Neuroscience and Biobehavioral Reviews 95 (2018) 315–335

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

Motor dysfunction as research domain across bipolar, obsessive-compulsive T

and neurodevelopmental disorders
⁎
Dusan Hirjaka, , Andreas Meyer-Lindenberga, Stefan Fritzea, Fabio Sambatarob,
Katharina M. Kuberac, Robert C. Wolfc
a
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
b
Department of Medicine, University of Udine, Udine, Italy
c
Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany

A R T I C LE I N FO A B S T R A C T

Keywords: Although genuine motor abnormalities (GMA) are frequently found in schizophrenia, they are also considered as
Motor dysfunction an intrinsic feature of bipolar, obsessive-compulsive, and neurodevelopmental disorders with early onset such as
Bipolar disorders autism, ADHD, and Tourette syndrome. Such transnosological observations strongly suggest a common neural
Obsessive-compulsive disorders pathophysiology. This systematic review highlights the evidence on GMA and their neuroanatomical substrates
Autism
in bipolar, obsessive-compulsive, and neurodevelopmental disorders. The data lends support for a common
ADHD
Tourette syndrome
pattern contributing to GMA expression in these diseases that seems to be related to cerebello-thalamo-cortical,
MRI fronto-parietal, and cortico-subcortical motor circuit dysfunction. The identified studies provide first evidence
for a motor network dysfunction as a correlate of early neurodevelopmental deviance prior to clinical symptom
expression. There are also first hints for a developmental risk factor model of these mental disorders. An in-depth
analysis of motor networks and related patho-(physiological) mechanisms will not only help promoting Research
Domain Criteria (RDoC) Motor System construct, but also facilitate the development of novel psychopharma-
cological models, as well as the identification of neurobiologically plausible target sites for non-invasive brain
stimulation.

1. Introduction defined 17 signs of this syndrome including posture, mutism, negati-

1.1. Historical background
The history of movement disorders is long, complicated and central
to the beginning of clinical neurology and psychiatry, especially during
the early 19th century (for extensive literature overview see also
(Berrios and Markova, 2017). The majority of neurologists and psy-
chiatrists have investigated patients exhibiting motor signs and symp-
toms and hence, this led to a very detailed clinical description of novel
syndromes and their putative physiological mechanisms. In 1845,
Wilhelm Griesinger (Griesinger, 2011) considered movement disorders
as essential clinical symptoms of psychological disorders (Berrios and
Markova, 2017). In his book, “Elementarstörungen der psychischen
Krankheiten” (elemental disturbances of psychological disorders)
(Griesinger, 1845), he described two types of motor abnormalities re-
lated to brain alterations (tics, tremor, rigidity, etc.) or intellectual/
emotional disorders (stereotypical movements) (Berrios and Markova,
2017). Later on, Karl Kahlbaum proposed the concept of catatonia and
vism, and catalepsy, respectively (Kahlbaum, 2007, 1874). Emil Krae-
pelin incorporated catatonia in his concept of dementia praecox
(Kreapelin, 1899; Berrios and Markova, 2017). In contrast, August
Hoch (Hoch, 1921) emphasized that catatonic symptoms are present in
different mental disorders, including dementia praecox and manic-de-
pression (Braunig et al., 1998). In January 1885, Gilles de la Tourette
described nine individuals with involuntary movements, echolalia,
echopraxia, coprolalia, and strange, uncontrollable sounds (Lajonchere
et al., 1996), soon to be labeled as „Tourette-Syndrome“. At the end of
the 19th century, motor symptoms have long been closely related with
the concept of hysteria and catatonia (Shorter, 2006). Charcot and
Marie (Charcot and Marie, 1892) and Janet (Janet, 1907) provided the
first modern description of hysteria and conversion disorders exhibiting
motor symptoms such as hysterical paralysis, which were presumed to
be of psychogenic origin. At the beginning of the 20th century, the
concept of movement disorders underwent a complex change, because
neurology and psychiatry have increasingly gone their separate ways.
For instance, Carl Wernicke considered motor symptoms to be

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

https://doi.org/10.1016/j.neubiorev.2018.09.009
Received 25 March 2018; Received in revised form 8 August 2018; Accepted 12 September 2018
Available online 17 September 2018
0149-7634/ © 2018 Elsevier Ltd. All rights reserved.
D. Hirjak et al.
pathognomonic features of psychiatric syndromes (Berrios and
Markova, 2017; Wernicke, 1900). In particular, he coined the term
“Motilitätspsychose” (motility psychosis) a disorder characterized by
hyperkinesia and impulsive movements (Jahn, 2004). In this tradition,
Karl Kleist described several cases of motility psychosis, which he later
on classified as “cycloid psychoses”, i.e. disorders characterized by psy-
chotic features and episodic course (Bräunig, 1995; Angst and
Marneros, 2001). This concept was further developed by Karl Leonhard,
who described three overlapping cycloid subtypes (anxiety-beatific,
excited-inhibited confusional, and hyperkinetic-akinetic motility dys-
function forms) (Salvatore et al., 2008). In the 20th century, several
lines of research have investigated the pathogenesis of motor signs and
symptoms across neuropsychiatric disorders, yet the focus of the studies
gradually shifted from an initially psychogenic concept to the notion of
organic syndromes. Eventually, after the first report of chlorpromazine-
induced movement disorder in 1956, drug-induced motor symptoms in
mental illness has been one major paradigm for the occurrence of motor
signs and symptoms, at least in psychotic disorders (Hirjak et al.,
2018a, b). As with other areas with considerable clinical and scientific
endeavors overlap (Shorter, 1998), the movement disorders domain
gradually shifted in the realm of Clinical Neurology, with very few
syndromes being primarily diagnosed and treated by psychiatrists, e.g.
drug-induced side effects or catatonia. This development resulted in
great uncertainty among clinicians about what kind of symptoms
(genuine or drug-induced) they were dealing with. This confusion still
persists, not least due to the diminished awareness that motor ab-
normalities are (also) a characteristic feature of mental disorders.
1.2. Clinical manifestation and diagnosis
In the last years, primary or genuine motor abnormalities (GMA)
have been again increasingly recognized as common phenomena in a
variety of mental disorders (Hirjak et al., 2017a). However, true rates of
occurrence are difficult to estimate, because GMA lost their former
conceptual and diagnostic significance in clinical psychiatry. Therefore,
GMA may go unnoticed in daily clinical practice, as is often the case
with neurological soft signs (NSS) (congruent with mild/minor neuro-
logical dysfunction, MND), akathisia, balance problems or impaired
manual dexterity. Still, an early recognition of GMA is important in
clinical practice for various reasons: First, GMA enable a sufficiently
accurate diagnosis to be made. GMA have high prevalence and in-
cidence rates affecting the majority of mental disorders. In bipolar,
obsessive-compulsive, and neurodevelopmental disorders, GMA con-
stitute an important part of the everyday clinical practice. Subtle neu-
rological signs might even precede the development of manifest motor
symptoms and flamboyant mental disorder (Hirjak et al., 2018a; Mittal
et al., 2010). A similar approach has been recently established in neu-
rological practice (Nonnekes et al., 2018). Second, GMA have a stig-
matizing effect on the patient and might lead to a reduction of his/her
daily activities. Early recognition and correct diagnosis provide gui-
dance on treatment and prognosis of the individual case. The assess-
ment of a psychiatric patients experiencing GMA should include the
following steps: (1) medical history; (2) physical examination (incl.
ECG, EEG, magnetic resonance imaging (MRI), cerebrospinal fluid
(CSF) analysis, etc.); (3) presumptive diagnosis; (4) differential diag-
nosis (neurological, psychogenic or medication-induced); (5) in-
vestigative procedures such as clinical rating scales and instrumental
assessments (eventually video recordings); (6) final diagnosis; and (7)
treatment/management of GMA in consideration of their underlying
disorder. It should be emphasized that clinicians should ask themselves
whether the observed GMA are truly genuine and what is the under-
lying psychiatric syndrome or disease? It might have serious adverse
consequences if disorders of movement associated with drugs (anti-
psychotic-induced pseudoparkinsonism, neuroleptic malignant syn-
drome, lithium-induced movement disorders, antidepressant-induced
myoclonus, etc.), neurologic (e.g. acute encephalitis, Wilson’s,
316
Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
Huntington’s or Parkinson’s disease, normal pressure hydrocephalus,
etc.) and/or psychogenic syndrome have been misdiagnosed. In the last
decades, several classifications of GMA have been published based on
clinical observation, rating scales, and instrumental assessments (Hirjak
et al., 2017b; van Harten et al., 2017; Willems et al., 2016). Although
GMA in mental disorders have been described in the early German
psychiatric literature by Karl Wernicke, Karl Kleist, Emil Kreapelin,
Eugen Bleuler, Karl Kahlbaum, and Karl Leonhard, it was not until mid-
90 s that computer tomography (CT) or MRI studies were undertaken in
order to investigate their neurobiological underpinnings. Indeed, most
of the brain regions suspected in the early scientific studies (case re-
ports, post-mortem studies, neurodegenerative disorders) have been
confirmed by modern neuroimaging (Hirjak et al., 2017a, a). To date,
we can not only benefit from the experience gained by earlier authors,
but we should also use this unique opportunity and promote develop-
ments in this area so that patients could receive individualized therapy
based on reliable, motor-system based biomarkers in the future.
1.3. Neuroscience research on genuine motor abnormalities
In the past few years, there have been exciting advances in neu-
roscience research on GMA such as NSS, abnormal involuntary move-
ments (AIMS), and catatonic symptoms in schizophrenia (Hirjak et al.,
2015a, c; Walther, 2015; Walther and Strik, 2012; Bernard and Mittal,
2015). Although historically neglected, one of the most consistent
findings in research on GMA is their high prevalence in antipsychotic-
naive first-episode schizophrenia patients (Peralta et al., 2010, 2013).
Substantial knowledge about underlying mechanisms of GMA in schi-
zophrenia populations comes from structural and functional MRI stu-
dies (for review see (Hirjak et al., 2015a, a)). Recent evidence suggests
that GMA gradually intensifies within a continuum ranging from
healthy persons exhibiting rather low degrees of NSS, to first-degree
relatives of schizophrenia patients experiencing various degrees of NSS,
to persons at ultra-high risk (UHR) for psychosis experiencing moderate
NSS or subtle AIMS and finally to schizophrenia patients presenting
with severe AIMS or catatonic symptoms (Hirjak et al., 2015a; Dazzan
and Murray, 2002). Whereas dysfunction of basal ganglia circuits is
responsible for motor excitation/inhibition leading to AIMS, the cere-
bello-thalamo-cortical circuit is crucial for motor timing and sensor-
imotor dynamics which might be disordered in schizophrenia or other
psychotic disorders patients exhibiting NSS or catatonic symptoms
(Bernard and Mittal, 2014). These findings have strengthened our un-
derstanding of how motor dysfunction mediates behavior and cognition
in schizophrenia patients. Very recently, motor system dysfunction has
been promoted as an essential addendum to the Research Domain
Criteria (RDoC) framework (Mittal et al., 2017; Bernard and Mittal,
2015).
