Schizophrenia Bulletin vol. 46 no. 2 pp.

272–285, 2020
doi:10.1093/schbul/sbz074
Advance Access publication 30 July 2019

Going Back to Kahlbaum’s Psychomotor (and GABAergic) Origins: Is Catatonia

More Than Just a Motor and Dopaminergic Syndrome?

Dusan Hirjak*,1, Katharina M. Kubera2, R. Christian Wolf2, and Georg Northoff3

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Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University,
1

Mannheim, Germany; 2Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg,
Germany; 3Mind, Brain Imaging and Neuroethics Research Unit, The Royal’s Institute of Mental Health Research, University of
Ottawa, Ottawa, ON, Canada
*To whom correspondence should be addressed; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health,
Medical Faculty Mannheim, University of Heidelberg, D-68159 Mannheim, Germany; tel: +49-621-1703-0, fax: +49-621-1703-2305,
e-mail: dusan.hirjak@zi-mannheim.de

In 1874, Karl Kahlbaum described catatonia as an in- Key words: catatonia/Kahlbaum/neuroimaging/North

dependent syndrome characterized by motor, affective, off Catatonia Rating Scale/CT/MRI/SPECT
and behavioral anomalies. In the following years, var-
ious catatonia concepts were established with all sharing
Introduction
the prime focus on motor and behavioral symptoms while
largely neglecting affective changes. In 21st century, cat- In 1874, Karl Kahlbaum systematically described a total of
atonia is a well-characterized clinical syndrome. Yet, its 21 psychotic patients presenting not only with hallucinations,
neurobiological origin is still not clear because method- formal thoughts disorders, and delusions, but also with flam-
ological shortcomings of hitherto studies had hampered boyant psychomotor abnormalities.1,2 In the traits of his ob-
this challenging effort. To fully capture the clinical pic- servations, Kahlbaum developed the concept of catatonia,
ture of catatonia as emphasized by Karl Kahlbaum, 2 dec- which he conceived an independent nosological entity char-
ades ago a new catatonia scale was developed (Northoff acterized by hypokinetic and hyperkinetic motor phenomena
Catatonia Rating Scale [NCRS]). Since then, studies (rigor, dyskinesia, festination, counteracting, posturing, cat-
have used NCRS to allow for a more mechanistic insight alepsy, etc.), affective symptoms (aggression, anxiety, flat
of catatonia. Here, we undertook a systematic review affect, affect incontinence, etc.), and disorders of behavior
searching for neuroimaging studies using motor/behav- (autism, mutism, echolalia, etc.).3–9 When Emil Kraepelin
ioral catatonia rating scales/criteria and NCRS published first reported on catatonia in 1896, he considered this syn-
up to March 31, 2019. We included 19 neuroimaging drome to be—similar to Karl Kahlbaum’s concept—an inde-
studies. Studies using motor/behavioral catatonia rating pendent diagnostic entity. Later on in 1899, when Kraepelin
scales/criteria depict cortical and subcortical motor re- separated dementia praecox from manic-depressive illness,
gions mediated by dopamine as neuronal and biochemical catatonia was attributed to one of the subtypes of dementia
substrates of catatonia. In contrast, studies relying on praecox, thereby limiting catatonia to motor and behavioral
NCRS found rather aberrant higher-order frontoparietal symptoms.10–12 Catatonia and its characteristic symptoms
networks which, biochemically, are insufficiently modu- were no longer accepted as a disease on its own, but as ir-
lated by gamma-aminobutyric acid (GABA)-ergic and reversible transition into dementia praecox. Kraepelin also
glutamatergic transmission. This is further supported spoke of the fact that there are no objective neuropatho-
by the high therapeutic efficacy of GABAergic agents logical findings that would point to a different pathogenesis
in acute catatonia. In sum, this systematic review points of catatonia and dementia praecox.5,10,11 Later on, Eugen
out the difference between motor/behavioral and NCRS- Bleuler incorporated catatonic motor disorders (motility is-
based classification of catatonia on both neuronal and sues, stupor, mutism, stereotypies, mannerism, negativism,
biochemical grounds. That highlights the importance of etc.) in his new concept of dementia praecox called “schiz-
Kahlbaum’s original truly psychomotor concept of cata- ophrenia.”13 Since that time, the concept of catatonia has
tonia for guiding both research and clinical diagnosis and been made almost invisible to clinicians and closely related
therapy. to that of dementia praecox and (after 1908) schizophrenia,

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 Going Back to Kahlbaum’s Psychomotor (and GABAergic) Origins

characterized mainly by motor and behavioral symptoms, as being intrinsic to catatonia was empirically supported
thus neglecting affective alterations.3,5,14 In contrast, earlier mainly by the following findings: (1) affective symptoms
description of catatonia being associated with affective psy- were significantly higher in catatonia patients than in psy-
chosis like depression and mania and numerous works by chiatric controls including both those with schizophrenia
contemporary American authors15–18 reporting catatonia in and affective psychosis3; (2) affective symptoms in NCRS
affective disorders remain in the background overshadowed were significantly associated with general catatonic symp-
by the predominant motor (and behavioral) characterization toms as reflected in NCRS total score37; (3) some affective
of catatonia as subtype of schizophrenia.19 symptoms on the perceptual-experiential level were specific
This tendency has also prevailed in modern no- to catatonia like the inability to control emotions and affects
sology and symptomatologic classification of cata- which, in turn, as experienced by the patients, strongly af-
tonia (see DSM-IV-TR and ICD-10) that emphasize fected their behavioral and motor functions38; (4) catatonia

