-
This new orientation, of which Jellife spoke, and of which
hehimself was a notable exemplar, did not involve merely combin-ing
neurological and psychiatric knowledge, but conjoiningthem, seeing
them as inseparable, seeing how psychiatric phe-nomena might emerge
from the physiological, or how, con-versely, they might be
transformed into it.
(O. Sacks 1989, p. 157)
Comparison between Parkinsons disease and catatonia re-veals
distinction between two kinds of modulation, verticaland
horizontal. Vertical modulation concerns cortical-sub-cortical
relations and apparently allows for bidirectionalmodulation. This
is reflected in the possibility of both top-down and bottom-up
modulation and the appearance ofmotor symptoms in Parkinsons
disease as well as catatonia.Horizontal modulation concerns
cortical-cortical relationsand apparently allows only for
unidirectional modulation.This is reflected in one-way connections
from prefrontal tomotor cortex and the absence of major affective
and be-havioural symptoms in Parkinsons disease. It is
concludedthat comparison between Parkinsons disease and
catatoniamay reveal the nature of modulation of cortico-cortical
andcortico-subcortical relations in further detail.
1. IntroductionDifferential diagnosis in neuropsychiatry is
often rather dif-ficult since similar symptoms may be related to
different
diseases, being either neurologic or psychiatric. For exam-ple,
the symptom of akinesia can be caused either byParkinsons disease
(PD), classified as a neurological dis-ease, or by catatonia,
usually classified as a psychiatric dis-ease. Moreover, the same
symptom, that is, akinesia may beaccompanied by different
psychological alterations: eitherdepression, as in PD, or
uncontrollable anxieties, as in cata-tonia. Consequently,
consideration of both symptomaticorigin and complexity makes
classification of diseases as ei-ther neurologic or psychiatric
rather difficult. This is re-flected in a so-called conflict of
paradigms pointing outthe inability to draw a clear dividing line
between neuro-logic and psychiatric disturbances (Rogers 1985).
If symptoms of different origin, either psychiatric or neu-
BEHAVIORAL AND BRAIN SCIENCES (2002) 25, 555604Printed in the
United States of America
2002 Cambridge University Press 0140-525X/02 $12.50 555
What catatonia can tell us abouttop-down modulation:A
neuropsychiatric hypothesis
Georg NorthoffLaboratory for Magnetic Brain Stimulation,
Department of Neurology, BethIsrael Deaconess Medical Center,
Harvard Medical School, Boston, MA
[email protected]
Abstract: Differential diagnosis of motor symptoms, for example,
akinesia, may be difficult in clinical neuropsychiatry. Symptoms
maybe either of neurologic origin, for example, Parkinsons disease,
or of psychiatric origin, for example, catatonia, leading to a
so-calledconflict of paradigms. Despite their different origins,
symptoms may appear more or less clinically similar. Possibility of
dissociationbetween origin and clinical appearance may reflect
functional brain organisation in general, and
cortical-cortical/subcortical relations inparticular. It is
therefore hypothesized that similarities and differences between
Parkinsons disease and catatonia may be accounted forby distinct
kinds of modulation between cortico-cortical and
cortico-subcortical relations. Catatonia can be characterized by
concurrentmotor, emotional, and behavioural symptoms. The different
symptoms may be accounted for by dysfunction in
orbitofrontal-prefrontal/parietal cortical connectivity reflecting
horizontal modulation of cortico-cortical relation. Furthermore,
alteration in top-down mod-ulation reflecting vertical modulation
of caudate and other basal ganglia by GABA-ergic mediated
orbitofrontal cortical deficits mayaccount for motor symptoms in
catatonia. Parkinsons disease, in contrast, can be characterized by
predominant motor symptoms. Mo-tor symptoms may be accounted for by
altered bottom-up modulation between dopaminergic mediated deficits
in striatum and pre-motor/motor cortex. Clinical similarities
between Parkinsons disease and catatonia with respect to akinesia
may be related with in-volvement of the basal ganglia in both
disorders. Clinical differences with respect to emotional and
behavioural symptoms may be relatedwith involvement of different
cortical areas, that is, orbitofrontal/parietal and premotor/motor
cortex implying distinct kinds of modu-lation vertical and
horizontal modulation, respectively.
Keywords: Bottom-up modulation; catatonia; horizontal
modulation; Parkinsons disease; top-down modulation; vertical
modulation
Georg Northoff, Visiting Associate Professor of theDepartment of
Neurology at Harvard University inBoston/USA, is the author of
numerous publicationsabout the psychopathology and pathophysiology
of cata-tonia. Since catatonia can be characterized by
severeemotional disturbances he focused most recently onfunctional
imaging of the neural correlates of emotions.In addition, he
investigates the neurophilosophical im-plications of both catatonia
and emotions having pub-lished several books and articles in the
field of neuro-philosophy.
-
rologic, show similar clinical appearance, one may assumesimilar
or at least overlapping pathophysiological substratesreflecting
functional brain organisation in general. Func-tional relation
between prefrontal/frontal cortex and basalganglia may account for
similarity between PD and catato-nia with respect to motor
symptoms. Relation between pre-frontal/frontal cortex and basal
ganglia can be character-ized by various functional circuits (see
Mastermann &Cummings 1997 for a nice overview) allowing for
bidrec-tional modulation with both top-down and bottom-upmodulation
as forms of vertical modulation. In additionto the
cortico-subcortical relation, one may consider thecortico-cortical
relation as well reflecting horizontal mod-ulation, which may be
rather unidirectional (see below).
Comparison between pathophysiological mechanismsunderlying PD
and those subserving catatonia may revealthe nature of these
distinct kinds of modulation of cortico-cortical/subcortical
relation in further detail. The followinghypothesis are postulated:
(1) apparent clinical similarityand underlying pathophysiological
differences in motorsymptoms between PD and catatonia; (2)
differences inpsychiatric (affective and behavioural) symptoms
betweenPD and catatonia; (3) double dissociation between cata-tonia
and PD with respect to underlying pathophysiologicalmechanisms
accounting for clinical differences; (4) oppo-site kinds of
vertical modulation between prefrontal/frontal cortex and basal
ganglia in PD and catatonia (bot-tom-up and top-down modulation)
accounting for subtledifferences in motor symptoms; (5)
presence/absence of al-terations in cortico-cortical relation
reflecting horizontalmodulation in catatonia and PD respectively,
accountingfor major differences in emotional-behavioural
symptoms.
First, we describe similarities and differences in
clinicalsymptoms and therapy between PD and catatonia. This
isfollowed by illustration of neuropsychological and
patho-physiological findings. Third, we develop pathophysiologi-cal
hypotheses for the different kinds of symptoms observedin PD and
catatonia. On the basis of these pathophysiolog-ical hypotheses, a
distinction between horizontal and ver-tical modulation of
cortico-cortical/subcortical relationswith respect to
directionality is suggested.
2. Catatonia as a psychomotor syndrome:Comparison with
Parkinsonism as motorsyndrome
2.1. Motor symptomsCatatonia is a rather rare (incidence: 2%8%
of all acuteadmissions) psychomotor syndrome. As such it can be
as-sociated with psychiatric disturbances such as schizophre-nia
(one subtype is denoted as catatonic schizophrenia)
andmanic-depressive illness, as well as with various neurologi-cal
and medical diseases (Gelenberg 1976; Northoff 1997a;Taylor 1990).
Some authors (see Northoff 1997a, for anoverview) consider periodic
catatonia as an idiopathic dis-ease showing psychomotor
characteristics of catatonic syn-drome while not being associated
with any other kind of dis-ease. Parkinsonism is a motor syndrome
which can beeither of idiopathic, that is, primary, or of
symptomatic, thatis, secondary, nature. In the first case one
speaks of Parkin-sons disease (PD), which may be considered as a
nosologi-cal analogue of periodic catatonia, whereas in the
secondcase one generally speaks of Parkinsonism which, similar
to
catatonia, may be associated with various neurological
andmedical diseases.
The most characteristic feature of catatonia is postur-ing,
where patients show a specific, uncomfortable, and of-ten bizarre
position of parts of their body against gravity,with complete
akinesia in which they remain for hours,days, and weeks (and in
earlier times even for years; see Fig.1). If that position is taken
actively and internally by the pa-tient himself, one speaks of
posturing; if such a positioncan be induced passively and
externally by the examiner,one speaks of catalepsy. Posturing can
occur in limbs(classic posturing), head (psychic pillow), and
eyes(staring).
We saw one patient who postured every morning duringshaving. He
started to shave himself and then remained,with the razor in his
hand and a lifted arm, for hours in thatposition until his wife
came in and depositioned him (seeNorthoff 1997a for detailed
description). Another exampleis a woman who, every morning when
opening her wardrobe,remained in a position with a lifted arm
keeping the door ofthe wardrobe open in her hand. Both patients
were admit-ted into the clinic where they neither spoke nor moved
atall. On admission, it was possible to position their limbsin the
most bizarre and uncomfortable positions againstgravity without any
resistance by the patients themselves.Once the examiner positioned
the limbs into one particularposition, they remained in that
position without showingeven the slightest change.
The cases demonstrated in Figure 1 are typical examplesof
posturing and catalepsy where patients are well able toinitiate and
execute movements but seem to be unable toreturn to the initial or
resting position in order to start a newmovement. Similar to PD,
catatonic patients do show aki-nesia, but, unlike Parkinsonian
patients, only in associationwith posturing and catalepsy.
Furthermore, in contrast toPD, catatonic akinesia is not
necessarily accompanied bymuscular hypertonus, that is, rigidity,
since patients mayalso show muscular normo- or hypotonus (Northoff
1997a).Even if catatonic patients show muscular hypertonus, it
isnot the kind of rigidity cogwheel rigidity that is typicalof PD.
Instead, they show a rather smooth type of rigiditywhich is called
flexibilitas cerea (Northoff 1997a). In ad-dition to hypokinetic
features, catatonic patients may showintermittent and fluctuating
hyperkinesias like stereotyp-
Northoff: What catatonia can tell us about top-down modulation:
A neuropsychiatric hypothesis
556 BEHAVIORAL AND BRAIN SCIENCES (2002) 25:5
Figure 1. Active posturing in a group of catatonic patients
(fromKraepelin 1927).