Most likely for historical reasons, the majority of GMA studies so far
have been restricted to schizophrenia patients (Hirjak et al., 2015a, c;
Walther, 2015; Walther and Strik, 2012; Bernard and Mittal, 2015). As
a result of this limitation, a clear delineation of a motor phenotype for
other psychiatric disorders has been lacking hitherto. Clinically, it is
evident that GMA are by no means restricted to patients with schizo-
phrenia, since they constitute a substantial transdiagnostic problem, at
least in terms of AIMS or severe catatonic symptoms (Hirjak et al.,
2016a; Wing and Shah, 2006). Because GMA are frequently found in
bipolar disorders (BD) (Chrobak et al., 2016), obsessive-compulsive
disorders (OCD) (Bihari et al., 1991), and neurodevelopmental dis-
orders (ND) with early onset such as autism-spectrum disorders (ASD)
(Dhossche, 2004, 2014; Hirjak et al., 2014), attention-deficit/hyper-
activity disorder (ADHD) (D’Agati et al., 2010) or Tourette-syndrome
(TS) (Cavanna et al., 2008b; Semerci, 2000), motor dysfunction is likely
one of the proximal causes contributing to various pathophysiological
pathways and symptom expressions throughout several psychiatric
disorders. Eventually, motor system dysfunction can be considered as
an objective marker of early neurodevelopmental deviance. Although
D. Hirjak et al. Neuroscience and Biobehavioral Reviews 95 (2018) 315–335

GMA are transnosologic phenomena, very few neuroimaging studies of multiple publications, the most up to-date or comprehensive in-
have attempted to characterize motor circuits in terms of structure and formation was used. Articles considered of interest were reviewed and
function in mental disorders other than schizophrenia. More recently, cross-checked independently by two authors (DH and KMK). In this
Mittal and colleagues (Mittal et al., 2017) outlined an RDoC-based systematic review, we integrate the wealth of reported neuroimaging
perspective in psychotic disorders that essentially includes basal findings to provide a unified model of motor dysfunction across dif-
ganglia, cerebello-thalamo-cortical, cortico-motor and psychomotor ferent psychiatric disorders. In the discussion we have chosen a similar
circuits dysfunction. The authors emphasized the benefits of in- approach that has been used previously in reviews on psychiatric dis-
vestigating the motor system domain to better understand psychotic orders (Baum et al., 2015; Ewers et al., 2011; Naismith et al., 2012;
disorders. Hirjak et al., 2018a) to minimize differences between studies and to
The goals of this systematic review are fourfold: First, we system- remain focused on the main goal of this review.
atically review the current literature on GMA-associated neuroanato-
mical correlates in BD, OCD, ASD, ADHD, and TS to provide a com-
3. Results
prehensive picture of transnosologic evidence for motor system
dsyfunction. Second, we aim at characterizing common and converging
We conducted a systematic literature search using the above men-
pathogenetic pathways underlying GMA in BD, OCD, ASD, ADHD, and
tioned search criteria and identified a high number of very hetero-
TS. Third, based on the extant data, we discuss eminent theoretical,
geneous studies (neuroimaging and psychophysiological results in a
clinical, and methodological questions for future research that aims at
format not sufficiently comparable with other studies). The systematic
delineating a novel intermediate phenotype of psychiatric disorders
literature search under the above mentioned terms resulted in a total of
based on motor dysfunction. Conclusions drawn from this innovative
7429 articles. After reviewing the titles and abstracts, a total of 7010
approach may improve the development of novel diagnostic categories
references were excluded from the analysis (e.g. case reports (< 3
based on neurobiologically reliable parameters. Finally, we discuss how
subjects), EEG studies, clinical studies examining medication effects,
motor system dysfunction might contribute to the development of novel
unclear setting or clinical rating scale, etc.). We excluded studies in-
psychopharmacological models and to the identification of novel target
vestigating broader aspects of the motor domain, such as those in-
structures for non-invasive brain stimulation.
vestigating perception of movement and movement observation. But,
we also included studies without healthy controls for the sake of the
2. Search strategy and study selection
descriptive data they provide. Further, we also report on MRI studies
specifically examining the inhibitory control (response inhibition)
The search strategy and study selection followed PRISMA guide-
across BD, OCD, and ND, as this is also an important aspect of the motor
lines. The literature was searched using MEDLINE (source PubMed,
domain. In general, the identified neuroimaging and behavioral studies
January 1, 1960 to July 15th, 2018), EMBASE (January 1, 1960 to July
have used different acquisition, processing and analysis modalities and
15th, 2018), and Google Scholar databases, and by additional hand
methods to observe different aspects of the disease process. While the
searches through reference lists and specialist psychiatric and neu-
diversity of identified studies prevented us to perform a meta-analysis,
roscience journals. The main goal was to identify putative studies re-
we performed a systematic review of 231 studies on GMA that have
porting the associations between GMA levels and brain structure or
been identified and approved by two authors (DH and KMK). The in-
function in BD, OCD, ASD, ADHD, and TS patients and their unaffected
dividual GMA categories and their prevalences are listed in Table 1.
first-degree relatives (parents, siblings, twins or offspring). Clinical
We identified 55 studies on GMA, motor impulsivity and inhibitory
trials investigating medication effects in BD, OCD, ASD, ADHD, and TS
control in BD (Bas et al., 2015; Chrobak et al., 2016; Goswami et al.,
patients, behavioural or MRI studies investigating patients with schi-
1998, 2007; Goswami et al., 2006; Minichino et al., 2015; Mrad et al.,
zophrenia, schizoaffective disorders and studies focusing on drug-in-
2016; Negash et al., 2004; Owoeye et al., 2013; Rigucci et al., 2014;
duced movement disorders (e.g. tardive dyskinesia, drug-induced par-
Sagheer et al., 2018; Sharma et al., 2016; Udal et al., 2009; Whitty
kinsonism or acute extrapyramidal-motor symptoms) were not included
et al., 2006; Zhao et al., 2013b; Mukherjee et al., 1984; Scappa et al.,
in the review. The following search terms were used: “neurological soft
1993; Mazzarini et al., 2010; Medda et al., 2015a; Nivoli et al., 2014;
signs”, “neurological signs”, “neurological hard signs”, “NSS”, “discrete
signs”, “subtle neurological deficits”, “abnormal involuntary move-
Table 1
ments”, “catatonia”, “catatonic symptoms”, “motor symptoms”, “bi- Prevalence of genuine motor abnormalities across BPD, OCD, ASD, ADHD and
polar disorders”, “mania”, “depression”, “obsessive compulsive dis- TS.
order”, “trichotillomania”,” autism”, “autism-spectrum disorder”,
Mental Disorder GMA category Number of studies GMA prevalance
“ADHD”, “Tourette-Syndrome”, “first-degree relatives”, “healthy con-
trols”, “MRI”, “neuroimaging”, “first-degree relatives”, “imaging ge- BD NSS 17 ca. 64%
netics”, “genetic polymorphism”, “phenotype”, and “genotype”. The AIMS 3 7-14%
automatic search was complemented by a manual check of the re- catatonic symptoms 5 11-61%
OCD NSS 27 n.a.
ference lists of the papers and relevant review articles identified by the
AIMS 2 ca. 58%
computerized literature search. We also searched for articles published catatonic symptoms 1 ca. 83%
in any language and scrutinized references from these studies to iden- ASD NSS 7 74-100%
tify other relevant studies. There were no language restrictions with AIMS 3 18-25%
respect to publication date, or country of origin, although the majority catatonic symptoms 4 4–17%
ADHD NSS 11 7–84%
of ultimately extracted articles were in English. Unpublished studies, AIMS 0 n.a.
conference abstracts or poster presentations were not included in this catatonic symptoms 0 n.a.
review. We imposed the following methodological restrictions for the TS NSS 1 ca. 57.5%
inclusion criteria: (a) Studies or relevant case studies (> 3 subjects) AIMS 1 n.a.
catatonic symptoms 1 ca. 87.5%
with and without MRI that investigated GMA (NSS, AIMS and catatonic
symptoms) in BD, OCD, and ND patients; (b) MRI studies that in- Abbreviations: BD bipolar disorders; OCD obsessive compulsive disorders; ASD
vestigated motor impulsivity and inhibitory control in BD, OCD, and autism spectrum disorders; ADHD attention/deficit and hyperactivity disorder;
ND patients; (c) Studies that were reported in an original article in a TST ourette syndrome; GMA genuine motor abnormalities; NSSneurological soft
peer-reviewed journal; (d) PET and SPECT studies on GMA (NSS, AIMS signs; AIMSabnormal involuntary movements. We have used the studies with
and catatonic symptoms) in the above-mentioned populations. In case the lowest and highest prevalence rates of GMA as a reference range for Table 1.