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catatonic motor signs. In the last 2 decades, however, is present in affective disorders15,39; (5) anxiety measured by
there has been a paradigm shift in modern research.20–24 psychopathologic scales was not significantly associated
Catatonia gained importance as an independent syn- with affective scores in catatonia scales3,40; and (6) there is
drome and has also been described in other psychiatric an outstanding and almost immediate effect of gamma-a-
diseases such as affective disorders16, autism25, and minobutyric acid (GABA)-ergic agents, eg, lorazepam that
organic mental disorders26 (eg, infective and immune rapidly relieves affective symptoms in catatonic patients.41
causes).27 This is also visible in DSM-5 where cata- Symptomatically, catatonia is characterized by a specific
tonia can be used as a specifier to better characterize constellation of motor, behavioral, and affective symptoms
an underlying psychiatric disease. However, despite (rather than being merely motor syndrome) with all 3 being
detailed recommendations provided by internation- closely intertwined in clinical presentation—this was well
ally acknowledged experts,6 DSM-5 does not provide pointed out by Kahlbaum2 and has been taken as basis for
a separate diagnostic code for catatonia besides “cat- the NCRS and subsequent neurobiological investigations.
atonia not otherwise specified”. In contrast to ICD- To characterize and point out the truly psychomotor na-
10, however, catatonia in DSM-5 can be associated ture of catatonia in the original sense of Kahlbaum, we here
with other mental disorders or specific medical con- proceed in 4 main parts. First, we systematically review the
ditions. This situation might change in the ICD-11, neuroimaging evidence for catatonia-related structural and
where catatonia could be recognized an independent functional brain abnormalities. In particular, we elucidate
diagnostic entity.28 Until then, the prime characteriza- the differences between neuroimaging studies using motor/
tion of catatonia by motor (and behavioral) symptoms behavioral catatonia rating scales/criteria such as RCS30,
remains—this is for instance well manifested in cata- MRS31,32, or BFCRS33,34 and NCRS. Second, we use the
tonia criteria and rating assessments such as Rosebush identified brain regions and networks to create an update of
criteria29, Rogers Catatonia Scale (RCS)30, Modified the catatonia model presented in 2000.23 Third, we point out
Rogers Scale (MRS)31,32, Bush-Francis Catatonia associated biochemical changes that mainly focus on do-
Rating Scale (BFCRS)33,34, Braunig Catatonia Rating pamine and GABAergic, glutamatergic and dopaminergic
Scale (BCRS)35, or KANNER (“Katatonia, Autism, transmission. Fourth, we highlight existing limitations, gaps
Neuropsychiatric and Neuromovement Examination in knowledge, and fertile avenues for future neuroimaging
Rating”) Scale36. Although these rating scales have and clinical research on catatonia in psychiatric disorders as
contributed to better understanding of the neurobio- well as the relevance of such truly psychomotor concept for
logical origin of catatonia, they paid only little atten- clinical diagnosis and therapy of catatonia. Finally, this sys-
tion to the clinical importance of affective symptoms tematic review advocate that catatonia should be included as
as originally emphasized by Karl Kahlbaum in 1874.3 an independent disease entity in future classification systems
One possible reason why affective symptoms have not been because it has its own specific pathophysiology.
considered as a part of catatonia in either clinical practice or
neurobiological research up to this point is that they were
Methods
seen as a genuine part of schizophrenia spectrum disorders
(SSD) or affective psychoses themselves.23 To overcome this The systematic literature search and study selection ap-
neglect of affective symptoms in psychopathologic evalua- proach followed PRISMA guidelines (figure 1; different
tion of catatonia, 20 years ago, the senior author (G.N.) de- sources: January 1, 1960 to March 31, 2019). A detailed
veloped the Northoff Catatonia Rating Scale (NCRS).3 The information on the literature search and study selection
NCRS offers clinicians and scientists the possibility not only approach is provided in supplementary material.
to assess the severity of motor and behavioral symptoms,
but also to determine whether and to what extent affective
Systematic Literature Search Results
symptoms are present and are specific to catatonia as distin-
guished from those associated with either schizophrenia or We identified 4 CT42–45 studies, 7 SPECT46–52 studies, and 8
affective psychosis. The consideration of affective symptoms MRI53–59 studies that were included in this systematic review.
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D. Hirjak et al

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Fig. 1. PRISMA flow chart of included neuroimaging studies on catatonia in mental disorders.

Ten studies used either the DSM-III/-IV-TR classification with SSD. (2) Neuroimaging studies using motor/be-
system, strict criteria for catatonia, or a motor/behavioral cat- havioral catatonia rating scales/criteria have identified
atonia rating scale (eg, MRS or BFCRS) in psychiatric pa- different cortico-subcortical brain circuits involving
tients (table 1) and depicted cortical and subcortical motor the dorsolateral prefrontal and cingulate cortex, in-
regions as neuronal substrates of catatonia (figure 2, left side). sula, thalamus, precentral gyrus, supplementary motor
Nine studies used NCRS in psychiatric patients (table 2) and area (SMA), and cerebellum as important neuronal
found aberrant higher-order frontoparietal networks insuffi- substrates of catatonia in SSD. Biochemically, these
ciently modulated by GABAergic and glutamatergic trans- cortical areas and their subcortical-cortical loops are
mission underlying catatonia (figure 2, right side). mediated mainly by dopamine, which also has been
found to be abnormal in SSD60,61 and parkinsonism62.
(3) Neuroimaging studies using NCRS proposed a neu-
rophysiological model of catatonia in SSD including
Discussion
rather right hemispheric neural network abnormalities
This systematic review sought to contrast the findings that include the medial and lateral orbitofrontal (OFC),
from 19 neuroimaging studies using motor/behavioral prefrontal, and posterior parietal cortex. Biochemically,
catatonia rating scales/criteria and NCRS. Three main these regions’ changes in catatonia are also associated
findings emerged: (1) To date, the vast majority of neu- with changes in GABAA receptors, as it has been shown
roimaging studies on catatonia investigated patients in various studies.23,53,55

