Progress in Neuropsychopharmacology & Biological Psychiatry 111 (2021) 110370

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Progress in Neuropsychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Progress in sensorimotor neuroscience of schizophrenia spectrum disorders:

Lessons learned and future directions
Dusan Hirjak a, *, Andreas Meyer-Lindenberg a, Fabio Sambataro b, c, Stefan Fritze a,
Jacqueline Kukovic d, Katharina M. Kubera e, Robert C. Wolf e
a
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
b
Department of Neuroscience (DNS), University of Padua, Padua, Italy
c
Padova Neuroscience Center, University of Padua, Padua, Italy
d
Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
e
Department of General Psychiatry at the Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: The number of neuroimaging studies on movement disorders, sensorimotor, and psychomotor functioning in
Sensorimotor domain schizophrenia spectrum disorders (SSD) has steadily increased over the last two decades. Accelerated by the
Psychomotor addition of the “sensorimotor domain” to the Research Domain Criteria (RDoC) framework in January 2019,
MRI
neuroscience research on the role of sensorimotor dysfunction in SSD has gained greater scientific and clinical
Schizophrenia spectrum disorders
Psychosis
relevance. To draw attention to recent rapid progress in the field, we performed a triennial systematic review
(PubMed search from January 1st, 2018 through December 31st, 2020), in which we highlight recent neuro­
imaging findings and discuss methodological pitfalls as well as challenges for future research. The identified
magnetic resonance imaging (MRI) studies suggest that sensorimotor abnormalities in SSD are related to
cerebello-thalamo-cortico-cerebellar network dysfunction. Longitudinal and interventional studies highlight the
translational potential of the sensorimotor domain as putative biomarkers for treatment response and as targets
for non-invasive neurostimulation techniques in SSD.

1. Introduction perspective, altered modulation of dopaminergic-based motor networks

Over the last three decades, the number of neuroimaging studies on
sensorimotor abnormalities in schizophrenia spectrum disorders (SSD)
and other mental disorders has grown steadily (Hirjak et al., 2020a;
Hirjak et al., 2018c; Mittal et al., 2017b; Walther and Strik, 2016;
Walther et al., 2020). Congruent evidence generated by multimodal
neuroimaging data analysis strategies provided a neuromechanistic
understanding of the sensorimotor domain and its dysfunction, partic­
ularly with respect to aberrant structure and function in the cortical–­
thalamic–cerebellar–cortical (CTCC) circuit. This is also in line with
models suggesting that schizophrenia is a “misconnection syndrome” of
the CTCC (Andreasen et al., 1998; Andreasen and Pierson, 2008). In
particular, Andreasen and co-workers emphasized that CTCC is crucial
for monitoring and coordination of mental activity (synchrony) and
hence, aberrant CTCC activity might lead to disordered cognition
(‘cognitive dysmetria’) and characteristic schizophrenia symptoms
(Andreasen et al., 1998; Wiser et al., 1998). From a biochemical
(e.g., increased dopaminergic turnover) driven by glutamate- and
GABAergic non-motor cortical networks, are crucial in the pathophysi­
ology of sensorimotor abnormalities (for review see also Hirjak et al.
(2020a); Northoff et al. (2020a)). Furthermore, several lines of evidence
indicate clinically relevant applications based on sensorimotor system
pathology, such as (1) sensorimotor abnormalities as vulnerability
markers in psychosis risk syndrome (Bernard and Mittal, 2014; Kent
et al., 2019; Kindler et al., 2019; Mittal et al., 2014, (2) sensorimotor
signs and symptoms as predictors of the clinical course of SSD (Cuesta
et al., 2018; Cuesta et al., 2014, (3) neural correlates of sensorimotor
functioning in SSD and related psychoses (Hirjak et al., 2019c; Martino
et al., 2020; Martino et al., 2018; Northoff et al., 2004; Walther et al.,
2017a; Walther et al., 2017b), and (4) sensorimotor system as a novel
target for transcranial magnetic stimulation (TMS; Mittal and Walther,
2019), respectively. However, despite the exponentially growing
research in the field of movement disorders, as well as sensori- and
psychomotor functioning in SSD in the last three decades (Hirjak et al.,

* Corresponding author at: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim D-68159, Germany.
E-mail address: dusan.hirjak@zi-mannheim.de (D. Hirjak).

