Feature Article Brain Imaging in Catatonia: Current Findings and aP; hysiol ic Model By Georg Northoff, MD, PhD ABSTRACT —_______________ Karl Ludwig Kahlbaum originally described eatatonia as ‘a piychomotor disease that encompassed motor, affective, and behavioral symptoms. In the beginning of the 20th century, catatonia was considered to be the motorie manifestation of schizophrenia; therefore, neuropathologic research mostly ‘focused on neuroanatomic substrates (ie, the basal ganglia ‘underlying the generation of movements). Ever though some alterations were found in basal ganglia, the findings in these subcortical structures are not consistent. Recently, there has been a reemergence of interest into researching catatonia. Brain imaging studies have shown major and specific alter- ‘lions in a right hemispheric neural network that includes the medial and lateral orbitofrontal and posterior parietal cortex. This neural network may be abnormally modulated by altered functional interactions between jraminobutyric ‘acid (GABA)-ergic and glutamatergic transmission. This may account for the interrelationship among motor, emo- tional, and behavioral alterations observed in both clinical phenomenology and the subjective experiences of patients ‘with catatonia. Such functional inerrelationships should be explored in further detail in catatonia, which may alto sere ‘as a paradigmatic model for the inestigation of paychorotor ‘and brain function in general. CNS Spectrums 2000;5(7):34-46 PON Catatonia was first desciibed by Kael Ladwig Kahlbaum in 1874" as a psychomotor syndrome characterized by ‘motor, affective, and behavioral alterations. Later, Kracpelin and Bleuler subsumed catatonia under the heading of dementia praecox, considering catatonia to be a subtype of schizophrenia. Because of this characterization, catatonia ‘was predominantly considered to be the motoric manifest tion of schizophrenia. In contrast, affective and behavioral Merations were seen to be associsted with schizophre rather than with catatonia itself. Neuropathologic studies have investigated the role ofthe basal ganglia in catatonia, because these subcortical structures are involved in gener- ating movements. For example, Kleis considered catatonia tobe an extrapyramidal disturbance. Inthe last 15 years, interest in catatonia has reemerged, and various studies of ts pathophysiology have been under- taken. The development of new imaging techniques has allowed the investigation of functional alterations in brain chemistry in this disorder. The purposes ofthis paper are: 1) to show the pathophysiologic findings in catatonia as seen with various imaging techniques; and 2) to develop a patho- af catatonic motor symptoms based 2 ni ‘Neuropathologic Findings “The various pathophysiologic findings related to catato- nia can be divided into neuropathologic, neurochemical, clectrophysiologic, and functional imaging findings (Table 1), Table 2 summarizes the findings in which the neu- ropathology of the basal ganglia (the caudate nucleus, nicleus accumbens, and pallidum) have predominated.™* Since these early studies yielded rather inconsistent results, they were never pursued, Furthermore, because these find- ings were made in patients with catatonic schizophrenia, it remains unclear whether these alterations are specifically related to catatonia itself or to schizophrenia. Although there are several case reporis with isolated brain lesions in organic catatonia, there are no systematic studies to date that investigate the underlying neuropathology of eatatonin in patients without schizophrenia. Most of the neuropathologic studies cited here were per- formed on the brains of patients with catatonic schizophre~ sia who were never expased to neuroleptics; therefore, these alterations in basal ganglia cannot be related to neuroleptic (entipeychotic) modulation, Nevertheless, findings should be considered rather cautiously, since the methods and techniques available when they were gathered may have produced artifacts Neurochemical Findings Dopamine has been the neurotransmitter of primary interest in catatonia, In early studies, Gjessing? found increased dopaminergic (homovanillic acid and vanillic acid) and adrenergic/noradrenergic (norepinephrine, rmetanephrine, end epinephrine) metabolites in the urine of acute catatonic patients with periodic catatonia. In addition, he found correlations between vegetative alter- ations and these metabolites. He suggested a close rele tionship between catatonia and alterations in posterior hypothalamic nucle 3 le la lo. p su the ic cal wh nol oy ye CA at nil tive phe tha the kin