrics such as
“concentration,” “density,” or “volume” of brain tis-
sue, any tissue property that affects the T1 relaxation
time, will affect voxel intensities on a T1-weighted
image, and hence will influence voxel-based compari-
sons even in the absence of volumetric changes.
Efforts have been made to develop more quantita-
tive techniques than VBM, which probe more directly
into the tissue microarchitecture and aim at revealing
the physical properties of water that govern MRI con-
trast to better characterize tissue properties.145 Major
quantitative contrast parameters include longitudinal
(T1) and transverse (T2/T2*) magnetization transfer
(MT), and diffusion indexes. MT is thought to corre-
late with the degree of myelination146 and axonal den-
sity.147 Diffusion imaging allows the calculation of
several indexes that characterize the overall displace-
ment of molecules and presence of obstacles to diffu-
sion (ie, mean diffusivity [MD]), the orientation of
diffusion (ie, FA), and the diffusion directions along
the main direction of diffusion (axial or longitudinal
diffusivity) and perpendicular to it (radial or trans-
verse diffusivity).148 Anisotropy relates to the presence
of oriented structures such as axons in fiber bundles,
such as membrane,149 myelin,150 axon diameter and
packing density,151 longitudinal filaments, and cyto-
skeleton. It is generally accepted that changes in axial
diffusivity mainly reflect axonal damage whereas
changes in radial diffusivity reflect myelin damage.
Because of the lack of specificity of the anisotropy and
diffusivities, diffusion microscopy techniques were
developed to directly probe tissue features such as
mean axon radius and neurite density.152
Cellular and Molecular Mechanisms
Underlying Changes in Brain Structure
Studies at the cellular and molecular level have iden-
tified potential candidates that may be associated with
extensive practice and overtraining, and are exten-
sively reviewed in Zattore et al.129 In gray matter,
changes may be of neuronal or non-neuronal origin.
At the neuronal level, changes may relate to differen-
ces in number and morphology of neurons and synap-
ses.129 Extraneuronal changes include increases in size
and number of glial cells. In white matter, changes in
the number of axons, axon diameter, the packing den-
sity of fibers, axon branching, axon trajectories, and
myelination may result in changes in diffusion met-
rics.129 In dystonia, overuse of the affected body part
952 Movement Disorders, Vol. 28, No. 7, 2013
may contribute to the explanation of the observed
structural changes. Primary cellular changes associated
with DYT1 mutation, such as altered protein folding,
abnormal cell trafficking, and altered cytoskeletal and
vesicle dynamics,7 may also contribute to differences
in water diffusion or relaxation parameters evidenced
in the affected brain of DYT1 carriers.97
Combined histological and MRI studies in animal
models of dystonia may help us better understand the
relationships between imaging and histological
changes. In normal mice, training with water-maze
tasks resulted in specific growth in the hippocampus
or the striatum, depending on the version of the
task.153 Volume growth correlated with GAP-43 stain-
ing, a marker of neuronal process remodeling, but not
with neurogenesis and numbers or sizes of neurons or
astrocytes. This suggested that plasticity-related
changes reflected remodeling rather than neurogenesis.
In animal models of dystonia, a recent study has
shown highly similar patterns of brain structural
changes in human non-manifesting DYT1 carriers and
DYT1 mutant mice that contain the torsin1A gene
mutation.154 Mutant mice, which did not display
abnormal movements, exhibited significant diffusion
tractography changes in the cerebello-thalamo-cortical
fiber tracts and in brainstem regions linking cerebellar
and basal ganglia motor circuits. In line with human
observations, metabolic activity using micro-PET in
the mice sensorimotor cortex correlated with integrity
measures of the cerebello-thalamo-cortical pathway.154
These findings indicated that DYT1 mutant torsinA
had similar effects in mice and humans, suggesting
that animal models may help elucidate the histological
correlates of diffusion and connectivity changes in
dystonia.
In summary, the understanding of the mechanisms
of dystonia using neuroimaging is thus limited,
because these changes are partially understood and are
not specific to the underlying cellular processes. In
addition, the molecular and cellular changes that were
associated with structural imaging changes are not
routinely investigated in histological studies, and com-
parisons with imaging data are scarce.
How Does Understanding Anatomy
Help Us to Think About New
Treatments?