https://doi.org/10.1016/j.pnpbp.2021.110370
Received 18 March 2021; Received in revised form 15 May 2021; Accepted 28 May 2021
Available online 1 June 2021
0278-5846/© 2021 Elsevier Inc. All rights reserved.
D. Hirjak et al.
2018a; Hirjak et al., 2020a; Hirjak et al., 2018b; Walther et al., 2020),
initial failures to replicate earlier findings, methodological shortcomings
(e.g. clinical scales of varying psychometric quality, lack of studies on
genetic factors, antipsychotic medication, small sample size, etc.), and
poor understanding of neurobiological mechanisms (e.g. interaction
between structure and function, the relationship between different
sensorimotor categories, association with other domains, etc.) have also
led to controversies.
Motivated by a number of promising studies demonstrating the high
relevance of sensorimotor dysfunction in mental disorders as well as by
contrary results and inconsistent conclusions, in January 2019, the
Research-Domain-Criteria (RDoC)-Initiative of the National Institute of
Mental Health (NIMH) introduced the sensorimotor domain to the RDoC
matrix. Through this addition, the RDoC Initiative seeks to foster earlier
and more precise identification of the role of sensorimotor dysfunction
in psychopathology and aid in the development of more effective
treatments for patients who are affected with sensorimotor abnormal­
ities (Mittal et al., 2017a). Two years after its introduction, it is timely to
summarize the results, corresponding progress, methodological pitfalls,
and future directions of sensorimotor neuroscience in SSD. We chose to
conduct a triennial review because the scientific evidence on sensori­
motor dysfunction in SSD and other mental disorders published until
mid 2018 had already been summarized and discussed in numerous
narratives (Hirjak et al., 2018a; Northoff et al., 2020a; Peralta and
Cuesta, 2017) and systematic reviews (Haroche et al., 2020; Hirjak et al.,
2020a; Hirjak et al., 2018b; Hirjak et al., 2018c; Walther et al., 2019b).
In order to draw attention to recent rapid progress in the field, the
goals of this triennial review were threefold: First, we systematically
reviewed the current literature on neuroanatomical and biochemical
correlates of movement disorders as well as sensorimotor dysfunction in
SSD to provide a comprehensive picture of neurotransmission and
neuromodulation of the sensorimotor system and its psychopathological
correlates. Second, based on very recent neuroimaging studies, we
discuss the most eminent methodological questions for future sensori­
motor neuroscience in SSD. Finally, we discuss how future neuroscience
research on sensorimotor system pathology might contribute to the
development of innovative treatment response markers and to novel
targets for psychopharmacological research in SSD.
2. Methods
2.1. Search strategy and study selection
The search strategy and study selection followed PRISMA guidelines.
The literature was searched using MEDLINE (source PubMed, January 1,
2018 to December 31st, 2020), and Google Scholar databases, and by
additional hand searches through reference lists and specialist psychi­
atric and neuroscience journals. The main goal was to identify neuro­
imaging studies reporting associations between sensorimotor system
dysfunction and brain structure or function in SSD. The following search
terms or their combinations were used: “schizophrenia”, “psychosis”,
“schizophrenia spectrum disorders”, “ultra-high risk”, “neurological soft
signs”, “neurological signs”, “NSS”, “discrete signs”, “subtle neurolog­
ical deficits”, “abnormal involuntary movements”, “catatonia”, “cata­
tonic symptoms”, “motor symptoms”, “sensorimotor symptoms”,
“parkinsonism”, “dyskinesia”, “tardive dyskinesia”, “akathisia”, “psy­
chomotor dysfunction”, “psychomotor slowing”, “magnetic resonance
imaging” (MRI), “MRI”, “positron emission tomography” (PET), “PET”,
“single-photon emission computerized tomography” (SPECT) and
“SPECT”. The automatic search was complemented by a manual check of
the reference lists of the papers and relevant review articles identified by
the computerized literature search. We also searched for articles pub­
lished in any language and scrutinized references from these studies to
identify other relevant studies. There were no language restrictions with
respect to publication date or country of origin, although the majority of
ultimately extracted articles were in English. Unpublished studies,
2
Progress in Neuropsychopharmacology & Biological Psychiatry 111 (2021) 110370
conference abstracts or poster presentations were not considered. We
imposed the following methodological restrictions for the inclusion
criteria: (a) Studies (>16 participants/group Friston (2012)) with MRI,
PET, or SPECT that investigated movement disorders as well as senso­
rimotor and psychomotor functioning in SSD; (b) Studies that were re­
ported in an original article in a peer-reviewed journal. In case of
multiple publications, the most up to-date or comprehensive informa­
tion was used. Articles considered of interest were reviewed and cross-
checked independently by three authors (DH, KMK, and JK). Similar
approach has been used previously in systematic reviews on SSD and
other mental disorders (Baum et al., 2015; Ewers et al., 2011; Hirjak
et al., 2018c; Naismith et al., 2012).
3. Results
We conducted a systematic literature search using the above-
mentioned search criteria and identified a total of 472 articles (Fig. 1).
After reviewing titles and abstracts, a total of 387 references were
excluded from the analysis (e.g., no information regarding the sensori­
motor dysfunction, case reports, EEG studies, clinical studies with
medication, unclear setting or clinical rating scale, etc.). 85 full-text
articles were assessed for eligibility. We identified 10 MRI studies on
NSS (Table 1; Ciufolini et al., 2018; Cuesta et al., 2020; Fritze et al.,
2019; Galindo et al., 2017; Herold et al., 2020; Hirjak et al., 2019c; Kong
et al., 2019a; Kong et al., 2019b; Quispe Escudero et al., 2020; Wolf
et al., 2020b), 8 MRI studies on AIMS (Table 2; Huber et al., 2018;
Magioncalda et al., 2020; Molina et al., 2018; Viher et al., 2019; Wertz
et al., 2019; Wolf et al., 2020a; Yu et al., 2018; Zhang et al., 2018) and 8
MRI studies on catatonia (Table 3; Dean et al., 2020; Foucher et al.,
2019; Foucher et al., 2018; Fritze et al., 2020; Hirjak et al., 2019a; Hirjak
et al., 2020c; Viher et al., 2020; Wasserthal et al., 2020) using several
structural (e.g. grey matter (GM) volume, white matter (WM) volume,
cortical thickness, local gyrification index, complexity of cortical folding
(CCF), fractional anisotropy (FA), clustering coefficient (CCO),
betweenness centrality (BC)) and functional metrics (regional homoge­
neity (ReHo), fractional amplitude of low-frequency fluctuations
(fALFF) and regional cerebral blood flow (rCBF), as measured by
continuous arterial spin labeling (CASL). There were no relevant PET or
SPECT studies published in the last 3 years. The identified MRI studies
on this topic have been approved by three authors (DH, JK, and KMK).
Two MRI studies on NSS (Cai et al., 2021; Li et al., 2021) and three MRI
studies on parkinsonism (Fritze et al., 2021; Wasserthal et al., 2021;
Wolf et al., 2021a) were published after the above mentioned period of
the systematic literature search.
For reasons of readability, to keep the heterogeneity of the results as
low as possible, and because of their transnosological value and trans­
lational potential, we focused on NSS, abnormal involuntary move­
ments, parkinsonism, akathisia, and catatonia and excluded
neuroimaging studies investigating basic aspects of sensorimotor func­
tion, such as those investigating inhibitory control (response inhibition),
finger-tapping, perception of movement, movement observation, and
gestures. The identified neuroimaging studies on this topic were
approved by three authors (DH, JK, and KMK).
4. Discussion
The rapidly growing body of research on the neuroimaging of
sensorimotor dysfunction is remarkable. The following five sections
discuss the lessons learned from current neuromechanistic studies on
sensorimotor dysfunction, methodological considerations, conceptual
refinement, translational promises, and key directions for future
neuroscientific and clinical research.
4.1. Refining neurobiological models of sensorimotor dysfunction in SSD
In the past two years, multimodal neuroimaging and advanced data
D. Hirjak et al. Progress in Neuropsychopharmacology & Biological Psychiatry 111 (2021) 110370

Records idenfied through Addional records idenfied

Identification
Pubmed searching through other sources (e.g.
(n = 472) systemac reviews)
(n = 0)

Records aer duplicates removed

(n = 472)
Screening

Records excluded
Records screened (n = 75)
(n = 160) -No relevant informaon
on sensorimotor
dysfuncon
-Other diagnosis
Eligibility

Full-text arcles excluded,

Full-text arcles assessed with reasons (studies on
for eligibility solely ultra-high risk
(n = 85) individuals, animal
studies, case reports,
other diagnosis, CT
studies, no detailed
informaon on
sensorimotor dysfuncon
MRI Studies included in etc.)
qualitave synthesis (n = 59)
(n = 26)
Included

MRI studies on NSS MRI studies on MRI studies on catatonia

(n = 10) parkinsonism, akathisia, (n = 8)
psychomotor slowing and
other AIMS
(n = 8)

Fig. 1. PRISMA flow chart of included neuroimaging studies on sensorimotor abnormalities in schizophrenia spectrum disorders patients.