-
ies, dyskinesias, and tics which, unlike in PD, are indepen-dent
of medication.
Catatonic patients are well able to plan, initiate, andexecute
movements which could be demonstrated in ballexperiments. We
performed systematic ball experiments in32 catatonic patients in an
acute akinetic state before theyreceived any medication (i.e.,
lorazepam; see Northoff et al.1995a). To our surprise almost all
patients, despite showingconcurrent akinesia and posturing, were
able to play ball ei-ther with the hands or with the legs. Patients
were able tocatch and throw the ball, doing slightly better during
exter-nal initiation (i.e., catching) than during internal
initiation(i.e., throwing). Most patients, however, remained in a
finalposture keeping the ball in a position against gravity,
ap-parently unable to change posture and terminate the re-spective
movement. Subjectively, catatonic patients experi-enced these ball
experiments as funny and relaxing and astaking off my inner tension
although they were not awareof their inability to terminate
movements, therefore pos-turing (Northoff et al. 1995a; 1998).
Furthermore, in con-trast to PD, posturing in catatonic patients
cannot be re-versed by external sensory stimulation, as for
example,drawing a line in front of their feet. Accordingly,
catatonicpatients did not experience any starting problems or
deficitsin internal initiation.
In summary, catatonia and PD can be characterized bothby
clinical similarities, as reflected in akinesia and rigiditiy,and
differences, as reflected in posturing/initiation andcogwheel
rigidity/flexibilitas cerea, with respect to motorsymptoms.
2.2. Behavioural and affective symptomsIn addition to motor
symptoms, catatonia can be charac-terized by concurrent behavioural
and affective anomalies.Behavioural anomalies include mutism
(patients do notspeak, as was the case in both patients described
above),stupor (no reaction to the environment), automatic
obedi-ence (patients do everything that they are asked to do),
neg-ativism (patients always do the opposite of what they
areasked), echolalia/praxia (patients repeat sentences or ac-tions
given by other persons several times or even end-lessly),
perseverative-compulsive behavior (uncontrollablerepetitive
behavioural patterns), and mitmachen/mitgehen(patients always
follow other persons and do the same asthey do). In contrast to
catatonia, such behavioural anom-alies cannot be observed in PD,
which is characterized pre-dominantly by motor symptoms.
Affective alterations in catatonia include strong anxietiesor
euphoria/happiness, staring, grimacing, and inadequateemotional
reactions. Catatonic patients may show compul-sive emotions
(involuntary and uncontrollable repetitiveemotional reactions),
emotional lability (labile and unstableemotional reactions),
aggression (often accompanied by ex-treme emotional states such as
anxiety or rage), excitement(extreme hyperactivity with extreme and
uncontrollableemotional reactions), affective latence (taking a
long timeto show emotional reactions), ambivalence
(simultaneouspresence of conflicting emotions), and flat affect
(de-creased and/or passive emotional reactivity). Such symp-toms
are not present in PD. Patients with PD can, rather,be
characterized by depression, where they neither show
anuncontrollable intensity of emotions nor a comparable va-riety of
emotional reactivity like that of catatonic patients.
In summary, catatonia can be characterized by strong af-fective
and bizarre behavioural anomalies, which do not oc-cur in PD.
2.3. TherapyTherapeutically, 60%80% of all acute catatonic
patientsreact to lorazepam, a GABA-A receptor potentiator,
eitheralmost immediately within the first 510 minutes, or within24
hours (Bush et al. 1996a; Northoff et al. 1995b; Rose-bush et al.
1990), whereas chronic catatonic patients showno improvements on
lorazepam (Ungvari et al. 1999). If lo-razepam does not work, some
catatonic patients show grad-ual and delayed improvements (within 2
to 4 days) on theNMDA-antagonist amantadine (Northoff et al.
1997;1999c) and/or on electroconvulsive treatment (ECT) (Finket al.
1993; Petrides et al. 1997).
Dopaminergic substances like L-Dopa and D1/2 recep-tor agonists
are therapeutically effective in PD. Unlike incatatonia, lorazepam
and other benzodiazepines remaintherapeutically ineffective in PD.
Similar to catatonia, theNMDA-antagonist amantadine is
therapeutically effectivein PD as well (Merello et al. 1999). In
addition to pharma-cotherapy, surgical therapies with implantation
of eitherelectrodes or fetal tissue in specific structures of the
basalganglia (putamen, caudate, subthalamic nuclei,
internalpallidum) may be applied especially in drug-resistant
pa-tients with PD.
In summary, treatment in catatonia and PD can be char-acterized
by differences (GABA-ergic agents versus dopa-minergic agents) and
similarities (NMDA-antagonists).
2.4. Subjective experienceIn order to further reveal the nature
of psychological alter-ations and their relation to motor symptoms,
we investi-gated subjective experience in catatonic patients with a
self-questionnaire. Due to mutism and akinesia in almost
allpatients with hypokinetic catatonia, such an
investigationremains possible only retrospectively. Catatonic
patientswere compared with akinetic Parkinsonian patients
andnoncatatonic depressive and schizophrenic patients (seeNorthoff
et al. 1998, for details).
Parkinsonian patients suffered severely from akinesia;for
example, one felt locked into my body, anotherwanted to move but
was unable to do so. A catatonic pa-tient, in contrast, did not
realize any alterations in mymovements and said that they [the
movements] werecompletely normal. When asked why they positioned
theirlimbs in a particular posture, catatonic patients either
an-swered There was nothing abnormal with my move-ments, or couldnt
say anything. The patient posturing dur-ing shaving said, My
movements were completely normaland I could shave in the normal
way. No patient said thathe subjectively suffered from any changes
in his move-ments. Moreover, no catatonic patient reported any
feelingof pain or tiredness even if he postured and remained in
thesame position for hours (n 5 5), days (n 5 10) or weeks (n5 5).
Instead of changes in their movements, many cata-tonic patients
reported extremely intense emotions, whichthey experienced as
uncontrollable and overwhelming.Patients felt totally blocked by
these emotions whichoverwhelmed them and led to a blockade of
[theirselves]. The dominating emotion was anxiety (due to para-
Northoff: What catatonia can tell us about top-down modulation:
A neuropsychiatric hypothesis
BEHAVIORAL AND BRAIN SCIENCES (2002) 25:5 557
-
noid delusions, acoustic hallucinations, depressive mood,
ortraumatic experiences). For example, the patient posturingduring
shaving as described above, said that I couldnt con-trol my
emotions anymore, they were overflooding me sothat I had the
feeling that I was just anxiety. Nevertheless,some patients
reported positive emotions like euphoria although, similar to
anxiety, they were unable to control thisanymore. One patient, for
example, became catatonic everytime she fell in love (5 times in
total), reporting the follow-ing: I am so happy when I fall in
love, this feeling reallyoverwhelms me so that I cant control it
anymore. Everytime I fall in love, I am admitted to clinic. I dont
under-stand this.
Catatonic patients did not subjectively experience anysensation
of effort during posturing. Although they kepttheir limbs or head
in a position against gravity, where everynormal person and patient
with PD would feel a sensationof tiredness or pain, catatonic
patients do not experienceany tiredness, pain, or a sensation of
effort during pos-turing. For example, catatonic patients lying in
bed maykeep their head up for hours or even days (i.e., a
so-calledpsychic pillow) without getting tired and/or reporting
anyfeeling of tiredness. When inquiring after these patientswith
such a psychic pillow, they usually answer, My headwas in a
completely normal position, I wasnt tired at all;they seem to,
instead, experience a sense of weightless-ness.
No catatonic patient was able to give an account of theposition
in which he kept his limbs, thus remaining unawareof posturing. It
seems as if they have no access to any kindof subjective experience
of the actual spatial position dur-ing posturing the objective
position and the corre-sponding subjective experience of the
spatial positionseem to be decoupled from each other.
Unfortunately,there are no data available whether post-acute
patients rec-ognize the posturing characterizing their acute state
as theirown. Such data could provide information about the
exactnature of the deficit in awareness. If they could recognizethe
posturing as their own, they would show only an alter-ation in
motor awareness but not in self-awareness. How-ever, if they were
unable to do so, there would have to be ageneral deficit in
self-awareness. Since, however, catatonicpatients are well able to
recognize themselves in a post-acute state, one may rather
hypothesize a deficit in motorawareness only.
Furthermore, catatonic patients are not aware of theconsequences
of their movements (Snowdon et al. 1998):The patient posturing
during shaving claimed that he fin-ished shaving every morning
completely without any timedelay so that he wasnt aware of the
consequences of pos-turing. Finally, catatonic patients do not show
any objec-tive or any kind of subjective sensory abnormality, so
alter-ations in subjective experience cannot be accounted for
bysensory dysfunction.
Almost all catatonic patients reporting strong, intense,and
uncontrollable emotions responded well to lorazepam,whereas
patients without such emotional experiences didnot respond well to
lorazepam (Northoff et al. 1998). Non-responders to lorazepam for
example, the patient de-scribed above as posturing in front of her
wardrobe hadexperiences such as a blockade of my will with
contradic-tory and ambivalent thoughts about my dresses since
Icouldnt decide myself. For several days this patient stoodin front
of her wardrobe remaining in the same quite un-
comfortable position with raised arms and standing tip-toe.She
wasnt aware of any alterations in her movements,denying any feeling
of tiredness during that position (Iwasnt tired at all). All
catatonic patients experienced theiradmission on a psychiatric ward
as terrible (I thought it wasthe hell) and/or could not understand
it (I was so happy,there was no reason for admission at this time.)
Moreover,they remembered very well the physician and other
personswho treated them on admission. Consequently,
catatonicpatients seem to show neither deficits in memory (except
inworking memory; see below), nor deficits in general
aware-ness.
In summary, subjective experience differs between cata-tonic and
Parkinsonian patients with respect to motorsymptoms (motor
anosognosia vs. motor awareness) andpsychological state (anxiety
vs. depressive reaction).