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Table 1. CT, SPECT, and MRI Studies Using Motor/Behavioral Catatonia Rating Scales in Mental Disorders

Neuroimaging
Study Sample characteristics Motor assessment method Important findings

Joseph et al45 CAT: n = 5, age = 65.4 y; CAT had all mutism, akinesia, CT scans on Siemens Catatonic patients showed at-
M:F = 2:3 and catalepsy plus at least 2 of Somatom 2 with a rophy of posterior fossa struc-
SP: n = 5, age = 66 y; the 4 symptoms such as nega- 256 × 256 matrix tures (vermis and brainstem).
M:F = 2:3 tivism, stereotyping, posturing, and 8-mm-thick
and mannerisms. slices
Wilcox44 CAT: n = 17 Criteria for CAT were mutism, CT scans on a Catatonia may be associated
SP: n = 30 with motor rigidity, irrational be- Picker-600 CT with cerebellar atrophy.

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noncatatonic SZ, n = 20 havior, and the absence of Scanner with a res-
with psychotic affec- frank neurological or metabolic olution power in the
tive disorder, n = 15 disease 1-mm range or better
nonpsychiatric controls
(matched for age and
gender)
Wilcox43 CAT: n = 30 patients Criteria for CAT were mutism, CT scans on a CAT patients with schizo-
(8 bipolar—32.58 y, 11 presence of bizarre motor ac- Picker-600 CT phrenia had larger ventricular/
schizophrenia—32.31 y, tivity including posturing, Scanner with a res- brain ratios compared with
6 schizoaffective—37.39 decrease in motor activity, or olution power in the nonschizophrenic CAT pa-
y, and 5 major depres- catatonic excitement character- 1-mm range or better tients.
sion—33.29 y of age), ized by intense bursts of agi-
M:F = 16:14 tated stereotypy.
Ebert et al52 CAT: N = 2 (48 and 24 y DSM-III-R schizophrenia di- rCBF studied Temporal hypoperfusion as a
old) agnosis via SPECT with neural correlate of aberrant
SP: N = 10 99
mTcHMPAO sensory input in catatonia
HC: n = 8
Satoh et al111 CAT: N = 6, age = 29.7 ± 6 schizophrenia patients who rCBF studied via Low rCBF, as indexed by IMP
8.6 y; M:F = 3:3; DOI: currently or at an earlier time SPECT with IMP perfusion, of the dorsal pa-
0.5–20 y had received a DSM-III-R rietal lobe was found in CAT
SP: N = 13, age = 31.4 ± subtype diagnosis of catatonic compared with SP.
11.6 y; M:F = 10:3; all pa- schizophrenia (symptoms in-
tients medicated cluded catatonic stupor or
excitement, posturing, manner-
isms, and negativism).
Galynker CAT: n = 1, age = 40 y; fe- One schizoaffective patient rCBF studied The patient with catatonia
et al51 male; DOI: 25 y presenting with severe psycho- via SPECT with showed decreased perfusion in
HC: n = 8, age = 36.1 y, motor retardation, negativism, 99
mTcHMPAO the left parietal and left motor
M:F = 5:3 and waxy flexibility cortices when compared with
healthy controls.
Escobar et al49 CAT: N = 9, age = 28.3 ± Diagnosis of catatonia was rCBF studied No SPECT differences be-
5.8 y; M:F = 8:1; 5 pa- done clinically, according to via SPECT with tween the 2 diagnostic groups.
tients with schizophrenia DSM-IV criteria. The severity 99
mTcHMPAO Significant increase in rCBF
and 4 patients with mood was assessed with Modified in parietal, temporal, and oc-
disorder Rogers Scale. cipital regions in patients with
mood disorder and no signifi-
cant changes in schizophrenia
patients
Walther et al56 CAT: N = 15, age = 35.9 ± Bush-Francis Catatonia Rating 3 Tesla MRT, SPM8 Excited and retarded catatonia
12.7 y; M:F = 11:4; edu- Scale. (VBM toolbox) differed in SMA perfusion.
cation: 12.0 ± 4.0 y; CPZ: Higher catatonia scores were
461.3 ± 346.4; DAE: associated with higher SMA
153.4 ± 143.9 mo perfusion.
SP: N = 27; age = 37.1 ±
10.6; M:F = 17:10; edu-
cation: 14.2 ± 3.1 y; CPZ:
373.6 ± 359.4; DAE:
126.4 ± 127.2 mo
HC: N = 41, age = 38.6 ±
13.6 y; M:F = 25:16; edu-
cation: 14.1 ± 2.7 y

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D. Hirjak et al

Table 1. Continued

Neuroimaging
Study Sample characteristics Motor assessment method Important findings
Walther et al58
SP: N = 46, age = 38.0 ± Bush-Francis Catatonia Rating 3 Tesla MRT, Func- Thalamocortical (bilat-
11.5 y; M:F = 30:16; edu- Scale and Modified Rogers tional Connectivity eral M1 to left thalamus)
cation: 13.5 ± 3.1 y; CPZ: Scale Toolbox (CONN, hyperconnectivity was linked
444.6 ± 337.0; DOI: 12.1 ± version 17.c) to catatonia in schizophrenia.
12.4 y
HC: N = 44, age = 38.0 ±
13.6 y; M:F = 25:16; edu-
cation: 14.1 ± 2.7 y

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CAT, catatonic patients; SP, schizophrenic patients/other mental disorders; HC, healthy controls; IMP , 123I-iodoamphetamine; DOI, du-
ration of illness; CPZ, chlorpromazine equivalent dose; OLZ, Olanzapine equivalent dose; CT, computer tomography; rCBF, regional
cerebral blood flow; OFC, orbitofrontal cortex; SMA, supplementary motor area; M, male; F, female; y, years; mo, months.