analysis techniques have substantially contributed to the progress in
sensorimotor neuroscience in SSD (for overview see Fig. 2). In addition
to the classic voxel-based morphometry (VBM) analysis focusing on GM
and WM volumes, structural MRI studies published in the last two years
have also used different methods (Fritze et al., 2019; Fritze et al., 2020)
and examined other structural parameters such as LGI, CCF, FA, CCO
and BC (Hirjak et al., 2019a; Wasserthal et al., 2020). In particular, there
is preliminary evidence that cortical features of distinct evolutionary
and genetic origin differently contribute to catatonia in SSD (Hirjak
et al., 2019a). In addition, two MRI studies using Freesurfer also showed
that brainstem structures play a crucial role in the pathogenesis of NSS
and catatonia (Fritze et al., 2019; Fritze et al., 2020). Two more recent
MRI studies found that WM alterations in the corticospinal tract and
CCO of the left orbitofrontal cortex, primary motor cortex, supplemen­
tary motor area, and putamen might contribute to catatonia in SSD
(Viher et al., 2020; Wasserthal et al., 2020). These studies warrant
replication given very recent negative findings (Dean et al., 2020). Using
MRI-based perfusion-imaging, Foucher and colleagues (Foucher et al.,
2019) found that so-called “periodic catatonia” (Leonhard, 1999) was
specifically associated with increased rCBF of the left pre-motor regions,
in-line with previous independent findings (Walther et al., 2017a).
Until 2018, MRI studies have been unimodal, mostly providing in­
formation on structural alterations or neural activity underlying senso­
rimotor dysfunction separately, with very few exceptions highlighting
both abnormal structure and function (Walther et al., 2017a; Walther
et al., 2017b), albeit on a descriptive level. In the past two years, sub­
stantial advances have been made by multimodal neuroimaging data
fusion analysis strategies (He et al., 2017; Sui et al., 2012; Sui et al.,
2013) in order to provide a more comprehensive understanding of brain
mechanisms in SSD patients with NSS, catatonia or parkinsonism. First,
Hirjak and colleagues used canonical correlation and joint independent
component analysis (mCCA + jICA) to investigate co-altered patterns of
GMV and intrinsic neural activity (INA) in SSD patients exhibiting NSS
(Hirjak et al., 2019c). This study found that NSS complex motor task
score was associated with joint frontocerebellar/frontoparietal net­
works. In a more recent landmark MRI study on NSS, Wolf and

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Table 1
MRI studies on NSS in SSD.
Study Sample characteristics Motor assessment Neuroimaging Important findings
method

Galindo et al., SP: N = 27, mean age = 37.60 years ± 7.0; m = 16, f Neurological 3.0 T MRI SP showed hyperconnectivity in dorsolateral prefrontal
2017 = 11; all patients medicated Evaluation Scale (NES) cortices and middle frontal gyri compared to HC.
REL: N = 23, mean age = 41.39 years ±10.30; m = for NSS
10, f = 13
HC: N = 35, mean age = 36.60 years ±8.0; m = 18, f
= 17
Ciufolini FEP: N = 60, mean age = 27.65 years ±7.94; m = NES 3.0 T MRI FEP with higher rates of NSS showed reduction of
et al., 2018 20, f = 40; DOI: 37 weeks; all patients medicated cortical thickness in postcentral and precentral gyri,
superior temporal, inferior-parietal and fusiform gyri
and smaller surface areas of superior temporal gyrus
and frontal regions.
Kong et al., UHR: N = 21, mean age = 17.81 years ±4.48; m = NSS score with the CIN 3.0 T MRI Higher NSS scores in UHR were associated with
2019a 11, f = 10 decreased GMV in the superior and medial frontal
cortex.
Fritze et al., FEP: N = 27, mean age = 31.41 years ± 11.15; m = Heidelberg NSS Scale 3.0 T MRI Correlation between pons volume and NSS in FEP; no
2019 15, f = 12; DOI = 0.11 months ± 0.32; 22 patients significant association between brainstem structures
medicated; all patients reached a partial remission and NSS in MEP.
for one week (> 25% reduction of symptoms)
MEP: N = 65, mean age = 41.48 years ± 11.14; m =
39, f = 26; DOI = 16.11 months ±9.89; 64 patients
medicated; all patients reached a partial remission
for one week (>25% reduction of symptoms)
Hirjak et al., SSD: N = 37, mean age = 34.41 years ±11.00; m = Heidelberg NSS Scale 3.0 T MRI This study highlights aberrant structure and function,
2019c 20, f = 17; DOI = 8.76 years ±9.81; all patients predominantly in cortical and cerebellar systems that
medicated and reached a partial remission for one critically subserve sensorimotor dynamics and
week (> 25% reduction of symptoms) psychomotor organization.
HC: N = 37, mean age = 34.08 years ± 11.83; m = AIMS, SAS and BARS
20, f = 17 for potential EPMS and
parkonism
Kong et al., SP: N = 101, mean age = 27.36 years ± 7.73 ; m = Heidelberg NSS Scale 1.5 T MRI Associations between NSS and cortical-subcortical-
2019b 63, f = 38; DOI: 20.36 months ±39.97; all patients cerebellar morphology in patients
medicated
Cuesta et al., SP: N = 48, mean age = 25.7 years ±5.8; m = 34, f UKU Scale for EPMS 1.5 T MRI Association between EPMS and NSS and iron load in left
2020 = 14; DOI: 4.57 months ±3.99; all patients basal ganglia.
medicated
HC: N = 23, mean age = 23.4 years ±5.9; m = 17, f Bush-Francis Catatonia
=6 Rating Scale for
catatonic signs
Neurological
Evaluation Scale for
NSS
Quispe SP: N = 81, mean age = 24.9 years ±4.8; m = 57, f Heidelberg NSS Scale 1.5 T MRI Correlation between GM reduction in frontal,
Escudero = 24; DOI: first episode; all patients medicated subcortical and cerebellar areas and NSS score
et al., 2020
Herold et al., CSP: N = 49 (middle-aged); DOI: 20.31 years ±14.0; Heidelberg NSS Scale 3.0 T sMRI with NSS correlated with GM reduction in the inferior and
2020 all but one patient medicated SPM12/CAT12 middle frontal gyri, thalamus and cerebellum.
HC: N = 29 analyses
Wolf et al., AVH: N = 42, mean age = 40.29 years ±13.12; m = Heidelberg NSS scale 3.0 T MRI Right inferior parietal lobule regional homogeneity
2020b 22, f = 20; DOI: 13.79 years ±11.44 (ReHo) and NSS integrative functions predicted AVH
nAVH: N = 34, mean age = 37.09 years ±9.52, m = BPRS severity.
18, f = 16; DOI: 9.18 years ±9.34
All patients reached a partial remission for one week

