Published in Behavioral and
Brain Sciences
Volume 25, Number 5: 555-577 (October 2002)
© 2002 Cambridge University Press
Below is the unedited, uncorrected, unquotable final draft preprint of a BBS target article that was accepted for publication. To order the final published version of this target article, with commentaries and authors’ response, please visit the BBS Homepage at Cambridge Journals Online.
What catatonia can tell us about
"top-down modulation": A neuropsychiatric hypothesis
George Northoff, MD PhD, PhD
Harvard University
Beth Israel Hospital
Dept. of Behavioral Neurology
Kirstein Building KS
330 Brookline Avenue
Boston, MA 02215
USA
Phone: 617-6670264
Fax: 617-7955322
gnorthof@caregroup.harvard.edu
"This 'new orientation', of which Jellife spoke,
and of which he himself was a notable exemplar,
did not involve merely combining neurological and
psychiatric knowledge, but conjoining them, seeing
them as inseparable, seeing how psychiatric phenomena
might emerge from the physiological, or how, conversely,
they might be transformed into it" (O.Sacks 1989,157)
KEY-WORDS: Catatonia; Parkinson's disease; Top-down modulation; Bottom-up modulation; Horizontal modulation; Vertical modulation
ABSTRACT (long)
Differentialdiagnosis of motor symptoms, as for example akinesia, may be difficult in clinical neuropsychiatry. They may be either of neurologic origin, as for example Parkinson's disease, or psychiatric origin, as for example catatonia, leading to a so-called "conflict of paradigms". Despite their different origin symptoms may appear clinically more or less similar. Possibility of dissociation between origin and clinical appearance may reflect functional brain organisation in general and cortical-cortical/subcortical relations in particular. It is therefore hypothesized that similarities and differences between Parkinson's disease and catatonia may be accounted for by distinct kinds of modulation between cortico-cortical and cortico-subcortical relations. Catatonia can be characterized by concurrent motor, emotional and behavioral symptoms. These 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 modulation" reflecting "vertical modulation" of caudate and other basal ganglia by gaba-ergic mediated orbitofrontal cortical deficits may account for motor symptoms in catatonia. Parkinson' disease in contrast can be characterized by predominant motor symptoms. Motor symptoms may be accounted for by altered "bottom-up modulation" between dopaminergic mediated deficits in striatum and premotor/motor cortex. Clinical similarities between Parkinson's disease and catatonia with respect to akinesia may be related with involvement of the basal ganglia in both disorders. Clinical differences with respect to emotional and behavioural symptoms may be related with involvement of different cortical areas i.e. orbitofrontal/parietal and premotor/motor cortex implying distinct kinds of modulation i.e. "vertical and horizontal modulation" respectively.
Comparison between Parkinson's disease and catatonia reveals distinction between two kinds of modulation "vertical and horizontal modulation". "Vertical modulation" concerns cortical-subcortical relations and allows apparently for bidirectional modulation. This is reflected in possibility of both "top-down and bottom-up modulation" and appearance of motor symptoms in both Parkinson's disease and catatonia. "Horizontal modulation" concerns cortical-cortical relations and allows apparently only for unidirectional modulation. This is reflected in one-way connections from prefrontal to motor cortex and absence of major affective and behavioural symptoms in Parkinson's disease. It is concluded that comparison between Parkinson's disease and catatonia may reveal the nature of modulation of cortico-cortical and cortico-subcortical relations in further detail.
Abstract (short)
Differentialdiagnosis of motor symptoms, as for example akinesia, may be difficult in clinical neuropsychiatry. They may be either of neurologic origin, as for example Parkinson's disease, or psychiatric origin, as for example catatonia, leading to a so-called "conflict of paradigms". Despite their different origin symptoms may appear clinically more or less similar. Possibility of dissociation between origin and clinical appearance may reflect functional brain organisation in general and cortical-cortical/subcortical relations in particular. It is therefore hypothesized that similarities and differences between Parkinson's disease and catatonia may be accounted for by distinct kinds of modulation between cortico-cortical and cortico-subcortical relations. Comparison between Parkinson's disease and catatonia reveals distinction between two kinds of modulation "vertical and horizontal modulation". "Vertical modulation" concerns cortical-subcortical relations and allows apparently for bidirectional modulation. This is reflected in possibility of both "top-down and bottom-up modulation" and appearance of motor symptoms in both Parkinson's disease and catatonia. "Horizontal modulation" concerns cortical-cortical relations and allows apparently only for unidirectional modulation. This is reflected in one-way connections from prefrontal cortex to motor cortex and absence of major affective and behavioural symptoms in Parkinson's disease. It is concluded that comparison between Parkinson's disease and catatonia may reveal the nature of modulation of cortico-cortical and cortico-subcortical relations in further detail.
1. INTRODUCTION
Differential
diagnosis in neuropsychiatry is often rather difficult since similar symptoms
may be related with different diseases being either neurologic or psychiatric. For
example the symptom of akinesia can be caused either by Parkinson's disease
(PD), classified as a neurological disease, or
catatonia, usually classified as a psychiatric disease. Moreover the same
symptom i.e. akinesia may be accompanied by different psychological alterations
either depression, as in PD, or uncontrollable anxieties, as in catatonia.
Consequently consideration of both symptomatic origin and complexity makes
classification of diseases as either neurologic or psychiatric rather difficult.