3. Neuropsychological and pathophysiologicalfindings in
catatonia and Parkinsons
Presentation of findings in this section focuses predomi-nantly
on comparison between catatonia and PD with re-spect to distinct
kinds of modulation. Therefore the wholevariety of differential and
subtle pathophysiological alter-ations obtained especially in PD
cannot be considered inthe present context. Furthermore, it should
be mentionedthat systematic pathophysiological investigations with
mod-ern techniques are rather rare in catatonia, which is a
cer-tain focus within my own studies.
3.1. Neuropsychological findingsWe pointed out that the ability
to registrate the spatial po-sition of movements, as required for
termination of move-ments (see above), involves spatial abilities
as potentiallyrelated to the right posterior parietal cortical
function. Wetherefore investigated post-acute akinetic catatonic
pa-tients with neuropsychological tests for measurement ofspatial
abilities (Northoff et al. 1999a). Among other mea-sures, we
applied the visual-object-space and perceptiontest (VOSP), a test
specifically designed for measurementof spatial abilities related
to right parietal cortical function.(See Table 1.)
Catatonic patients showed significantly lower perfor-mance in
VOSP compared to psychiatric and healthy con-trols (Northoff et al.
1999a). No significant differences be-tween catatonic and
noncatatonic psychiatric patients wereobtained in any other
visuo-spatial test unrelated to rightparietal cortical function, or
in any other neuropsycholog-ical measure such as general
intelligence, attention, and ex-ecutive functions. Furthermore,
catatonic patients showedsignificant correlations between right
parietal cortical vi-suo-spatial abilities (as measured with VOSP)
and atten-tional abilities (as measured with d2 and CWI), which
werepresent neither in psychiatric controls nor in healthy
sub-jects (Northoff et al. 1999a). In addition, motor symptomsin
catatonia correlated significantly with both visuo-spatialabilities
and attentional function. Catatonia may be char-acterized by
relatively intact psychological functions con-cerning attention,
executive functions, general intelli-gence, and non-right parietal
visuo-spatial abilities. Incontrast, visuo-spatial abilities
specifically related to rightparietal cortex may be altered in
catatonic patients, distin-
Northoff: What catatonia can tell us about top-down modulation:
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558 BEHAVIORAL AND BRAIN SCIENCES (2002) 25:5
-
guishing them from noncatatonic psychiatric controls.
Also,catatonic patients show severe deficits in a gambling
test(unpublished observations) requiring emotionally
guideddecisions and intact orbitofrontal cortical function
(Bech-ara et al. 1997).
In contrast, patients with PD show severe neuropsycho-logical
deficits in executive functions (Wisconsin Card Sort-ing test,
verbal fluency, etc.). These include, among others,abilities of
categorization, shifting, sequencing, and so on,as subserved by
dorsolateral prefrontal cortical function. Incontrast to catatonia,
PD can be characterized neither bydeficits in visuo-spatial
attention as specifically related toright parietal cortical
function, nor by alterations in thegambling test specifically
designed for orbitofrontal corti-cal function.
In summary, catatonia can be characterized by specificdeficits
in visuo-spatial abilities, related to right parietalcortical
function, and by emotionally guided intuitive deci-sions, related
to orbitofrontal cortical function. PD, in con-trast, can be
characterized by specific alterations in execu-tive functions
predominantly related to lateral prefrontalcortical function.
3.2. Postmortem findingsEarly postmortem studies in the
preneuroleptic time re-vealed discrete but not substantial
alterations in basal gan-glia (caudate, N. accumbens, pallidum) and
thalamus (seeBogerts et al. 1985 and Northoff 1997a, for an
overview).Because these early investigations yielded rather
inconsis-tent results, they were not pursued. Most studies were
per-formed on brains of patients who were never exposed
toneuroleptics, implying that these alterations in basal
gangliacannot be related to neuroleptic (antipsychotic)
medica-tion. Nevertheless, findings should be considered
rathercautiously since the methods and techniques available at
that time may have produced artifacts themselves. Fur-thermore,
these findings were obtained in patients withcatatonic
schizophrenia. Therefore, it remains unclearwhether these
alterations are specifically related to eithercatatonia itself or
the underlying disease of schizophrenia.Neuropathologic
investigations of catatonic syndrome ingeneral, rather than of
catatonic schizophrenia in particu-lar, are currently not
available.
In contrast to catatonia, substantial alterations in post-mortem
investigation can be obtained in PD. PD can becharacterized by
degeneration of dopaminergic cells in sub-stantia nigra pars
compacta, leading consecutively to de-generation in striatum
(especially putamen and caudate). Inmany cases of Parkinsonism,
vascular or other kinds of al-terations may be observed in
striatum.
In summary, valid postmortem results in catatonia arecurrently
not available since those obtained showing dis-crete alterations in
basal ganglia relied on insufficientmethods. In contrast, PD can be
characterized by major de-generation of dopaminergic cells in
substantia nigra and itspathways to striatum.
3.3. Animal modelsDeJong and Baruk (1930) performed various
experimentswith the D2-receptor antagonist bulbocapnine.
Accordingto DeJong and Baruk, bulbocapnine induced catatonia
inanimals with a neocortex (mice, rats, cats), whereas in an-imals
without a neocortex, catatonic symptoms could notbe induced. Lower
(12 mg) doses of bulbocapnine leadto catalepsy, whereas higher
doses (45 mg) induced im-pulsive and convulsive reactions. As
demonstrated byLoizzo et al. (1971), amantadine as an
NMDA-antagonistled to reversal of bulbocapnine-induced catatonia;
how-ever, relying on my own experiments (unpublished
obser-vations), bulbocapnine-induced catatonia rather resem-
Northoff: What catatonia can tell us about top-down modulation:
A neuropsychiatric hypothesis
BEHAVIORAL AND BRAIN SCIENCES (2002) 25:5 559
Table 1. Comparison between catatonia and Parkinsons disease
Catatonia Parkinsons
Neuropsychology Visuospatial attention Executive
functionsOn-line monitoringEmotionally-guided decisions
Postmortem Caudate, N. accumbens, Pallidum, Substantia nigra,
Putamen, CaudateThalamus
Animal models Bulbocapnine, Stress, GABA 6-OHDH, MPTPStructural
imaging Prefrontal and parietal cortex Basal gangliaFunctional
imaging Right prefronto-parietal CBF SMA/MC
Right OFC Lateral prefrontal cortexPrefrontal connectivity
Fronto-striatal connectivity
Electrophysiology Late and postural RP Early RPRP modulation by
Lorazepam RP modulation by dopamine
Neurochemistry GABA-A receptors D-2 receptors in striatumNMDA
receptors NMDA receptors5 HT1a/2a 5 HT2a
Abbreviations:RP 5 Readiness PotentialSMA 5 Supplementary motor
areaOFC 5 Orbitofrontal cortexMC 5 Motor Cortex
-
bled haloperidol-induced catalepsy. Furthermore, it couldnot be
determined by lorazepam, as is the case in humancatatonia (see
above). Bulbocapnine exerts an inhibitoryeffect on dopamine
synthesis (Shin et al. 1998). Conse-quently, it remains unclear
whether DeJong and Baruk re-ally describe catatonia, or, rather, a
kind of catalepsy anal-ogous to neuroleptic-induced catalepsy.
Stille and Sayers (1975) induced a catatonia-like reactionin
animals using strong sensory stimuli (electric footshock).They
postulated an excitement of the ascending arousal sys-tem, that is,
formatio reticularis with overexcitation of thestriatal system via
thalamic nuclei. Injection of the GABA-A antagonist bicucullin into
dopaminergic cells of the ven-tral tegmental area (VTA) induced a
catatonia-like picturein cats with increased arousal, withdrawal,
anxiety, staring,and catalepsy (Stevens 1974). Furthermore,
injection ofmorphine may lead to a so-called morphine-induced
cata-tonia (Northoff 1997a). Despite the existence of these
var-ious models, none of them has really been established as
ananimal model of human catatonia.
Freezing as an isolated phenomenon independent fromcatatonia has
been studied in animals and humans. Lesionsin amygdala and/or in
the periaqueductal gray may inducefreezing in animals whether these
results can be extrapo-lated to humans remains unclear (Fendt &
Fansolow 1999).
Animal models of PD focus on specific lesion of nigro-striatal
dopaminergic cells and pathways as provided by 6-OHDH in rats and
MPTP in nonhuman primates.
In summary, no animal model of human catatonia has yet been
established. The ones available focus either onGABA-ergic- or
morphine-induced lesions. In contrast, an-imal models of PD focus
on lesions of nigrostriataldopamine by either 6-OHDH or MPTP.
3.4. Structural imagingA computerized tomographic (Head CT)
investigation of37 patients with catatonic schizophrenia showed a
diffuseand significant enlargement in most cortical areas
(seeNorthoff et al. 1999d). Alterations in temporal cortical ar-eas
were present in all three subtypes of schizophrenia,whereas
catatonic schizophrenia could be specifically char-acterized by
prefrontal and parietal enlargement. More-over, prefrontal and
parietal enlargement correlated signif-icantly with illness
duration in catatonic schizophrenia.
Other authors (Joseph et al. 1985; Wilcox 1991) observeda
cerebellar atrophy in catatonic patients, which was inves-tigated
neither systematically nor quantitatively. To myknowledge, no study
specifically investigating catatonicsyndrome (and not only
catatonic schizophrenia as a sub-type) has been published so
far.
In summary, findings in structural imaging in catatoniasuggest
cortical involvement predominantly in prefrontaland parietal
cortex, whereas in PD subcortical structures,that is, the basal
ganglia are altered.
3.5. Functional imaging3.5.1. Regional cerebral blood flow.
Investigation of re-gional cerebral blood flow (r-CBF) in single
catatonic pa-tients showed the following findings: (1) right-left
asym-metry in basal ganglia with hyperperfusion of the left sidein
one patient (Luchins et al. 1989); (2) hypoperfusion inleft medial
temporal structures in two patients (Ebert et al.
1992); (3) alteration in right parietal and caudal perfusionin
one patient (Liddle 1994); (4) decreased perfusion inright parietal
cortex in six patients with catatonic schizo-phrenia (Satoh et al.