Fig. 2. Relevant neural circuits underlying catatonia in mental disorders. Summary of findings from neuroimaging studies using motor/
behavioral catatonia rating scales (left). Summary of findings from neuroimaging studies using Northoff Catatonia Rating Scale (right).

Neuroimaging Studies Using Motor/Behavioral In another study, Wilcox showed that patients with cata-
Catatonia Rating Scales/Criteria tonic schizophrenia have significantly larger ventricular/
As early as 1985, Joseph et al45 examined 5 catatonic patients brain ratios than patients with nonschizophrenic catatonia
(4 patients had affective disorder and 1 patient had temporal (P < .05).43 Northoff et al corroborated these CT studies
lobe epilepsy) who showed atrophy of cerebellar vermis and by showing a relationship between catatonic syndrome and
brainstem when compared with psychiatric controls. Later, significant enlargements in almost all cerebrospinal fluid
Wilcox found that significantly more catatonia patients spaces, especially in the left frontotemporal area.42 These 4
(29%) showed cerebellar atrophy when compared with pa- CT studies42–45 were complemented by a number of SPECT
tients with noncatatonic schizophrenia, affective psychosis, studies in catatonic syndrome: Ebert et al52 showed ab-
and nonpsychiatric individuals (P < .05 in each category).44 normal regional cerebral blood flow (rCBF) in the limbic

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Table 2. CT, SPECT, and MRI Studies Using NCRS in Mental Disorders

Sample character-
Study istics Motor assessment Neuroimaging method Important findings

Northoff CAT: N = 10, 10 patients with rCBF and benzodiazepine The study found significant relations of
et al48 age = 41.6 ± 5.3 catatonia according to receptor distribution were motor and affective catatonic symptoms
(21–63) y; criteria by Lohr and studied via SPECT with with left upper frontal and right lower
M:F = 4:6 Wiesniewski (1987), 123
I-iomanezil prefrontal cortical iomazenil binding as
SP: n = 10, Rosebush et al (1990), well as with right lower parietal rCBF.
age = 40.8 ± 4.9 y BFCRS, and NCRS
HC: N = 20,

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age = 40.1 ± 6.2 y
Northoff CAT: N = 2, 2 patients with cata- 1.5 Tesla MRT, task: CAT showed higher activity reduction in
et al53 age = 27 and 31 y; tonia according to Lohr sequential finger opposition, the contralateral primary sensory-motor
M:F = 1:1 and Wiesniewski (1987), AFNI cortex during sequential finger opposi-
DOI: 2 and 6 mo Rosebush et al (1990), tion after lorazepam application when
HC: N = 2, and DSM-III-R (APA, compared with HC.
age = 27 and 31 y 1987)
Northoff CAT: N = 10, 10 patients with rCBF studied via SPECT CAT showed decreased rCBF in right
et al47 age = 41.6 ± 5.3 catatonia according to with Tc-99mECD prefrontal and parietal cortex compared
(21–63) y; criteria by Lohr and with psychiatric and healthy controls as
M:F = 4:6 Wisniewski, Rosebush well as significantly poorer performance
SP: n = 10, Catatonia Scale, BFCRS, in visual–spatial abilities associated with
age = 40.8 ± 4.9 y NCRS right parietal function.
HC: N = 20,
age = 40.1 ± 6.2 y
Northoff CAT: N = 10, NCRS, Rosebush Cat- 3 Tesla MRT, ROI-Analysis, Affective and behavioral catatonic
et al54 age = 41.6 ± 5.3 y; atonia Scale, Lohr Cat- SEM, CoCoMac; task: affec- symptoms were associated with activity
M:F = 5:5; educa- atonia Symptom Scale, tive/motor paradigm using changes in OFC. Motor catatonic symp-
tion: 9.5 ± 1.8 y; and the Northoff Self- positive toms were associated with prefrontal
CPZ: 180.2 ± 177.5; estimation Scale and negative stimuli from the cortex activity.
DAE: 5.1 ± 4.2 y International Affective
SP: N = 10, Picture System (IAPS)
age = 40.8 ± 4.9 y;
M:F = 5:5; educa-
tion: 9.9 ± 1.8 y;
CPZ: 167.0 ± 153.2
De Tiege CAT: n = 1, NCRS Positron emission Patient with catatonia showed a de-
et al50 age = 14, fe- tomography, SPM99, crease of metabolism in a large pre-
male, NCRS total masking analysis frontal area, the right anterior cingulate,
score = 19 the right medial prefrontal and dorsolat-
HC: n = 29, eral cortices when compared with HC.
age = 32,
M:F = 13:16
Scheuerecker CAT: N = 12, NCRS, Rosebush Cat- 1.5 Tesla MRT, SPM5 CAT showed reduced activity during
et al57 age = 36.2 ± 9.5 atonia Scale, Lohr Cat- self-initiated movements in the right su-
y; M:F = 5:7; atonia Symptom Scale, perior frontal gyrus, both middle frontal
CPZ = no informa- and the Northoff Self- gyrus, inferior frontal gyrus, and pari-
tion available estimation Scale etal cortex compared with HC.
DAE: no informa-
tion available
HC: N = 12,
age = 35.8 ± 9 y;
M:F = 5:7
Richter et al55 CAT: N = 6, NCRS, Rosebush Cat- 3 Tesla MRT, KHOROS 2.1 CAT showed higher activity reduction
age = 41.6 ± 5.3 y; atonia Scale, Lohr Cat- with the extension in OFC, middle prefrontal cortex and
M:F = 1:5; educa- atonia Symptom Scale KHORFU, task: emotional premotor cortex after lorazepam appli-
tion: information and the Northoff Self- stimulation using the Interna- cation.
not available; CPZ: estimation Scale tional Affective Picture
198.3 ± 188.3 System (IAPS)
DAE: 6 ± 3.58 y
HC: N = 6, no fur-
ther information
available