This is reflected in a so-called "conflict of paradigms" pointing out
the inability to draw a clear dividing line between neurologic and psychiatric
disturbances (
If symptoms
of different origin i.e. psychiatric or neurologic show similar clinical
appearance one may assume similar or at least overlapping pathophysiological
substrates reflecting functional brain organisation in general. Functional
relation between prefrontal/frontal cortex and basal ganglia may account for
similarity between PD and catatonia with respect to motor symptoms. Relation
between prefrontal/frontal cortex and basal ganglia can be characterized by
various "functional circuits" (see Mastermann and Cummings 1997 for a
nice overview) allowing for bidrectional modulation with both "top-down
and bottom-up modulation" as forms of "vertical modulation". In
addition to cortico-subcortical relation one may consider cortico-cortical
relation as well reflecting "horizontal modulation" which may rather
be unidirectional (see below).
Comparison
between pathophysiological mechanisms underlying PD and those subserving
catatonia may reveal the nature of these distinct kinds of modulation of
cortico-cortical/subcortical relation in further detail. The following
hypothesis are postulated: (i) apparent clinical similarity and underlying
pathophysiological differences in motor symptoms between PD and catatonia; (ii)
differences in psychiatric i.e. affective and behavioral symptoms between PD
and catatonia; (iii) "double dissociation" between catatonia and PD
with respect to underlying pathophysiological mechanisms accounting for
clinical differences; (iv) opposite kinds of "vertical modulation"
between prefrontal/frontal cortex and basal ganglia in PD and catatonia
("bottom-up and top-down modulation") accounting for subtle
differences in motor symptoms; (v) presence/absence of alterations in
cortico-cortical relation reflecting "horizontal modulation" in
catatonia and PD respectively accounting for major differences in emotional-behavioral
symptoms.
First we
describe similarities and differences in clinical symptoms and therapy between
PD and catatonia. This is followed by illustration of neuropsychological and
pathophysiological findings. Third we develop pathophysiological hypothesis for
the different kinds of symptoms observed in PD and catatonia. On the basis of these pathophysiological hypothesis distinction between
"horizontal and vertical modulation" of cortico-cortical/subcortical
relation with respect to directionality is suggested.
2. CATATONIA AS A PSYCHOMOTOR SYNDROME: COMPARISON WITH PARKINSON'S AS A
MOTOR SYNDROME
2.1. Motor Symptoms
Catatonia
is a rather rare (incidence: 2-8% of all acute admissions) psychomotor
syndrome. As such it can be associated with psychiatric disturbances such as
schizophrenia (one subtype is denoted as "catatonic schizophrenia")
and manic-depressive illness as well as with various neurological and medical
diseases (Gelenberg 1976, Taylor 1990, Northoff 1997). Some authors (see Northoff
1997 for an overview) consider periodic catatonia as an idiopathic disease
showing psychomotor characteristics of catatonic syndrome while not beeing
associated with any other kind of disease. Parkinsonism is a motor syndrome
which can be either of idiopathic i.e. primary or symptomatic i.e. secondary
nature. In the first case one speaks of Parkinson's disease (PD), which may be
considered as a nosological analogue of periodic catatonia. Whereas
in the second case one generally speaks of Parkinsonism which, similar to
catatonia, may be associated with various neurological and medical diseases.
The most
characteristic feature of catatonia is posturing where patients show a
specific, uncomfortable, and often 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 Figure 1). If that position is
taken actively and internally by the patient himself one speaks of 'posturing',
if such a position can 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").
Figure 1: "Active posturing" in a group of catatonic patients
We saw one patient who postured
every morning during shaving. He started to shave himself and remained then,
with the razor in his hand and a lifted arm, for hours in that position until
his wife came in and "depositioned" him (see Northoff 1997 for
detailed description). Another example is a woman who, every morning by opening
her wardrobe, remained in a position with a lifted arm keeping the door of the
wardrobe in her hand. Both patients were admitted into clinic where they did
neither speak nor move at all. On admission it was possible to
"position" their limbs in the most bizarre and uncomfortable
positions against gravity without any resistance by the patients themselves. Once
the examiner positioned the limbs into one particular position they remained in
that position without showing even the slightest change.
These cases
are typical examples of posturing and catalepsy where patients are well able to
initate and execute movements but seem to be unable to return to the initial or
resting position in order to start a new movement. Similar to PD, catatonic
patients do show akinesia but, unlike parkinsonian patients, only in
association with posturing and catalepsy. Furthermore, in contrast to PD,
catatonic akinesia is not necessarily accompanied by muscular hypertonus i.e.
rigidity since patients may also show muscular normo- or hypotonus (Northoff
1997). Even if catatonic patients show muscular hypertonus it is not the kind of
rigidity i.e. cogwheel rigidity being typical for PD. Instead they rather show
a smooth type of rigidity which is called flexibilitas cerea (Northoff 1997).
In addition to hypokinetic features catatonic patients may show intermittent
and fluctuating hyperkinesias like stereotypies, dyskinesias and tics which,
unlike in PD, are independent from medication.
Catatonic
patients are well able to "plan", "initiate" and
"execute" movements which could be demonstrated in ball-experiments.
We performed systematic ball-experiments in 32 catatonic patients in an acute
akinetic state before they received any medication (i.e. lorazepam) (see
Northoff et al. 1995a). To our surprise almost all patients, despite showing
concurrent akinesia and posturing, were able to play ball either with the hands
or with the legs. Patients were able to catch and throw the ball, being
slightly better during external intiation (i.e. catching) than during internal
initiation (i.e. throwing). Most patients however remained in a final posture
keeping the ball in a position against gravity being apparently unable to
change posture and terminate the respective movement. Subjectively catatonic
patients experienced these ball-experiments as ""funny and
relaxing" and as "taking off my inner tension" while they were
not aware of their inability to terminate movements i.e. posturing (Northoff et
al. 1995a, 1998). Furthermore, in contrast to PD, posturing in catatonic
patients can not be reversed by external sensory stimulation, as for example,
drawing a line in front of the feet. Accordingly catatonic patients did not
experience any starting problems or deficits in "internal
initiation".