1993); (5) decreased perfusion in pari-etal cortex with improvement
after ECT in one patient(Galynker et al. 1997). A systematic
investigation of r-CBFin SPECT in 10 post-acute catatonic patients
showed de-creased perfusion in right posterior parietal and right
infe-rior lateral prefrontal cortex compared to noncatatonic
psy-chiatric and healthy controls (Northoff et al. 2000c).
Furthermore, abnormal correlation between right pari-etal
cortical function and visual-spatial and attentionalabilities were
obtained (Northoff et al. 2000c). In psychi-atric and healthy
controls, VOSP correlated significantlywith right lower parietal
and right lower lateral prefrontalcortical r-CBF and iomazenil
binding (reflecting the func-tion of GABA-A receptors), whereas in
catatonia none ofthese correlations were found (Northoff et al.
1999e;2000c). Decreased perfusion in right parietal cortex
cor-related significantly with motor and affective
symptoms.Catatonic motor symptoms correlated significantly
withVOSP, right lower parietal r-CBF and iomazenil binding inright
lower lateral prefrontal cortex (Northoff et al. 1999e;2000c).
PD can be characterized by deficits of r-CBF in SMA,motor cortex
and caudate, whereas no major alterations inprefrontal and parietal
cortex can be observed (see Jahan-shahi & Frith 1998).
In summary, investigation of regional cerebral blood flowshows
deficits in right lower inferior prefrontal and rightparietal
cortex in catatonia. PD, in contrast, may rather becharacterized by
predominant r-CBF deficits in motor cor-tex, SMA, and basal
ganglia.
3.5.2. Motor activation. Functional imaging performedduring
motor activation (i.e., sequential finger opposition)showed reduced
activation of the contralateral motor cor-tex (MC) in right hand
performance. Ipsilateral activationwas similar for both patients
and (medication-matched)controls (Northoff et al. 1999b). There
were no differencesin activation of the supplementary motor area
(SMA). Dur-ing left hand performance, right-handed patients
showedmore activation in ipsilateral motor cortex than in
con-tralateral MC. This must be considered as a reversal in
lat-erality since usually the contralateral side shows four to
fivetimes more activation than the ipsilateral side (Northoff etal.
1999b). It should be noted that these results were ob-tained in
only two post-acute catatonic patients. However,assumption of
basically intact cortical motor activation (in-dependent from
laterality) is further supported by resultsfrom an fMRI/MEG study
during emotional-motor stimu-lation in 10 catatonic patients
(Northoff et al. 2001a). Cor-tical motor function showed no
alteration in these investi-gations.
During motor activation, patients with PD show majordeficits
predominantly in SMA, which receives most affer-ences from thalamic
(motor) nuclei, and the basal ganglia,predominantly the striatum.
Furthermore, decreased acti-vation can be observed also in MC
though to a lesser degreethan SMA. This may be due to the fact that
the MC doesnot receive as many afferences from thalamic (motor)
nu-clei as SMA does. In contrast to catatonia, no alteration
inlaterality during motor performance can be observed in
PD(Jahanshahi & Frith 1998).
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In summary, catatonia may be characterized by alter-ations in
laterality in the motor cortex during motor perfor-mance, while
activation in SMA seems to remain basicallyintact. PD, in contrast,
shows major deficits in activation ofSMA and, to a lesser degree,
in the motor cortex, the lattershowing no alterations in
laterality.
3.5.3. Emotional-motor activation. Based on subjective
ex-perience showing intense emotional-motor interactions,
anactivation paradigm for affective-motor interaction was
de-veloped. This paradigm was investigated in fMRI and
MEG(magnetoencephalography) in catatonic patients compar-ing them
with noncatatonic psychiatric and healthy controls(Northoff et al.
2001a). During negative emotional stimu-lation, catatonic patients
showed a hyperactivation in or-bitofrontal cortex and a shift of
main activation to anteriorcingulate and medial prefrontal cortex.
Furthermore, cata-tonic patients showed abnormal
orbitofrontal-premotor/motor connectivity (Northoff et al. 2001a).
Behavioural andaffective catatonic symptoms correlated
significantly withreduced orbitofrontal cortical activity, whereas
motor symp-toms correlated with premotor/motor activity.
PD, in contrast, can be characterized by altered activa-tion in
left dorsolateral prefrontal cortex and anterior cin-gulate during
emotional stimulation, whereas orbitofrontalcortical function
remained unaffected (see Mayberg et al.1999).
In summary, catatonia can be characterized by reducedright
orbitofrontal cortical activation and abnormal
orbito-frontal-premotor/motor connectivity during negative
emo-tional stimulation. PD, in contrast, shows alterations only
inleft dorsolateral prefrontal cortex and anterior cingulate,not in
orbitofrontal cortex.
3.5.4. On-line monitoring. Posturing as an inability to
ter-minate movements may be related with alterations in on-line
monitoring. Since on-line monitoring must be consid-ered as an
essential part of working memory (Leary et al.1999; Petrides 1995),
we investigated a one-back/two-backtask in fMRI in catatonia
(Leschinger et al. 2001). Catatonicpatients showed significantly
decreased activation in rightlateral orbitofrontal, including
ventrolateral prefrontal cor-tex (VLPFC), during the working memory
task in fMRI(Leschinger et al. 2001). In contrast to orbitofrontal
activ-ity, activation in right dorsolateral prefrontal cortex
wasrather increased. Catatonic behavioural symptoms corre-lated
significantly with activation in right lateral orbito-frontal
cortex, whereas motor symptoms showed a signifi-cant relationship
with right dorsolateral prefrontal activity.
Catatonic patients showed significantly worse behav-ioural
performance in both one-back and two-back tasks,and their deficit
seems not to be limited to active storage/retrieval. In the latter
case one would have expected worseperformance in the two-back task
only. Instead, catatoniamay rather be characterized by principal
problems in on-line processing and monitoring, which accounts for
badperformance in both one-back and two-back task.
Investigation of working memory in PD revealed alter-ation in
lateral prefrontal cortex, especially in left dorso-lat-eral
prefrontal cortex (DLPFC), whereas orbitofrontal cor-tical
function, including the ventrolateral prefrontal cortex,remained
intact (Jahanshahi & Frith 1998).
In summary, catatonia can be characterized by majordeficits in
on-line monitoring and right lateral orbitofrontal,
that is, ventrolateral prefrontal cortical (VLPFC)
function,whereas PD shows deficits in left dorso-lateral
prefrontalcortical (DLPFC) function.
3.6. Electrophysiological findings3.6.1. Initiation in catatonia
and Parkinsons disease.Generation of willed action can be
characterized by Plan/Strategy, Initiation, and Execution, which
are sup-posed to be reflected in movement-related cortical
poten-tials (MRCP) (see Northoff et al. 2001b).
We investigated MRCPs during finger tapping in 10post-acute
akinetic catatonic patients, 10 noncatatonic psy-chiatric controls
(same underlying diagnosis, same medica-tion, same age and sex),
and 20 healthy controls (Northoffet al. 2000a; Pfennig 2001;
Pfennig et al. 2001). We foundno significant differences in
amplitudes between catatonicand noncatatonic subjects in early
MRCPs; that is, in earlyreadiness potential (early RP) reflecting
Plan/Strategyand Initiation of movements in DLPFC and anteriorSMA.
Amplitudes in late MRCPs, that is, in late readinesspotential (late
RP) and movement potential (MP) reflectingExecution of movements in
posterior SMA and motorcortex, revealed differences.
Patients with PD show reduction of amplitude in earlyand late
MRCPs, which can be modulated by dopaminer-gic agents resulting in
an increase of amplitude (Dick et al.1987; 1989; Jahanshahi et al.
1995; Jahanshahi & Frith1998).
In summary, catatonia can be characterized by intactearly and
late readiness potentials, reflecting the apparentlypreserved
ability of Plan/Strategy, Initiation, and Exe-cution of movements
in these patients. In contrast, pa-tients with PD show severe
deficits in Initiation and Ex-ecution as electrophysiologically
reflected in alterations inearly and late readiness potentials.
3.6.2. Termination in healthy subjects. Phenomena likeposturing
and catalepsy can be observed in patients withright parietal
cortical lesions, although they do not showany deficits in
Initiation and Execution (Fukutake etal. 1993; Saver et al. 1993).
This suggests that visuo-spatialattention and right parietal
cortical function may be nec-essary for on-line monitoring and
consecutive terminationof movements. In a first step, we therefore
investigatedtermination of movements in healthy subjects with
elec-trophysiological measurements of movement-related cor-tical
potentials (MRCP) (Northoff et al. 2001a; Pfennig2001).
We compared normal MRCP as obtained by finger tap-ping with MRCP
for simple lifting. The finger had to bekept up without going back
into the initial position (MRCP1) reflecting Plan/Strategy,
Initiation, and Execu-tion of finger tapping with exclusion of
Termination.Termination of movements was measured by lowering ofthe
finger after some seconds of posturing (MRCP 2), re-flecting
initiation of termination and execution of termi-nation (see
below). MRCP 1 and 2 differed significantly invarious onsets and
amplitudes from MRCP, so that neitherMRCP 1 nor MRCP 2 can be
equated with MRCP for sim-ple finger tapping. In addition, we
obtained significant dif-ferences between MRCP 1 and MRCP 2, the
latter show-ing significantly lower amplitudes in early parietal
MRCPs,earlier onset of movement potential and more posterior
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parietal localization of underlying dipoles, than the
former(Northoff et al. 2001b; Pfennig et al. 2001).
Lorazepam as a GABA-A potentiator had a differentialinfluence on
early and late components of MRCPs duringInitiation and
Termination. During Initiation, loraze-pam led to a delay in onsets
of late MRCPs in frontal elec-trodes (MRCP 1), whereas during
Termination (MRCP2), early onsets in parietal electrodes were
delayed. Theseresults were further supported by dipole source
analysis.MRCP 1 reflecting Plan/Strategy, Initiation, and
Ex-ecution showed dipole sources in anterior/posterior SMAand motor
cortex. In contrast, MRCP 2 reflecting Termi-nation was
characterized by initial location of the early di-pole in right
posterior parietal cortex, later shifting to pos-terior SMA and
motor cortex (Pfennig et al. 2001).