De. Nonhf s atoiae profesor in the Deparment of Payshitry t Oto-on-Cusriche University in Magdeburg, Gomany Volume 5 Number 7 «July 2000, 34 CNS SPECTRUMS VoiunRecent investigations of the dopami ‘otabelite homovanillic acid inthe plasma of ‘32 acute catatonic patients showed increased levels in the acute catatonic state," partiou- larly in those patients who responded well to lorszepazn,"* However, the dopamine agonist apomorphine exerted no therapeutic effect at all in acute catatonia patients." These data suggest thatthe dopaminergic system may be hyperactive in acute catatonia, Nevertheless, the finding of hyperactivity of the dopaminer- gic system contradicts the observation that ‘catatonia ean be induced by neuroleptic med- ications (neuroleptic-induced catatonia), which suppress dopaminergic metabolism and, therefore, should be therapeutic, These contradictory data suggest that catstonia can- not be subsumed into one entity with regard to dopaminergic metabolism, Recent interest in neurochemical alter- ations in catatonia has focused on aminobu- tyric acid A (GABA,) receptors because the GABA, receptor potentiator lorazepam is efi- cacious in 60% to 80% of all acute catatonic patients." One study investigated iomaze~ nil binding in 10 catatonic patiens wit afeo- tive ar schizophrenic psychosis using single photon emission computed tomography (GPECT) scanning, Since iomazenil i ligand that binds to the benzodiazepine subunit of the GABA, receptors without inducing any kind of alteration in the activity of the ecep- ‘TABLE 1. PATHOPHYSIOLOGIC FINDINGS IN CATATONIA Neuropathologic Caudave nucleus Nucleus accumbens Pellidurm Substanta nigra pars compacta Thalamus Neurocherical Dopamine GABA Glutamate Serotonin Electrophysiologic EEG Readiness potenti MRCPs Sea ad Funct imging i rete crt een Fit prc coer sinobsori add, EEGelacroencophalogr- hr movements occa poor tor iomazenil binding reflects the number and function of GABA, receptors. The fomazenil binding in these 1b eatatone patients were compared with the jomazeil binding in 10 noncatalonic psychiatric controls wit afec- tive or schizophrenie psychosis and 20 healthy controls." The eatatonie patients showed significantly lower GABA, receptor binding and altered right lft relatins inthe left sensorimotor cortex compared withthe two other groups In alton, the catatonic, patients exhibited significantly lower GABA, binding in the right lateral orbitofrontal and right posterior parietal cortex, correlating sig nificantly with motor and affective (but not ‘ith behavioral catatonic symptoms. Movoment-related cortial potentials (MRCPe) in catatonic patients both before and after lorazepam administration shoved abnor nal and inverse cleetophysiclogic reactivity. In addition, all eatatanie patients (ven thse in a postacute state) showed « paradoxical reaction to lorazzpam, reacting wit agitation rather than with sedation (as was the casein all psychiatric and healthy contos).* These studies indicate that catatonia may be asoei= ated with sbnonalites inthe GABAergic system, particulany the GABA, receptor, and tha these ebnormalities maybe ental o the pathophysiology of easton “The gitamatergi system, particularly the ‘N-methy|-0-aspatate (NMDA) receptors, may also be involved in catatonia, Some catatonic patients who were nonresponsve to lorazeparn have heen successfully treated with the NMDA antagonist amantadine. Therapeutic recovery occurred rather gradually." Such gradual improvement suggests thet NMDA receptors may he secondarily involved in catatonia whereas GABA, receptors appear tobe primarily involved. this assumption speculative, since nether the NMDA recep tors nor thei interactions with GABA, recep- tors have been invetgnted in atti In alton, the serotonergic (S-hydrox- steyptophan (5-H) system may also py 8 ole in the development of eatatoni Catatonia may be characterized by a dysequi- Ibrium in the serotonergie system wih upreg- ulated 5-HT, receptors and downregulated S-HTyq receptors.” However, since there are no imaging studies wit regard tothe 5-117 system in catatonia, this hypothesis remains speculative ee peo sweet cet CABA, mer “the dopamine ‘agonist spomorphine cxerted no thenpeutic cffectatallin acute catatonia patients, "These data suggest that the dopaminergic system maybe hyperactive in acute catatonia. Volume 5 Namber7 uly 2000 3 ONS SPECTRUM Sf Feature Article the right onitfronta, right parietal, and right basal ganglia with hyperperfusion ofthe ef ‘sersotimortor cortices in catatonia, There is evi- side in one patient,* a hypoperfusion in left} Senos for involvement ofthe glutamatergic