SP = schizophrenia patients; REL = unaffected relatives; HC = healthy controls; FEP = patients with a first-episode schizophrenia; UHR = individuals at ultra-high risk
for psychosis; MEP = patients with a multiple-episode schizophrenia; SSD = schizophrenia spectrum disorders; CSP = chronic schizophrenia patients; AVH =
schizophrenia patients with auditory verbal hallucinations; nAVH = schizophrenia patients without auditory verbal hallucinations; DOUI = duration of untreated
illness; DOI = duration of illness; m = male; f = female; EPMS = extrapyramidal motor symptoms; NSS = neurological soft signs; GM = grey matter.
CIN = Cambridge Neurological Inventory.
AIMS = Abnormal Involuntary Movement Scale.
SAS = Simpson and Angus scale.
BARS = Barnes Akathisia Rating Scale.

colleagues (Wolf et al., 2020b) showed that right inferior parietal lobule
ReHo as well as NSS scores are able to predict auditory verbal halluci­
nations (AVH) in schizophrenia patients. This multimodal MRI study
provided the first evidence for a common pathophysiological mecha­
nism that could lead to different clinical phenotypes such as NSS and
AVH. Similarly, other studies have also pointed to the link between
motor and sensory alterations in SSD. On one side, NSS are associated
with alterations of the inferior frontal gyrus, paracentral gyrus, inferior
parietal lobe (IPL), bilateral putamen, cerebellum and both the superior
and middle temporal gyri (STG and MTG; Hirjak et al., 2018c; Hirjak
et al., 2015b; Zhao et al., 2013). On the other side, the IPL, STG, and the
transverse temporal gyrus (Heschl's gyrus) are crucial regions in the
pathogenesis of AVH (Dierks et al., 1999; van Lutterveld et al., 2014).
Further, sensorimotor dysfunction in the form of aberrant self-
monitoring could lead to a misattribution of inner speech as externally
generated and finally to AVH (Allen et al., 2007; Fletcher and Frith,
2009; Shergill et al., 2014). Another interesting connection arises be­
tween sensorimotor and affective domain. For instance, Williams and
colleagues showed that similar neural mechanisms serve motor control
and emotional regulation, so that subsequent motor actions are tightly

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Table 2
MRI studies on other abnormal involuntary movements in SSD.
Study Sample characteristics Motor assessment Neuroimaging Important findings
method

Molina et al., SP: N = 22, mean age = 33.94 years ±8.09,
2018 m = 10, f = 12; DOI: 64.66 months ±78.98;
all patients medicated
HC: N = 14, mean age = 36.70 years
±10.90; m = 6, f = 8
Zhang et al., TD group: N = 26, mean age = 45.6 years
2018 ±10.6; m = 15, f = 11; DOI: 21.9 years
±10.2
NTD group: N = 26, mean age = 45.5 years
±7.8; m = 16, f = 10; DOI: 22.3 years ± 8.5
HC: N = 30, mean age = 46.4 years ±8.4; m
= 19, f = 11
Yu et al., 2018 TD group: N = 32, mean age = 46.9 years
±10.0; m = 20, f = 12; DOI: 22.8 years
±10.2
NTD group: N = 31, mean age = 45.7 years
±7.5; m = 19, f = 12; DOI: 22.6 years ±8.4
All patients medicated
HC: N = 32, mean age = 45.6 years ±7.7, m
= 19, f = 13
Huber et al., 56 UHR, 55 FEP and 25 HC;
2018 BPRS-EC high group: N = 49, mean age =
25.5 years ±6.1; m = 37, f = 12;
BPRS-EC low group: N = 62, mean age =
26.1 years ±7.0; m = 44, f = 18; HC: N = 25,
mean age = 27.7 years ±4.5; m = 11, f = 14
Viher et al., SP: N = 19, mean age = 32.6 years ±8.4, m
2019 = 75%; DOI: 110.63 months ±67.27
All patients medicated
HC: N = 16, mean age = 30.6 years ±6.7; m
= 89.5%
Wertz et al., SP: N = 49, mean age = 32.71 years ±8.61;
2019 m = 32, f = 17; DOI: 11.35 years ±8.40
HC: N = 54, mean age = 33.13 years ±7.70;
m = 36, f = 18
Magioncalda Study Dataset 1:
et al., 2020 SCZ (LPM): N = 18, mean age = 40.1 years
±11.6; m = 9, f = 9
HC: N = 19, mean age = 34.3 years ±5.6; m
= 6, f = 13
Study Dataset 2:
SCZ (ToS): N = 43, mean age = 36.7 years
±8.8; m = 32, f = 11
SCZ (HPM): N = 20, mean age = 38.4 years
±8.1; m = 16, f = 4
SCZ (nPM): N = 23, mean age = 35.3 years
±9.3; m = 16, f = 7
HC: N = 108, mean age = 30.9 years ±8.5;
m = 59, f = 49
Wolf et al., SZ-nonP: N = 22, mean age = 38.64
2020a years±12.96; m = 14, f = 8; DOI: 11.36
years ±11.37
SZ-P: N = 22, mean age = 40.41 years
±11.38; m = 14, f = 8; DOI: 15.50 years
±10.87
SAS
Brief Assessment in
Schizophrenia Scale for
cognitive assessment
Schooler and Kane's TD
criteria, AIMS
Schooler and Kane's TD
criteria, AIMS
Excited Component of the
Brief Psychiatric Rating Scale
(BPRS-EC)
NES, St. Hans Rating Scale for
EPMS, Salpetriere
Retardation Rating Scale
AIMS, BARS and SAS
A multisensory attention/
response inhibition task
Psychomotor Items in PANSS,
YMRS, Hamilton Depression
Scale (HAMD)
SAS
3.0 T MRI Total SAS scores were negatively correlated with
fractional anisotropy in right rostral middle prefrontal-
caudate tract in SP.
3.0 T MRI SP with TD showed a correlation between reduced brain
activity in the occipital lobe compared to HC and
decreased fALFF in the left cuneus compared to the NTD
group.
3.0 T MRI The study showed larger GM volume in brainstem and
inferior frontal and precentral gyri in patients with tardive
dyskinesia. Lower GMV in cuneus and lingual gyri
correlated positively with AIMS scores.
3.0 T MRI Patients with higher BPRS-EC showed a smaller left
lingual GM volume than HC.
3.0 T MRI Patients showed decreased functional connectivity
between bilateral dorsolateral prefrontal cortex and left
caudate nucleus. Reduced functional connectivity
between left putamen and bilateral supplementary motor
area was found.
3.0 T MRI Hyperactivity in left sensorimotor cortex (SMC) during
proactive response inhibition, along with decreased
cortical connectivity with left SMC in patients with SP.
3.0 T MRI SCZ patient with psychomotor inhibition showed
decreased functional connectivity (FC) between thalamus
and sensorimotor network and reduced FC between
substantia nigra and basal ganglia/thalamus and between
raphe nuclei and basal ganglia/thalamus. SCZ patients
with psychomotor excitation showed an increase of FC
between thalamus and sensorimotor network and a
reduction of FC between raphe nuclei and basal ganglia/
thalamus.
3.0 T MRI There was a correlation between SAS tremor score and
loadings of the cortical sensorimotor network. This study
showed an association between the SAS glabella-
salivation score and loadings of the frontothalamic/
cerebellar and cortical sensori- motor network.