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D. Hirjak et al

Table 2. Continued

Sample character-
Study istics Motor assessment Neuroimaging method Important findings
Hirjak et al67
CAT: N = 25, NCRS, Abnormal Invol- 3 Tesla MRT, Freesurfer CAT showed reduced cortical area in
age = 39.1 ± 11.4 untary Movement Scale, (cortical thickness, area, and OFC and reduced LGI in temporal
y; M:F = 14:11; ed- Simpson and Angus gyrification) gyrus when compared with SP. CAT
ucation: 13.4 ± 2.3 Scale, and Barnes Aka- showed hypergyrification in OFC com-
y; OLZ: 17.4 ± 8.1; thisia Rating Scale pared with SP.
DAE: 13.6 ± 11.9 y
SP: N = 22;
age = 40.1 ± 11.8;

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M:F = 11:11; edu-
cation: 13.3 ± 3.3 y;
OLZ: 16.3 ± 10.5;
DAE: 8.5 ± 9.5 y
Hirjak et al59 CAT: N = 24, NCRS, Abnormal Invol- 3 Tesla MRT, SPM12, NCRS behavioral scores were associated
age = 38.9 ± 11.6 untary Movement Scale, CAT12, data-driven fusion with a joint structural and functional
y; M:F = 14:10; Simpson and Angus method called multiset canon- system that predominantly included
education: 13.4 ± Scale, and Barnes Aka- ical correlation analysis + cerebellar and prefrontal/cortical motor
2.4 y; OLZ: 17.1 ± thisia Rating Scale joint independent component regions. NCRS affective scores were
8.18; DAE: 13.38 ± analysis (mCCA + jICA) associated with frontoparietal intrinsic
12.15 y neural activity.
SP: N = 22;
age = 40.1 ± 11.8;
M:F = 11:11; edu-
cation: 13.3 ± 3.3 y;
OLZ: 16.3 ± 10.5;
DAE: 8.5 ± 9.5 y

CAT, catatonic patients; SP, schizophrenic patients/other mental disorders; HC, healthy controls; DOI, duration of illness; CPZ, chlor-
promazine equivalent dose; OLZ, Olanzapine equivalent dose; OFC, orbitofrontal cortex; SMA, supplementary motor area; M, male;
F, female; BFCRS, Bush-Francis Catatonia Rating Scale; NCRS, Northoff Catatonia Rating Scale; M, male; F, female; y, years; mo,
months.

system and hippocampus of 2 patients with catatonic syn- of learned motor plans.64 However, it took another
drome compared with 8 healthy and 10 psychiatric con- 30 years for the first fMRI study to prove the involvement
trols. The authors postulated that temporal hypoperfusion of subcortical regions in the pathogenesis of catatonia.
might be caused by the loss of sensory input in catatonia.52 Walther et al found that the catatonia is associated with
Another study also focused on rCBF in 6 patients who cur- functional connectivity between the left thalamus and bi-
rently or at an earlier time had received a DSM-III-R diag- lateral M1.58 Furthermore, Walther et al also examined
nosis of catatonic schizophrenia (eg, stupor or excitement, resting-state rCBF and gray matter in SSD patients with
posturing, mannerisms, and negativism) using SPECT with and without catatonia according to BFCRS.56 SSD pa-
123
I-iodoamphetamine (IMP).46 These patients showed re- tients with catatonia showed significant SMA and ventral
duced IMP perfusion in the dorsal part of the parietal premotor area hyperperfusion when compared with SSD
lobe.46 Later on, similar rCBF alterations were found in patients without catatonia. Interestingly, the SMA perfu-
one schizoaffective patient presenting with severe catatonic sion differed between excited and retarded (hypokinetic)
symptoms.51 This patient showed decreased rCBF in the catatonia.56 In addition, there was an increased gray
frontal, posterior temporal, and parietal cortices, as well as matter volume in the cerebellar region VIIb in catatonic
in the motor cortex when compared with healthy controls.51 patients.56 Furthermore, newer studies, which may have
The authors concluded that hypoperfusion in frontoparietal used more sensitive neuroimaging techniques, have also
regions might be associated with catatonic state rather than identified much more precise alterations in subcortical re-
the diagnosis of catatonic schizophrenia.46 gions (eg, thalamus and cerebellum).56,58
What all the studies mentioned above have in common On the one side, studies using motor/behavioral rating
is the fact that they could not identify any catatonia- scales found altered structure as well as aberrant perfu-
specific alterations of the basal ganglia; most likely due sion of motor regions in the parietal lobe. On the other
to the inadequate imaging method. As suggested by side, differences in perfusion findings between earlier
earlier histopathological studies,63,64 dysfunction of sub- and newer rCBF studies in premotor and motor areas
cortical structures such as basal ganglia, thalamus, cere- can be explained by different catatonic states (excited
bellum, and brainstem might lead to aberrant execution vs. retarded).56 This is also in line with a recent review