sys- medial temporal structures in two patient” tems in particu, the NMDA receptors may be an alteration in vight parietal and caudal per ysrogslated by a primary abnormality in fusion in one patient," a decreased perfusion GADA, receptors, Dopaminergic and S-HT in the right parietal cortices in six patients” tranemssion may be altered in catatonia as and a decreased perfusion inthe parietal cor * a decreased ‘Wel, although thee is only indirect evidence for tex with improvement fllowing electroconral- the involvement ofboth systems in this disorder, sive therapy in one patient.” In addition, a perfasion in theright sytematic investigation of CBF with SPECT Structural and imaging in 10 postacute catatonic patients parietal cortexcorrelated Functional Imaging Findings with affective or schizophrenic psychos ‘A head computed tomography (CT) investi- showed decreased perfusion in the right pos significantly with motor gation of 37 patients with catatonic schizo- terior parietal and ight inferior lateral pr Phrenia showed a diffuse enlargement in frontal cortices compared with noneatatonie and affective symptoms, almost all cortical areas, particulary in frontal psychiatric controls with affective or schizo Cortical regions compared with hebephrenie phrenic psychosis and healthy controls." ‘aswellas abnormally and paranoid schizophrenic patients.” A sig- Furthermore, decreased perfusion inthe right nificant corelation between left frontotempo- parietal cortex correlated significantly with vwith visuospatial tal areas and illness duration was also motor and affective symptoms, as well as demonstrated in this stady. Other authors® abnormally with visuospatial and attentional and attentional observed a cerebellar atrophy in catatonic neuropsychologcal abilities. patients, but this has been investigated nei- Only three functional imaging studies in europsychological __ ther systematically nor quantitatively. catatonia have been performed to date due to Tnvestigations of cegional cerebral blood the zareness ofthis disorder and difficulty in abilities” flow (¢CBF) in catatonic patients with schizo- _ its investigation. Two eatstonic patients with phrenia showed a right-left asymmetry in the ‘TABLE 2, NEUROPATHOLOGICAL FINDINGS Neuropatholoai Caudate Nucleus “Degeneration of large and small cells Lack of lange eels ‘Decreased diameter of interneurons Nucleus Accumbens “Degeneration of large and small cells ‘Decreased diemeter of Golgi type 2 neurons Pallidum igre pans compacta ‘Decoleation without degeneration Thalamus ‘Decreased cll density in the mediodorsal nucl investigations of the brains of patients with catatonia schizophrenia have shown alterations in the following regions™: ‘Atrophied cells, increase of lipofuscin, decrease of cells, increase of Niel substance ‘Dectease of ell, increase of lipofuscin and Nissl substance ‘Atrophied cells, decreased cells, increase of lipofuscin ‘Lack of pyramidal cells, abeormal mineralzations and gliosis Decreased volume of interne pallidum with normal volume of the external pallidum Significantly lover number af nerve calls in internal and extemal pallidum end substentia, ‘Reciuoed volume of the lateral past with normal cell number ews ‘Volume 5 ~ Namber7 » uy 2000, Ey ONS SPECTROMcontinued trom page 36 schizophrenic psychosis were investigated using functional magnetic resonance imaging ((MRD) with a motor activation paradigra." Immediately after seceiving lorazepam, both patients were imaged while exhibiting postur- ing during performance of e motor task (sequential finger opposition). Catatonie patients showed a different patter of lateral- ization, with altertions predominantly in the right motor cortex. This contrasts with find- ings in Parkinson's disease, because no alter- ations in supplementary motor areas (SMAs) were observed. Based on subjective experiences showing intense emotional-motor interactions, an acti- vation paradigm for afectve-rotor interaction ‘was developed and investigated using fMRI ‘and magnetoencephalography in 10 postacute catatonic patients with affective or schizo- phrenic psychosis, 10 noncatatoni psychiatric patients with affective or schizophrenic ps chosis, and healthy controls.” The catatonic, patients showed alterations in the right medial orbitofrontal/lateral orbitofrontal-prefrontal activation/deactivation pattem and in early ‘magneto fields (which may be localized inthe ‘medial prefrontal cotes) during negative emo- tional stimulation, Behavioral and affective ccatatonie symptoms correlated significantly with reduced orbitofrontal cortical activity, ‘whereas motor symptoms correlated with pre- rmotor/motor activity. Negative emotional pro- cessing in the right medial orbitafrontal cortex, say be particuladly altered in cattoni, with ‘an abnormal functional connectivity to the pre- rmotorimetor cortex. A third study investigated auditory working ‘memory in MRI in sx catatoni patients with alfective or schizophrenic psychosis compared with noneatatonie psychiatric patients with adlective or schizophrenic paychoss and healthy cnntrol.