In summary
catatonia and PD can be characterized by both clinical similarities, as it is reflected
in akinesia and rigiditiy, and differences, as it is reflected in
posturing/initiation and cogwheel rigidity/flexibilitas cerea, with respect to
motor symptoms.
2.2. Behavioral and
affective symptoms
In addition
to motor symptoms, catatonia can be characterized by concurrent behavioral and
affective anomalies. Behavioral anomalies include mutism (patients do not speak
anymore at it was the case in both patients described above), stupor (no
reaction to the environment), automatic obedience (patients do everything what
they are asked for), negativism (patients do always the opposite of what they
are asked for), echolalia/praxia (patients do repeat sentences or actions from
external persons several times or even endless), perseverative-compulsive behavior
(uncontrollable repetetive behavioral patterns) and mitmachen/mitgehen
(patients do always follow other persons and make the same as they do). In
contrast to catatonia such behavioral anomalies cannot be observed in PD which
can be characterized predominantly by motor symptoms.
Affective
alterations in catatonia include strong anxieties or euphoria/happiness,
staring, grimacing, and inadaequate emotional reactions. Catatonic patients may
show compulsive emotions (involuntary and uncontrollable repetetive emotional
reactions), emotional lability (labile and unstable emotional reactions),
agression (often accompanied by extreme emotional states such as anxiety or
rage), excitement (extreme hyperactivity with extreme and uncontrollable
emotional reactions), affective latence (long time to show emotional
reactions), ambivalence (simultaneous presence of conflicting emotions) and
flat affect (decreased and/or passive emotional reactivity). Such symptoms are
not present in PD. Patients with PD can rather be characterized by depression
whereas they do neither show such an uncontrollable intensity of emotions nor a
comparable variety of emotional reactivity as catatonic patients.
In summary
catatonia can be characterized by strong affective and bizarre behavioral
anomalies which as such do not ocurr in PD.
2.3. Therapy
Therapeutically
60-80% of all acute catatonic patients react to lorazepam, a GABA-A receptor
potentiator, either almost immediately within the first 5-10 minutes or within
24 hours (Rosebush et al. 1990, Northoff et al. 1995b, Bush et al. 1996)
whereas chronic catatonic patients show no improvements on lorazepam (Ungvari
et al. 1999). If lorazepam does not work some catatonic patients show gradual
and delayed improvements (within 2 to 4 days) on the NMDA-antagonist amantadine
(Northoff et al. 1997, 1999c) and/or on electroconvulsive treatment (ECT) (Fink
et al. 1993, Petrides et al. 1997).
Dopaminergic
substances like L-Dopa and D1/2 receptors agonists are therapeutically
effective in PD. Unlike in catatonia, lorazepam and other benzodiazepines
remain therapeutically ineffective in PD. Similar to catatonia the
NMDA-antagonist amantadine is therapeutically effective in PD as well (Merello
et al. 1999). In addition to pharmacotherapy surgical therapies with
implantation of either electrodes or fetal tissue in specific structures of the
basal ganglia (putamen, caudate, subthalamic nuclei, internal
pallidum) may be applied especially in drug-resistant patients with PD.
In summary
treatment in catatonia and Parkinson's can be characterized by differences
(Gaba-ergic agents versus dopaminergic agents) and similarities
(NMDA-antagonists).
2.4. Subjective
experience
In order to
further reveal the nature of psychological alterations and their relation to
motor symptoms we investigated subjective experience in catatonic patients with
a self-questionaire. Due to mutism and akinesia in almost all patients with
hypokinetic catatonia such an investigation remains possible only
retrospectively. Catatonic patients were compared with akinetic parkinsonic
patients and non-catatonic depressive and schizophrenic patients (see Northoff
et al. 1998 for details).
Parkinsonian
patients severely suffered from akinesia, they felt "locked into my
body", and "wanted to move but was unable to do so". Catatonic
patients, in contrast, did not realize "any alterations in my
movements" and said that "they (the movements) were completely
normal". Asked why they positioned their limbs in a particular posture
they either answered "There was nothing abnormal with my movements"
or couldn't say anything. The patient posturing during shaving said "My
movements were completely normal and I could shave in the normal way". No
patient said that he subjectively suffered from any changes in his movements. Moreover no
catatonic patient reported any feeling of pain or tiredness even if he postured
and remained in the same position for hours (n=5), days (n=10) or weeks (n=5).
Instead of changes in their movements many catatonic patients reported
extremely intense emotions which they experienced as "uncontrollable and
overwhelming". Patients "felt totally blocked" by these emotions
which "overwhelmed me" and "lead to a blockade of my self".
The dominating emotion was anxiety (due to paranoid delusions, acoustic
hallucinations, depressive mood or traumatic experiences). For example, the
patient posturing during shaving as described above,
said that "I couldn't control my emotions anymore, they were overflooding
me so that I had the feeling that I was just anxiety". Nevertheless some
patients reported rather positive emotions like euphoria which, however,
similar to anxiety, they were unable to control anymore. One patient, for
example, became catatonic every time (5 times in total) when she fall in love reporting the following: "I am so happy
when I fell in love, this feeling really overwhelms me so that I can't control
it anymore. Every time when I fell in love I am admitted to clinic I don't
understand this".