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 Going Back to Kahlbaum’s Psychomotor (and GABAergic) Origins

on structure and neural mechanisms of catatonia con- movements. The majority of catatonic patients are not
ducted by Walther et al65 that conceptualized catatonia as aware of their motor symptoms whereas they might expe-
a psychomotor syndrome based on disorder of cerebral rience intense and overwhelming emotional experience.38
motor network. In conclusion, the use of either DSM- What may seem little surprising is the fact that the
based catatonia diagnosis or motor/behavioral rating neuroimaging studies published so far did not identify
scales/criteria primarily depicts brain regions within the an association between affective symptoms and dysfunc-
cerebello-thalamo-motor circuit as neuronal substrates tions of the limbic system (eg, hypothalamus, amygdala,
of catatonia, with the regions appearing to be affected mammillary body, hippocampus, etc.) typically involved
differently depending on the symptoms’ quality. in emotional processing. Nevertheless, we believe that the
affective domain and its dysfunction play a major role
Neuroimaging Studies Using NCRS in the pathogenesis of catatonia. There are important

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In one of the first studies, which used NCRS, 10 akinetic reasons that seem to support this notion: First, catatonia
patients with catatonia, 10 psychiatric controls (similar has been associated with limbic and temporal lobe le-
diagnosis but without catatonia), and 20 healthy controls sions.68 Second, in numerous historical reports, intense af-
were investigated with SPECT 2 hours after injection of fects such as fear and anxiety have been listed as triggers
123
I-Iomazenil.48 Catatonic patients showed significantly of absolute tonic immobility.69 Therefore, a subgroup of
lower Iomazenil binding with significant right-left alter- patients might become catatonic (motor, behavioral, and
ations in the left sensorimotor cortex.48 Furthermore, affective) in reaction to either an internal cognitive/mental
there was a significantly reduced rCBF and significant event (like delusion, hallucination, or disturbing sadness)
right-left alterations in the right lower prefrontal and pa- or external environmental event (like personally relevant
rietal cortex in catatonic patients. However, the specific life events or stressful environment the patients are living
cortical activation and connectivity patterns between in). Still, we need further MRI studies on larger popu-
frontal, parietal, and temporal cortical areas in cata- lations to investigate motor, behavioral, and affective
tonic patients were not examined until 2004. In 2004, phenotypes/clusters separately. Third, numerous studies
Northoff et al examined 10 akinetic catatonic patients in have proven the administration of GABAA agonists (eg,
a postacute state and compared them with 10 psychiatric lorazepam) as a relevant and often life-saving therapeutic
controls without catatonia during an emotional-motor option in catatonia.70 Strong D2 antagonists (eg, anti-
stimulation using fMRI.54 Catatonic patients showed psychotics) might increase the GABAB activity and lead
aberrant OFC activation and functional connectivity to to the development of antipsychotic-induced catatonia.71
the premotor cortex in negative and positive emotions Catatonia might be caused by an abnormal balance be-
compared with healthy controls. Georg Northoff’s team tween GABAA and GABAB receptors.72 Few authors
succeeded in replicating these results in another patient reported that catatonia might be induced by benzodiaze-
sample consisting of 3 schizophrenia and 3 bipolar pa- pine withdrawal as well.73,74 These findings show that anx-
tients.55 The authors were also able to show that loraz- iolytic medication in the sense of GABAA agonists can
epam induced higher signal decreases in OFC.55 This modulate catatonic affective symptoms. This justifies the
said, application of lorazepam can compensate for the observation that a massive affective dysregulation mani-
dysfunction of the OFC and lead to better emotional reg- fests itself as a physical-motor symptomatology either
ulation in catatonia. This observation may explain the ef- in the sense that the patients become akinetic or hyper-
fectiveness of lorazepam in treating catatonia, especially kinetic. Both forms of catatonia can be traced back to
intense and uncontrollable anxieties and at the same time the disbalance between GABA and dopaminergic trans-
the so-called “scared stiffness”.66 Recent MRI study sup- mission. This supports the notion that the affective do-
ported the concept that OFC alterations might lead to main is a central part of the complex pathomechanism
catatonia by showing reduced surface area in the right of catatonia. Fourth, both previous and current MRI
medial OFC and left superior parietal gyrus in catatonia studies identified an association between catatonic af-
according to NCRS.67 Furthermore, catatonic patients fective symptoms and functional abnormalities in brain
showed hypergyrification in the left medial OFC and ros- regions responsible for processing of negative stimuli.
tral anterior cingulate cortex. This study illuminates the Northoff et al found decreased density of GABAA re-
neurodevelopmental hypothesis of catatonia by showing ceptors in the left sensorimotor cortex in akinetic cat-
an association between markers of early cortical devel- atonia.48 More recently, Hirjak et al59 have shown that
opment and catatonia in SSD.67 Another study suggested catatonic affective symptoms are associated with intrinsic
coaltered structure/function interactions in cerebellar, neural activity in frontoparietal network, which consists
prefrontal/cortical motor regions, and frontoparietal of the superior, middle, medial, and inferior frontal cor-
areas underlying catatonia in SSD.59 Overall, multiple tices which also contain the OFC. The role of the OFC
lines of evidence from above-mentioned rCBF and MRI is complex, because of its manifold interconnections with
studies suggest that alterations of the parietal cortex amygdala, hippocampus, thalamus, cingulate/medial pre-
lead to disturbed motor attention and preparation of frontal, premotor, and parietal areas.54,59 Basically, OFC
279
D. Hirjak et al

is responsible for decision making, mood regulation, humans with regard to the pathogenesis of catatonia as a
and impulse control.37,75,76 In catatonia, aberrant OFC- psychomotor syndrome?
prefrontal/parietal cortical connectivity reflects disrupted First, the cognitive control of negative emotions is
“horizontal modulation” of cortico-cortical relation, modulated by GABAA receptors in various prefrontal
which might lead to disturbed affective/mood regulation regions, such as the OFC and medial prefrontal cortex
(eg, fear), and consequently impulsive behavior and/or (PFC).85,86 Alterations of GABAergic neurotransmis-
aggressiveness.54,77 sion/inhibition in the OFC and PFC together with
Taken together, neuroimaging studies using NCRS hyperdopaminergic neurotransmission can lead to psy-
have revealed more higher-order cortical changes within chotic states and impaired processing of negative stimuli
cortico-motor circuits than the neuroimaging studies associated with the experience of anxiety.87–89 In line with
using motor/behavioral catatonia rating scales did.2,23 this, catatonic patients showed increased levels of dopa-