* The catatonic patients showed signti- ‘cantly worse performance in working memory tasks and significantly deeeased activity in the lateral orbitofrontal and cartices com pared with the other two groups. Behavioral ‘atalonic symptoms comelated sigaficanty with orbitofrontal and premotor cortical activity, ‘whereas motor sympioms were relate to left t- cal prefrontal cortical activity Tn summary, imaging studies have demon- strated thatthe parietal cortex, particularly the right parietal cortex, may be involved in ‘catatonia. In addition, the orbitofrontal cortex nay be altered, as demonstrated using {MRI during working memory and emotionsl-motor activation. Imaging studies suggest that the network between the orbitofrontal cortex, pre~ ‘motor/sersorimotor cortex, and posterior pari- etal cortex inthe right hemisphere may be altered in catatonia. This hypothesis remains speculative, since this mode! is based only on single findings, and the right orbitfrontal- sensorimotorparietal netvork has not beet. investigated in its entirety daring functional activation or inthe acute catatonic state. orkng memory an miobuttic ce SMAsupplementary motor areas; ;~magnetoencephalograpy. races fad atesion ‘overt Ec newphay aasariereuiton of eciton ‘torment SCT FIGURE 1. Pathophisiologicel Sndings in catatonia, id) SPECT=single photon emission computed tomography, netonal magnetic resonance imaging, Feature Article ‘Votume 5 Number 7 «Jul 2000, 3 ONS SPECTROMS“Wohi patients with Parkinson's disease show distinct alterations in MRCPs, reflecting their difficulty in initiation of movements, the alterations in MRCPs ofcatatonic patients reflect their inability to fully execute and ‘terminate movements.” Electrophysiologic Findings ‘Since single catatonic symptoms can be observed in patients with epileptic seinures, a relationship between catatonia and epilepsy hhas been postulated." Therefore, a so-called nonictal paroxysmal subcortical dysrythmis ‘and/or an alteration in O-rhythm have been theorized in catatonia, However, no systematic clectroencephalographic (EEG) investigations have been performed in catatonic patients. Descriptive observations of BEG in systematic ‘studies have yielded neither major nor minor shnormalities in EEG." Since catatonia is characterized by impressive motor features, MRCPs have been investigated in this disorden. In this study, 10 postacute catatonic patients with affective or schizophrenic psychosis were investigated and compared with 10 noneata- tonic psychiatric patients with affective or schizophrenic psychosis and 20 healthy con- trols. Catatonic patients showed a signifi- cantly delayed onset of late readiness and movement potential in central electrodes compared with the noncatatonic psychiatric patients and controls, This delayed onset correlated significantly with catatonic motor symptoms end movement duration, In addi- tion, lorazepam led to significantly stronger delays of late readiness potential in fron- toperietal electrodes in the eatatonie patients compared with the other two groups. While patients with Parkinson's disease show distinct alterations in MRCPs, reflecting their difficulty in initiation of movements, the alterations in MRPs of eatatonic patients reflect their inability o fully execute and ter- ts. Therefore, unlike in the primary deficit in catatonia appears to be one of termination rather than one of initiation A third study investigated auditory working ‘memory using {MRI in six eatatonic patients with affective or schizophrenic psychosis, roneatatonie psychiatric patients with affec- tive or schizophrenic psychosis, and healthy controls." The catatonic patients showed sig- nificantly worse performance in working memory tasks as well as significantly decreased activity in the lateral orbitofrontal ‘and premotor compared with the other two ‘goups. Behavioral catstonic symptoms corre- lated significantly with orbitofrontal and pre motor cortical activity, whereas motor symptoms were related to left lateral pre- frontal cortical activity. maging studies have demonstrated that the right parietal cortex is altered in catato- nia, Functional MRI findings during working, ‘memory and emotional-motor