Catatonic patients did not subjectively
experience any "sensation of effort" during posturing. Although they
kept their limbs or head in a position against gravity, where every normal
person and patient with PD would feel a "sensation of tiredness or
pain", catatonic patients do not experience any "tiredness",
pain, or a "sensation of effort" during posturing. For example,
catatonic patients lying in the bed may keep up their head for hours or even
days (i.e. a so-called ,psychic pillow‘) without
getting tired and/or reporting any feeling of tiredness. Asking these patients
with such a "psychic pillow" they answer "My head was in a
completely normal position, I wasn't tired at all"; instead they rather
seem to experience a "sense of weightlessness".
No
catatonic patient was able to give an account of the position in which he kept
his limbs thus remaining unaware of posturing. It seems as if they have no
access to any kind of subjective experience of the actual spatial position
during posturing – the "objective position" and the corresponding
"subjective experience" of the spatial position seem to be decoupled
from each other. Unfortunately there are no data available whether postacute
patients recognize the posturing characterizing their acute state as their own.
Such data could provide information about the exact nature f the deficit in
awareness. If they could recognize the posturing as their own they would show
only an alteration in motor awareness but not in self-awareness. If in contrast
they would be unable to do so there must be a general deficit in
self-awareness. Since however catatonic patients are well able to recognize
their own person in a postacute state one may rather hypothesize a deficit in
motor awareness only.
Furthermore
they are not aware of the "consequences of their movements" (Snowdon
et al. 1998): The patient posturing during shaving claimed that he finished
shaving every morning completely without any time delay so that he wasn't aware
of the "consequences of posturing". Finally catatonic patients do
neither show any objective nor any kind of subjective sensory abnormality so
that alterations in subjective experience cannot be accounted for by sensory
dysfunction.
Almost all catatonic patients
reporting strong, intense and uncontrollable emotions responded well to
lorazepam whereas patients without such emotional experiences did not respond
well to lorazepam (Northoff et al. 1998). Non-responders to lorazepam, as for
example the above described patient posturing in front of her wardrobe, rather
experienced a "blockade of my will with contradictory and ambivalent
thoughts about my dresses since I couldn't decide myself". For several
days this patient stood in front of her wardrobe remaining in the same quite
uncomfortable position with raised arms and on the tip of her toes. She wasn't
aware of any alterations in her movements denying any feeling of tiredness
during that position ("I wasn't tired at all"). All catatonic
patients experienced their admission on a psychiatric ward as terrible ("I
thought it was the hell") and/or could not understand it ("I was so happy, there was no reason for admission this time").
Moreover they very well remembered the physician and other persons who treated
them on admission. Consequently catatonic patients seem to show neither deficits
in memory (except in working memory; see below) nor in general awareness.
In summary
subjective experience differs between catatonic and parkinsonian patients with
respect to motor symptoms (motor anosognosia versus motor awareness) and
psychological state (anxiety versus depressive reaction).
3. NEUROPSYCHOLOGICAL
AND PATHOPHYSIOLOGICAL FINDINGS IN CATATONIA AND PARKINSON'S
3.1.
Neuropsychological findings
We pointed
out that the ability to registrate the spatial position of movements, as
required for "Termination of movements" (see above), does involve
spatial abilities as potentially related with right posterior parietal cortical
function. We therefore investigated postacute akinetic catatonic patients with
neuropsychological tests for measurement of spatial abilities (Northoff et al.
1999a). Among other measures we applied the Visual-Object-Space and Perception
Test (i.e. VOSP) a test specifically designed for measurement of spatial
abilities related to right parietal cortical function.
Table
1 Neuropsychological and pathophysiological findings in catatonia and
Parkinsonąs disease
|
|
Catatonia |
Parkinson |
|
Neuropsychology |
- Visuospatial attention - On-line monitoring - Emotionally-guided decisions |
- Executive functions |
|
Postmortem |
- Caudate, N.accumbens, Pallidum, Thalamus |
- Substantia nigra, Putamen, Caudate |
|
Animal models |
- Bulbocapnine, Stress, GABA |
- 6-OHDH, MPTP |
|
Structural imaging |
- Prefrontal and parietal cortex |
- Basal ganglia |
|
Functional imaging |
- Right prefronto-parietal CBF - Right OFC - Prefrontal connectivity |
- SMA/MC - Lateral prefrontal cortex - Fronto-striatal connectivity |
|
Electrophysiology |
- Late and postural RP - RP modulation by lorazepam |
- Early RP - RP modulation by dopamine |
|
Neurochemistry |
- GABA-A receptors - NMDA receptors - 5 HT1a/2a |
- D-2 receptors in striatum - NMDA receptors - 5 HT2a |
Abbreviations:
RP = Readiness Potential
SMA = Supplementary motor area
OFC = Orbitofrontal cortex
MC = Motor Cortex
Catatonic patients showed
significantly lower performance in VOSP compared to psychiatric and healthy
controls (Northoff et al. 1999a). Neither in any other visuo-spatial test
unrelated to right parietal cortical function nor in any other
neuropsychological measure such as general intelligence, attention and
executive functions significant differences between catatonic and non-catatonic
psychiatric patients were obtained. Furthermore
catatonic patients showed significant correlations between right parietal
cortical visuo-spatial abilities (as measured with VOSP) and attentional
abilities (as measured with d2 and CWI) which were neither present in
psychiatric controls nor in healthy subjects (Northoff et al. 1999a). In
addition motor symptoms in catatonia correlated significantly with both
visuo-spatial abilities and attentional function.