The following conclusions with respect to Terminationof
movements can be drawn. First, some kind of initiationmust be
involved, because otherwise there would havebeen no readiness
potential we call this the initiation oftermination. Second, the
initiation for execution (i.e.,MRCP 1) and the initiation for
termination (i.e., MRCP2) can apparently be distinguished from each
other, sinceotherwise there would have been no differences in
ampli-tudes between MRCP 1 and MRCP 2 in early MRCPs.Third, MRCPs
during Termination could be characterizedby right posterior
parietal localization. In order to avoid ter-minological confusion,
we reserve the term Initiation forthe Initiation of Execution,
whereas the initiation of Ter-mination will be subsumed under the
term Termination.Fourth, Execution and Termination involve
differentmovements (lifting and lowering), which is reflected in
dis-tinct movement potentials in MRCP 1 and MRCP 2. Fifth,the
Termination of movements seems to be particularlyrelated with right
parietal cortical function and GABA-ergic neurotransmission.
Otherwise, there would have beenno differences between MRCP 1 and
MRCP 2 in parietalcortical dipole source location and reactivity to
lorazepam.
In summary, Termination of movements may be char-acterized by
two distinct aspects, initiation and execution.These may be
subserved by involvement of right parietalcortical function and
GABA-ergic neurotransmission. Neu-ropsychologically, on-line
monitoring of the spatial positionof the ongoing movement, as
related to right parietal corti-cal function, may be considered as
crucial for Termina-tion, distinguishing it from Plan/Strategy,
Initiation,and Execution.
3.6.3. Termination in catatonia. Kinematic measurementsduring
Initiation and Termination of finger tapping re-vealed that
catatonic patients needed significantly longerfor Termination than
psychiatric and healthy controls. Incontrast, no deficits were
observed in Initiation (Pfennig2001; Pfennig et al. 2001). These
results contrast with thosein patients with PD who needed
significantly longer timeduration for Initiation, but not for
Termination.
Catatonic patients showed no abnormalities in MRCPsof
Initiation, that is, lifting (MRCP 1). Instead, theyshowed
significantly delayed onsets in early MRCPs in cen-tral and
parietal electrodes during Termination, that is,lowering (MRCP 2),
compared to psychiatric and healthycontrols (Pfennig et al. 2001).
The fact that the early onsetwas altered only in MRCP 2 but not in
MRCP 1, indicatesa delay specifically in initiation of termination,
while Ini-tiation itself seems to remain principally intact. This
is fur-
ther supported by results from dipole source analysis show-ing
decreased source strength in right posterior parietalcortex in
catatonic patients, while sources in SMA showedno abnormalities. In
addition, catatonic motor and behav-ioural symptoms correlated
significantly with delayed earlyonset in MRCP 2 in parietal
electrodes.
In summary, posturing in catatonia may be characterizedby a
specific deficit in Termination of movements whilePlan/Strategy,
Initiation, and Execution seem to re-main basically intact. Such an
assumption is supported byobservation of alterations in temporal
duration, onset ofearly MRCPs, right parietal cortical localization
andGABA-ergic reactivity in MRCPs specifically related
toTermination of movements.
3.7. Neurochemical findings3.7.1. GABA. Recent interest in
neurochemical alterationsin catatonia has focused on GABA-A
receptors. The GABA-A receptor potentiator lorazepam is
therapeutically effec-tive in 6080% of all acute catatonic patients
(Bush et al.1996a; Northoff et al. 1995b; Rosebush et al. 1990).
Onestudy investigated iomazenil-binding, reflecting number,and
function of GABA-A receptors in 10 catatonic pa-tients in single
photon emission computerized tomography(SPECT) and compared them
with 10 noncatatonic psy-chiatric controls and 20 healthy controls
(Northoff et al.1999e). Catatonic patients showed significantly
lowerGABA-A receptor binding and altered right-left relations
inleft sensorimotor cortex. In addition, catatonic patientscould be
characterized by lower GABA-A binding in rightlateral orbitofrontal
and right posterior parietal cortex, cor-relating significantly
with motor and affective (but not withbehavioural) catatonic
symptoms.
Furthermore, emotional-motor stimulation in fMRI/MEG (see above)
was performed after neurochemical stim-ulation with lorazepam (see
Northoff et al. 2001d; Richteret al. 2001). After lorazepam,
healthy subjects activationshifted from orbitofrontal cortex to
medial prefrontal cor-tex, resembling the pattern of activity from
catatonic pa-tients before lorazepam. Catatonic patients, in
contrast,showed a reversal in activation/deactivation pattern
afterlorazepam: Activation in medial prefrontal cortex was
re-placed by deactivation, and deactivation in lateral pre-frontal
cortex was transformed into activation. It was con-cluded that
prefrontal cortical activation/deactivationpattern during negative
emotional processing may be mod-ulated by GABA-A receptors.
In addition to fMRI and MEG, kinematic measurementsand
movement-related cortical potentials were investigatedin catatonic
patients before and after lorazepam (Northoffet al. 2000a; Pfennig
et al. 2001). After injection of theGABA-A potentiator lorazepam,
time duration for Termi-nation reversed between groups and was now
significantlyshorter in catatonic patients than in psychiatric and
healthycontrols. In contrast, no influence of lorazepam was
ob-served on temporal duration of Initiation in either group.After
lorazepam, the early onset in parietal electrodes inMRCP 2 was
reversed between groups, being now signifi-cantly earlier in
catatonics than in psychiatric and healthycontrols. Lorazepam thus
normalized that is, shortened delayed early onsets in MRCPs during
Termination incatatonia. In contrast, it delayed early onsets in
both psy-chiatric and healthy controls. In contrast to MRCP 2,
lo-
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razepam had no abnormal influence on MRCP 1 in cata-tonic
patients (Pfennig et al. 2001). Moreover, it should benoted that,
psychologically, lorazepam induced a paradox-ical reaction in all
catatonic patients. Instead of reactingwith sedation, as was the
case in psychiatric and healthycontrols, they became rather
agitated.
In contrast to catatonia, GABA-ergic transmission in
or-bitofrontal and prefrontal cortex, does not seem to revealany
abnormalities in PD, whereas there are subcorticalGABA-ergic
alterations in basal ganglia.
In summary, catatonia can be characterized by major al-terations
and abnormal reactivity of GABA-A receptors inright orbitofrontal,
motor cortex, and right parietal cortex.In PD, in contrast, no such
orbitofrontal cortical GABA-ergic abnormalities can be
observed.
3.7.2. Dopamine. In early studies, Gjessing (1974)
foundincreased dopaminergic (homovanillic acid and vanillicacid)
and adrenergic/noradrenergic (norepinephrine, meta-nephrine, and
epinephrine) metabolites in the urine of patients with periodic
catatonia. In addition, he obtainedcorrelations between vegetative
alterations and these metab-olites. He suggested a close
relationship between catatoniaand alterations in posterior
hypothalamic nuclei. Recent in-vestigations of the dopamine
metabolite homovanillic acidin the plasma of 32 acute catatonic
patients showed in-creased levels in the acute catatonic state
(Northoff et al.1996), particularly in those responding well to
lorazepam(Northoff et al. 1995b). Accordingly, the dopamine
agonistapomorphine exerted no therapeutic effect at all in
acutecatatonic patients (Starkstein et al. 1996). Instead, one
wouldexpect therapeutic efficacy of dopamine-antagonists
likeneuroleptics. However, neuroleptics such as haloperidol
mayrather induce a catatonia, that is, so-called
neuroleptic-induced catatonia (Fricchione et al. 2000). Involvement
ofthe striatal dopaminergic system, especially of D-2 recep-tors in
catatonia, therefore remains controversial. No sys-tematic studies
investigating D2 receptors in catatonia havebeen reported so
far.
In contrast to catatonia, dopamine is the major transmit-ter
affected in PD. Several studies showed decreased stri-atal
D2-receptor binding in patients with PD.
In summary, exact involvement of the dopaminergic sys-tem in
catatonia remains unclear. In contrast, PD can becharacterized by
reduction of striatal D-2 receptors.
3.7.3. Glutamate. The glutamatergic system, in particularthe
NMDA-receptors, may be involved in catatonia as well. Some
catatonic patients being nonresponsive to lo-razepam have been
treated successfully with the NMDA-antagonist amantadine.
Therapeutic recovery occurredrather gradually and delayed (Northoff
et al. 1997; 1999c).Such gradual and delayed improvement suggests
thatNMDA-receptors may be involved only secondarily in cata-tonia,
whereas GABA-A receptors seem to be primarily altered. Such an
assumption remains rather speculative,since neither the
NMDA-receptors nor their interactionswith GABA-A receptors have
been investigated in cata-tonia.
In PD, a modulation of glutamatergic-mediated corti-co-striatal
pathway by NMDA-antagonists has been sug-gested as a model for
explanation of therapeutic efficacy ofamantadine/memantine (Merello
et al. 1999). Alterna-tively, modulation of glutamatergic pathways
within basal
ganglia themselves, that is, between subthalamic nuclei
andinternal pallidum, has been discussed.
In summary, both catatonia and PD may be character-ized by
glutamatergic abnormalities especially in NMDA-receptors.
Amantadine as a NMDA antagonist is thera-peutically effective in
both diseases and may modulateglutamatergic-mediated cortical and
subcortical connec-tivity.
3.7.4. Serotonin. The serotonergic system has been as-sumed to
be involved in catatonia. Atypical neurolepticsthat have
serotonergic properties may induce catatonic fea-tures (Carroll
2000). Therefore, it has been hypothesizedthat catatonia may be
characterized by a dysequilibrium inthe serotonergic system with
up-regulated 5-HT1a recep-tors and down-regulated 5-HT2a receptors
(Carroll 2000).However, no investigations of the serotonergic
system incatatonia have yet been reported, so that this hypothesis
re-mains speculative.
Similar to catatonia, the serotonergic system may be in-volved
in PD, which may be related to dopaminergic ab-normalities.
In summary, the serotoninergic system seems to be in-volved in
both catatonia and PD. This may reflect sec-ondary modulation by
another primarily altered transmit-ter system, that is, GABA in
catatonia and dopamine in PD.
4. Pathophysiological hypothesis
The present hypothesis focuses predominantly on similari-ties
and differences between PD and catatonia with respectto distinct
kinds of modulation. Similar to the presentationof data (see sect.