activation have demonstrated that the orbitofrontal coxtex may also be altered. Thus, the network between the orbitofrontal, premotor/sensori- ‘motor, and posterior parietal cortices in the right hemisphere may be particularly altexred in catatonia. This hypothesis remains specu lative, sine itis based only on a single sturdy finding, To date, the right orbitofrontal-sen- sorimotor-parietal network has not been. investigated fully during functional acti va~ tion orin the acute catatonie state. PATHOPHYSIOLOGIC HYPOTHESIS ‘Early studies focused on the basal ganglia in patients without any exposure to neurolep- tic medications. Current studies have focused on cortical regions, since the basal ganglia can only be partially visualizecl in imaging, Most catatonic patients investigated in imaging studies have been medicated. In the studies by Northoff,"2"™ medication use was controlled for by using noncatstoniic psychiatric controls who received the same ‘medication. Nevertheless, the suggestion that medication use led to secondary alterutions in activation and deactivation patterns can- not be entirely excluded. Most imaging stad ies have investigated catatonic patients only in a postacute state, not in an acute state; therefore, the findings reflect a trait marker rather than a state marker. ‘Taking these methodologic limitations into account, the goal should be to develop a pathophysiologic hypothesis for catatonia, relying on clinical phenomenology and patho- physiologic findings. Since catatonic symp- toms are quite complex, it must _be presupposed that distinot categories of cata- tonic symptome are subserved by distinct underlying neural networks. Therefore it can be assumed that distinct pathophysiologic ‘mechanisms and underlying neural networks ‘exist for motor, affective, and behavioral symptoms in eatalonia.* Pathophysiology of Motor Symptoms Motor symptoms in catatonia have been ‘compared to those in Parkinson's disease, Since akinesis is a prominent symptom shared by both disorders, one expects similar ‘alterations in MRCPs and fMRI findings chur- ‘Volume 5~Nariber 7» Jay 2008, 0 ONS SPECTRUM Sing the generation of movements. However, {n contrast to Patkinson’s disease," catatonia can be characterized neither by alterations in the SMA not in the early readiness potential, ‘as related to function of SMA. Since the SMA itself does not appear tobe primarily affected in catatonia, there seems to be no primary deficit in internal initiation of movements. This has been shown by the diminished abil. ity of catatonic patients to respond to the ball test, which requires patients to catch, throw, stop, and kick @ ball while in the acute catatonic state* Catatonic patients are well able to initiate ‘movements, but they are apparently unable to terminate the movement once initiated in an appropriate way. In contrast to initiation neural networks, the study of underlying ter- rmination of movements has been neglected in the research to date. In healthy individuals, termination of movements is believed to involve the right posterior parietal cortex, because the registration and on-line monitor- ing of the respective spatial position of the movement may be of central importance for an appropriate termination.® Since findings in imaging and neuropsychology indicate rela- between deficits in visual-construc- tive functions and decreased rCBF in the right posterior parietal cortex, alterations in the right posterior parietal cottical function may account for the deficit in termination of move ments in catatonia that result in the motor symptom of posturing. This assumption is far- ther supported by our findings in late MRCPs well a (MRI, reflecting alterations in ter- rmination rather than initiation. Ifregstration and on-line monitoring ofthe spatial position of movements (as related to right posterior parietal cortical function) are deficient in catatonia, this should lead to an unawareness of the respective spatial position, This is indeed the case since catatonic patients (unlike Parkinson's disease patients) suffer fiom anosognosia of posturing,” ‘This model of motor symptoms may explain the finding by Saponik et al” of catalepsy in 2,3% of patients with stroke. Catalepsy was demonstrated in the non- paetic side, and head CT scanning revealed ischemic infarcts in the middle cerebral avery teritory in most cases Tn summary, alterations in the right poste- xior parietal cortex—related to registration ‘and on-line monitoring ofthe spatial positon cof movements and, thus of termination—and ‘Volare 5 Namber 7 «Jay 2000, GABAcigic neurotransmission may be of pie ‘ary importance in the pathophysiology of ‘motor symptoms in catatonia (Figure 1). Involvement ofthe basal ganglia, as indicated by earlier neuropathologe findings remains unclear, sinoe these ere dificult to visualize in funotional imaging. Pathophysiology of Affective Symptoms There are strong affective alterations in catatonia that eannot be essocated entirely with an underlying lfetive payshosis. This ‘observation is supported by the therapeutic effectiveness of the anxiolytic lorazepam, as well as the subjective experiences ofthese patients who report strong, intense, and uncontrollable anxieties that make them immobilized by anxiety.”