APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.

Neuropsychiatry
Neural Correlates of Catatonia
E. Mohandas, V. Rajmohan
Elite Mission Hospital, Koorkkencherry, Thrissur, Kerala

Kahlbaum described a psychomotor syndrome Some groups have mentioned that 25% or more of
in 1874 (in his monograph ‘Die Katatonie oder das manic patients have enough catatonic features to
Speannungsirresein’) most commonly associated meet the DSM criteria and that more than half of
with affective disorder. Bleuler identified this catatonic patients have manic-depressive illness.
phenomenon as occurring with motor symptoms Catatonia occurs in general medical conditions like
exclusively in schizophrenia. His description metabolic disturbances, endocrinopathies, viral
ignored the other dimensions of catatonia especially infections (including HIV), typhoid fever, heat
the affective symptoms. 1 Currently catatonia is stroke, and autoimmune diseases Drug intoxications
considered as a complex psychomotor syndrome and withdrawals may also induce catatonic
(much like Kahlbaum’s description) which can be symptoms. Around 10%–15% of patients with
manifested across a wide range of neuropsychiatric catatonia meet the criteria for schizophrenia.2
conditions. Despite hundred years of research the The most common signs are mutism, posturing,
neural underpinnings of this syndrome have not negativism, staring, rigidity, and echophenomena.
been clearly delineated. Neuroimaging data suggest These signs occur in two principal forms, a retarded-
possible involvement of certain brain areas in stuporous variety and an excited-delirious variety.
catatonic syndromes. Multiple neurotransmitter Though 17 signs were described by Kahlbaum,
systems may also be involved in the mediation of other authors have extended it to 40 or more
catatonic symptoms. The nosological status, phenomena. The presence of two prominent signs
pathophysiology, the assessment methods and is sufficient for the patient to meet the current DSM
definitive treatment have to be further clarified criteria without any mention of duration criteria.
through future research. However, scales employed to assess catatonia
consider a duration criteria of several to 24 hours.2
Catatonia in Neuropsychiatry
Catatonia is defined in DSM (Diagnostic and NEUROANATOMY
Statistical Manual of Mental Diseases) classifica- Animal Models of Catatonia
tions mainly as a subtype of schizophrenia. The Studies have shown that catatonia is seen only
classification disregards the ubiquitous nature of in animals with neocortex. Animal experiments
catatonia and discourages its recognition in other using bulbocapnine (a D2 receptor antagonist),
psychiatric illnesses. Further, it limits treatment of show that low doses of this agent cause catalepsy,
catatonia to protocols focusing on antipsychotic but whether this resembles catatonia or neuroleptic
drugs.2 induced catalepsy is open to debate. Catatonia like
Prevalence of catatonia among psychiatric state is also produced by the injection of bicuculline
patients ranges from 7.6% to 38%. Catatonia is (a GABA-A antagonist) into the ventral tegmental
found in about 10% of acutely ill psychiatric area (VTA). Excitation of the ascending reticular
inpatients and is more commonly observed in activating system via strong sensory stimuli
persons with mood disorder than in those with (footshock stress) induces catatonia like reaction
schizophrenia. Kraepelin had mentioned that 50% in animals. This process involves the excitation of
of catatonic attacks begin with a depressive episode. the striatal system via thalamic nuclei. These