SCZ = patients with schizophrenia; V = violent behavior; SP = schizophrenic patients/other mental disorders; HC = healthy controls; TD = patients with tardive
dyskinesia; NTD = patients without tardive dyskinesia; CHR = Clinical High Risk for Psychosis; UHR: ultra-high risk individuals; ESZ = Early Illness Schizophrenia;
FEP = first-episode psychosis patients, HV = healthy volunteers; LPM = low level of psychomotor activity; ToS = total score; HPM = high level of psychomotor activity;
nPM = non-altered psychomotricity; SZ-nonP=SCZ patients without parkinsonism; SZ-P=SCZ patients with parkinsonism; fALFF = fractional amplitude of low-
frequency fluctuations.
DOI = duration of illness; m = male; f = female; TD = tardive dyskinesia.
BPRS-EC = Excited Component of the Brief Psychiatric Rating Scale.
NES = Neurological Evaluation Scale.
AIMS = Abnormal Involuntary Movements Scale.
BARS=Barnes Akathisia Scale.
SAS=Simpson Angus Scale.
YMRS=Young Mania Rating Scale.
PANSS=Positive and Negative Syndrome Scale.

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Table 3
MRI studies on catatonia in SSD.
Study Sample characteristics Motor assessment Neuroimaging Important findings
method

Foucher et al., PC: N = 20, mean age = 38 years ± 13; m = 10, f = 10; BFCRS 3.0 Tesla MRI Patients with PC showed an increased rCBF in the left motor
2018 DOI: 15.60 years ±12.70 and premotor areas.
C: N = 9, mean age = 38 years ± 7; m = 4, f = 5; DOI:
14.40 years ±6.40; all but 3 patients medicated
HC: N = 27, mean age = 39 years ± 9; m = 13, f = 14
Hirjak et al., SSD with catatonia: N = 25, mean age = 39.12 years NCRS 3.0 Tesla MRI Patients with catatonia had a reduced surface area in parietal
2019a ±11.42; m = 14, f = 11; DOI: 13.68 years ±11.99 and medial orbitofrontal cortex; reduced LGI in temporal
SSD without catatonia: N = 22, mean age = 40.18 gyrus, and higher LGI in rostral cingulate and medial
years ±11.83; m = 11, f = 11; DOI: 8.50 years ±9.54 orbitofrontal gyrus.
Hirjak et al., SSD with catatonia: N = 24, mean age = 38.92 years NCRS 3.0 Tesla MRI SSD patients with catatonia showed abnormalities in
2020c ± 11.62; m = 14, f = 10; DOI: 13.38 years ± 12.15 frontothalamic and corticostriatal networks. NCRS affective
SSD without catatonia: N = 22, mean age = 40.18 scores associated with frontoparietal intrinsic neural activity.
years ±11.83; m = 11, f = 11; DOI: 8.50 years ± 9.54
Foucher et al., Patients from 2 studies: iADAPT, RETONIC DSM-5 criteria and Wernicke- 3.0 Tesla MRI rCBF increases in left SMA and lateral premotor cortex
2019 PC: N = 8 (RETONIC), N = 1 (iADAPT), mean age = Kleist-Leonhard classification reached positive predictive values of 94%, only when used in
40 years ±13; m = 6, f = 3; DOI: 17 years ±12; 8 for diagnosis combination with clinical criteria.
patients medicated with AP, 5 with AD
Depressed patients with non-PC (iADAPT): N = 23, BFCRS
mean age = 52 years ±12; m = 9, f = 14; DOI: 21 years
±14; 10 patients medicated with AP, 13 with AD
pCC patients with non-PC (RETONIC): N = 3, mean
age = 35 years ±9; m = 2, f = 1; DOI: 18 years ±7; all
patients medicated with AP and AD
HC: N = 37, mean age = 43 years ±11; m = 18, f = 19
Wasserthal SSD with catatonia: n = 30, mean age = 39.40 years NCRS 3.0 Tesla MRI Variations of left corticospinal tract, left orbitofrontal cortex,
et al., 2020 ±10.49; m = 16, f = 14; DOI: 12.27 years ±11.53 primary motor cortex, SMA and putamen were present in SSD
SSD without catatonia: N = 29, mean age = 38.0 years patients with catatonia.
±11.25; m = 14, f = 15; DOI: 7.31 years ±8.86
All SSD patients reached a partial remission for one
week; all but 5 medicated
HC: N = 28, mean age = 35.14 years ±14.18; m = 20,
f=8
Dean et al., SSD with catatonia: N = 43, mean age = 27.4 years BFCRS 3.0 Tesla MRI SSD patients with a history of catatonia showed decreased GM
2020 ±8.15; m = 32, f = 11 volume in anterior cingulate, insular, temporal and medial
SSD without catatonia: N = 43, mean age = 27.9 years frontal cortices compared to HC.
±6.63; m = 35, f = 8
HC: N = 86, mean age = 29.9 years ±9.24; m = 64, f
= 22
Viher et al., SSD with catatonia: N = 13, mean age = 40.7 years ± BFCRS 3.0 Tesla MRI SSD patients with catatonia had a higher fractional anisotropy
2020 13.6; DOI: 17.3 years ± 13.1 in left lateralized white matter regions like internal and
SSD without catatonia: N = 35, mean age = 37.4 external capsule, superior longitudinal fascicle and
years ± 11.4; DOI: 11.3 years ± 12.2 corticospinal tract compared to HC.
All SSD patients: m = 30, f = 18; 44 patients
medicated
HC: N = 43, mean age = 38.6 years ± 13.7; m = 25, f
= 18
Fritze et al., SSD patients with catatonia: N = 30, mean age = NCRS 3.0 Tesla MRI Patients with catatonia had smaller midbrain volumes in
2020 39.40 years ±10.49; m = 16, f = 14; DOI: 12.27 years comparison to non-catatonic patients. NCRS motor scores in
±11.53 catatonic patients correlated with whole brainstem volumes.
SSD patients without catatonia: N = 29, mean age =
38.00 years ±11.25; m = 14, f = 15; DOI: 7.31 years
±8.86

PC = patients with periodic catatonia; C = patients with cataphasia; HC = healthy controls; SSD = schizophrenia spectrum disorders; pCC = pseudocompulsive
catatonia; DOI = duration of illness; m = male; f = female; BFCRS: Bush Francis Catatonia Rating Scale; NCRS = Northoff Catatonia Rating Scale; rCBF = regional
cerebral blood flow; LGI = local gyrification index; GM = grey matter.