* Consequently, the affective dimension should be included ‘as one symptomatic category in catatonia,” although it may be difficult to distinguish it from the affective alterations related tothe underlying diseases of either affective or schizophrenic psychosis Based on subjective experiences of the strong interrelatonship between efective and ‘motor symptoms, an emotional-motor activa- tion paradigm has been developed and inves- tigated in catatonia, In this paradign, calatoni patients showed an abnormal sctive~ tion/deactivation patter in the medial orbitofrontal and lateral orbitofrontal/pre~ frontal cortices during negative emotional stimulation, exhibiting deactivation inthe medial orbitofrontal region and activation in the lateral orbitfrontal/prefrontal cortex. This patter is almost inverse to that observed in healthy controls. Since the medial nbitofrontal cortex is reciprocally connected ‘withthe amygdala itis strongly involved, par ticularly in negative emotional processing "* Reduced and altered ectivation in the orbitofrontal cortex may account for alfective alterations in catatonia as reflected by patients nability to contol and reduce negae tive emotional experiences. In addition, we have found alterations in functional connectivity between the medial orbitofrontal and premotor/motor cortices in catatonic patients with affective or chizo- phrenic psychosis compared with noncata- tonio psychiatric patients with affective or schizophrenic psychosis and healthy con- trols? These findings suggest that a disturbed functional connectivity between the orbitofrontal and premotovinotorcutices may > a Feature Article “Since findings inimaging and neuropsychology indicate a relationship between deficits in visual-constructive fanetionsand decreased CBF in theright posterior atictal cortex, alterations in the sight posterior parietal ‘cortical function may account forthe deficit intermination of movements in catatonia that result in the motor symptom of posturing.” ONE sPeCTRUMSFeature Article be closely related to the generation of motor symptoms. The origin of motor symptoms in catatonia may stem from an alteration in the relationship between emotional and motor functions (ie, between the mediel orbitofrontal and premotor/moter cortices). This hypothesis caresponds with the early characterization of Alterations in the amygdala and medial poral structures may be of central import in catatonia; however, the origin of distur activity pattems in the orbitofrontal cortex reruains unclear (Figure 1), and their respec: tive roles may differ depending on the pri ‘mary psychiatric illness (affective 0 “In catatonia, catatonia as 2 psychomotor disease by _ schitophrenic psychosis) Homburger, as well as with the subjective decreased inhibition experiences of these patients. Pathophysiology of “The activation/desctivation pattern in the Behavioral Symptoms (reduced GABAergic medial and lateral orbitofrontal cortices dur- Tn addition to motor symptoms, catston ing emotional stimulation appears to be mod- patients often show bizarre behavioral alter ‘eansmission) renders ulated by GABAergic transmission, since ations. These predominantly include repetitive use of the GABAergic agent lorazepam in phenomena, such as echolalia, stereotypes, the orbitofrontal healthy controls leads to a reversal of the perseveratons, etc. They may also exhibit dis sotivationideactivation pattem in exactly the turbances of will, such as automatic obedi cortex unable to same way as has been observed in catatonic ence, negaivisms, ete. Such phenomena imply patients not taking lorazepam.” Alterations that calatonio patients are no longer able to cxertits'gating’ in the activation/deactivation pattern in the control their behavior either involuntarily or redial and lateral orbitofrontal cortices in voluntarily i an appropriate manner function on further catatonia may be related to GABAergic dys- Control of behavior implies on-line moni- function. This accords with findings in toring, which