Catatonia
may be characterized by relatively intact psychological functions concerning
attention, executive functions, general intelligence and non-right parietal
visuo-spatial abilities. In contrast visuo-spatial abilities specifically
related to right parietal cortex may be altered in catatonic patients
distinguishing them from non-catatonic psychiatric controls. In addition
catatonic patients show severe deficits in a gambling test (unpublished
observations) requiring emotionally-guided decisions and intact orbitofrontal
cortical function (Bechara et al. 1997).
Patients
with PD in contrast show severe neuropsychological deficits in executive
functions (Wisconsin Card Sorting test, Verbal fluency, etc.). Among others
these include abilities of categorization, shifting, sequencing etc. as
subserved by dorsolateral prefrontal cortical function. In contrast to
catatonia PD can neither be characterized by deficits in visuo-spatial
attention as specifically related to right parietal cortical function nor by
alterations in the gambling test specifically designed for orbitofrontal
cortical function.
In summary
catatonia can be characterized by specific deficits in visuo-spatial abilities,
as related to right parietal cortical function, and emotionally-guided
intuitive decisions, as related to orbitofrontal cortical function. PD in
contrast can be characterized by specific alterations in executive functions as
predominantly related to lateral prefrontal cortical function.
3.2. Postmortem
findings
Early
postmortem studies in the preneuroleptic time revealed discrete but not
substantial alterations in basal ganglia (Caudate, N. accumbens, Pallidum) and
thalamus (see Bogerts et al. 1985 and Northoff 1997 for an overview). Since
these early investigations yielded rather inconsistent results they were never
pursued later. Most studies were performed on brains of patients who were never
exposed to neuroleptics implying that these alterations in basal ganglia cannot
be related to neuroleptic (antipsychotic) medication. Nevertheless findings
should be considered rather cautiously since the methods and techniques
available at that time may have produced artifacts by themselves. Furthermore
these findings were obtained in patients with catatonic schizophrenia.
Therefore it remains unclear whether these alterations are specifically related
with either catatonia itself or underlying disease of schizophrenia.
Neuropathologic investigations of catatonic syndrome in general rather than of
catatonic schizophrenia in particular are currently not available.
In contrast
to catatonia substantial alterations in postmortem investigation can be
obtained in PD. PD can be characterized by degeneration of dopaminergic cells
in substantia nigra pars compacta leading consecutively to degeneration in
striatum especially putamen and caudate. In many cases of parkinsonism
vascular or other kinds of alterations may be observed in striatum.
In summary
valid postmortem results in catatonia are currently not available since those
being obtained showing discrete alterations in basal ganglia relied on rather
insufficient methods. In contrast PD can be characterized by major degeneration
of dopaminergic cells in substantia nigra and its pathways to striatum.
3.3. Animal models
DeJong
(1930) performed various experiments with the D2-receptor antagonist
bulbocapnine. According to DeJong bulbocapnine induced catatonia in animals
with neocortex (mice, rats, cats) whereas in animals without neocortex
catatonic symptoms could not be induced. Lower (1-2mg) doses of bulbocapnine
lead to catalepsy whereas higher doses (4-5mg) induced impulsive and convulsive
reactions. As demonstrated by Loizzo et al. (1971) amantadine as an
NMDA-antagonist lead to reversal of bulbocapnine-induced catatonia. However
relying on own experiments (unpublished observations) bulbocapnine-induced
catatonia rather resembled haloperidol-induced catalepsy. Furthermore it could
not be resoluted by lorazepam, as it is the case in human catatonia (see
above). Bulbocapnine exerts an inhibitory effect on dopamine synthesis (Shin et
al. 1998). Consequently it remains unclear whether DeJong really describes
catatonia or rather a kind of catalepsy analogous to neuroleptic-induced
catalepsy.
Stille and
Sayers (1975) induced a catatonic-like reaction in animals with strong sensory
stimuli (electric footshock). They postulated an excitement of the ascending
arousal system i.e. formatio reticularis with overexcitation of the striatal
system via thalamic nuclei. Injection of the GABA-A
antagonist bicucullin into dopaminergic cells of the ventral tegmental area
(VTA) induced a catatonic-like picture in cats with increased arousal,
withdrawal, anxiety, staring and catalepsy (Stevens 1974). Furthermore
injection of morphine may lead to a so-called "morphine-induced
catatonia" (Northoff 1997). Despite these various models none of them has
been really established as an animal model of human catatonia.
Freezing as
an isolated phenomenon independently from catatonia has been studied in animals
and humans. Lesions in amygdala and/or periaquaductal gray may induce freezing
in animals – whether these results can be extrapolated to humans remains
unclear (Fendt and Fensolow 1999).
Animals
models of PD focus on specific lesion of nigrostriatal dopaminergic cells and
pathways as provided by 6-OHDH in rats and MPTP in non-human primates.
In summary
no animal model of human catatonia has been established yet. The ones available
focus either on gaba-ergic - or morphin-induced lesions. In contrast animal
models of PD focus on lesions of nigrostriatal dopmine by either 6-OHDH or
MPTP.
3.4. Structural
imaging
A computerized
tomographic (
Other
authors (Joseph et al. 1985, Wilcox 1991) observed a cerebellar atrophy in
catatonic patients which however was neither investigated systematically nor
quantitatively. To my knowledge no study specifically investigating catatonic
syndrome (and not only catatonic schizophrenia as a subtype) has been published
so far.
In summary
findings in structural imaging in catatonia suggest cortical involvement
predominantly in prefrontal and parietal cortex whereas in PD subcortical
structures i.e. the basal ganglia are altered.