linked to emotions (Williams et al., 2020). From a clinical perspective,
sensorimotor abnormalities (e.g., akinesia, akathisia, or psychomotor
slowing) may occur together with affective symptoms (e.g., anxiety,
aggressiveness, or apathy). This situation is visible not only in negative
syndrome of SSD but also in affective disorders. Overall, these findings
shed light on how the sensorimotor dysfunction mediates other di­
mensions such as negative/positive valence systems, cognitive systems
or social processes in SSD.
Another multimodal data fusion technique (as described in (Hirjak
et al., 2019c)) was used to investigate differences between SSD patients
with and without catatonia. Hirjak and colleagues (Hirjak et al., 2020c)
detected frontothalamic and frontoparietal networks that represent
joint, co-altered GMV-INA components that differ between catatonic
and non-catatonic SSD patients. The authors suggested that GMV
reduction in the frontothalamic network may impact on the INA of the
frontoparietal circuit, resulting in impaired processing of negative
emotional stimuli and cessation of sensorimotor functioning, which can
lead to affective and behavioral catatonic symptoms (Hirjak et al.,
2020c). Finally, unlike in the previous decades of neuroimaging
research in SSD, parkinsonism has been the subject of an in-depth
investigation by multimodal imaging. Wolf and colleagues (Wolf et al.,
2020a) found that correlational coefficients of interrelated frontotha­
lamic/cerebellar sMRI component and a cortical sensorimotor rs-fMRI
component differed significantly between patients with and without
parkinsonism. The authors suggested that parkinsonism in SSD is a
multidimensional clinical construct in which subcortical deficits,
particularly in the thalamus and cerebellum, could lead to an alteration
in bottom-up (“vertical”) modulation of sensorimotor cortical regions