317
D. Hirjak et al.
Fein and McGrath, 1990; Perugi et al., 2017; Gupta et al., 2007; Lage
et al., 2013; Bauer et al., 2017; Fleck et al., 2011; Fortgang et al., 2016;
Gilbert et al., 2011; Henry et al., 2013; Hidiroglu et al., 2013; Izci et al.,
2016; Karakus and Tamam, 2011; Leibenluft et al., 2007; Lijffijt et al.,
2015; Lombardo et al., 2012; Mahon et al., 2012; Mathias de Almeida
et al., 2013; Matsuo et al., 2009, 2010; Nandagopal et al., 2011; Nery
et al., 2013; Passarotti et al., 2010; Ponsoni et al., 2018; Rote et al.,
2018; Saunders et al., 2016; Swann et al., 2008; Fears et al., 2015;
Ramirez-Bermudez et al., 2016; Ajilore et al., 2015; Altshuler et al.,
2005; Diler et al., 2014; Elvsashagen et al., 2013; Poldrack et al., 2016;
Singh et al., 2010; Strakowski et al., 2008), 45 studies on GMA in OCD
(Anderson and Savage, 2004; Aylward et al., 1996; Bolton et al., 1998,
2000; Caramelli et al., 1996; Dhuri and Parkar, 2016; Focseneanu et al.,
2015; Guz and Aygun, 2004; Hollander et al., 2005, 1990; Karadag
et al., 2011; Malhotra et al., 2017; Mataix-Cols et al., 2003; Mergl and
Hegerl, 2005; Nickoloff et al., 1991; Ozcan et al., 2016; Peng et al.,
2012; Poyurovsky et al., 2007; Sevincok et al., 2006, 2004; Stein et al.,
1997, 1993; Stein et al., 1994; Tapanci et al., 2018; Thienemann and
Koran, 1995; Towey et al., 1993; Tripathi et al., 2015; Tumkaya et al.,
2012; Kruger et al., 2000; Lim, 2006; Benatti et al., 2014; Bersani et al.,
2013; Blaszczynski, 1999; Chamberlain et al., 2006, 2007; Melca et al.,
2015; Mersin Kilic et al., 2016; Voon et al., 2017; Blum et al., 2018;
Carlisi et al., 2017; Heinzel et al., 2018; Menzies et al., 2007; Bari and
Robbins, 2013a; de Wit et al., 2012; Fan et al., 2017), 23 studies on
GMA, motor impulsivity and inhibitory control in ASD (Hirjak et al.,
2014, 2016b; Mayoral et al., 2010; Tani et al., 2006; Breen and Hare,
2017; Ohta et al., 2006; Stoppelbein et al., 2005; Wing and Shah, 2006;
Floris et al., 2016; Travers et al., 2015b, 2013; Gulsrud et al., 2018;
Papadopoulos et al., 2013; Morrison et al., 2018; De Jong et al., 2011;
Brasic et al., 2000; Fink et al., 2006; Halayem et al., 2009; Carlisi et al.,
2017; Daly et al., 2014; Karten and Hirsch, 2015; Duerden et al., 2013;
Kenet et al., 2012), 85 studies on GMA, motor impulsivity and in-
hibitory control in ADHD (Abdel Aziza et al., 2016; Bari and Robbins,
2013b; Brossard-Racine et al., 2012; Cardo et al., 2008; Cavanna et al.,
2008a; Chan et al., 2010; Chiang et al., 2017; Crosbie and Schachar,
2001; Cubillo et al., 2010; Curatolo et al., 2010; Czerniak et al., 2013;
D’Agati et al., 2010; Depue et al., 2010; Di Tommaso, 2012; Dibbets
et al., 2009; Dillo et al., 2010; Edebol et al., 2013; Fan et al., 2014; Feng
et al., 2005; Ferrin and Vance, 2012; Fontenelle and Mendlowicz, 2008;
Freeman and Tourette Syndrome International Database, 2007; Gong
et al., 2015; Goulardins et al., 2017; Gustafsson et al., 2000; Hart et al.,
2014; Hovik et al., 2017; Huisman-van Dijk et al., 2016; Janssen et al.,
2015a; Kaneko et al., 2016; Klimkeit et al., 2005; Kofman et al., 2008;
Krain and Castellanos, 2006; Lei et al., 2015; Liotti et al., 2005; Lipkin
et al., 2003; Lisdahl et al., 2016; Liu et al., 2017; Lo-Castro et al., 2011;
Mahajan et al., 2016; Mahone, 2012; Mahone et al., 2006; Makris et al.,
2008; Mao et al., 2014; Mersin Kilic et al., 2016; Miguel et al., 2016;
Morein-Zamir et al., 2014; Newman et al., 2016; Niedermeyer, 2001;
Niedermeyer and Naidu, 1997; O’halloran et al., 2017; Pan et al., 2009;
Papadopoulos et al., 2013; Passarotti et al., 2010; Patankar et al., 2012;
Pitcher et al., 2002; Pitzianti et al., 2016b, a; Pitzianti et al., 2017;
Poblano et al., 2014; Qiu et al., 2009; Rickson, 2006; Roessner et al.,
2007; Rubia et al., 1999, 2005; Sagvolden et al., 2005; Schachar et al.,
2005; Schneider et al., 2006; Shaw et al., 2011; Sheppard et al., 2000;
Shilon et al., 2012; Slaats-Willemse et al., 2005; Smith et al., 2006;
Stray et al., 2010; Suskauer et al., 2008a, b; Szekely et al., 2017; Tuisku
et al., 2003; Udal et al., 2009; Uslu et al., 2007; van Rooij et al., 2015;
Wodka et al., 2007; Wu et al., 2014b; Yurtbasi et al., 2018; Ziereis and
Jansen, 2016) and 22 studies on GMA, motor impulsivity and inhibitory
control in TS (Semerci, 2000; Cavanna et al., 2008b; Kerbeshian et al.,
2009; Janik et al., 2007; Kompoliti and Goetz, 1998; Comings and
Comings, 1987; Frank et al., 2011; Laverdure et al., 2013; Draper et al.,
2015; Eddy et al., 2014; Eichele et al., 2010; Ganos et al., 2014; Heise
et al., 2010; Hovik et al., 2017; Johannes et al., 2001, 2003; Jung et al.,
2013; Mahone et al., 2018; Orth et al., 2005; Ozonoff et al., 1998; Wylie
et al., 2013; Plessen et al., 2007). We acknowledge the possibility that
318
Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
we were not able to identify all relevant studies on GMA in BD, OCD,
and ND because the information regarding GMA, motor impulsivity and
inhibitory control in the abstract was missing.
4. Summary of current findings and discussion of evidence
4.1. Bipolar disorders (BD)
The core behavioral features of BD include hyperactivity, reckless
actions, impulsivity and agitation within the manic episode, as well as
physical and mental sluggishness, akinesia, volitional inhibition, and
decreased activity levels within the depressive phase of illness.
Regarding GMA, BD patients show significantly higher NSS scores
(prevalence ca. 64%) than healthy persons (Peralta and Cuesta, 2017;
Nasrallah et al., 1983). In line with previous significant observations,
recent studies found that BD and schizophrenia patients did not differ in
NSS total and subscales scores (Chrobak et al., 2016; Zhao et al., 2013b;
Negash et al., 2004; Whitty et al., 2006). Interestingly, non-affected
FDR of BD patients and healthy controls did not show significant NSS
performance differences (Sharma et al., 2016). More recently, Su-
granyes and colleagues (Sugranyes et al., 2017) investigated whether
neurodevelopmental factors such as NSS are able to discriminate be-
tween young offsprings of schizophrenia and BD patients. The authors
concluded that both are characterized by a neurodevelopmental insult
in terms of NSS (Sugranyes et al., 2017). According to an earlier study,
prevalence rates of AIMS were ranging between 7.1% and 14.3% de-
pending on the body area (Fenton et al., 1997). In contrast, the pre-
valence rates of catatonic phenomena in BD are much higher ranging
between 11% and 61% (Braunig et al., 1998; Kruger et al., 2003; Taylor
and Abrams, 1977; Kruger and Braunig, 2000). Still, prevalence of
catatonia is almost equivalent in BD and schizophrenia patients,
strongly supporting the notion of common pathomechanisms (Grover
et al., 2015).
In line with epidemiological findings that NSS are also linked to BD,
i.e. they are not specific to schizophrenia. Correspondingly, few whole-
brain neuroimaging studies showed a significant relationship between
NSS disinhibition item and vulnerability to impulsive responding in
terms of go/no-go task (failed motor inhibition) and activation changes
in the frontal gyrus, the temporal gyrus, the precuneus, and the anterior
as well as the posterior cingulate gyrus in patients with BD (Kaladjian
et al., 2009a,b; Mazzola-Pomietto et al., 2009; Fleck et al., 2011;
Townsend et al., 2012; Liberg et al., 2013a,b; Weathers et al., 2012).
However, it is unclear how neural activity that is captured by the go/
no-go task can be distinctly related to various sensorimotor NSS sub-
processes (Zhao et al., 2013a).
In the 1970s and 1980s, Beigel and Murphy (Beigel and Murphy,
1971) as well as Himmelhoch and colleagues (Detre et al., 1972;
Himmelhoch et al., 1972; Kupfer et al., 1972) investigated volitional
inhibition and motor retardation in depressed phase of BD (70% in
bipolar I and 90% in bipolar II patients). Comparing volitional inhibi-
tion of bipolar depression with akinesia of Parkinson’s disease, the
authors suggested a close relationship between both symptoms do-
mains, which they found to be essentially characterized by decrease in
instrumental behavior (Detre et al., 1972; Himmelhoch et al., 1972;
Kupfer et al., 1972). Further investigations revealed other important
parallels between BD and Parkinson’s disease related to motor and
behavioral symptoms. For example, switch periods, rapid cycling or
mixed states in BD and „on-off“ phenomena in Parkinson’s disease
(Fabbrini et al., 1988; Mouradian et al., 1988) are clinically very si-
milar. Keshavan and colleagues (Keshavan et al., 1986) were among the
first, who have described a patient with idiopathic Parkinson’s disease
where the „on“-phase (dyskinesia) coincided with the manic state and
the „off“-phase (akinesia) was associated with depressive symptoms.
These early observations are in agreement with the paradoxical effect of
lithium on antipsychotic-induced Parkinsonism and tardive dyskinesia
(TD) (van Harten et al., 2008; Gallager et al., 1978; Pert et al., 1978).
D. Hirjak et al.
Long-lasting blockade of the postsynaptic dopamine receptors by anti-
psychotic medication leads to dopamine-receptor hypersensitivity and
cholinergic hypofunction, both mechanisms that might cause TD
(Klawans and Rubovits, 1972; Rubovits and Klawans, 1972). Following
preliminary reports, lithium has neuroprotective and neurotrophic ef-
fects mediated by upregulation of bcl-2 (B-cell lymphoma/leukemia 2
gene) levels, inhibition of glycogen synthase kinase 3ß (GSK-3ß), and
increase in brain tissue volume (van Harten et al., 2008; Manji et al.,
1999, 2000; Moore et al., 2000a, b). These results suggest a potential
protective effect of lithium therapy on TD in some schizophrenia pa-
tients treated with antipsychotics (van Harten et al., 2008). Taken to-
gether, the above-mentioned studies once again support the hypothesis
that dysfunction of similar motor circuits closely tied to excitatory/in-
hibitory pathways within the basal ganglia circuits (e.g. motor cortex,
thalamus, subthalamic nuclei, putamen, globus pallidus) might be re-
lated to either BD, spontaneous Parkinsonism, or TD. However, there
are not yet unifying theories of pathogenic and pathophysiological
mechanisms involved in motor symptoms of both disorders mainly due
to the lack of MRI studies in patients’ populations.
Of particular interest are previous studies and case reports de-
scribing catatonic features in BD (Greenberg et al., 2014; Medda et al.,
2015a, b; Lin et al., 2016; Perugi et al., 2017). Although there are no
neuroimaging studies investigating catatonic phenomena in BD pa-
tients, these findings are in close agreement with medial prefrontal-
motor cortico-cortical circuit (MPMCCC) deficits. This neurobiological
model suggests a strong neurobiological link between emotional pro-
cessing (Phan et al., 2004) and bodily movements, accurately mapping
typical catatonic and BD symptoms such as abnormal emotional in-
tensity and hypo- or hyperkinetic movements (Northoff et al., 2004;
Fink et al., 2016). Future research on cortico-motor circuits such as
MPMCCC in BD could more accurately parse out distinct neural pa-
thomechanisms, which in turn could inform tailored pharmacother-
apeutic strategies (Berrettini, 2000; Buckholtz and Meyer-Lindenberg,
2012). Bearing in mind that we did not identify any resting-state fMRI
studies investigating GMA-related neural correlates in BDP patients or
their FDR, BD patients shows a strong overlap of clinical motor phe-
notypes and alterations in neurocognition, psychophysiology, and
neurocircuitry with schizophrenia (Rimol et al., 2010). The overlap of
clinical features is especially prominent for the acute phase of schizo-
phrenia and BD.
4.2. Obsessive-compulsive disorder (OCD)
OCD is a debilitating disorder that is characterized by automated,
repetitive, and uncontrollable, and time-consuming reoccurring
thoughts (obsessions), and behaviors (compulsions). The patients feel
the urge to repeat these habit behaviors and experience serious pro-
blems to resist. Recent evidence suggests that OCD patients experience
certain GMA such as NSS, AIMS or catatonic phenomena (Hermesh
et al., 1989; Fontenelle et al., 2007; Fontenelle and Mendlowicz, 2008;
Jaafari et al., 2013; Kruger et al., 2000). In particular, the majority of
hitherto studies found a higher prevalence of NSS in OCD patients than
in healthy controls (Bihari et al., 1991; Hollander et al., 2005;
Poyurovsky et al., 2007; Tapanci et al., 2017). Detailed examination of
this evidence was presented within a recent meta-analysis that included
15 studies (combined 498 patients and 520 controls) and showed large
effect sizes (Hedges' g = 1.27, 95% confidence interval 0.80–1.75),
confirming previous suggestion of increased NSS in OCD patients
(Jaafari et al., 2013). Interestingly, a distinct pattern of NSS expression
is found in OCD, i.e. NSS related to motor coordination and sensory
integration, along with the occurrence of primitive reflexes (Hollander
et al., 2005). Besides NSS, one-third of OCD patients also experience
AIMS such as dyskinesia, tics, and spontaneous Parkinsonism (Bolton
et al., 1998; Jaafari et al., 2011; Hollander et al., 1990; Pasquini et al.,
2010). Krüger and colleagues (Kruger et al., 2000) examined both AIMS
and catatonic symptom in schizophrenia and OCD patients. The authors
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found high prevalence of AIMS (58%) and catatonia (83%) in OCD.