3), various subtle aspects of pathophysiol-ogy, especially in PD,
will therefore not be discussed in de-tail. In addition, the
present hypothesis primarily focuseson catatonic responders to
lorazepam. This is important tomention, since responders and
nonresponders may be char-acterized by distinct underlying
pathophysiological mecha-nisms (Northoff et al. 1995b; 1998;
Ungvari et al. 1999). In-stead of giving an overview of the
pathophysiology in itsentirety, the focus will be on the distinct
kinds of modula-tion.
4.1. Pathophysiology of motor symptoms4.1.1. Deficit in
Execution of movements: Akinesia.Both catatonia and PD can be
characterized by akinesiawhich may be related to functional
alterations in the so-called direct motor loop. The motor loop
includes con-nections from MC/SMA to putamen, from putamen to
in-ternal pallidum, and from there via mediodorsal thalamicnuclei
back to MC/SMA (Masterman & Cummings 1997).Decrease in striatal
dopamine leads to down-regulation ofthe direct motor loop
(exclusion of external pallidum) andconcurrent up-regulation of the
indirect motor loop (in-clusion of external pallidum), resulting in
a net effect of de-creased activity in premotor/motor cortex.
In contrast to PD, functional imaging studies during
per-formance of movements yielded no alterations in SMA andMC in
catatonia. However, effective connectivity rangingfrom
orbitofrontal cortex to premotor/motor cortex was sig-nificantly
reduced during emotional-motor stimulation incatatonic patients.
Premotor/motor cortical function re-
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mains apparentely intact during isolated motor
stimulation,whereas it seems to become dysregulated during
emotionalstimulation via cortico-cortical connectivity in
orbito-frontal/prefrontal cortex. Consequently, the motor
loopitself seems to remain intact in catatonia, whereas it is
dys-regulated by orbitofrontal and prefrontal cortex via
cor-tico-cortical, that is, horizontal modulation.
In summary, akinesia is closely related to down-regula-tion of
the motor loop. This down-regulation may becaused either by
dopamine and subcortical-cortical bot-tom-up modulation, as in PD,
or by GABA and cortico-cortical, that is, horizontal modulation
with consecutivetop-down modulation, as in catatonia.
4.1.2. Deficits in Initiation of movements: Starting prob-lems.
Parkinsonian patients could be characterized by def-icits in
initiation, which may be considered as one essentialcomponent of
the willed action system.
Movements have to be planned and a strategy formed,to get an
idea what kind of movement shall be performedwhich may be closely
related to lateral orbitofrontal corti-cal function (Deecke 1996).
This aspect is referred to as
the Plan/Strategy of movements, later in this article.There must
be an idea of how to move, including a deci-sion to perform a
movement, which can be initiated eitherinternally (i.e., voluntary)
or externally (i.e., involuntary).Internally initiated movements
can be considered as willedmovement/actions, which may be subserved
by a so-calledwilled action system involving the dorsolateral
prefrontalcortex (DLPFC), the anterior cingulate, the anterior
sup-plementary motor area (SMA), and fronto-striatal
circuits(Deecke 1996; Jahanshahi et al. 1995; Jahanshahi &
Frith1998, pp. 494, 51799.). This aspect is referred to as
Ini-tiation in the further course of the article. Once a move-ment
is initiated, it can be executed which probably isclosely related
to function of posterior SMA and the mo-tor cortex (Deecke 1996;
Jahanshahi & Frith 1998); this isreferred to as Execution in
the rest of this article. Theexecuted movement can be characterized
by dynamic andkinematic properties. Dynamic properties refer to
forceand velocity of the movements that may be encoded pri-marily
in neurons of the motor cortex (Dettmers et al.1995). Fronto-mesial
structures such as the SMA, as wellas the putamen and the
ventrolateral thalamus, may be im-
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Table 2. Pathophysiological correlates of symptoms in catatonia
and Parkinsons disease
Catatonia Parkinsons
Motor symptoms Akinesia Cortico-cortical
Subcortico-corticalGABA-ergic Dopaminergic
Starting problems Top-down-regulation of SMA/ Deficit in SMA/MC
in relation toMC altered bottom-up modulation
Posturing Right orbitofrontalRight posterior parietal
Rigidity Top-down modulation of striatal Deficit in striatal D-2
receptorsD-2 receptors
Behavioural Motor anosognosia Network between
ventrolateral,symptoms dorsolateral, and parietal cortex
Mutism and stupor Anterior cingulate and medial prefrontal
cortex
Preservative- Concomitant dysfunction incompulsive behavior
dorso- and ventrolateral
prefrontal cortexAffective Anxieties Medial orbitofrontal
cortex
symptoms Unbalance between medial and lateralprefrontal cortical
pathway
Inability to control Unfunctional relation between
medialanxieties and lateral orbitofrontal cortex
Depression Anterior cingulateTherapeutic GABA GABA-ergic
mediated neuronal
agents (lorazepam) inhibition in medial orbitofrontal cortex
Modualtion of functional andbehavioural inhibition
NMDA Down-regulation of Down-regulation of
glutamatergic-glutamatergic-mediated mediated overexcitation in
(amantadine) overexcitation in prefrontal and subcortical
pathwaysorbitofrontal-parietal pathways
dopamine Top-down modulation of striatal Compensation for
striatal D-2D-2 receptors predisposing for receptor deficit
withneuroleptic-induced catatonia normalization of bottom-up
modualtion
-
portant for coding of temporal properties, that is, the tim-ing
of movements (Deecke 1996, Jahanshahi & Frith 1998,p. 493).
Kinematic properties describe spatial characteris-tics of movements
such as angles, and so on, which may beencoded by neurons in
parietal cortex (areas 5, 39, 40)( Jeannerod 1997, pp. 5758, 7273;
Kalaska 1996.). Fi-nally, the movement must be terminated, which is
referredto as Termination, implying postural change with
on-linemonitoring of the spatial position of the movement.
PD can be characterized by severe deficits in SMA,which, as part
of the willed action system, is closely re-lated to the ability of
Initiation. Parkinsonian patients doindeed show severe deficits in
internal initiation, althoughthey are well able to execute them
once they have overcometheir initiation problems. Consequently, PD
may be char-acterized by disturbance in the willed action system
withproblems in the voluntary generation of movements by it-self
(Jahanshahi & Frith 1998).
In contrast to PD, catatonia cannot be characterized byprimary
alterations in the willed action system, since bothInitiation and
the function of SMA seem to remain moreor less intact in these
patients. Therefore, voluntary gener-ation and initiation imply
that the willed action systemitself remains basically intact.
Instead, the willed actionsystem becomes dysregulated by
cortico-cortical connec-tivity so that it only appears as if there
is a deficit in Initi-ation in catatonia.
In summary, initiation as part of the willed action sys-tem is
disturbed in PD, clinically accounting for startingproblems.
Whereas, in catatonia, the intact functioningwilled action system
becomes dysregulated by cortico-cortical modulation, resulting in
motor similarity betweencatatonic and Parkinsonic patients.
4.1.3. Deficit in Termination of movements: Posturing.In order
to terminate a movement, on-line monitoring ofthe spatial position
of the respective movement is neces-sarily required.
Neuropsychologically, such on-line moni-toring may be subserved by
visuo-spatial attention, asclosely related to function of the right
posterior parietal cor-tex.
The posterior parietal cortex has been shown to bespecifically
involved in location and direction of the spatialposition of
movements and limbs in relation to intraper-sonal space of the body
(Anderson 1999; Colby & Duhamal1996; Roland et al. 1980.). On
the basis of spatial attentionwith a redirection to extrapersonal
or sensory space, move-ments will be selected in orientation on the
respective spa-tial context. Providing the spatial frame of
reference, theposterior inferior parietal cortex, as contrasted to
the pos-terior superior parietal cortex, is specifically involved
in ab-stract spatial processing and exploration (Karnath 1999).
Assuch, the right posterior inferior parietal cortex may pro-vide
the intrapersonal spatial frame of reference of thebody necessary
for the conscious organization of move-ments thus making spatial
codes available for prefrontalcortical representation (Vallar 1999,
p. 45). In addition tospatial monitoring, the posterior inferior
parietal cortexseems to be specifically involved in early
initiation of move-ments (Castiello 1999; Desmurget et al. 1999;
Driver &Mattingley 1998; Mattingley et al. 1998; Snyder et al.
1997),which, in the present context, may be interpreted as a
spe-cific relationship between initiation of Termination
andposterior inferior parietal cortical function. Consequently,
posterior inferior parietal cortical function may provide
thelinkage between spatial registration as internal
spatialmonitoring, and initiation of Termination as
necessarilyrequired for postural change and consecutive execution
ofTermination.
In catatonia, alterations in right parietal cortical
functionwere found in neuropsychology and SPECT.
Neuropsycho-logically, catatonic patients showed deficits in
visuo-spatialabilities correlating with attentional function. SPECT
re-sults revealed decreased r-CBF in right parietal cortex
andabnormal correlations with visuo-spatial abilities. Involve-ment
of right posterior parietal cortex in pathophysiology ofcatatonia
is further supported by consideration of anatomo-functional
parcellation in this region. Distinct areas repre-senting eye
movements, arm movements, and head move-ments may be distinguished
within posterior parietal cortex(Anderson 1999; Colby & Duhamel
1996). Such distinctrepresentational areas for eyes, head, and arm
coincide withclinical observations that posturing in catatonia can
occur ineyes, arms, and/or head. Posturing of eyes may be
reflectedin staring, posturing of head is reflected in psychic
pillow,and posturing of arm is the classical type of posturing
(seeabove). All three kinds of posturing can occur simultane-ously,
but they may also dissociate from each other, so that,for example,
patients may show only the psychic pillowwithout staring and
posturing of limbs. It is therefore pos-tulated that such a
clinical dissociation between these threekinds of posturing may
have its physiological origin inanatomo-functional parcellation in
posterior parietal cortex.
It may be hypothesized that the deficit in right
parietalvisuo-spatial attention in catatonic patients leads to an
in-ability in initiation of Termination. The spatial position ofthe
ongoing movement can no longer be registrated in anappropriate way,
resulting in an impossibility to initiate theterminating movement.