6
D. Hirjak et al.
(Wolf et al., 2020a).
4.2. Methodological considerations
Despite the introduction of the RDoC sensorimotor domain, there is
still ongoing skepticism regarding the validity and clinical relevance of
sensorimotor neuroscience in SSD and beyond. We suggest several pit­
falls and methodological practices that can increase the credibility of
neuroscience research on the sensorimotor domain in SSD: (1) Modern
studies increasingly use sensing and wearable technologies (smartphone
apps, wrist devices, and other smartwatches) to assess different aspects
of sensorimotor behavior. This is a very promising development, but at
the same time, only a few studies have been published validating these
new technologies against more traditional clinical rating scales (Damme
et al., 2020). Therefore, it is currently not known to what extent
instrumental assessment of sensorimotor dysfunction correlates with
well-established clinical rating scales. This issue requires cross-
validation, replication, and tests of generalizability. (2) The identified
MRI studies have used different acquisition, processing, and analysis
modalities and methods to observe different aspects of the sensorimotor
system disruption. As shown by the extant MRI fusion data, acquisition
and simultaneous processing of >2 data modalities yield clear advan­
tages over conventional unimodal and regionally confined brain local­
ization approaches. Therefore, we strongly acknowledge multimodal
neuroimaging studies followed by fine-grained spatiotemporal con­
nectomics analyses. (3) Another methodological limitation of previous
MRI studies on sensorimotor abnormalities is the overlap of different
sensorimotor symptoms and signs. The above mentioned studies sepa­
rated study groups based on the presence of either catatonia or
parkinsonism and hence, they used overlapping patients' samples.
However, from a clinical point of view, some patients may show both
catatonic and parkinsonian symptoms. This said, it is not always possible
to distinguish between catatonia and parkinsonism using clinical rating
scales. This might be a possible explanation for overlapping brain re­
gions underlying catatonia and parkinsonism. Only large-scale and
deeply phenotyped patient samples might be able to disentangle the
effects of various hypo- and hyperkinetic behaviors on a technical/sta­
tistical level. (4) Although it would be very beneficial to study
antipsychotic-naive SSD patients, the recruitment and inclusion of this
particular patient group is not always possible for both ethical and
practical reasons. The contemporary clinical imperative to initiate
antipsychotic treatment vitiates undertaking such complex in­
vestigations in the antipsychotic-naïve state. However, the above
mentioned investigations were made among deeply phenotyped SSD
patients without and with sensorimotor dysfunction in the course of
stable antipsychotic treatment, to reflect the reality of intrinsic processes
as risk factors for antipsychotic drug-exacerbated effects. Therefore, the
authors suggest that developmentally determined cortical abnormalities
(Hirjak et al., 2019a; Hirjak et al., 2015a; Hirjak et al., 2016) are
pervasive findings and a strong candidate for elements in cortical-
striatal-thalamocortical network dysfunction that underlie intrinsic
sensorimotor system disruption and confer vulnerability to further
dysfunction in that network during treatment with antipsychotic drugs
(Wolf et al., 2021a).
4.3. Conceptual refinement
There are different terms and definitions in the literature concerning
sensorimotor behavior in patients with mental disorders. In recent years,
several research initiatives have been launched to create new framework
conditions for modern sensorimotor neuroscience: Since the late 1990s,
the Systems Neuroscience of Psychosis (SyNoPsis; www.synopsis.net)
project aims at linking a revised phenomenology of psychoses and brain
circuits, without the use of intermediate neurophysiological or neuro­
psychological constructs (Strik et al., 2017). In particular, SyNoPsis has
introduced three neurobiologically informed behavioral dimensions
7
Progress in Neuropsychopharmacology & Biological Psychiatry 111 (2021) 110370
(Strik et al., 2017): language, affectivity, and motor behavior. However,
the SyNoPsis framework has been specifically developed for psychotic
disorders. Thus, a direct translation of this framework to other mental
disorders is difficult and very likely also premature prior to a decidedly
transnosological refinement of SyNoPsis. An internationally important
initiative to develop a research classification system for mental disorders
based upon dimensions of neurobiology and observable behavior i.e.,
the Research Domain Criteria (RDoC) project was launched in 2009 by
the National Institute of Mental Health (NIMH; Cuthbert, 2014; Cuthbert
and Insel, 2013). The near-term goal of the RDoC initiative is to define a
new framework of research that can produce pioneering new findings
and approaches to inform future versions of psychiatric nosologies
(Cuthbert, 2014; Cuthbert and Insel, 2013). Still being developed, the
NIMH RDoC initiative has added the “sensorimotor domain” to the RDoC
matrix (Garvey and Cuthbert, 2017; Mittal et al., 2017b; Sanislow et al.,
2019). However, the major criticism of the current RDoC sensorimotor
domain is that this approach primarily targets motor-related changes in
dopaminergic cortico-striato-pallido-thalamo-cortical motor circuits
(Mittal et al., 2017b; Walther et al., 2019a). Therefore, in recent years
(but originally beginning in the early 1800s), the “psycho-motor”
concept in its literal sense has been revived, specifically focusing on
psycho-motor (rather than motor) mechanisms of mental disorders
(Northoff et al., 2020a). More specifically, this concept involves both
domains, namely, that of “psycho” (i.e., cognition and affectivity) and
that of “motor” (movement). From a clinical perspective, psychomotor
dysfunction can be characterized by specific symptom patterns, that is,
specific constellations of motor (rigor, dyskinesia, festination, counter­
acting, posturing, catalepsy, etc.), affective (aggression, anxiety, flat
affect, affect incontinence, etc.), and cognitive (disorganized thinking,
slow thinking, poor concentration, impaired higher or ‘executive’
functioning, impairment of short term working memory, etc.) symptoms
(Bernard and Mittal, 2015; Mittal et al., 2017b; Sarkheil et al., 2020). A
recent comprehensive publication by Northoff and colleagues provides a
highly informative narrative review of biochemical modulations of
psychomotor dysfunction in psychiatric disorders (Northoff et al.,
2020a, 2020b). On a neural level, Northoff and colleagues (Northoff
et al., 2020a, 2020b) proposed that psychomotor mechanisms (assuming
a direct interaction between psychic and motor function) can be char­
acterized as interactions between the (i) dopamine- and substantia
nigra-based subcortical–cortical motor circuit modulated by primarily
non-motor subcortical raphe nucleus and serotonin via basal ganglia and
thalamus (as well as by glutamate and GABA); (ii) cortical motor net­
works to other networks like default-mode and sensory networks; and
(iii) global cortical activity to motor cortex (Northoff et al., 2020a,
2020b). More precisely, the third psychomotor mechanism is defined as
an alteration of the global distribution/signal (GS) of neural activity
manifested in specific local regions (Zhang et al., 2020). This mechanism
has significant transdiagnostic implications, because it might be
involved in different phases of bipolar disorders. Whereas altered GS in
bilateral motor cortex was shown to characterize manic states, aberrant
GS spatial topography in hippocampus was found in depressive states
(Zhang et al., 2019). Overall, these three promising concepts provide a
mixed picture of the sensorimotor domain, but overall suggest its rele­
vance for clinical practice. Still, further discussion and detailed, fine-
grained examination details (particularly using the new armamen­
tarium of instrumental and ecological momentary assessments) of each
concept are needed to redefine and therapeutically exploit the sensori­
motor behavior of patients with mental disorders.
4.4. Translational promises
Sensorimotor neuroscience exhibits diagnostic and therapeutic
relevance (i) for early diagnosis of at-risk mental states and manifest
mental disorders (Mittal et al., 2014; Osborne et al., 2020), (ii) for early
detection of motor side effects of antipsychotic medications as well as
clinical outcome monitoring (Cuesta et al., 2014; Peralta and Cuesta,
D. Hirjak et al.
Fig. 2. Core brain networks frequently associated with catatonia and parkinsonism in schizophrenia spectrum disorders (Abbreviations: GMV = grey matter volume;
WM = white matter; INA = intrinsic neural activity; rCBF = regional cerebral blood flow).
2011; Sambataro et al., 2020), (iii) treatment of psychomotor syndromes
(e.g. catatonia; Cuesta et al., 2018; Cuesta et al., 2014), and (iv) iden­
tification of new targets for non-invasive brain stimulation (e.g., trans­
cranial magnetic stimulation, TMS; or transcranial direct current
stimulation, tDCS; Cuesta and Peralta, 2018; Hirjak et al., 2019b; Mittal
and Walther, 2019; Stevens, 1974; Walther et al., 2019a; Walther and
Strik, 2012; Walther et al., 2020), respectively. As mentioned for recent
discoveries made with the above mentioned techniques, a better un­
derstanding of the sensorimotor domain has begun to emerge. Although
there is still much to learn about CTCC network dysfunction in the
pathophysiology of aberrant sensorimotor behavior, the cerebellum is
increasingly considered to play an important role in sensorimotor
neuroscience and beyond.
Cerebellar circuits are strongly interconnected with the limbic re­
gions of the basal ganglia and multiple motor and non-motor regions of
the cortex (Bostan and Strick, 2018). Cerebellum modulates multi-