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The data suggest neural changes both in primary cog- minergic metabolites homovanillic and vanillic acid.90,91
nitive and affective regions, such as OFC and prefrontal Therefore, the administration of antipsychotics seems
cortex, and in parietal cortex—this renders catatonia to be rather controversial because it can lead to drug-
truly psychomotor rather than merely motor. Therefore, induced catatonia.92,93
neuroimaging studies using NCRS has provided scien- Second, the disturbed emotional processing can lead
tific evidence for a truly psychomotor concept of cata- to fluctuations in response inhibition due to activation/
tonia from the perspective of symptoms, nosology, and deactivation of the sensorimotor network comprising
neurobiology. the inferior frontal gyrus, PFC, inferior parietal lobule,
and pre-SMA. On the one side, lack of behavioral in-
hibition can lead to motor and behavioral catatonic
Dopamine vs GABA: Different Biochemical Substrates symptoms such as mannerisms, echolalia/echopraxia,
of Motor and Affective Symptoms grimacing, perseveration, and compulsive behavior. On
the other side, excessive motor inhibition might cause ri-
There is preliminary evidence that more severe catatonic gidity, akinesia, posturing, “Gegenhalten,” mutism, and
signs in SSD patients (n = 1,095) are associated with the stupor. In particular, switching between retarded and
loss-of-function allele of a myelin-specific gene (copy excited catatonia may be grounded in the hypoactivity
number polymorphism [CNP] rs2070106-AA) (AA = in- and hyperactivity of dopaminergic transmission.94 The
dividuals homozygous for the A allele).78 Interestingly, great clinical heterogeneity of catatonic symptoms can
the same study found that healthy individuals carrying be explained by the constantly changing activity of dif-
CNP rs2070106-AA showed white matter alterations in ferent neurotransmitter systems and brain networks.72
terms of higher axial diffusivity in frontotemporal and In particular, the GABAergic, glutamatergic (in partic-
subcortical brain regions.78 The authors concluded that ular the NMDA receptors) and serotonergic systems (ie,
these MRI findings indicate low-grade inflammation in upregulation of 5-HT1a and downregulation of 5-HT2a
healthy AA individuals. Furthermore, this study showed receptors95) may be involved in catatonia. This assump-
that 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) tion is supported by the good efficacy of benzodiazepines
null mutant mice showed neuroinflammation associated modulating GABAergic system and clozapine because
with catatonic signs at age of 8 weeks. This finding deter- of its broad receptor profile.96 Benzodiazepines induce
mines the causality between reduced expression of Cnp anxiolysis through positive allosteric modulation at the
(loss-of-function genotype), secondary low-grade inflam- GABAA receptor in prefrontal areas and might help to
mation/neurodegeneration leading to microgliosis and to release the affective symptoms.70 Furthermore, adminis-
catatonic signs (eg, bar test).78,79 tration of a GABAA receptor agonist lorazepam might
Another study on mice could show that D2-receptor- directly ameliorate GABAergic deficits in premotor and
deficient mouse show severe motor abnormalities such primary motor cortices (M1).23,41,97 Because GABA is
as aberrant locomotor-initiation and spontaneous cat- one of the main inhibitory neurotransmitter within the
atonia.80 Furthermore, late-onset loss of D2-receptors M1, the application of lorazepam or electroconvulsive
leads to aberrant execution of previously learned move- therapy (ECT) might increase the excitability of GABA-
ment sequences.80 These results once again underline the related inhibitory circuits in the motor cortex.66,80,97 This
fundamental role of dopaminergic neurotransmission assumption was also supported by a case report that
in motor skill learning and motor cortex synaptic plas- showed a successful amelioration of catatonic symp-
ticity.80,81 In addition, GABAergic neurotransmission toms following ECT and at the same time an increase of
plays an important role in catatonia as well. Earlier an- intracortical inhibition (ICI) (possibly due to an increases
imal studies demonstrated induction and reversal of in GABAergic transmission) as determined by double-
akinesia/posturing after injection of GABAA agonists pulse transcranial magnetic stimulation.98 This said, the
into motor cortex.82–84 What conclusions can be drawn application of lorazepam or ECT can balance the ICI
from basic animal research and neuroimaging studies in of the partially overactivated motor regions—as we can
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observe in catatonia56,58 or dystonia99—and normalize experiencing a renaissance. A number of authors is going

motor and behavioral disturbances.100 From an immuno- back to the origin of catatonia emphasizing its psycho-
logical perspective, GABAergic modulation can also sup- motor nature (increasingly including affective symptoms)
press the response of the immune system by reduction in a truly literal sense as it was understood by Kahlbaum
of proinflammatory cytokines and often help to relieve and formalized 20 years ago in terms of a rating scale
an infection-induced (viral meningitis or encephalitis, by Northoff.3,40,105 For the majority of catatonia rating
syphilis, systemic bacterial infection, etc.) catatonic syn- scales, high inter-rater reliability (correlation coefficient
drome.27,101 Furthermore, the glutamatergic hypofunction or Cohen’s kappa) was estimated: BCRS35 (r > .83), RCS30
(often caused by N-methyl-d-aspartate receptor enceph- (r = .81), MRS31,32 (Cohen’s kappa = 0.87), BFCRS33,34
alitis) might also lead to (autoimmune) catatonia.27 This (r = .93), and NCRS (r = .80–.96) (for further details, see
said, catatonia can be caused by an imbalance of excita-