3.5. Functional
imaging
3.5.1. Regional cerebral blood flow. Investigation of regional cerebral
blood flow (rCBF) in single catatonic patients showed the following findings:
(i) right-left asymmetry in basal ganglia with hyperperfusion of the left side
in one patient (Luchins 1989); (ii) hypoperfusion in left medial temporal
structures in two patients (Ebert et al. 1992); (iii) alteration in right
parietal and caudal perfusion in one patient (Liddle 1994); (iv) decreased
perfusion in right parietal cortex in six patients with catatonic schizophrenia
(Satoh et al. 1993); (v) decreased perfusion in parietal cortex with
improvement after ECT in one patient (Galynker et al. 1997). A systematic
investigation of rCBF in SPECT in 10 postacute catatonic patients showed
decreased perfusion in right posterior parietal and right inferior lateral
prefrontal cortex compared to non-catatonic psychiatric and healthy controls
(Northoff et al. 2000c).
Furthermore
abnormal correlation between right parietal cortical function
and with visual-spatial and attentional abilities were obtained
(Northoff et al. 2000c). In psychiatric and healthy controls VOSP correlated
significantly with right lower parietal and right lower lateral prefrontal
cortical r-CBF and Iomazenil binding (reflecting the function of GABA-A
receptors) whereas in catatonia none of these correlations were found (Northoff
et al. 1999e, 2000c). Decreased perfusion in right parietal cortex correlated
significantly with motor and affective symptoms. Catatonic motor symptoms
correlated significantly with VOSP, right lower parietal r-CBF and iomazenil
binding in right 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 in prefrontal and parietal cortex can be observed (see
Jahanshahi and Frith 1998).
In summary
investigation of regional cerebral blood flow shows deficits in right lower
inferior prefrontal and right parietal cortex in catatonia. PD in contrast may
rather be characterized by predominant r-CBF deficits in motor cortex, SMA and
basal ganglia.
3.5.2. Motor activation. Functional imaging performed during
motor activation (i.e. sequential finger opposition) showed reduced activation
of the contralateral motor cortex (i.e. MC) in right hand performance,
ipsilateral activation was similar for both patients and (medication-matched)
controls (Northoff et al. 1999b). There were no differences in activation of
the supplementary motor area (i.e. SMA). During left hand performance
right-handed patients showed more activation in ipsilateral motor cortex than
in contralateral MC. This must be considered as a reversal In
laterality since usually the contralateral side shows four to five times more
activation than the ipsilateral side (Northoff et al. 1999b). It should be
noted that these results were obtained in only 2 postacute catatonic patients.
However assumption of basically intact cortical motor activation (independent
from laterality) is further supported by results from an fMRI/MEG study during
emotional-motor stimulation in 10 catatonic patients (Northoff et al. 2001a).
Cortical motor function showed no alteration in these investigations.
During
motor activation patients with PD show major deficits predominantly in SMA,
which receives most afferences from thalamic (motor)
nuclei, and the basal ganglia predominantly the striatum. Furthermore decreased
activation can be observed also in MC though to a lesser degree than SMA. This
may be due to the fact that the MC receives not as many afferences from
thalamic (motor) nuclei) as SMA. In contrast to catatonia no alteration in
laterality during motor performance can be observed in PD (Jahanshahi and Frith
1998).
In summary
catatonia may be characterized by alterations in laterality in motor cortex
during motor performance while activation in SMA seems to remain basically
intact. PD in contrast shows major deficits in activation of SMA and to a
lesser degree in motor cortex the latter showing no alterations in laterality.
3.5.3. Emotional-motor activation. Based on subjective experience
showing intense emotional-motor interactions, an activation paradigm for
affective-motor interaction was developed. This paradigm was investigated in
fMRI and MEG (magnetoencephalography) in catatonic patients comparing them with
non-catatonic psychiatric and healthy controls (Northoff et al. 2001a). During
negative emotional stimulation catatonic patients showed a specific deficit in
orbitofrontal cortical activation which instead shifted to anterior cingulate
and medial prefrontal cortex. Furthermore catatonic patients showed abnormal
orbitofrontal-premotor/motor connectivity (Northoff et al. 2001a). Behavioral
and affective catatonic symptoms correlated significantly with reduced
orbitofrontal cortical activity whereas motor symptoms correlated with
premotor/motor activity.
PD in
contrast can be characterized by altered activation in left dorsolateral
prefrontal cortex and anterior cingulate during emotional stimulation whereas
orbitofrontal cortical function remained unaffected. (see
Mayberg et al. 1999).
In summary
catatonia can be characterized by reduced right orbitofrontal cortical activation
and abnormal orbitofrontal-premotor/motor connectivity during negative
emotional stimulation. PD in contrast shows alterations only in left
dorsolateral prefrontal cortex and anterior cingulate but not in orbitofrontal
cortex.
3.5.4. On-line monitoring. Posturing as an inability to
terminate movements may be related with alterations in on-line monitoring.
Since on-line monitoring must be considered as an essential part of working
memory (Petrides 1995, Leary et al. 1999) we investigated a one-back/two-back
task in fMRI in catatonia (Leschinger et al. 2001). Catatonic patients showed
significantly decreased activation in right lateral orbitofrontal including
ventrolateral prefrontal cortex (i.e. VLPFC) during the working memory task in
FMRI (Leschinger et al. 2001). In contrast to orbitofrontal activity activation
in right dorsolateral prefrontal cortex was rather increased. Catatonic
behavioral symptoms correlated significantly with activation in right lateral
orbitofrontal cortex whereas motor symptoms showed a significant relationship
with right dorsolateral prefrontal activity.