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experiments demonstrate the role of dopaminergic/ tomography (CT) and magnetic resonance imaging
GABAergic modulation and stress induction in (MRI) show cortical enlargement especially the left
simulating human catatonia.1,3,4 frontoparietal area in catatonics. Although temporal
cortical enlargement is present in the schizophrenic
Postmortem studies subtypes, preferential prefrontal and parietal
Pre-neuroleptic era postmortem studies could enlargement have been observed in catatonic
not demonstrate any substantial alterations in the schizophrenia. 5
basal ganglia and thalamus of catatonic patients. ii) Functional imaging
These studies were on patients with catatonic
Regional cerebral blood flow (rCBF) studies
schizophrenia, and it is controversial whether these
in catatonia have shown right left asymmetry in
findings reflected the changes in catatonia or
basal ganglia, hypoperfusion of left medial temporal
schizophrenia. 1
area, and hypoperfusion in the right parietal cortex.
Neuropsychological Explorations Single photon emission computerized tomography
(SPECT) shows decreased perfusion of right
Neuropsychological studies have shown that posterior parietal and right inferior lateral prefrontal
catatonics perform poorly in the visual-object-space cortex. The right parietal hypoperfusion also
and perception test (VOSP) compared to psychiatric correlates significantly with impaired visuospatial
and healthy controls. The ability to process spatial ability and the motor and affective symptoms in
position of movements is required for termination catatonia. In addition to this, it is observed that
of movements, a defect of which results in isolated lesions of the right parietal cortex result in
posturing. VOSP test is specific for right parietal posturing.1
cortical function. Orbitofrontal cortex (OFC) Functional imaging during motor activation
dysfunction has also been documented by shows deficits in the orbitofrontal activation (OFC)
neuropsychological data suggesting a failure of the during negative emotional states. Ther e is
ability to take emotionally guided intuitive decisions neuroimaging evidence that the orbitofrontal
and an inability to perform online monitoring connectivity with the motor/premotor cortex is
required for decision making. These studies suggest abnormal in catatonics. The right orbitofrontal
the probable role of both right parietal and OFC in activation during negative emotional stimulation is
catatonia.1 altered and the activation is shifted to the anterior
cingulate and medial prefrontal cortex. There is
Electrophysiological Evidence evidence that behavioral and affective symptoms
The generation of movements involves the of catatonia correlates with reduced orbitofrontal
phases like ‘Plan/strategy’, ‘Initiation’ and activity and the motor symptoms correlate with
motor/premotor activity.1
‘Execution’. The investigation using movement
Catatonic patients show a significant decrease
related cortical potentials (MRCP) shows that
in right lateral orbitofrontal cortex (including
catatonia is characterized by a preserved ability of
ventrolateral prefrontal cortex) activation during
‘Plan/strategy’, ‘Initiation’ and ‘Execution’. MRCP
working memory tasks. This deficit in working
studies show that while initiation is normal in
memory may be related to a deficit in the online
catatonics, the initiation of termination is delayed. monitoring of spatial position of movements.6
Initiation of termination of movements as measured
with MRCP in catatonics show a significant delay NEUROCHEMISTRY
of MRCP in the parietal electrodes. This deficit may 1) GABA
reflect a delay in the online monitoring of spatial The efficacy of lorazepam in allaying the
position of movements by right parietal cortex.1 symptoms of catatonia has increased the focus on
NEUROIMAGING IN CATATONIA GABA in catatonia. SPECT study of Iomazenil
binding which reflects the number and function of
i) Structural imaging
GABA-A receptors shows significantly lower
Structural imaging with computer ized binding of GABA-A in the right orbitofrontal cortex

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and right posterior parietal cortex. There is also a and a down-regulated 5HT2a receptor in the genesis
significantly lesser GABA-A binding in the left of catatonia. 9 However,recent studies have
sensorimotor cortex in catatonic patients.1 Study of demonstrated beneficial effects in catatonia with
catatonia with functional magnetic resonance olanzapine.10,11
imaging (fMRI) and magneto-encephalogram Analysis of studies shows that no single
(MEG) shows that prefrontal cortical activation/ neurotransmitter system is solely responsible for
deactivation pattern during negative emotion is catatonia. This has lead to the suggestion of a
modulated by GABA-A receptors. 1 Studies also ‘universal field hypothesis of catatonia, which states
show that lorazepam shortens the MRCP delay that the interaction of these neurotransmitter
during ‘initiation of termination’ in catatonia. systems is responsible for catatonia. The hypothesis
Zolpidem a GABA-Aa agonist is another agent also points to a neurochemical predisposition for
useful in catatonia. Although still controversial, the development of catatonia.9
some studies have opined that agonism
Pathophysiology of Catatonic Symptoms
(stimulation) of GABA-Ab receptor (e.g. valproic
acid) in the context of reduced GABA-Aa efficacy Though the neural correlates of the symptoms
can cause catatonia. This has lead to the GABA- that form the syndrome of catatonia are unclear, a
Aa versus GABA-Ab hypothesis of catatonia.7 tentative hypothesis regarding the possible
neuropathology of the symptoms is proposed based
2) Dopamine
on the neuroanatomic and neurochemical
Vanillylmandelic acid (VMA) and homo- explorations.
vanillic acid (HVA) estimation in the urine samples Mutism and Stupor: The neuroimaging
of patients with periodic catatonia shows an studies have shown that the orbitofrontal
increase in the levels of these dopamine metabolites, connectivity with the motor/premotor cortex is
suggesting a dopaminergic excess in catatonia. abnormal in catatonics. The right orbitofrontal
Recent evidence also hints at an increase in activation during negative emotional stimulation is
dopamine particularly in those patients responding altered and the activation is shifted to the anterior
to lorazepam. These findings may appear to be cingulate and medial prefrontal cortex. This shift
contradictory to the observation that dopamine in function especially to the anterior cingulate,
blockers like antipsychotics induce catatonia. This probably results in a heightened activity of the
has to be understood in the context of the specific affective division of the anterior cingulate. This then
sites of dopaminergic alterations occurring in leads to an almost complete down-regulation of the
catatonia. The drug induced catatonic states may motor portion of the anterior cingulate which may
be due to striatal dopaminergic blockade. account for mutism. The shift of function to the
3) Glutamate medial prefrontal cortex, an area involved in social
The observation that catatonia improves with cognition and the perception of movements and
the NMDA glutamate antagonist amantidine and mental states of others, may lead to an altered
memantine suggest a possible role of glutamatergic function of this area. The medial prefrontal
system The primary alteration may be in the GABA- dysfunction may result in total inability of verbal
ergic system with secondary involvement of and non verbal contact with others resulting in
glutamatergic system. The glutametergic excess stupor.1
seen especially in the posterior parietal areas is also Posturing: In catatonia, the maintenance of
speculated to be due to the reduced GABA levels postures is hypothesized to be due to a failure in
in the orbitofrontal area and supplementary motor the termination of movements. It involves the
area.8 interaction of areas involved in spatial attention and
the ‘initiation of termination’ of movements. The
4) Serotonin right inferior parietal cortex is proposed to be the
The atypical antipsychotics with serotonergic structure involved in these functions and
antagonism may suggest a serotonergic dys- dysfunction here possibly results in posturing.1
equilibrium with an up-regulated 5HT1a receptor Perseverative behaviour: Catatonia has