This may result in an inability ofexecution of Termination with a
consecutive blockade inpostural change, which clinically is
reflected in posturing.Assumption of relation between posturing and
right pari-etal cortical dysfunction is supported by
electrophysiologi-cal findings during termination (Pfennig 2001;
Pfennig etal. 2001). Furthermore, patients with lesions in right
pari-etal cortex show posturing as well (Fukutake et al. 1993;Saver
et al. 1993).
Due to additional disturbances in orbitofrontal cortex,catatonia
has to be distinguished from disorders related toisolated lesions
in right parietal cortex as, for example, ne-glect showing the
following differences: (1) patients withneglect do not show
posturing; (2) unlike patients with ne-glect, catatonic patients
neither deny the existence of limbsor parts of their body, nor
overlook these body parts in re-lation to the environment, so that
they do not strike withthese body parts against walls, doors, and
so on; (3) patientswith neglect show attentional deficits, whereas
in catatonicpatients no such deficits could be found; (4) patients
withneglect do often show sensory deficits which cannot be
ob-served in catatonia; (5) unlike patients with neglect,
cata-tonic patients do not show a right-left pattern with respectto
their symptoms, that is, posturing; (6) unlike patientswith
neglect, catatonic patients do not suffer from alter-ations in
peripersonal and extrapersonal space (as reflectedin successful
ball experiments; Northoff et al. 1995),whereas they may be
characterized by alterations in per-sonal space, being unable to
locate the position of his/herown limbs in relation to the rest of
the body. Since personal
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and peri/extrapersonal space may be subserved by distinctneural
networks (Galati et al. 1999), distinction betweenboth kinds of
spaces may be not only phenomenologicallyrelevant but
physiologically as well. Hence, catatonia can-not be compared with
neglect as an attentional disorder, sothat posturing cannot be
accounted for by disturbances inattention, which is further
supported by neuropsychologi-cal findings showing no specific
alterations in attentionalmeasures (see above).
Other disorders related to right posterior parietal corti-cal
dysfunction must be distinguished from catatonia aswell. Patients
with Balint Syndrome show symptoms like aninability to fixate
objects and an optic ataxia, neither ofwhich can be observed in
catatonia. Since Balint Syndromeand especially optic ataxia
indicate involvement of rightposterior superior parietal cortex,
differences betweencatatonia and Balint Syndrome do further
underline theparticular importance of the right posterior inferior
parietalcortex in catatonia.
In contrast to catatonia, Parkinsonian patients show nei-ther
posturing nor alterations in right parietal cortex.
In summary, catatonia can be characterized by specificdeficits
in initiation of termination, while PD showsdeficits in initiation
of execution, implying functional dis-sociation between both
diseases with respect to initiation ofmovements. Whereas the
deficit in initiation of termina-tion seems to be related with
dysfunction in right posteriorinferior parietal cortex, lack of
initiation of executionseems to be accounted for by functional
deficits in SMA.
4.1.4. Alteration in tonus of movements: Cogwheel rigid-ity and
flexibilitas cerea. Parkinsonian patients could becharacterized by
muscular hypertonus with a so-calledcogwheel rigidity which may be
accounted for by a deficitin striatal D2-receptors and consecutive
dyscoordination ofactivity in internal pallidum.
Catatonic patients may show muscular hypertonus butwithout
cogwheel rigidity instead, they show a smoothkind of rigidity, a
so-called flexibilitas cerea. Since there isno primary, that is,
direct deficit of striatal D2-receptors incatatonia,
dyscoordination of the internal pallidum may benot as strong as in
PD, implying that there may be some kindof smooth muscular
hypertonus without cogwheel rigidity.Assumption of discrete
down-regulation of striatal D2-receptors may be supported by
symptomatic overlap be-tween catatonia and neuroleptic malignant
syndrome, pos-sibility of neuroleptic-induced catatonia, and
central roleof striatum in animal models of catatonia (see Carroll
2000).
Origin of down-regulation in striatal D2-receptors incatatonia
remains, however, unclear. Down-regulation ofstriatal D2-receptors
may be related to cortical alterations:Orbitofrontal cortical
alterations may lead to down-regula-tion in D2-receptors in caudate
via top-down modulationwithin the orbitofrontal cortical loop (see
Fig. 4 below).Or striatal D2-receptors may be top-down
modulatedwithin the motor loop, which by itself may be
dysregu-lated by cortico-cortical connectivity. However, due to
lackof specific investigation of basal ganglia in catatonia,
bothassumptions remain speculative.
In summary, rigidity may be related to alterations in in-ternal
pallidum as induced by down-regulation of striatalD2-receptors.
Abnormal modulation of D2-receptors maybe due to alterations in
either subcortical-subcortical con-nectivity, as in PD, or abnormal
cortico-cortical connectiv-
ity with consecutive horizontal modulation and concur-rent
cortico-subcortical top-down modulation, as may bethe case in
catatonia.
4.2. Pathophysiology of behavioral symptoms4.2.1. Deficit in
on-line monitoring: Motor anosognosia.Subjective experience in
catatonic patients could be char-acterized by unawareness of
posturing and movement dis-turbances in general, whereas
Parkinsonian patients werewell aware of their motor deficits. This
raises the questionof difference between catatonic and Parkinsonian
patientswith respect to internal monitoring of the movement.
Itshould be noted that catatonic patients showed unaware-ness only
with respect to their motor disturbances, sincethey were well aware
or even hyperaware of emotional al-terations, which excludes the
possibility of a deficit in gen-eral awareness.
Awareness of movements is closely related to the abilityof
on-line monitoring as an internal monitoring, which byitself
necessarily requires generation of an internal modelof the
respective movement. According to Miall andWolpert (1996), distinct
kinds of models can be distin-guished (see Fig. 2). There is a
causal representation of themotor apparatus that can be described
as a Forward dy-namic model. The model of the behavior and the
environ-ment can be called Forward output model. Finally, anInverse
model can be assumed where the causal flow ofthe motor system is
inverted by representing the causalevents that produced the
respective motor state (for moredetailed discussion, see Miall
& Wolpert 1996).
In orientation on the model by Miall and Wolpert
(1996),predicted and actual state are compared with eachother,
necessarily presupposing the estimation of the actualspatial
position. Both estimation of spatial position andcomparison between
actual and predicted state seem to bedisturbed in catatonia, as
indicated by quadrats with crossesleading consecutively to
alterations in initiation and exe-cution of Termination, and
finally resulting in postur-ing, which is the most bizarre symptom
in catatonia. Parkin-sons disease, in contrast, may rather be
characterized bydeficit in Initiation leading to difficulties in
Executionwhereas, unlike in catatonia, estimation of spatial
positionand comparison between actual and predicted spatial
stateremain intact by themselves.
Note that there is double dissociation between catatoniaand
Parkinsons disease with regard to feedforward and feed-back:
Feedback is disturbed in catatonia and feedforwardseems to be
preserved by itself, whereas in Parkinsons dis-ease, feedforward is
disturbed with feedback remaining in-tact.
The internal monitoring of movements could itself beeither
implicit or explicit. Following Jeannerod (1997),only certain
aspects of movements are internally monitoredin an explicit mode of
processing. Plan/Strategy and, tosome extent, Initiation are
accessible to consciousnessand can be characterized by explicit
internal monitoring.In contrast Execution by itself is not
accessible to con-sciousness and can be related only with implicit
internalmonitoring (Jeannerod 1997). Accordingly, Jeannerod
dis-tinguishes between an implicit How system and an ex-plicit Who
system of movements/action, the former beingresponsible for
Execution, whereas the latter includesPlan/Strategy and
Initiation.
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Figure 2. Forward model (in orientation on Miall and Wolpert
1996) of physiological motor control in catatonia and
ParkinsonsdiseaseLegendh1 5 Disturbance in Parkinsons diseaseh3 5
Disturbance in catatonia* 5 Hypofunction in catatoniaThe figure
shows the forward model as established by Miall and Wolpert (1996)
supplemented by the distinct aspects of movementsPlan/Strategy,
Initiation, Execution. In addition distinct processes involved in
Termination of movements, feedback, estimatedspatial position,
initiation and execution of Termination are included. In
orientation on the model by Miall and Wolpert (1996) pre-dicted and
actual state are compared with each other necessarily presupposing
the estimation of the actual spatial position. Both es-timation of
spatial position and comparison between actual and predicted state
seem to be disturbed in catatonia as indicated by quadratswith
crosses leading consecutively to alterations in initiation and
execution of Termination finally resulting in posturing as the
mostbizarre symptom in catatonia. Parkinsons disease in contrast
may rather be characterized by deficit in Initiation leading to
difficultiesin Execution whereas, unlike in catatonia, estimation
of spatial position and comparison between actual and predicted
spatial state re-main intact by themselves.Note that there is
double dissociation bewteen catatonia and Parkinsons disease with
regard to feedforward and feedback: Feedback isdisturbed in
catatonia while feedforward seems to be preserved by itself whereas
in Parkinsons disease feedforward is disturbed withfeedback
remaining intact.
-
Empirically, such an assumption is further supported bya study
from Grafton et al. (1995) investigating whetherpersons were
conscious or unconscious of a particular or-der of sequences of
movements they performed con-sciousness of the order of sequence
necessarily presuppos-ing an explicit internal monitoring of
Plan/Strategy.Subjects showing consciousness of the order of
sequencecould be characterized by activation in right
dorsolateralprefrontal cortex (Area 9), right posterior parietal
cortex(Area 40), and right premotor cortex (Area 6), compared
tothose subjects who were unconscious. Increasing demandof explicit
internal monitoring, as induced by mirror ex-periments, led to
activation in right lateral dorsolateral pre-frontal cortex (Area 9
and 46) and right posterior parietalcortex (Area 40) (Fink et al.
1999).