Catatonic
patients showed significantly worse behavioural performance in both one-back
and two-back tasks such that their deficit seems not to be limited to active
storage/retrieval. In the latter case one would have expected worse performance
in the two-back task only. Instead catatonia may rather be characerized by
principal problems in on-line processing and monitoring accounting for bad
performance in both one-back and two-back task.
Investigation
of working memory in PD revealed alteration in lateral prefrontal cortex
especially in left dorso-lateral prefrontal cortex (i.e. DLPFC) whereas
orbitofrontal cortical function including the ventrolateral prefrontal cortex remained
intact (Jahanshahi and Frith 1998).
In summary
catatonia can be characterized by major deficits in on-line monitoring and
right lateral orbitofrontal i.e. ventrolateral prefrontal cortical (VLPFC)
function whereas PD shows deficits in left dorso-lateral prefrontal cortical
(i.e. DLPFC) function.
3.6.
Electrophysiological findings
3.6.1. Initiation in catatonia and Parkinson's.
Generation of
"willed action" can be characterized by "Plan/Strategy",
"Initiation" and "Execution" which are supposed to be
reflected in movement-related cortical potentials (i.e. MRCP) (see Northoff et
al. 2001b).
We investigated MRCP's during finger
tapping in 10 postacute akinetic catatonic patients, 10 non-catatonic
psychiatric controls (same underlying diagnosis, same medication, same age and
sex) and 20 healthy controls (Northoff et al. 2000b, Pfennig et al. 2001,
Pfennig 2001). We found neither significant differences in amplitudes between
catatonic and non-catatonic subjects in early MRCP's; i.e. in early readiness
potential (early RP) reflecting "Plan/Strategy" and
"Initiation" of movements in DLPFC and anterior SMA. Nor amplitudes
in late MRCP's i.e. in late readiness potential (late RP) and movement
potential (MP) reflecting "Execution" of movements in posterior SMA
and motor cortex revealed any differences.
Patients
with PD show reduction of amplitude in early and late MRCP's which can be
modulated by dopaminergic agents resulting in an increase of amplitude (Dick et
al. 1987, 1989, Jahanshahi et al. 1995, Jahanshahi and Frith 1998).
In summary
catatonia can be characterized by intact early and late readiness potentials
reflecting the apparently preserved ability of "Plan/Strategy",
"Initiation" and "Execution" of movements in these
patients. In contrast patients with PD show severe deficits in
"Initiation" and "Execution" as it is
electrophysiologically reflected in alterations in early and late readiness
potentials.
3.6.2. Termination in healthy subjects. Phenomena like posturing and
catalepsy can be observed in patients with right parietal cortical lesions
while they do not show any deficits in "Initiation" and
"Execution") (Saver et al. 1993, Fukutake et al. 1993). This suggests
that visuo-spatial attention and right parietal cortical function may be necessary
for on-line monitoring and consecutive termination of movements. In a first
step we therefore investigated termination of movements in healthy subjects
with electrophysiological measurements of movement-related cortical potentials
(MRCP) (Northoff et al. 2001b , Pfennig 2001).
We compared ,normal' MRCP (i.e. MRCP) as obtained by finger
tapping with MRCP for simple lifting. The finger had to be kept up without
going back into the intial position (MRCP 1) reflecting
"Plan"/"Strategy", "Initiation", and
"Execution" of finger tapping with exclusion of
"Termination". "Termination" of movements was measured by
lowering of the finger after some seconds of posturing (MRCP 2) reflecting
"initiation of termination" and "execution of termination"
(see below). MRCP 1 and 2 differed significantly in various onsets and
amplitudes from MRCP so that neither MRCP 1 nor MRCP 2 can be equated with MRCP
for simple finger tapping. In addition we obtained significant differences
between MRCP 1 and MRCP 2 the latter showing significantly lower amplitudes in
early parietal MRCP's, earlier onset of movement potential and more posterior
parietal localization of underlying dipoles than the former (Northoff et al.
2001b, Pfennig et al. 2001).
Lorazepam
as a GABA-A potentiator had a differential influence on early and late
components of MRCP's during Initiation and Termination. During Initiation
lorazepam lead to a delay in onsets of late MRCP's in frontal electrodes (MRCP
1) whereas during Termination (MRCP 2) early onsets in parietal electrodes were
delayed. These results were further supported by dipole source analysis. MRCP 1
reflecting "Plan"/"Strategy", "Initiation", and
"Execution" showed dipole sources in anterior/posterior SMA and motor
cortex. In contrast MRCP 2 reflecting "Termination" was characterized
by initial location of the early dipole in right posterior parietal cortex
later shifting to posterior SMA and motor cortex (Pfennig et al. 2001).
The
following conclusions with respect to "Termination" of movements can
be drawn. First some kind of initiation must be involved since otherwise there
would have been no readiness potential – we call this the "initiation of
termination". Second the "initiation for execution" (i.e.MRCP 1)
and the "initiation for termination" (i.e. MRCP 2) can apparently be
distinguished from each other since otherwise there would have been no
differences in amplitudes in early MRCP‘s between MRCP 1 and MRCP 2. Third
MRCP's during Termination could be characterized by right posterior parietal localization.
In order to avoid terminological confusion we reserve the term
"Initiation" for the "Initiation of Execution" whereas the
"initiation of Termination" will be subsumed under the term
"Termination". Fourth "execution" and
"termination" involve different movements (lifting and lowering)
which is reflected in distinct movement potentials in MRCP 1 and MRCP 2. Fifth
the "Termination" of movements seems to be particularly related with
right parietal cortical function and gaba-ergic neurotransmission. Otherwise
there would have been no differences between MRCP 1 and MRCP 2 in parietal
cortical dipole source location and reactivity to lorazepam.