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behavioral features like negativism, sterotypies, to the motor cortex (horizontal or cortico-cortical
perseveration, echolalia and echopraxia. These are regulation) may down-regulate the striatal D2
posited to be the result of a defect in the lateral part within the motor loop and result in hypertonus.1
of the orbitofrontal cor tex including the Affective symptoms: The affective sympto-
ventrolateral prefrontal (VLPFC) cortex, the matology of catatonia possibly results from a defect
dorsolateral prefrontal cortex (DLPFC) and the in the balance between lateral and medial
posterior parietal cortex (PPC). The lateral part of orbitofrontal cortex. The medial orbitofrontal cortex
the orbitofrontal cortex including the VLPFC is area via the amygdala especially its basal nucleus
related to control of complex behavior while the has rich limbic connections and is involved in the
DLPFC is involved in planning of complex processing of emotions. The shift in function during
behaviour. Both OFC and DLPFC have reciprocal negative emotions as described earlier leads to
connections with PPC. The VLPFC deficit leads to greater activation of the medial orbitofrontal cortex
lack of suppression of behaviors once they have with resultant affective features.1
started leading to perseveration. The DLPFC defect
Conclusion
leads to an inability to plan.1
Waxy flexibility and Rigidity: There is a Neuropsychological and neuroimaging find-
striatal, especially globus pallidus internum ings generated renewed interest in understanding
dysfunction, leading to the rigidity and waxy the functional neuroanatomy of catatonic
flexibility in catatonia. This however is not as robust symptoms. The major brain substrates include
as in Parkinson’s disease and catatonia is probably OFC, DLPFC, premotor loop, striatum and PPC.
char acterized by a kind of smooth muscle (Figure 1) The neurotransmitter abnormalities in
hypertonus without r igidity causing the catatonia include the low GABA A activity (in the
characteristic catatonic rigidity and waxy flexibility. OFC), low D2 activity (striatal D2), the alterations
This hypertonus is due to a striatal D2 down- in NMDA glutamatergic system, (increased
regulation. The orbitofrontal top-down regulation posterior parietal glutamate) and a high 5HT1A
of the D2 loop in the caudate in the orbitofrontal activity. The neurotransmitter abnormalities in
loop is a possible way of D2 down-regulation. It is catatonia have provided valuable clues to the
also speculated that the orbitofrontal connectivity effective treatment of catatonia. Future research is

Figure 1: Neural Circuit of Catatonia

Glu Initiation of Termination

T
PPC
O
P
Affective DLPFC (plan)
D
O Med.
W OFC Lat. OFC (Behavior) Premotor/ Motor
N Cortex
GABA DA
R
E
G
U Thalamus Putamen Thalamus
L CN
A
T DA(D2) DA (D2)
I
O GPi/ SN GPe/SN
N
OFC loop Motor loop
Med.- Medial, Lat.- Lateral, CN- Caudate nucleus, GPi- Globus pallidus interna, Gpe- Globus pallidus externa SN-Substantia
nigra, DA- Dopamine, Glu- Glutamate, OFC-orbitofrontal cortex, PPC- posterior parietal cortex, DLPFC- dorsolateral prefrontal
cortex. (Modified from Northoff, 2002)1

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APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1

needed to elucidate the exact neuroanatomic and 6. Leschinger A, Baumgart F, Bürger E, et al.
neurochemical abnormalities associated with Orbitofrontal cortical dysfunction and
catatonia. behavioral anomalies in catatonia: Auditory
working memory in fMRI. Psychiatry Research
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