is usually regarded as a part of prefrontal and frontal SPECT imaging af benzodiazepine receptors, working memory. Behavioral investigation a! which show reductions in the right inferior working memory has shown severe deficits cortical areasso that prefrontal (ie, the orbitofrontal) cortex. In catatonic patients that cannot be related to Catatonia, decreased inhibition (reduced reduced ability of storage but rather to severe prefrontal activity GABAergic transmission) renders the deficits in on-line monitoring, since catatonic orbitofrontal cortex unable to exert its “gat- patients may be characterized by significanty becomes dysregulated ing” function on further prefrontal and more mistakes in both one-back and two-beck frontal cortical areas so that prefrontal activ- tasks compared with noncatatoni psychiatie Smits entirety.” ity becomes dysregulated in its entirety. This patients and healthy controls" may account for alterations in orbitofrontal. In addition, SMI has show that catatonic premotor/motor cortical connectivity. patients may demonstrate significant However, the assumption of a relationship decreased activation in the leteral between alterations in the activation/deacti- orbitofrontal and premotor cortices predomi vation pattern in the medial and lateral nantly on the right side, correlating signif- orbitofrontal cortices (and reduced GABA, cantly with behavioral symptoms, Behaviord receptors) remains speculative, since there is alterations in catatonia may be related to dye no direct evidenve for bilateral dependency. function in the lateral orbitofrontal corte. Catatonia may be characterized by alter- Lesion studies in patients with orbitofrontal ations in the medial and lateral ozbitofrontal cortical lesions show repetitive phenoment totivation and deactivation patterns during and disturbances of will that are similar o temotional-motor stimulation. This extends to those observed in catatonia, The medial ad alfective symptoms and (via a disturbance in lateral orbitofrontal cortex may be subject orbitafrontal-premotor/motor functional con- inverse and reciprocal kinds of activity (eth nectivity) to motor symptoms. In addition, activation or deactivation); these appear tobe tlterations in the activation/deactivation pat- mutually dependent on each ather.™® tee in the medial and lateral orbitofrontal In addition, dysfunction in the lateral cortices may be closely related to alterations orbitofrontal cortex may be closely related o in GABAergic transmission, (Direct evidence alterations in negative emotional processing a for this, however, is still lacking.) Catatonia the medial orbitofrontal cortex, which may may be regarded as a true psychomotor dis- account forthe close relationship between turbance, where alterations in neural net- behavioral and affective symptoms in catate ‘works underlying emotional functions are nia. Furthermore, the lateral orbitofrontal or transformed into abnormal movements. tex is reciprocally connected anatomically ‘Velume 5~ Nomber7 «fay 2000, a CNS SPECTRUM SMAI ARAN EN vaxwith the posterior parietal cortex via long association fibers, Ths relationship between the lateral orbitofrontal and posterior parietal cortices may aceount for the deficit in on-line ‘monitoring of the spatial position of move- ‘ments, which may be a central factor inthe pathophysiology of posturing (characterized by an inability to terminate movements). In the working memory study,” lateral orbitofrontal cortical function is closely related to the ability of on-line monitoring, ‘whereas posterior parietal cortical function ‘accounts for spatial registration. Consecutive tasks requiting both on-line monitoring and spatial registration/spatial attention lead to coactivation in both the right lateral orbitoftontalower lateral prefrontal cortices, as well as the right posterior parietal cortex.® Based on the author's findings, it appears that the alterations that are predominantly present in the right medial/lateral orbitofrontal and right posterior parietal cor- tices invoke dysfunetion in the right medial/leteral orbitoftontal-posterior pazi- etal cortical neural network during on-line monitoring of the spatial position of move- ‘ments, This hypothesis remains speculative, since neither region (orbitofrontal or pari- etal) has been investigated within the same session in functional imaging or during ter- ‘mination of movements, In contrast to the relationship between the medial and lateral orbitofrontal cortices, which appears to be primarily modulated by GABAergic (ie, inhibitory) transmission, the relationship between the lateral orbitofrontal ‘and posterior parietal cotices must be primar ‘ly modulated by glutamatergic (, excitatory) ‘anamission, since long association fibers are excitatory. The relationship between GABAergic and glutatamergic transmission may be altered in catatonia, which may account for the therapeutic efficacy of both orazepam (« GABA, potentiator) and aman- tadine (an NMDA atiagonist). Nevertheless, the exact mechanisms involved in catatonia remain unclear and cannot be supported by Girect empiric evidence. Since the orbitofrontal cortex has direct connections to the basal ganglia, particularly to the caudate nucleus, alterations in the orbitofrontal cortex may lead to consecutive ‘modulation in the function of the basal gax- glia. This direct orbitofrontal-caudate rela- Cionship may account for the generation of abnormal movements in relation to behavioral ‘Volume 5 = Number 7 «uy 2000 alterations as well es for eerler neuropatho- logie findings in the basal ganglia. Sine the basal ganglia are difficult to investigate in functional imaging, this assumption remains tobe proven. In sumumary, behavioral alterations in ceta- tonis may be closely related to defic behavioral controls, as reflected in a reduced capacity fr on-line monitoring. This deficit in on-line monitoring may be subserved by altered end reduced activation in the lateral onbitofrontal and premotor cortex, as demon strated in working memory during {MRI Since the lateral orbitofrontal cortex is recip- reeally connected to the posterior parietal cor- tex, right-hemispheric dysfunctional connections between both regions may account for deficits in on-line monitoring of the spatial position of movements and for deficits in the posterior parietal cortex (as observed in SPECT imaging) (Figure 1). Furthermore, the dysfunctional lateral orbitofrontal-posterior parietal connection may be modulated by interactions between GABAergic and glutamatergic trmsmission. ON Catatonia was originally described by Kahlbaum as a psychomotor disease with a peculiar constellation of motor, effective, and behavioral symptoms. Early in this century, the conceptualization of catatonia was zeduoed to motor symptoms, and research focused consecutively on the corresponding ‘anatomic structures of the brain (i, the basal ganglia), In the following decades, research into eatatonie decreased considerably. However, inthe pest 10-20 yeas, interest in catatonia has reemerged. It became clear that catatonia ean neither be equated with motor symptoms, nor be subsumed exclusively under schizophrenia. Therefore, catatonia 5 currently considered to be a “psychomotor syndrome as a final eommon functional path- vray of affeative and schizophrenic psychosis” (and other medical and psychiatric diseases). Despite methodologic problems, modera ‘maging techniques allow for imaging of the neural networks that potentially undery cata- tonic symptoms. Brain imaging results indi- cate functional alterations in the neural network between the right medial and lateral ‘orbitofrontal cortices and the right posterior parietal cortex, This may account forthe close interrelationship between emotional and tmotor symptoms, as wel as forthe interela- > s Feature Article on-line monitoring ofthe spatial postion of movements.” ONS SPECTRUMSFeature Article tionship between affective and behav- ioral symptoms observed in clinical symptoms reported in the subjective ‘experience ofthese patients. Tis right hemispheric medial/lateral nbitofrontal-posterior parietal cortical network may be modulated by interac- tions between GABAergic and gluta- ‘matergic transmission. Consequently, research into the pathophysiology of catatonia should return to Kahlbaum's initial description of catatonia as & paychomotar disordes Investigation of such functional interrelationships may be of interest not only for catatonia itself, but because it also may provide a better understanding ofthe healthy brain, In this way, catalonia may be considered a paradigmatic model for psychomotor and brain research in general I ES 4. Kablbaum “K. Die Kwatonle ofer das Spacnangsimee. Iv Bie Fam Poyeischer Krai Ban, Germany: Hirsch 1674 2, Klein K. Die haan (Cerna), Newnan. aise. 8, Bogart B, Mera, chil ‘engl ond lib stam pele in ehiz- iors rch Gx Pcl. 1985 2:79 791, 4, Dom R, de Sadeler R, Bogets B, otal (Quantaive eyo nays of bal px li in exten eigen. la: Penis C, Stune G, Jansson By ods, Biological Prychiaty, Amsterdam, ‘The Nethsands: levi 1981-723-S726, 5, Hopf A Orintienndeuntersacung ur ge pathoenatonicher yertnderigen im pal dum and eritus beiechiophrenie (Gera). 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