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Sienaert et al106). However, only Northoff et al3 reported
tory glutamatergic neurons and by inhibitory GABAergic on the association between NCRS and Rosebush criteria,29
neurons.27,102 BFCRS, and MRS (all P < .0001; r = .72–.88). Although
In sum, supported on biochemical grounds, motor these scales define no severity criteria of catatonia,106
symptoms in catatonia seem to be modulated by changes Northoff et al3 were able to demonstrate that NCRS total
in dopamine, whereas affective symptoms may be score of >7 separates patients with from patients without
mainly associated with GABA and glutamate changes. catatonia with a sensitivity and specificity of 100%.
This is supported by the outstanding therapeutic ef- Although the BFCRS have fewer items (n = 23), it in-
fects of GABAergic (lorazepam) and glutamatergic cludes some symptoms that NCRS classifies as “affective”
(amantadine)103 agents on affective and motor catatonic (eg, combativeness, impulsivity, excitement, staring, and
symptoms.104 We thus conceive catatonia as truly psycho- ambitendency) as well. Accordingly, there is an overlap be-
motor syndrome that combines both GABAergic and tween the rating scales in terms of catatonic symptoms, even
glutamatergic higher-order cortical and dopaminergic though some are not defined the same way or named the
motor subcortical-cortical changes in a unique way.48,54,55 same way. The different terminologies may have contributed
to the different results of the MRI studies. In the future, the
Limitations clinically relevant, but somehow artificial differentiation be-
Several limitations apply to the body of neuroimaging research tween the individual symptom domains and the different
on catatonia and thus also to the present systematic review. catatonia rating scales require a standardization based on
Among the main methodological obstacles are ethical aspects empirical evidence and consensus of international scholars
of catatonia, dispersion of study samples, missing consensus to capture affective, motor and behavioral catatonic symp-
on the catatonia definition, overlapping patients’ samples, toms of an individual patient as one dimension. Such an ini-
and a wealth of different (partially older and less accurate) tiative would make it possible to better compare the findings
neuroimaging techniques, respectively. For instance, the MRI of individual studies and achieve further meta-analytical
scanning of patients with severe catatonic symptoms is only evidence on both neurobiology and treatment of catatonia.
rarely acceptable from an ethical point of view. Another limi-
tation is the limited availability of patients with catatonic sub- To date, however, the majority of studies examined pa-
type of schizophrenia. Therefore, we strongly acknowledge tients suffering from SSD with little attention being paid
a paradigm shift when investigating the pathomechanisms to the other mental disorders.48,54 Therefore, we strongly
of catatonia, ie, from a restricted motor–behavioral view to advocate transnosologic neuroimaging studies on cat-
a broader psychomotor framing that focuses on the interac- atonia that accurately map the neurobiological link be-
tion between affective, motor, and behavioral features. Future tween hypokinetic and hyperkinetic motor symptoms,
studies should focus on the assessment of catatonic symp- behavioral anomalies, and affective alterations as em-
toms using appropriate scales, neuroimaging, genetic and phasized by Kahlbaum. Taken in such transnosologic
biochemical methods in all mental disorders. Another lim- way, the catatonic syndrome can be conceived a para-
itation of our review may be the exclusion of clinical trials digmatic example of the recently introduced RDoC-
on the treatment of catatonia because a number of different nosological characterization that emphasizes syndromes
rating scales yielded similar results across different cohorts over categories. Future transdiagnostic MRI studies
of patients, questioning the specificity of affective domain. that examine catatonic symptoms need to show that if
However, the present systematic review examined whether the the criteria of catatonia are met, there are clearly delin-
putative pathomechanisms of catatonic syndrome depends eated structural and functional brain abnormalities un-
on the clinical rating scale used. derlying catatonic symptoms. This was also the aim of
recent 2 MRI studies59,67 in which we did not compare
Concluding Remarks patients with healthy volunteers but SSD patients with
For about 30 years, scientific research on motor abnormal- and without catatonia. A transnosologic approach will
ities in general and the catatonic symptoms in particular is decisively help to distinguish catatonia from SSD as well
281
D. Hirjak et al

as other mental disorders and establish catatonia as an to D.H. and WO 1883/6-1 to R.C.W.). The DFG had
independent diagnostic entity. no further role in the study design; collection, analysis
Nevertheless, in addition to numerous differences between and interpretation of data; writing of the report; and
the individual studies, there are also many overlaps between in the decision to submit the paper for publication. GN
the identified brain regions. What became evident in all men- is grateful for financial support from PSI and CIHR in
tioned studies is that regions of the motor system are—re- Canada.
gardless the diagnosis—important neuronal substrates of
catatonia. It may be that all studies—independent of the
methodology—represent the final stage of a catatonic devel- Acknowledgments
opment, ie, they might point to a motor system deficit as a The authors thank Frank Geisler for his support in cre-
consequence of aberrant affective/mood regulation (eg, fear).

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ating figure 2. The authors have declared that there are no
Moreover, catatonia paradigmatically exemplifies that no conflicts of interest in relation to the subject of this study.
symptom domains occurs in isolation. The clinical, nosolog-
ical, and neurobiological studies reviewed here and Kahlbaum’s
original description clearly demonstrate that catatonia is not a References
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