Interestingly, OCD patients exhibiting higher spontaneous Parkin-
sonism scores showed lower IQ, poorer cognition performance, and
more severe compulsions than patients without spontaneous Parkin-
sonism (Pasquini et al., 2010). To date, only one study investigated
catatonic phenomena in OCD (Bolton et al., 1998). OCD patients
showed lower catatonia scores than schizophrenia patients, but higher
scores than healthy persons (Bolton et al., 1998).
In the last two decades, refined models on OCD etiology and related
sensorimotor dysfunction have been suggested (Grant et al., 2016).
With regard to the neurobiological mechanism of GMA, several studies
reported that aberrant response inhibition is associated with hyper-
activity of circuits linking basal ganglia, thalamus, supplementary
motor, and premotor areas (de Wit et al., 2012; Rapoport and Wise,
1988). These findings suggest putative neurostimulation targets, e.g. for
transcranial magnetic stimulation (TMS) including theta burst stimu-
lation and deep brain stimulation (Wu et al., 2014a; Grant et al., 2016).
More recently, Vaghi and colleagues (Vaghi et al., 2017) found ab-
normal functional connectivity within fronto-striatal networks in pa-
tients with obsessive-compulsive disorder exhibiting deficits in goal-
directed behavior. Importantly, these regions are critically involved in a
dysfunction of sensorimotor integration leading to the release of motor
compulsion (Russo et al., 2014). Remarkably, Friedman and colleagues
(Friedman et al., 2017) showed dorsal anterior cingulate cortex (dACC)
hypermodulation of the putamen in OCD patients during a simple uni-
manual visuo-motor task and suggested a dysfunctional network in-
teraction between dACC and extended motor regions underlying this
disorder. Nevertheless, although aberrant response inhibition may in-
form and shape neurobiological models of OCD, it is unclear so far to
what extent such deficit may be driven by primary motor system dys-
function in contrast to other higher-order processes. Thus, direct evi-
dence on neural substrates underlying GMA (such as NSS or AIMS) in
OCD is needed to broaden a model that essentially relies on interactions
between networks subserving sensorimotor integration and response
inhibition, respectively.
4.3. Autism-spectrum disorders (ASD)
ASD are highly heritable, phenotypically heterogeneous, and severe
neurodevelopmental disorders with an onset in early childhood. ASD
are complex disorders, with difficulties in communicating and inter-
acting with others, and repetitive/stereotype behaviors. In some pa-
tients, stereotype behaviors and sensorimotor difficulties are the most
prominent symptoms that can seriously impact social and occupational
functioning. Sensorimotor deficits in ASD include NSS, AIMS, repetitive
and/or stereotyped patterns of behavior, clumsy gait, poor muscle tone,
imbalance, and impairment of motor skills, respectively (Mostofsky
et al., 2006; Muller et al., 2001; Hirjak et al., 2014). NSS levels in ASD
are similar to those observed in schizophrenia (Hirjak et al., 2014; Tani
et al., 2006). De Jong and colleagues (De Jong et al., 2011) showed that
74% of children with ASD show minor neurological dysfunction com-
pared to 6% of healthy controls. The prevalence rates of AIMS (in-
cluding spontaneous Parkinsonism) in ASD are between 18% and 25%
(Starkstein et al., 2015; Campbell et al., 1990). The prevalence of
catatonic symptoms in ASD adolescents and adults is estimated with
4–17% (Dhossche, 2004, 2014; Dhossche et al., 2010; Shorter and
Wachtel, 2013). Given that these symptoms are variously described in
the literature, with considerable overlap, it is often difficult to establish
a clear-cut qualitative distinction. So far, the majority of neuroimaging
studies in ASD used task-based fMRI to study GMA or aberrant response
inhibition in this population. These studies have yielded a great amount
of promising findings in terms of brain alterations within both cortical
and subcortical sensorimotor circuits. Within the sensorimotor network,
the following regions have been found to exhibit abnormal neural ac-
tivity in ASD: medial frontal, calcarine, and middle temporal gyrus
(Sharer et al., 2015), sensorimotor cortex, thalamus, primary motor
D. Hirjak et al.
cortex (M1) (Mostofsky et al., 2007), supplementary motor area (SMA),
precuneus (Travers et al., 2015b), cingulate cortex (Sharer et al., 2015),
basal ganglia (Qiu et al., 2010), cerebellum (Hannant et al., 2016a, b;
Hanaie et al., 2013; Fatemi et al., 2012), and brainstem (Travers et al.,
2015a). Previous findings at least partially support the hypothesis of
abnormal neural activity at rest and inability to engage in typical
resting thoughts, eventually leading to aberrant top-down regulation of
behavior in ASD (Kennedy et al., 2006; Cerliani et al., 2015; Mostert-
Kerckhoffs et al., 2015). Of note, structural alterations of two brain
regions namely striatum and corpus callosum are the most consistent
neuroanatomical findings in ASD. Abnormalities of the striatum are
associated with repetitive and stereotyped behavior and, hence they are
related to dopamine-3-receptor gene (DRD3) polymorphism (Staal,
2015; Staal et al., 2015, 2012), pointing towards a pharmacological
target when treating motor symptoms in ASD. The latter suggests an
aberrant interhemispheric connectivity closely related to abnormalities
in sensory and motor processing (Fingher et al., 2017; Frazier and
Hardan, 2009). Although MRI studies using DTI tractography did not
confirm associations between corpus callosum and motor deficits as
defined by Movement Assessment Battery for Children 2 (M-ABC 2)
(Henderson et al., 2007) in ASD (Hanaie et al., 2014; Mengotti et al.,
2011), there are only few studies that explicitly investigated NSS in this
particular population (Hirjak et al., 2016b; Tani et al., 2006). Hirjak
and colleagues (Hirjak et al., 2016b) found that higher NSS were as-
sociated with increased cortical thickness in the precentral and middle
frontal gyrus. The authors concluded that schizophrenia patients and
ASD adults share disorder-specific structural cortex variations under-
lying NSS (Hirjak et al., 2016b).
With respect to AIMS and catatonic symptoms, we are aware of very
few controlled studies and case reports describing these motor domains
in ASD (Shorter and Wachtel, 2013; Costanzo et al., 2015; Mazzone
et al., 2014; Ishitobi et al., 2014). According to Ishitobi (Ishitobi et al.,
2014), basal ganglia alterations in terms of idiopathic basal ganglia
calcification might represent a vulnerability factor for developing a
mood disorder in ASD presenting with catatonic phenomena. In line
with this observation, earlier studies pointed to a strong genetic link
between ASD, BD and early onset schizophrenia, suggesting common
pathomechanisms (Chagnon, 2006; DeLong, 2004; Dhossche, 2004).
Although both motor features are suggestive of distinct neuroanato-
mical underpinnings, we did not identify any MRI, PET or SPECT stu-
dies investigating catatonic phenomena or AIMS in ASD individuals.
Taken together, to the extent that particular GMA in ASD individuals
are similar to those previously reported in other psychiatric disorders
(Huisman-van Dijk et al., 2016), the current evidence supports the
existence of an overlap of clinical and brain morphological overlap,
possibly involving motor control and planning functions specifically
subserved by basal ganglia and cerebellar-subcortical circuits. How-
ever, the current evidence generally lacks such a translational analysis
of clinically related psychiatric disorders, yet it is important for our
understanding of the etiology and etiopathogenesis of GMA.
4.4. Attention deficit and hyperactivity disorder (ADHD)
Another severe cognitive/behavioral neurodevelopmental disorder
with an onset in early childhood is ADHD. ADHD is characterized by
impairments of motor behavior including hyperactivity, impulsivity,
and behavioral distractibility, respectively (Mostofsky et al., 2006;
Muller et al., 2001). ADHD affects about 8–12% children, but falls with
age. However, about half of the children feature the characteristic
symptoms during adulthood leading to enormous individual suffering
and financial burden on patients and on society (Fontenelle and
Mendlowicz, 2008). Hyperkinetic symptoms are a core symptom of the
disorder and abnormal motor impulsivity levels have been robustly
documented in ADHD (Rubia et al., 2009; Goulardins et al., 2017). Yet
very surprising, in the last two decades few studies have examined GMA
such as NSS and overflow movements in ADHD (Pitzianti et al., 2016b;
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Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
D’Agati et al., 2010; Kaneko et al., 2016; Dickstein et al., 2005). The
prevalence of NSS in ADHD is estimated with 7–84% depending on the
mean age of the study population (Patankar et al., 2012; Pitzianti et al.,
2016b; Abdel Aziza et al., 2016; Hadders-Algra, 2003; Karande et al.,
2007). Older children show lower NSS scores than younger children,
possibly due to advanced structural and functional brain development
and maturation during puberty (Abdel Aziza et al., 2016). Although we
could not identify any studies on genuine AIMS or catatonic symptoms
in ADHD, there are a large number of case reports and studies on an-
tipsychotics-associated motor disorders, especially after taking me-
thylphenidate and risperidone (Lipkin et al., 2003, 1994). This is an
important and clinically relevant fact that the clinicians should be
aware of (Spiller et al., 2013).
Among the first studies on movement disorders in ADHD, Dickstein
and colleagues (Dickstein et al., 2005) found that children with ADHD
were slower on repetitive motor response when compared to HC. These
findings are in agreement with other studies that showed aberrant re-
petitive motor response in ADHD (Rubia et al., 2010, 2005; Morein-
Zamir et al., 2014). Early functional MRI studies suggest a dysfunction
of motor and premotor areas such as the contralateral primary motor
cortex (Mostofsky et al., 2006) and pre-SMA (Suskauer et al., 2008a, b)
as important sites in the pathogenesis of overflow movements and NSS.
From a clinical point of view, NSS have been discussed to be useful
parameters to monitor the effectiveness of treatment with methylphe-
nidate in ADHD (Pitzianti et al., 2016b).