Improved knowledge of the anatomy of dystonia
contributes to a better understanding of brain dysfunc-
tion and may therefore help develop new therapeutic
strategies targeting the affected structures. As detailed
above, neuroanatomical and imaging studies improved
our understanding of the anatomical substrate of dys-
tonia by showing that regions implicated in the disease

involved not only basal ganglia networks but also cer-
ebellar networks. Understanding dysfunction in these
networks will help us understand how they contribute
to the different forms of dystonias. For instance, a
better knowledge of the physiological interac-
tions between the basal ganglia-thalamo-cortical and
cerebello-thalamo-cortical networks using animal
models,105 and maging,126 or electrophysiology123 in
humans will help clarify the functional significance of
abnormal interactions between these networks in dys-
tonia. Another example comes from dopa-responsive
dystonia in which a differential striosome-matrix pat-
tern of dopaminergic loss was hypothesized to contrib-
ute to the genesis of dystonia symptoms.90,92 Drugs
targeting this imbalance may be relevant to other
types of dystonia.
Imaging can also be used to monitor the effect of
therapy in dystonia patients. In patients with writer’s
cramp, the pathophysiological basis of rehabilitation
therapy was investigated using MEG.155 After recover-
ing a legible handwriting, patients presented normal
somatotopic organization of the fingers in the sensory
cortex controlling the dystonic limb, whereas this rep-
resentation was disorganized in untreated patients.
These results suggested that prolonged tailored reha-
bilitation in writer’s cramp induced long-term plastic-
ity changes, specifically lateralized to the cortex
controlling the dystonic hand.155 Several investigators
have studied the effect of botulinum toxin using
fMRI. Botulinum toxin treatment partly reversed over-
activity of somatosensory areas and caudal SMA in
Meige syndrome patients, but did not improve
impaired motor activation.139 The authors concluded
that overactivity in the somatosensory cortex in orofa-
cial dystonia could be modulated by treatment. The
same group has shown that botulinum toxin treatment
reduced the activation of the thalamus and contralat-
eral putamen during forehead stimulation in patients
with blepharospasm and Meige’s syndrome, although
it did not modulate impaired primary and secondary
somatosensory cortical activation.156 Using resting-
state fMRI, the sensorimotor and the default-mode
networks presented abnormal functional connectivity
in writer’s cramp, with reduced connectivity in the left
postcentral area and increased connectivity in basal
ganglia.157 These changes were not reversed after
treatment with botulinum toxin.157 Last, the duration
of botulinum toxin treatment correlated with diffusiv-
ity values in the prefrontal cortex in cervical
dystonia.41
In summary, anatomical knowledge can guide the
development of treatments targeting affected structures
and provide imaging biomarkers than can be used to
monitor the effects of these treatments. Longitudinal,
multicenter studies designed to develop standardized
quantitative imaging markers for dystonia, in
A N A T O M I C A L B A S I S O F D Y S T O N I A
combination with clinical and genetic biomarkers,
could also expand the application of imaging to the
investigation of the anatomical and physiological bases
and differences of the different forms of dystonias, as
was successfully done for Alzheimer’s disease.158
Conclusion
While dystonias are traditionally viewed as resulting
primarily from basal ganglia dysfunction, neuroana-
tomical and imaging studies in animal and humans
have provided evidence that primary dystonia may be
a neurodevelopmental circuit disorder, involving the
cortico-striato-pallido-thalamo-cortical and cerebello-
thalamo-cortical pathways. Key questions are to
understand the role of each region in the networks
and whether differential dysfunction of regions in
these networks explains the variability between sub-
groups. It is also important to determine whether there
is a final common pathway for all dystonias. Second,
imaging studies suggested that some structural changes
in these networks were primary, whereas others were
modulated by the expression of the disease. Third, a
better understanding of the cellular processes underly-
ing neuroimaging changes observed in dystonia may
help us better understand the pathophysiological basis
of dystonia and guide future histological studies. Last,
better knowledge of the anatomical lesions associated
with dystonia may help guide the development of
treatments directed toward new target structures and
circuits and to evaluate treatment effects.
Acknowledgments: We are grateful to H.A. Jinnah, Departments
of Neurology, Human Genetics, and Pediatrics, Emory University,
Atlanta, GA, for helpful discussion.
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