transmitter based motor, cognitive and limbic networks, which are
responsible for action planning (Bostan and Strick, 2018). More specif­
ically, the cerebellar modulation of dopamine-based subcortical–cortical
motor network is crucial in the pathogenesis of motor, social, emotional,
and cognitive features of psychiatric disorders across the life span. This
said, the cerebellum is not only involved in clinically relevant abnor­
malities in motor balance, gait, coordination, timing, integration and
learning in ultra-high risk individuals (Bernard et al., 2014; Bernard
et al., 2018), but also in manifest SSD characterized by typical psycho­
motor syndromes such as catatonia and parkinsonism. Furthermore, the
cerebellum is responsible for temporal coordination (incl. Time
perception and production (Andreasen and Pierson, 2008)) of distinct
regions (Moussa-Tooks et al., 2019) in order to provide temporal map to
all three, motor, affective, and cognitive function (Bostan and Strick,
2018; Northoff et al., 2020b; Northoff et al., 2020c). According to
Andreasen et al. (1998), cerebellar dysfunction in SSD can lead to so
called ‘dysmetria’ which may be better parsed out into ‘motor dysme­
tria’, ‘affective dysmetria’, and ‘cognitive dysmetria’. But cerebellar
involvement in impaired motor performance and psychomotor func­
tioning does not only apply to SSD, but has been consistently demon­
strated in major depressive disorder (MDD), BD (Depping et al., 2018),
autism (Mostofsky et al., 2009) and ADHD (for review see Hirjak et al.
8
Progress in Neuropsychopharmacology & Biological Psychiatry 111 (2021) 110370
(2018b)). In particular, gray matter volume increase of left cerebellar
area VIIa crus I (region ascribed to the “affective/limbic cerebellum”)
after treatment with electroconvulsive therapy (ECT) was associated
with overall symptom relief (Depping et al., 2017). Another study
showed that SSD Patients with AVH have lower GMV in cerebellar
lobule VIIIa when compared to SSD patients without AVH (Cierpka
et al., 2017) and hence, lobule VIIIa GMV was negatively associated with
overall positive symptoms. In Tourette syndrome (TS), cerebellar
disinhibition might lead to hyperactivity of cortical regions such as
primary motor cortex resulting in development of motor tics (Caligiore
et al., 2017). Finally, both increase and decrease of a neurotransmitter
within the cerebellar networks can influence the psychomotor activity of
a person. Imbalance between the individual neurotransmitters within
the affective, cognitive and motor parts of the cerebellum might lead to
psychomotor dysfunction (Northoff et al., 2020b). However, there is
little evidence for this assumption, e.g. the GABAergic dysregulation in
SZ and catatonia (Nair et al., 2020). For instance, pharmacological ef­
fects on cerebellar metabolic factors (pH or glucose) has been found in
BD patients with lithium (Johnson et al., 2015). These findings along
with the most sophisticated developments in biochemical neuroimaging
have a strong potential to facilitate the development of novel psycho­
pharmacological models based on psychomotor mechanisms in mental
disorders (Hirjak et al., 2021).
4.5. Key directions for future research and clinical practice
Sensorimotor neuroscience needs to translate neuroimaging findings
into vulnerability prediction and multimodal treatments. We propose
distinct multi-omics layers to guide neuroscience and clinical research
(for overview see Fig. 3; Hirjak et al., 2019d):
First, the above-mentioned studies shed light on the intersection of
sensorimotor, affective, and cognitive networks in the pathogenesis of
sensorimotor abnormalities, but they provide only a limited amount of
information on complex spatial and temporal interactions between
networks. Sensorimotor abnormalities may essentially arise from
spatiotemporally unstable within and between functional network
connectivity (FNC) interactions that eventually could lead to deficient
adaption of sensorimotor function to constantly changing
D. Hirjak et al.
environmental demands, as may be the case in catatonia (Northoff et al.,
2020a).
Second, the precise functional interactions between different senso­
rimotor brain regions and their neurotransmitter systems have not been
explored in any depth. Therefore, we strongly acknowledge proton
magnetic resonance spectroscopy (1H-MRS), PET, and SPECT studies in
SSD, which examine in fine detail the activity profiles of GABAergic,
dopaminergic, glutamatergic, and serotoninergic systems. In particular,
catatonia is a paradigmatic model for RDoC-based investigation of
GABAergic system, because there is (1) a mechanistic animal model of
catatonia, (2) catatonic symptoms can be easily measured using modern
examination methods, and (3) catatonia is based on a complex interplay
between dysfunctions and dynamics of neural circuitry (Braun et al.,
2018) underlying sensorimotor function, behavior, affective processing,
and cognition (Hirjak et al., 2019d). A neurochemical model that
received some support in the past years suggests that catatonia is caused
by a disbalance between GABAA (decrease) and GABAB (increase) receptor
activity (Carroll et al., 2007; Hirjak et al., 2020b). Furthermore, a recent
umbrella review by van der Burg et al. (2020) showed that genetic
variations in 10 genes (e.g. DRD3, DRD2, CYP2D6, HTR2A, COMT,
HSPG2, and SOD2) may increase the odds of tardive dyskinesia.
Therefore, it is obvious that dysregulation of both GABAergic and
dopaminergic systems might modulate the development of sensorimotor
abnormalities.
Third, we still do not know whether the use of psychotropic illegal
drugs (cannabis, cocaine, amphetamine, etc.) and their signaling path­
ways might contribute to the vulnerability of the sensorimotor system or
Fig. 3. Key methods and directions for future neuroscientific and clinical research on sensorimotor abnormalities (Abbreviations: SMA = supplementary motor area;
M1 = primary motor cortex; mPFC = medial prefrontal cortex; BG = basal ganglia; OFC = orbitofrontal cortex; MB = midbrani; Cer = cerebellum).
9
Progress in Neuropsychopharmacology & Biological Psychiatry 111 (2021) 110370
even to the development of sensorimotor abnormalities in SSD (Wolf
et al., 2021b). In particular, cannabinoids modulate motor (e.g. cata­
lepsy, decreased motor activity, hyperactivity or stereotypy) and
cognitive performance in both humans (Fernandez-Ruiz, 2009; Muller-
Vahl et al., 2020) and rats (for review see (Rodriguez de Fonseca et al.,
1998)). A recent study in regular cannabis users showed an increased
postural sway, possibly reflecting disrupted cerebellar processing of
incoming peripheral nervous system information (Bolbecker et al.,
2018). Yet, cannabinoids might also have a positive influence on
sensorimotor functioning in TS patients with psychiatric comorbidities
(Fernandez-Ruiz, 2009; Muller-Vahl et al., 2020).
Fourth, from a translational perspective, a comprehensive charac­
terization and long-term monitoring of the above mentioned modulators
of the sensorimotor system is needed. Future studies should increase the
arsenal of methods (e.g., combination of multiple sensor data, multi­
modal MRI, and machine learning algorithms) and conduct longitudinal,
pharmacological, and preferably transnosological trials to answer key
questions about whether early administration of pharmacological agents
can prevent the development of neuroanatomical and neurophysiolog­
ical sensorimotor system abnormalities associated with SSD and other
mental disorders (Hirjak et al., 2018b)(Hirjak et al., 2021). We strongly
acknowledge that researchers should focus on transdiagnostic domain-
related processes that correspond better to known neurocircuitry than
do ICD-10 or DSM-5 mental disorders. In line with this, the RDoC
sensorimotor domain should be extended to include psychomotor and
psychosensory abnormalities and hence, future studies should consider
recruiting patients with a specific domain-related dysfunction or
D. Hirjak et al.
symptoms presentation (e.g., sensorimotor abnormalities) and examine
multiple levels of information (e.g. genetics, MRI, instrumental assess­
ments, etc.) (Walther et al., 2020).
4.6. Concluding remarks
Summarizing the above mentioned findings, modern neuroimaging
research provides a mixed picture, but overall sketches an increasingly
complex presentation of the cerebello-thalamo-cortico-cerebellar
network dysfunction involved in aberrant sensorimotor behavior in
SSD. Still, the proposed neurobiological integration of the bottom-up
and top-down aspects of sensorimotor abnormalities in SSD awaits
further experimental confirmation. More sophisticated neuroimaging
techniques that move beyond simple one-modality analysis are likely
necessary to decipher the neurobiological mechanisms of sensorimotor
dysfunction in SSD. Although MRI research in patients with mental
disorders will remain of the essence to identify the neuromechanistic
origin of sensorimotor dysfunction, biochemical neuroimaging using
MRS, PET, and SPECT will have to complement the therapeutic potential
of pharmacological compounds that modulate GABAergic, dopami­
nergic, glutamatergic, and serotonergic transmission.
Funding sources
This review was supported by the German Research Foundation
(DFG; grant numbers HI 1928/2-1 to D.H., WO 1883/6-1 to R.C.W. and
EB 187/8-1 to S.F.). The funding entity had no further role in study
design; in the collection, analysis and interpretation of data; in the
writing of the report; and in the decision to submit the article for pub­
lication. All authors report no biomedical financial interests or potential
conflicts of interest.
Ethical statement
For this systematic review, the authors did not perform any studies
on humans or animals. The authors declare that this work was con­
ducted in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
Acknowledgements
Fig. 3 was created with BioRender.com.
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