These results are partially in agreement with the majority of more
recent fMRI studies, which demonstrated aberrant functional patterns
underlying response inhibition largely characterized by smaller extent
of fMRI activation in the prefrontal cortex, the inferior frontal cortex,
the caudate nucleus, the thalamus, the primary motor cortex, the SMA,
the superior and inferior parietal lobes (IPL), the precuneus, and the
anterior as well as the posterior cingulate gyrus (Massat et al., 2016;
Shaw et al., 2016; Gaddis et al., 2015; Janssen et al., 2015a, b; Lei et al.,
2015; Hove et al., 2015; Hart et al., 2014; McLeod et al., 2014; Morein-
Zamir et al., 2014; Mulligan et al., 2014, 2011; Cubillo et al., 2010;
Rubia et al., 2010; Buderath et al., 2009; Mostofsky et al., 2006; Rubia
et al., 2005; Smith et al., 2006; Suskauer et al., 2008b; O’halloran et al.,
2017). Another important pathophysiological pathway is the nigros-
triatal dopaminergic branch, which might cause aberrant modulation of
motor and cognitive functioning and lead to NSS and impaired response
inhibition (Sagvolden et al., 2005). Impaired response inhibition has
been found to be present in family members and therefore might be
seen as an indicator of genetic vulnerability for the development of
ADHD (Schachar et al., 2005; Crosbie and Schachar, 2001). ADHD
patients are impaired at supressing overflow movements and impulsive
behavior, thus reflecting a dysfunction of basal ganglia circuits and
motor excitation/inhibition pathways as well as their neurotransmitter
interactions. Still, mechanisms of mutual interplay between motor
system dysfunction and impairment of executive functions (e.g. atten-
tional control, cognitive inhibition, inhibitory control, working
memory, and cognitive flexibility) in ADHD are not clear (Ziereis and
Jansen, 2016). Earlier studies showed that ADHD patients score lower
on motor inhibition and working memory (for a review see (Pennington
and Ozonoff, 1996). Correspondingly, more recent studies have found
that hyperactivity including impulsive behavior is closely related to
deficient visuospatial working memory in ADHD (Patros et al., 2017a,
b; Liu et al., 2017). In line with these observations, one might speculate
that executive functions deficits are primary and motor phenomena
such as hyperactivity, impulsivity, and behavioral distractibility are a
secondary response to them. The clinical picture of ADHD is conducive
to this interpretation while patients exhibiting motor phenomena such
as GMA without any cognitive deficits have not been reported yet. Al-
though these two features represent coexisting clinical dimensions, we
suggest that these two phenomena are likely to follow different neu-
robiological patterns. On one hand, deficient processes required to
perform novel or difficult goal-directed tasks have been closely linked
D. Hirjak et al.
Fig. 1. Brain regions frequently associated with genuine motor abnormalities (GMA) in psychiatric disorders including Bipolar Disorders, Obsessive Compulsive
Disorder, Autism Spectrum Disorder, Attention deficit and hyperactivity disorder and Gilles de la Tourette’s syndrome.
to alterations of the prefrontal cortex among ADHD patients (Bradshaw,
2001; Pennington and Ozonoff, 1996). On the other hand, motor
symptoms in ADHD have been closely linked to a dysfunction of fron-
tostriatal pathways. For instance, Oldenhinkel and colleagues
(Oldehinkel et al., 2016) found a putative relationship between hy-
peractivity/impulsivity and aberrant fronto-striatal connectivity in
ADHD. Current evidence suggests that there are some pathophysiolo-
gical aspects that the two dimensions share (Rigoli et al., 2012), while
being distinct in other aspects (Mahone, 2012). However, we are not
aware of neuroimaging studies simultaneously investigating both sys-
tems in ADHD patients.
4.5. Gilles de la Tourette's syndrome (TS)
TS is a hereditary, childhood-onset, neuropsychiatric disorder of
neurodevelopmental origin with an average onset between the ages of 3
and 9 years (Morand-Beaulieu et al., 2017). Patient suffering from TS
often experience repetitive, stereotyped, involuntary movements and
vocalizations, i.e. tics. Yet only 10–15% of TS patients present ex-
clusively with tics (Martino et al., 2017; Robertson et al., 2017). The
majority of TS patients suffer from comorbid disorders such as ADHD,
OCD, intermittent explosive disorder, and sexually inappropriate be-
havior (Freeman and Tourette Syndrome International Database, 2007;
Pringsheim et al., 2007; Roessner et al., 2007). It is noteworthy that
DSM-V, unlike DSM-IV or ICD-10 includes TS in the group of "neuro-
developmental disorders", thus supporting the notion of potentially
common etiopathogenetic pathways (Cravedi et al., 2017). According
to recent evidence, the prevalence rates of ADHD, intermittent ex-
plosive disorder (including explosive outbursts), and OCD range be-
tween 20% and 70% in TS patients (Freeman and Tourette Syndrome
International Database, 2007). TS and other compulsive disorders share
some clinical features, and this makes the clinical distinction between
compulsions, motor impulsivity, and complex motor tics very difficult
(Martino et al., 2017). Like OCD and ADHD patients, preliminary evi-
dence suggests that the majority of TS individuals exhibit impulsive
behavior, catatonic signs, and overflow movements such as NSS as well
(Semerci, 2000; Cavanna et al., 2008a, b). Although we do not have
exact prevalence determinations of NSS in TS, there is initial evidence
that more than half of TS patients (57.5%) exhibit higher NSS scores
than healthy individuals (Semerci, 2000). The prevalence of catatonic
symptoms according to Bush-Francis Catatonia Rating Scale might be
even higher, namely approx. 87.5% (Cavanna et al., 2008b). However,
exact prevalence rates for AIMS in TS are not yet available. Given the
high prevalence of NSS and motor tics it is not surprising that the basal
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Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
ganglia and their connections with thalamo-cortical loops are key re-
gions in the pathophysiology of TS (Morand-Beaulieu et al., 2017;
Caligiore et al., 2017). In particular, the excess of striatal dopamine
might cause disinhibition of thalamo-cortical circuits leading to hy-
peractivity in frontal (Jung et al., 2013), prefrontal (Jackson et al.,
2011), and motor (Jung et al., 2013) cortices. This model has been
supported by previous studies on deficient inhibitory controls in TS (for
meta-analysis see (Morand-Beaulieu et al., 2017). However, more re-
cently, Caligiore and colleagues (Caligiore et al., 2017) proposed an
extended computational model for the etiopathogenesis of motor tics in
TS. The authors put forward the hypothesis that the increased activity
in the subthalamic nucleus affects cerebellar activity via disynaptic
pathways involving glutamatergic pontine nuclei (Caligiore et al.,
2017). The activated cerebellum might on the other side affect the basal
ganglia and the descending motor pathways (Caligiore et al., 2017).
Both the cerebellar and basal ganglia disinhibition might, in turn, lead
to hyperactivity of cortical regions such as primary motor cortex re-
sulting in development of premonitory urges and motor tics (Caligiore
et al., 2017). Taken together, current etiopathogenetic theories of
motor tics in TS assume a dysfunction in the basal ganglia-cerebellar-
thalamo-cortical circuits. Although these regions cut across several
other GMA, we could not identify any neuroimaging studies on NSS,
AIMS other than tics, and catatonic symptoms in TS. Therefore, the
source of NSS, AIMS, and catatonic symptoms as described in few stu-
dies without neuroimaging is still very poorly understood.
4.6. Summary of neuroimaging findings
The rapidly growing body of research on neuroimaging in psy-
chiatric disorders is remarkable. This said, it is even more remarkable
that the current evidence on GMA in mental disorders other than
schizophrenia is not proportional in nature as there are only few MRI
studies that investigated motor domain in BD, OCD, ASD, ADHD, and
TS. Nevertheless, the increasing body of structural and functional
neuroimaging research studies suggest that similar motor regions and
circuits may contribute to GMA in BD, OCD, ASD, ADHD, and TS. This
review identified a highly overlapping set of the following brain re-
gions: (1) frontal lobe, (2) prefrontal cortex, (3) primary motor cortex,
(4) supplementary motor area, (5) cingulate cortex, (6) IPL, (7) basal
ganglia, (8) thalamus, and (9) cerebellum (Figs. 1 and 2).
(1) One of the most important brain region responsible for different
aspects of behavior and high-order motor control is the frontal lobe
(Tabibnia et al., 2011; Lieberman, 2007; Whelan et al., 2012;
D. Hirjak et al.
Chamberlain and Sahakian, 2007; Swann et al., 2009). Due to its
sub-regions, structural and functional abnormalities in frontal lobe
contribute to many neuropsychiatric disorders and their typical
symptoms such as GMA. The above-mentioned studies showed that
alterations in the frontal cortex may contribute to involuntary
movements in BD (Kaladjian et al., 2009a, b; Mazzola-Pomietto
et al., 2009; Fleck et al., 2011; Townsend et al., 2012). Although
there is preliminary evidence that functional abnormalities of the
inferior frontal cortex are associated with aberrant response in-
hibition in ADHD (Niedermeyer, 2001; Niedermeyer and Naidu,
1997) suggesting its role in abnormal movements, expressed NSS
and AIMS, the exact pathophysiological link between frontal cortex
and GMA in ADHD and BD is not clear yet.
(2) The prefrontal cortex is a crucial part of the frontal lobe and has
been found to be implicated in different higher-order cognitive and
executive functions (e.g. working memory, spatial attention, etc.) in
humans (Wise, 2008; Arnsten et al., 2012; Vijayraghavan et al.,
2017). Prefrontal cortices are the principal source of cortical pro-
jections into primary motor cortex (Arciniegas, 2013). According to
recent neuroimaging studies, abnormalities of the prefrontal cortex
are associated with the inability to cancel actions and inhibit
movements (Guo et al., 2018). This is in line with above-mentioned
data from MRI studies in psychiatric patients with ADHD or TS
exhibiting aberrant inhibitory control leading to overflow move-
ments (Depue, 2012; Depue et al., 2010, 2016; Rubia et al., 2010;
Caligiore et al., 2017). According to a recent meta-analysis con-
ducted by Polyanska and colleagues (Polyanska et al., 2017), the
greater patients' tic severity, the greater the functional alterations in
premotor and prefrontal regions, encompassing the SMA, premotor
cortex, and middle frontal gyrus.
(3) The primary motor cortex (M1, Brodman area 4) is crucial for the
control of localized movements in different parts of the body and
response inhibition (Li et al., 2006; Abboud et al., 2017). The
above-mentioned data suggest similar mechanisms in the patho-
genesis of involuntary movements such as NSS and AIMS in patients
with BD, ASD, and ADHD rooted in the dysfunction of the primary
motor cortex (Gaddis et al., 2015; Mostofsky et al., 2007, 2006).
(4) Another important region implicated in the pathophysiology of
GMA is the supplementary motor area (SMA, Brodman area 6). On
the one hand, SMA is responsible for planning, initiation, and an-
ticipation of bodily movements (Abboud et al., 2017). On the other
hand, (rostral) pre-SMA is crucial for initiation and updating of non-
automatized internally generated movements (Abboud et al.,
2017). There is an increasing agreement among previously
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Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
Fig. 2. Brain networks alterations associated
with genuine motor abnormalities (GMA) in
Bipolar Disorders, Obsessive Compulsive
Disorder, Autism Spectrum Disorder, Attention
deficit and hyperactivity disorder and Gilles de
la Tourette’s syndrome. Yellow-dashed areas
have been identified through neuroimaging
meta-analyses in a specific disorder but never
tested for their motor role in its pathophy-
siology (For interpretation of the references to
colour in this figure legend, the reader is re-
ferred to the web version of this article).
published fMRI studies that decreased activation in the pre-SMA
might lead to compensatory higher prefrontal activity during No/
Go events in ADHD patients (Suskauer et al., 2008a). Remarkably,
SMA has been postulated as a target region for continuous theta
burst stimulation in order to reduce motor cortical network activity
and tics in TS (Wu et al. 2014). Two recent MRI studies found si-
milar results indicating increased regional cerebral blood flow in
the SMA of patients with periodic and current catatonia (Foucher
et al., 2018; Walther et al., 2017a). Thus, further neuroimaging
studies are needed to better characterize the role of SMA in the
pathogenesis of GMA across psychiatric disorders.