Following distinction between implicit and explicitinternal
monitoring, an analogous hypothesis shall be de-veloped for
Termination. Initiation of Termination andexecution of Termination
can be distinguished from eachother, emphasizing the particular
importance of internalspatial monitoring for initiation of
Termination. Follow-ing phenomenological accounts of movements, one
maywell be conscious about the spatial position from which
oneinitiates the terminating movement initiation of Ter-mination
may be characterized by explicit internal moni-toring. In contrast,
execution of Termination may be as-sociated only with implicit
internal monitoring. Hence,the spatial position from which the
Termination is initi-ated may be accessible to consciousness, that
is, explicit in-ternal monitoring, whereas execution of the
terminatingmovement itself may rather remain unconscious, because
itmay be characterized only by implicit internal monitor-ing.
Internal monitoring of the spatial position of move-ments may be
regarded as a subset of on-line monitoring ingeneral and can be
considered as an essential componentof working memory. On-line
monitoring in general isclosely related to functional activity in
ventrolateral anddorsolateral prefrontal cortex (i.e., VLPFC and
DLPFC)(see Leary et al. 1999; Petrides 1995). Therefore, it may
behypothesized that on-line monitoring of the spatial positionof
their respective movements, may be subserved by aright-hemispheric
network between VLPFC, DLPFC, andposterior parietal cortex (i.e.,
PPC). Consequently, func-tional connections between right posterior
parietal, rightdorsolateral prefrontal, and right lateral
orbitofrontal/ven-trolateral prefronal cortex may be of crucial
importance forimplicit and explicit internal monitoring of the
spatialposition of movements. As based on the
above-mentionedstudies of motor awareness, the VLPFC seems to be
relatedto implicit internal monitoring, whereas the DLPFC maybe
involved in explicit internal monitoring.
The lateral orbitofrontal/ventrolateral prefrontal cortexshows
similar cytoarchitectonic subdivisions as the poste-rior parietal
cortex (Carmichael & Price 1994), and receivesreciprocal
connections from both posterior parietal anddorsolateral prefrontal
cortex that project to similar areas(Cavada & Goldman-Rakic
1989; Morecraft et al. 1992;1998; Selemon & Goldman-Rakic
1988). In accordancewith such reciprocal connectivity,
co-activation of thesethree regions has been demonstrated in tasks
requiring be-havioral flexibility and implicit and explicit spatial
moni-toring (Athwal et al. 1999; Meyer-Lindenberg et al. 1999;Nobre
et al. 1999; Quintana & Fuster 1999; Stephan et al.
1999). The orbitofrontal cortex may modulate activity
indorsolateral and posterior parietal cortex, which has alreadybeen
demonstrated in both animals (Quintana et al. 1989)and humans
(Bchel et al. 1997; Drevets & Raichle 1998;Mayberg et al.
1999). Furthermore, the right orbitofrontalcortex shows a higher
density of neurons and neuronal con-nections, which may account for
predominance of righthemispheric activation (see below).
Consequently, the righthemispheric neural network between posterior
parietal,dorsolateral prefrontal, and lateral
orbitofrontal/ventrolat-eral prefrontal cortex may be crucially
involved in implicitand explicit internal monitoring of the spatial
position ofmovements, resulting in updating of spatial location
andrepresentation of movements (Colby 1999).
Catatonia can be characterized by major deficits in on-line
monitoring and alterations in right ventro/dorsolateralprefrontal
cortex (i.e., VLPFC, DLPFC) and right poste-rior parietal cortex
(PPC) as has been demonstrated inSPECT and fMRI (see above). This
right hemispheric net-work between VLPFC, DLPFC, and PPC may be
alteredin catatonia, which may account for deficit in on-line
mon-itoring of the spatial position of movements,
consecutivelyleading to posturing. One may assume that both kinds
ofon-line monitoring implicit and explicit internal mon-itoring may
be deficient in catatonia: Catatonic patientsare neither able to
terminate their movements requiringimplicit monitoring, nor are
they aware of their motor dis-turbances requiring explicit internal
monitoring, result-ing in concurrent posturing and motor
anosognosia.
Furthermore, one may hypothesize that primary in-volvement of
GABA-ergic transmission may be somehowrelated to motor anosognosia.
Similar to catatonia patientswith movement, disturbances with
primary alteration inGABA, such as Huntingtons chorea and
Parkinsonian dys-kinesia, do show unawareness of their motor
anomalies,that is, motor anosognosia (Snowdon et al. 1998).
However,the exact relationship between GABA-ergic transmissionand
motor anosognosia remains unclear.
In contrast to catatonia, Parkinsonian patients showdeficits
neither in on-line monitoring in general, nor in im-plicit and
explicit internal monitoring of movements inparticular.
Physiologically, this may be reflected in the ab-sence of major
deficits of function in VLPFC and GABA-ergic transmission, implying
that these patients remain fullyaware of their motor
disturbances.
In summary, catatonia can be characterized by ventrolat-eral
prefrontal cortical dysfunction with consecutive def-icits in
on-line monitoring in general. This deficit may leadto
dysregulation of the right-hemispheric network betweenVLPFC, DLPFC,
and PPC, resulting in lack of implicitand explicit internal
monitoring of the spatial position ofmovements. Clinically, such a
dysregulation is reflected inconcurrent occurrence of posturing and
motor anosognosiain catatonic patients.
4.2.2. Deficit in verbal and nonverbal contact: Mutismand
stupor. One of the most impressive clinical features incatatonic
patients is mutism or even stupor, implying thatthere is no longer
any kind of verbal contact (mutism) and/or nonverbal contact
(stupor) with other persons neithermutism nor stupor occur in
PD.
Catatonia could be characterized by alterations in medialand
lateral orbitofrontal cortex during negative emotionalprocessing.
These alterations shift the patterns of activity
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towards anterior cingulate/medial prefrontal cortex and lat-eral
prefrontal cortex, resulting in functional lack of balancebetween
medial and lateral pathway in prefrontal cortex(see sect. 3).
The anterior cingulate (areas 24 and 32, according toBrodmann)
shows anatomical, cytoarchitectonic, connec-tional, and functional
subdivision into an affective (area24a), cognitive (area 24b), and
motor (area 24c) part. Rela-tion between these three subdivisions
may be characterizedby reciprocal suppression (Devinsky 1997): For
example,strong emotional processing leads to activation in the
af-fective part and concurrrent suppression of the cognitivepart,
and vice versa (see Bush et al. 2000).
Because the patterns of activity shifted from orbito-frontal
cortex to anterior cingulate/medial prefrontal cor-tex, there may
be extremely strong and high activity in theaffective part (i.e.,
24c) of the anterior cingulate. Via recip-rocal suppression, one
may assume almost complete down-regulation of functional activity
within the motor part of theanterior cingulate. Down-regulation of
the motor part inthe anterior cingulate may account for mutism as
an inabil-ity to speak (that is, making verbal contact with other
per-sons). Such an assumption would be supported by observa-tion of
mutism in patients with isolated lesions in theanterior cingulate.
In addition, these patients can be char-acterized by a combination
of akinesia and mutism aki-netic mutism, which, of course, is in
full accordance withcatatonia. However, comparison between
catatonia and aki-netic mutism should be restricted to concurrent
occurrenceof akinesia and mutism. Unlike in catatonia, patients
withakinetic mutism show neither hyperkinesias nor other
be-havioral anomalies (like negativism, perseverative and
com-pulsive behavior, etc.).
In addition to anterior cingulate alterations, catatonic
pa-tients showed functional alterations in medial prefrontalcortex
during negative emotional processing. The medialprefrontal cortex
is involved in social cognition as well as inperception of
movements and mental states of other per-sons (see Castelli et al.
2000). Shift of pattern of activityfrom orbitofrontal to medial
prefrontal cortex may lead todysfunction of the latter. Medial
prefrontal cortical dys-function may in turn result in
deterioration of the ability toperceive movements and mental states
from other persons.Clinically, this may be reflected in stupor, or
the inability tomake either verbal or nonverbal contact with other
personsat all.
In summary, deficit in orbitofrontal cortical activationduring
negative emotional processing in catatonia leads toa shift of
patterns of activity towards anterior cingulate andmedial
prefrontal cortex. Clinically, dysfunction in anteriorcingulate and
medial prefrontal cortex may be reflected inmutism and stupor.
4.2.3. Deficit in inhibitory control and planning of behav-iour:
Perseverative-compulsive behaviour. In contrast toPD, catatonia can
be characterized by bizarre behaviouralanomalies including
negativism, stereotypies, persevera-tions, echolalia/praxia, and so
on (see above), which may beclassified as perseverative and
compulsive behaviour. Thesebizarre perseverative and compulsive
behavioural anom-alies may be closely related with dysfunction in
the or-bitofrontal cortex.
The orbitofrontal cortex, and especially the lateral
partincluding the ventrolateral prefrontal cortex (VLPFC), may
be associated with control and monitoring of complex be-haviour
(Deecke 1996), whereas planning of its detailsseems to be subserved
rather by the dorsolateral prefrontalcortical function (DLPFC)
(Jahanshahi & Frith 1998).Control and monitoring of complex
behaviour may be ex-erted by inhibition (Dias et al. 1996; 1997)
realized by sup-pression as an inhibitory control. Similar to
VLPFC, theDLPFC shows reciprocal connections with posterior
pari-etal cortex (PPC) (Cavada & Goldman-Rakic 1989; Sele-mon
& Goldman-Rakic 1988). Therefore, control and mon-itoring of
behaviour may be closely associated withregistration of the spatial
position of the respective move-ment. It is the neural network
between VLPFC, DLPFC,and PPC which may consequently subserve the
control andmonitoring of complex behaviour.
Due to deficits in medial and lateral orbitofrontal corti-cal
activation in catatonia, the VLPFC may be unable to ex-ert
inhibitory control and monitoring of complex behaviour.Behaviour
can no longer be controlled by inhibition, re-sulting in lack of
suppression of once started behavior withconsecutive
perseverations. It is this inability to suppressonce started
behaviour that may account for perseverativesymptoms like
stereotypies, echolalia/praxia, persevera-tions, and so on.
Furthermore, alterations in lateral or-bitofrontal cortex are
closely associated with compulsivebehaviour, for example, in
obsessive-compulsive disorder.This may further support our
assumption of a relation be-tween perseverative-compulsive
behavioural anomaliesand dysfunction in VLPFC in catatonia.
Dysfunction in VLPFC may lead to functional alterationin DLPFC
as well, because both