(5) From a neurobiological perspective, it is very remarkable that the
mid-cingulate cortex, also referred to as the dorsal anterior cingu-
late cortex (dACC), modulates motor behavior by acting as a major
interface between sensorimotor (more posterior part involved in
skeletomotor control, body orientation and pain processing) and
cognitive networks (the anterior has a role in decision making, re-
ward, attention and conflict monitoring) (Asemi et al., 2015). Pre-
vious studies have indicated a crucial role of the network encom-
passing dACC, SMA and primary motor cortex in modulating motor
behavior (Asemi et al., 2015; Diwadkar et al., 2017). In particular,
the dACC directly modulates the SMA activity during a motor task
(Diwadkar et al., 2017). The anatomical, cytoarchitectonic, neuro-
chemical and functional diversity of the dACC is crucial for its
specific role during motor coordination of valenced and context
dependent movement (Vogt, 2016). Evidence from neuroimaging
studies has indicated that dACC is involved in the pathophysiology
of motor abnormalities in OCD, BD, and ADHD (Liotti et al., 2005;
Koyama et al., 2017; Zhang et al., 2017; McGovern and Sheth,
2017; Weathers et al., 2012). However, not all findings have been
consistent across these disorders, with some data showing altered
activation of the posterior cingulate cortex during motor impair-
ment in BD (Liberg et al., 2013a, b). Furthermore, recent studies in
schizophrenia have indicated that dACC has reduced functional
connectivity with the SMA (Wang et al., 2015). Interestingly, the
cerebral blood flow/global functional connectivity ratio in dACC,
an index measuring the relationship between perfusion and neural
activity, is reduced in these patients, thus suggesting altered neu-
rovascular coupling (Zhu et al., 2017). Unfortunately, these studies
were carried out only on patients with chronic schizophrenia,
mostly treated with one or more antipsychotics that can modulate
brain function and connectivity (Sambataro et al., 2010). Pre-
liminary studies suggest that antipsychotic treatment can normalize
dACC perfusion levels and the extent of this change could predict
D. Hirjak et al.
cognitive performance improvement in drug naïve patients with
schizophrenia (Pardo et al., 2011). It would be interesting, how-
ever, to extend these initial observations to longitudinal studies in
patients with FEP to ascertain motor network connectivity changes
in these patients and the effects of antipsychotic treatment. In
particular, the question whether long-term changes of resting-state
functional connectivity and structural connectivity between dACC
and motor regions such as SMA, M1 and cerebellum modulate GMA
and cognitive performance could help us to better assess social
outcomes in schizophrenia treatment.
(6) Previous neurophysiological studies consistently reported that IPL
is responsible for the immediate guidance of our bodily actions in
space (Gharabaghi et al., 2006; Karnath, 2001). In particular, IPL
has a crucial role in organization and control of visuomotor acts for
processes such as reaching in space and grasping of objects
(Karnath, 2001). In ADHD, IPL showed reduced brain activation
during inhibition tasks (Mulligan et al., 2011; Cubillo et al., 2010)
and sensorimotor timing (Valera et al., 2010). In OCD, structural
alterations of IPL have been associated with characteristic OCD
symptoms, especially the 'contamination/washing' dimension
clearly suggesting a relationship to motor behavior (van den Heuvel
et al., 2009).
(7) Other brain regions responsible for regulating motor activity and
for the programming and termination of action are the basal ganglia
(caudate nucleus, nucleus accumbens, substantia nigra, putamen
and globus pallidus) (Aron et al., 2007; Graybiel, 2005;
Chakravarthy et al., 2010). Convergent evidence shows that struc-
tural and functional alterations of the basal ganglia, especially
cortico-striato-thalamo-cortical circuits (e.g. a failure of striato-
thalamic inhibition), are involved in the pathophysiology of OCD,
ASD and TS (Singer and Minzer, 2003; Qiu et al., 2010). Other
studies have supported the importance of interactions between
basal ganglia and premotor areas, SMA and cingulate motor areas
in the pathophysiology of complex tics (Mink, 2006). This data
supports once again the idea that tics are etiologically and neu-
roanatomically heterogenous motor phenomena involving motor
and cognitive networks.
(8) The thalamus is a collection of smaller nuclei that integrate in-
formation from sensory and motor systems. In particular, somato-
sensory inputs from the thalamus to the motor cortex are crucial for
motor execution. A recent study by Cauda and colleagues (Cauda
et al., 2018) found patterns of co-alterations distribution encom-
passing inferior frontal areas, precentral gyri and thalamus among
patients with schizophrenia, ASD and OCD. This study corroborates
previous findings of thalamic alterations being associated with
motor impairment in schizophrenia (Hirjak et al., 2012), ASD
(Mostofsky et al., 2009), and OCD (Hollander et al., 2005) sug-
gesting atypical connectivity patterns between specific subcortical
regions and cortical areas.
(9) The human cerebellum is crucial for coordination, planning and
execution of movements as well as control of muscle tone and
balance. In particular, Lobules V and VI of the anterior cerebellum
have been suggested to be key regions of the fine motor and vi-
suomotor adaptation skills (Bernard and Seidler, 2013a, b; Stoodley
and Schmahmann, 2009, 2010). Previous MRI studies have shown
atypical cerebellar morphology in the pathogenesis of impaired
motor performance across different psychiatric disorders such as
ASD and OCD (Mostofsky et al., 2009; Hirjak et al., 2015b; Hannant
et al., 2016a; Fan et al., 2017; Tobe et al., 2010). Although recent
MRI studies showed that cerebellum contributes to some of the
symptoms associated with BD and ADHD (Di Tommaso, 2012;
Jenkins et al., 2016; Lee et al., 2014), the role of cerebellum in the
pathophysiology of GMA or aberrant motor behavior in these dis-
orders is not clear yet. Still, future theories will incorporate cere-
bellum as soon as the extant evidence can be translated into a
mechanism underlying aberrant motor functioning. In particular,
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Quansah and colleagues (Quansah et al., 2018) showed that the
psychostimulant methylphenidate reduces metabolites associated
with inhibitory neurotransmission, including GABA and glycine in
adolescent rats. In contrast, metabolites associated with energy
consumption and excitatory neurotransmission such as glutamate,
glutamine, N-acetyl aspartate, and inosine were increased after
acute methylphenidate treatment (Quansah et al., 2018). Similar
pharmacological effects on cerebellar metabolic factors (pH or
glucose) via T1ρ mapping has been found in BD patients under the
treatment with lithium (Johnson et al., 2015). These findings will
facilitate the development of novel psychopharmacological models
based on aberrant cerebellar structure and function in mental dis-
orders.
In conclusion, there is a strong correspondence between the above-
mentioned MRI studies that the neuroanatomical basis of GMA can be
detectable across multiple neuroimaging techniques. The currently
available evidence suggests that the pathophysiology of GMA should
not be confined to basal ganglia circuit dysfunction, but also involves
dorsolateral prefrontal, orbitofrontal, parietal, limbic, and cerebellar
circuits. In particular, patients with mental disorders show alterations
of the inferior frontal cortex, SMA, and ACC during inhibition (Hart
et al., 2013). However, the extant data elucidates only to a limited
extent the pathomechanisms of NSS and AIMS in mental disorders of
significant neurodevelopmental origin and early disease onset. While it
has long been acknowledged that motor behavior is solely modulated
by motor regions, emerging data suggest that brain regions traditionally
involved in cognition and executive functions also contribute to GMA as
a part of aberrant cerebello-thalamo-cortical, fronto-parietal, and cor-
tico-subcortical networks (Fig. 1). In line with this, the above-men-
tioned findings provide interesting insights that shed light on the in-
tersection of motor and cognitive networks in the pathogenesis of GMA.
What still eludes explanation is the complex interaction between motor
and cognitive control networks, which are sensitive to genetic influ-
ences and balance patient’s behavior. Thus, an important next step will
be to characterize the interaction between motor and cognitive net-
works in patients with GMA using parcellation protocols that provide
measures of functionally relevant fronto-parietal components (Ranta
et al., 2014), statistically derived patterns of co-alterations distribution
from multimodal neuroimaging data (Cauda et al., 2018), and dynamic
network approach (Bassett and Sporns, 2017; Betzel and Bassett, 2017),
respectively.
5. How can GMA be reliably measured in mental disorders?
In a clinical setting, but also for research purposes, there are several
ways to approach the diversity of GMA in mental disorders. First, GMA
are visible to clinicians. Experienced clinicians are able to give a clear
description of different GMA that they can observe and draw a rea-
sonable inferences from the patient's behavior. Clinicians do regularly
and carefully monitor and evaluate the severity and progress of GMA of
their patients. However, these skills require a great deal of experience
and time effort in order to differentiate one or more motor domains in
different diseases. Second, in the last decades many different motor
rating scales have been introduced into clinical practice (Bracht et al.,
2012; Northoff et al., 1999). Rating scales have achieved a high degree
of reliability in a daily clinical routine. They allow a sophisticated and
thorough assessment of all domains of motor dysfunction in psychiatric
patients. One of the main problems is that rating scales can be poten-
tially confounded by observer bias. Also, they often require substantial
clinical experience and extensive training in order to achieve high inter-
rater reliability. Furthermore, clinical rating scales are not able to de-
tect subtle motor abnormalities in the period preceding manifest GMA.
Instrumental measurements offer these benefits to clinicians and re-
searchers. In a recent review, van Harten and colleagues (van Harten
et al., 2017) presented different instrumental assessments to evaluate a
D. Hirjak et al.
broad range of different motor phenomena. Among these newer
methods are those measuring duration and speed of movement (e.g.
bradykinesia), instrumental assessment of rigidity through quantifica-
tion of displacement, actigraphy, accelerometers embedded in smart-
phones to quantify frequency and amplitude of tremor, detection of
postural sway or inertial sensors to measure bradykinesia (van Harten
et al., 2017). These assessments aids might improve the reliable ex-
amination of GMA in psychiatry. Because of the many different ways to
access GMA severity in patients, we strongly advocate that clinicians
and neuroscientists reach a consensus and take a decision on how to
enhance clarity and comparability among future studies (Hirjak et al.,
2017b). Finally, GMA might show both qualitative and quantitative
fluctuations over time, and this needs to be considered when they are
assessed in both clinical and research setting. However, the above-
mentioned studies did not specify a particular assessment time for pa-
tients experiencing GMA. To overcome these circumstances, future
studies should assess GMA on a micro- (momentary and day-to-day)
and macro-level (month and year) (Nelson et al., 2017). Such a re-
peated longitudinal assessment of GMA would appear more promising
and include a lifelike depiction of motor system parameters for re-
vealing the pathophysiological mechanisms of aberrant motor behavior
in mental disorders.
6. Future strategies for transdiagnostic studies of motor system
dysfunction
The structural and functional neuroanatomy underlying GMA in BD,
OCD, and ND very likely reflects interplay of genetic, developmental,
and environmental factors. Leads are provided by our partial under-
standing of NSS, stereotyped and repetitive behavior, hyperactivity,
and motor tics across different psychiatric disorders assuming an
overlapping cerebello-thalamo-cortical, fronto-parietal, and cortico-
subcortical motor circuit dysfunction (Peralta and Cuesta, 2017). Al-
though several important questions remain, the above-mentioned stu-
dies point towards specific areas that clearly require further attention
and consideration in future research.
First, currently available clinical rating scales for the examination of
GMA such as NSS, AIMS and catatonic symptoms show large overlaps
with regard to individual symptoms and signs. Capturing motor beha-
vior based on rigid categories does not correspond with the daily
clinical reality in which patients with various mental illnesses often
exhibit more than one symptom or sign group. Patients with mental
disorders may exhibit catatonic symptoms or AIMS in parallel to NSS.
Therefore, future studies will need to consider clinical practice and the
dimensional nature of motor behavior and dysfunction. In addition to
clinical rating scales, electronic assessments should have a broad ap-
plication in clinical neuroscience and daily routine. This methodical
approach can help to better understand motor behavior and its dy-
namics in everyday life.
Second, NSS are now established as being characteristic for BD,
OCD, and ND such as ASD and ADHD. Although we are not aware of
transdiagnostic neuroimaging studies comparing more than two above-
mentioned disorders regarding NSS-related pathomechanisms, what
becomes evident is that ADHD patients may be more vulnerable to
exhibit aberrant response inhibition than are ASD individuals. To the
extent that these findings are similar to those reported in schizophrenia
patients, the preliminary evidence suggests structural and functional
alterations in both subcortical (e.g. basal ganglia, cerebellum, and
brainstem) and cortical (prefrontal cortex, M1, and SMA) regions
clearly suggesting an overlapping mechanism underlying GMA in both
ND. Correspondingly, schizophrenia and ADHD patients have both
common and distinct motor dysfunctions during execution and inhibi-
tion of movements possibly leading to GMA. In ASD, thalamic, callosal,
parietal, and cerebellar abnormalities (Hannant et al., 2016a, b) un-
derlying sensorimotor difficulties are similar to those previously re-
ported in schizophrenia. However, not all the of the GMA-related
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Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
regions identified in ADHD or ASD studies are similar with those found
in schizophrenia per se, but, rather reflect disruption along complex
motor circuits involving fronto-parietal (e.g. frontal lobe, prefrontal
cortex, M1, and SMA) and fronto-cerebellar networks that are patho-
logically involved in these highly heritable ND with early onset. Thus, it
is not entirely surprising that some of these regions have been found
even in UHR individuals, e.g. caudate nucleus (Mittal et al., 2010),
cerebellum (Bernard et al., 2014), and fronto-parietal (Chan et al.,
2015) areas. Overall, to the extent that these findings are clinically si-
milar to those reported in schizophrenia patients, UHR individuals and
healthy adults exhibiting NSS, the preliminary evidence suggests par-
tially overlapping neurobiological mechanism, perhaps along an ana-
tomical continuum of exclusively cortical and cortico-subcortical net-
works, underlying NSS in psychiatric disorders. Future neuroimaging
studies on NSS in psychiatric disorders should use multivariate fusion
techniques that should integrate (micro)-structural within the func-
tional data analyses (Sui et al., 2012a, b). This is important since it is
unclear how disrupted brain structure translates into abnormal brain
activity. Multivariate data fusion analysis techniques essentially allow
the direct integration of multimodal data. They offer new insights into
pathophysiological mechanisms of mental disorders, such as schizo-
phrenia, BD, OCD, and ND, where fusion techniques have been suc-
cessfully applied to identify common patterns of abnormal structure
and function, as well as interdependencies between brain volume and
neural activity (Sui et al., 2015, 2014; Sui et al., 2013, 2012b).
Third, neuroimaging studies on AIMS and catatonic phenomena in
BD, OCD, and ND are underrepresented in the current scientific lit-
erature. This might be rooted in the lack of consensus regarding the
precise clinical definition of AIMS, and hence there is no standard as-
sessment scale covering all major domains of AIMS such as SP, dyski-
nesia, dystonia or akathisia. Therefore, we acknowledge a consistent
clinical delineation of AIMS in all psychiatric disorders exhibiting GMA.
Only in applying this principle can modern neuroscience succeed in
continually developing a motor assessment capturing the whole motor
and behavior domain. Research on AIMS could also benefit from ob-
jective instrumental assessments, in order to capture even more subtle
dyskinesia manifestation (van Harten et al., 2017). Furthermore, AIMS
such as orofacial dyskinesia can lead to increased head movement of
the subjects during image acquisition. Since the microstructural GMA
correlates could be very subtle, a robust motion and artifact correction
is inevitable in order to avoid biases in the derived microstructural
tissue characteristics and in order to be able to identify the effect at
interest (Hering et al., 2014a, b). Therefore, effective image-based
correction is important for higher-order models that include larger
numbers of free parameters and a generally higher sensitivity to noise.
For instance, future MRI studies should establish a motion and distor-
tion correction method that exploits a combination of multiple objec-
tives using an advanced memetic optimization scheme (Bach et al.,
2014; Krasnogor and Smith, 2005). Another serious shortcoming is the
small number of studies on catatonic symptoms in psychiatric disorders
other than schizophrenia. Future studies should not only focus on
catatonic schizophrenia, but also investigate the neurobiological origin
of motor, affective, and behavioral catatonic symptoms across BD, OCD,
and ND. This approach might determine particular brain networks
(ventral vs. dorsal circuits), which might be able to predict whether the
patients develop more motor, affective or behavioral symptoms. Fur-
ther, the investigation of catatonic symptoms across different disorders
could benefit from different microstructural parameters from the dif-
fusion-weighted images. These could include the Free-water Elimination
and Mapping (FWE (Pasternak et al., 2009)) and Neurite Orientation
Dispersion and Density Imaging (NODDI, (Zhang et al., 2012) models. The
second order symmetric tensor and its derived parameters (fractional
anisotropy, axial diffusion, and radial diffusion might also contribute to
better understand of catatonic syndrome.
Fourth, the above-mentioned results suggest that GMA are not only
manifest in schizophrenic psychoses, but they can be observed in a
D. Hirjak et al.
variety of other mental diseases such as BD, OCD, ASD, ADHD, and TS.
This results in further advantages in the context of clinical neu-
rosciences research on GMA. GMA can be conceptualized as a marker of
motor dysfunction, which manifests itself in mental disorders with a
possibly transnosologically significant neuronal deficit. Furthermore,
current discussions about the connection between GMA and cognitive
or emotional symptoms in psychotic disorders have paved the way for
further scientific approaches in the diagnosis and therapy of mental
disorders (Hirjak et al., 2018a; Mittal et al., 2017). However, unlike in
psychosis research, little is known about motor-cognition interaction in
BD, OCD, ASD, ADHD, and TS. Although there are first hints that al-
terations in GMA-associated brain regions might have an influence on
cognitive abilities in patients with BD and ADHD (Hartberg et al., 2011;
Dickstein et al., 2005; Leibenluft et al., 2007), we did not identify any
neuroimaging studies simultaneously investigating aberrant motor
system and deficient executive or emotional functioning in adult ADHD
patients. In contrast, in ASD there is strong evidence that motor dys-
function contributes to higher cognitive and social impairment
(Moseley and Pulvermuller, 2018), i.e. to key clinical features of ASD.
However, the question arising from these considerations whether
mental disorders exhibiting GMA and cognitive impairment have a
common pathophysiological mechanism anchored in the motor system
cannot be answered empirically on the basis of previous MRI studies.
Therefore, future studies may not only investigate one psychiatric dis-
ease, but several at the same time in order to better delineate neuronal
correlates of GMA in a transdiagnostic context. Furthermore, we
strongly acknowledge a detailed comparison of brain alterations un-
derlying the two systems to better delineate the origin of GMA in-
cluding motor impulsivity in ADHD. Future investigations of aberrant
fronto-striatal connectivity across different psychiatric disorders might
contribute to the development of biomarkers of impulsive behavior.
Fifth, structural and functional abnormalities within motor circuits
in above-mentioned disorders might, after years of illness, lead to
several adaptive brain mechanisms (Worbe et al., 2015) that we might
capture through multiple neuroimaging parameters such as regional
brain activity, cortical thickness, local gyrification index, fractional
anisotropy, betweenness centrality or clustering coefficients. Future
studies should combine parameters from more than one imaging
modality, and be more firmly embedded and coordinated among dif-
ferent study centers in order to develop novel diagnostic and prognostic
tools of disease progression as well as for the prediction biomarkers of
therapy response. Further, this multidimensional approach will identify
reliable biomarkers permitting an early prediction of cognitive dys-
function in patients with mental disorders in order to inform clinical
decision making before complications in daily living are clinically ap-
parent. We suggest that detecting young patients with first-episode of
mental illness and poor psychosocial functioning will help clinicians to
provide these patients with a more intensive rehabilitation (Cuesta
et al., 2017). This kind of prognostic tools might substantially improve
the patients’ treatment by informing clinical decision-making before the
commencement of pharmacological or non-pharmacological treatment.
Sixth, the investigation of the interaction between genetic factors
and environmental influences, which can contribute to the develop-
ment of GMA, is certainly a considerable challenge for future studies.
Genetic factors together with environmental effects can have a sig-
nificant impact on the developmental trajectory of the human motor
system and person's motor skills. Although genetically-mediated var-
iance is affecting phylogenetically younger and older regions differently
(Lenroot et al., 2009), behavioral studies showed that two candidate
genetic polymorphisms might be a factor influencing motor control and
motor learning in humans (Missitzi et al., 2013). First, the brain derived
neurotrophic factor (BDNF) val66met single-nucleotide polymorphism
(SNP) has an influence on motor cortex plasticity and motor learning
(Cirillo et al., 2012, Kleim et al., 2006). Second, the catechol-O-me-
thyltransferase (COMT) Val158Met polymorphism, a genetic factor
known to influence the functionality of the dopaminergic system, has a
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Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
significant influence on response inhibition, motor learning and per-
formance in adults (Mione et al., 2015, Noohi et al., 2014). Further-
more, motor system structure and function can change significantly
during the first years of life depending on environmental influences
(Moffitt et al., 2006, Rutter et al., 2006). For instance, premature birth,
obstetric complications, and perinatal difficulties might have an im-
portant impact on the development of motor regions and lead to
aberrant psychomotor functioning in humans (Bouyssi-Kobar et al.,
2018; Rizzo et al., 1995). However, the question which environmental
influences may have the most influence on motor system development
that could also explain individual differences in motor performance and
learning cannot be answered sufficiently on the basis of current evi-
dence (Defazio et al., 2017). Another problem of the extant evidence is
the fact that the majority of hitherto studies did not distinguish between
genetic and environmental factors regarding their impact on motor
system development and motor behavior in healthy persons and in in-
dividuals with mental disorders (Lenroot et al., 2009). The first in-
dications of a different influence of genes and environment on motor
development come from studies in infants and children. A recent study
by Smith and colleagues (Smith et al., 2006) showed in a twin birth
cohort of 2402 families that environmental influences (e.g. parental
intervention, encouragement and modelling (Hinkley et al., 2008)) are
significantly related to movement activity levels and motor develop-
ment in infants. Genetic factors in turn play an important role in the
development of walking abilities in infants (Smith et al., 2006). In
particular, the variance in infant motor activity level was explained to
48% by genetic influences and to 45% by environmental factors (Smith
et al., 2006). To date, however, imaging studies that particularly in-
vestigate the impact of the interaction between genes and environ-
mental influences on human motor system are lacking. Such studies
could help to explain the origin of motor abnormalities before the onset
of a manifest mental illness. Such studies could potentially support the
implementation of individualized exercise therapy in children with
aberrant motor development.
Seventh, high phenotypic heterogeneity and GMA overlap within
BD, OCD, and ND have stimulated a fruitful discussion on dimensional
characterization of psychiatric disorders (Bernard and Mittal, 2015;
Mittal et al., 2017). This approach corroborates the hypothesis that
homogeneous neurobiological mechanisms, comprising dimensional
constructs including basal ganglia, cerebellar, and cortico-motor cir-
cuits might underlie the above mentioned psychiatric disorders ex-
hibiting GMA. Accordingly, multimodal analyses based on different
GMA dimensions and multiple neuroimaging parameters might reveal
motor system-related brain alterations that have not been detected by a
traditional “patients versus healthy controls” approach (Oldehinkel
et al., 2016). Ideally, elucidation of genetic architecture in schizo-
phrenia, BD, OCD, and ND will lead to a motor system based nosology
that might more accurately reflects the pathophysiology and more
readily suggests pharmacotherapeutic targets (Berrettini, 2000). A
major step in this endeavour would be the transdiagnostic study of a
motor biotype in patients with schizophrenia, BD, OCD, and ND and
their unaffected FDR. While genetic factors are now recognized as most
important for the development of schizophrenia, BD, OCD, and ND, the
research must continue to search after gene defects involved in the
pathophysiology of these disorders. In line with this, the role of future
studies in FDR of patients with psychiatric disorders can best be ap-
preciated against the background of current knowledge about the her-
itability of GMA. However, the exact nature of motor system dysfunc-
tion and its underlying genes in FDR of schizophrenia, BD, OCD, ASD,
or ADHD patients, however, is not clear at present. This effort would
also benefit from studying animal models, since this essentially allows
motor system dysfunction to be examined in much greater detail than is
possible in patient studies. For instance, animal models can help to
examine the effects of well-established risk factors such as genetic
mutations on motor circuits and motor behaviour. A combination of
both approaches would span many different levels of analysis, which
D. Hirjak et al. Neuroscience and Biobehavioral Reviews 95 (2018) 315–335

will reveal diverse forms of neural circuit dysfunction and underlying instruments/assessments (van Harten et al., 2017) and motor-circuits-
genes common for psychiatric disorders characterized by GMA. based biomarkers might be used as reliable and promising prognostic
Therefore, we propose a multiple-stage continuum of motor system tools in daily clinical practice to ascertain changes in brain morphology
dysfunction leading to development of manifest GMA-related disorders induced by pharmacological and non-pharmacological therapies. Of
that might be assessed with different methods of modern neuroscience particular importance, activity within the motor network (e.g. activa-
(DeRosse and Karlsgodt, 2015): (1) familial and genetic vulnerability tion of M1 and SMA) might provide a sensitive parameter to adapt the
(studies on animal models, unaffected FDR, Val66Met (BNDF) and therapy intensity (e.g. neuroimaging guided tDCS) and to detect early
Val158Met (COMT) polymorphism carriers), (2) molecular ultra-high therapy response.
risk state (PET and SPECT imaging in FDR and healthy persons ex-
hibiting aberrant motor development or NSS), (3) environmental fac-
7. Limitations
tors (e.g. premature birth, obstetric complications, perinatal difficulties,
parental intervention, urban upbringing, migration, etc.), (4) beha-
Although we identified very promising findings on GMA across
vioral dysfunction without clinical manifestation (studies in healthy
psychiatric disorders other than schizophrenia, several limitations
individuals and FDR), (5) beginning of degeneration (instrumental as-
apply to the present review. For the purpose of this review, we iden-
sessment of GMA, combined structural and functional MRI), (6) first
tified dozens of relevant publications and assessed the dispersion of
clinical manifestation (first-episode patients with AIMS) and relapses
study samples, motor scales and neuroimaging techniques in the cur-
(patients with multiple psychotic episodes or chronic psychotic states
rent evidence on GMA in BD, OCD, and ND (Borenstein et al., 2009). A
and AIMS or catatonia) (Linden and Fallgatter, 2009; McGorry et al.,
similar issue regarding the selection of the most informative articles on
2014). Future studies using such tailored setup will help to design
GMA in psychiatric disorders has been addressed previously in the
motor-network-oriented pharmacological and non-pharmacological
community (Peralta and Cuesta, 2017). Because of different motor
therapeutics (Fig. 3; for the original three-stage model, see also (Hirjak
symptom assessments and neuroimaging modalities in the above-men-
et al., 2015a). The fact that motor symptoms are transnosologic features
tioned studies we were not able to synthesize the present data on GMA
makes the motor domain particularly suitable for the development of
across psychiatric disorders in order to perform an activation likelihood
transdiagnostic screening instruments. For instance, future research
estimation (ALE)-meta-analysis (Rosenthal and DiMatteo, 2001).
should identify vulnerability genes as well as structural and functional
However, motor dysfunction in mental disorders is a heterogeneous and
alterations in terms of multimodal parameters, which characterize the
broad dimension that has not yet been clearly defined. Many different
at-risk state before transition to manifest disease. This approach might
variables and phenomena can be hidden under the term motor dys-
define structural and functional target brain loci for dopaminergic
function or motor symptoms in mental diseases. This fact has made it
modulation via non-invasive stimulation (transcranial direct current
difficult for the authors to conduct a systematic search and qualitative
stimulation - tDCS or transcranial magnetic stimulation - TMS) in order
analysis of current studies on motor behavior in BD, OCD, and ND. It is
to prevent the conversion to a manifest psychiatric disorder (Teo et al.,
therefore possible that important studies were not mentioned because
2016). These stimulation methods will be able to induce neuroplasticity
they could not be identified due to the different terminology. A further
and reduce undesired hyperactivity in particular regions within the
major problem remains to be solved, namely that the above-mentioned
motor network such as prefrontal cortex, primary motor cortex, SMA,
studies did not use instrumental measures and experimental paradigms
ventral striatum, thalamus or cerebellum (Caligiore et al., 2017). In line
to assess motor dysfunction (Walther et al., 2009; Mentzel et al., 2016).
with these considerations, a recent fMRI study in schizophrenia sug-
As there are many different ways to approach the diversity of GMA in
gested that functional connectivity changes associated with motor ab-
psychiatric disorders (Peralta and Cuesta, 2017), first of all a unified
normalities would be an excellent target selection for noninvasive brain
neurobiological theory of GMA in psychiatric disorders and a consensus
stimulation (Walther et al., 2017b). Finally, objective GMA
on GMA assessment tools used in neuroscientific research is mandatory.

Fig. 3. Pathophysiological mechanisms from genes to behavior, genuine motor abnormalities (GMA) and clinical symptoms with different units of observation as well
as models and the tools for their investigation. BDNF=Brain-derived neurotrophic factor; COMT= Catechol-O-methyltransferase.

326
D. Hirjak et al.
As an inherent limitation of cross-sectional studies, it is unclear if the
relationship between GMA and brain morphology is longitudinally
stable, or whether disease-related or external confounders modulate
this link. Another difficulty in studying GMA in psychiatric diseases is
the potential influence of medication on GMA and brain morphology. In
addition to antipsychotic medication, other psychotropic drugs can
contribute to the development of motor disorders and therefore re-
present a significant methodological challenge when investigating pa-
tients with BD, OCD, ASD, ADHD, and TS. In particular, non-dopami-
nergic substances such as cardiac medications (antihypertensive or
antiarrhythmic drugs), anticonvulsants (such as valproic acid), mood
stabilizer (e. g. lithium), immunosuppressants (cyclosporine), anti-
fungal agents, chemotherapeutic agents (vincristine or methotrexate)
and others (procaine, propiverine, buformin, tacrin, interferon, etc.)
may contribute to the development of drug-induced parkinsonism (DIP)
or other drug-induced movement disorders in BD, OCD, ASD, ADHD,
and TS (Friedman, 2017, 1998; Silver and Stewart, 2015). The fact that
DIP can occur in various mental illnesses makes it challenging for
clinicians and scientists to distinguish it from GMA or even Parkinson's
disease. It is important to know the time of the initial manifestation. In
the case of DIP, the initial manifestation is often associated with the
onset or increase of the prescribed medication. Bilateral symptoma-
tology also speaks in favour of DIP. The age of the patient also plays an
important role in the differential diagnosis, because experience shows
that patients with DIP are younger than those with Parkinson's disease.
Eventually, DIP is often associated with other antipsychotic-induced
symptoms, such as akathisia, tremor or dyskinesia (Friedman, 2017,
1998; Silver and Stewart, 2015). Therefore, future studies should en-
sure that the study subjects do not take any medication in order to keep
the confounder effects as low as possible. Last but not least, we are still
lacking PET-MRI studies on GMA in psychiatric disorders other than
schizophrenia. This approach might reveal the association between
dopamine hypersensitivity and GMA. The investigation of dopamine
receptor profiles would be beneficial for identification of patients with
higher risk for developing extrapyramidal motor disorders before the
treatment with highly affine and selective dopamine receptor antago-
nists.
8. Concluding remarks
This systematic review provides an overview on brain correlates as
well as theoretical framework for future investigation of GMA in BD,
OCD, and ND. We identified and discussed significant articles in order
to develop a preliminary concept on aberrant networks contributing to
GMA across psychiatric disorders other than schizophrenia. Although
the studies identified by the systematic literature search are far from
conclusive, the current data lends support for a common pattern con-
tributing to GMA expression in BD, OCD, and ND that seems to be re-
lated to basal gangliar, cerebellar, and cortico-motor circuit dysfunc-
tion. Nevertheless, there is a surprising dearth on transdiagnostic
studies investigating motor domain across different psychiatric dis-
orders and we might only speculate whether the motor dysfunction is
rooted in neurodevelopmental, functional or neurodegenerative brain
processes. To achieve this ambitious goal, large-scale longitudinal stu-
dies should attempt to systematically elucidate the aspects of motor
dysfunction that eventually could facilitate the detection of novel tar-
gets for pharmacological and non-pharmacological treatments across
psychiatric disorders exhibiting GMA.
Declaration of interest
A.M.-L. has received consultant fees from Blueprint Partnership,
Brainsway, Boehringer Ingelheim, Daimler und Benz Stiftung, Elsevier,
F. Hoffmann-La Roche, ICARE Schizophrenia, K. G. Jebsen Foundation,
L.E.K. Consulting, Lundbeck International Foundation (LINF), R.
Adamczak, Roche Pharma, Science Foundation, Sumitomo Dainippon
327
Neuroscience and Biobehavioral Reviews 95 (2018) 315–335
Pharma Co., Academic Medical Center of the University of Amsterdam,
University of Cambridge, Dt. Zentrum für Neurodegenerative
Erkrankungen, Universität Zürich, Synapsis Foundation - Alzheimer
Research Switzerland, and System Analytics. All other authors declare
no potential conflicts of interests.
Role of the founding source
This review was supported by the German Research Foundation
(DFG) (grant number DFG HI 1928/2-1 to D.H. and WO 1883/6-1 to
R.C.W.). 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 publication.
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