In summary
"Termination" of movements may be characterized by two distinct aspects,
initiation and execution. These may be subserved by involvement of right
parietal cortical function and gaba-ergic neurotransmission.
Neuropsychologically on-line monitoring of the spatial position of the ongoing
movement, as related to right parietal cortical function, may be considered as
crucial for "Termination" distinguishing it from
"Plan"/"Strategy", "Initiation" and
"Execution".
3.6.3. Termination in catatonia. Kinematic measurements during
"Initiation" and "Termination" of finger tapping revealed
that catatonic patients needed significantly longer for "Termination"
than psychiatric and healthy controls. In contrast no deficits were observed in
"Initiation" (Pfennig 2001, Pfennig et al. 2001). These
results contrasts with those in patients with PD who needed
significantly longer time duration for "Initiation" but not for
"Termination".
Catatonic
patients showed no abnormalities in MRCP's of "Initiation" i.e.
lifting (MRCP 1). Instead they showed significantly delayed onsets in early
MRCP‘s in central and parietal electrodes during "Termination" i.e.
lowering (MRCP 2) compared to psychiatric and healthy controls (Pfennig et al.
2001). The fact that the early onset was altered only in MRCP 2 but not in MRCP
1 indicates a delay specifically in "initiation of termination" while
"Initiation" itself seems to remain principally intact. This is
further supported by results from dipole source analysis showing decreased
source strength in right posterior parietal cortex in catatonic patients while
sources in SMA showed no abnormalities. In addition catatonic motor and
behavioral symptoms correlated significantly with delayed early onset in MRCP 2
in parietal electrodes.
In summary
posturing in catatonia may be characterized by a specific deficit in "Termination"
of movements while "Plan"/"Strategy",
"Initiation" and "Execution" seem to remain basically
intact. Such an assumption is supported by observation of alterations in
temporal duration, onset of early MRCP's, right parietal cortical localization
and gaba-ergic reactivity in MRCP's specifically related to
"Termination" of movements.
3.7. Neurochemical
findings
3.7.1. GABA. Recent interest in neurochemical alterations in
catatonia has focused on GABA-A receptors. The GABA-A receptor potentiator lorazepam
is therapeutically effective in 60-80% of all acute catatonic patients
(Rosebush et al. 1990, Bush et al. 1996, Northoff et al. 1995b). One study
investigated Iomazenil-binding, reflecting number and function of GABA-A
receptors, in 10 catatonic patients in Single Photon Emission Computerized
Tomography (SPECT) and compared them with 10 non-catatonic psychiatric controls
and 20 healthy controls (Northoff et al. 1999e). Catatonic patients showed
significantly lower GABA-A receptor binding and altered right-left relations in
left sensorimotor cortex. In addition catatonic patients could be characterized
by lower GABA-A binding in right lateral orbitofrontal and right posterior
parietal cortex correlating significantly with motor and affective (but not
with behavioral) catatonic symptoms.
Furthermore
emotional-motor stimulation in FMRI/MEG (see above) was performed after
neurochemical stimulation with lorazepam (see Northoff et al. 2001d, Richter et
al. 2001). After lorazepam healthy subjects activation
shifted from orbitofrontal cortex to medial prefrontal cortex resembling the
pattern of activity from catatonic patients before lorazepam. Catatonic
patients in contrast showed a reversal in activation/deactivation pattern after
lorazepam: Activation in medial prefrontal cortex was replaced by deactivation
and deactivation in lateral prefrontal cortex was transformed into activation.
It was concluded that prefrontal cortical activation/deactivation pattern
during negative emotional processing may be modulated by GABA-A receptors.
In addition to FMRI and MEG
kinematic measurements and movement-related cortical potentials were
investigated in catatonic patients before and after lorazepam (Northoff et al.
2000b, Pfennig et al. 2001). After injection of the GABA-A potentiator
lorazepam time duration for "Termination" reversed between groups and
was now significantly shorter in catatonic patients than in psychiatric and
healthy controls. In contrast no influence of lorazepam was observed on temporal
duration of "Initiation" in either group. After lorazepam the early
onset in parietal electrodes in MRCP 2 was reversed between groups being now
significantly earlier in catatonics than in psychiatric and healthy controls.
Lorazepam thus ‚normalized‘ i.e. shortened delayed
early onsets in MRCP's during "Termination" in catatonia. In contrast
it delayed early onsets in both psychiatric and healthy controls. In contrast
to MRCP 2 lorazepam had no abnormal influence on MRCP 1 in catatonic patients
(Pfennig et al. 2001). Moreover it should be noted that psychologically
lorazepam induced a "paradoxical" reaction in all catatonic patients.
Instead of reacting with sedation as it was the case in psychiatric and healthy
controls they became rather agitated.
In contrast
to catatonia gaba-ergic transmission in orbitofrontal and prefrontal cortex
does not seem to reveal any abnormalities in PD whereas there are subcortical
gaba-ergic alterations in basal ganglia.
In summary
catatonia can be characterized by major alterations and abnormal reactivity of
GABA-A receptors in right 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) found
increased dopaminergic (homovanillic acid and vanillic acid) and
adrenergic/noradrenergic (norepinephrine, metanephrine, and epinephrine)
metabolites in the urine of patients with periodic catatonia. In addition he
obtained correlations between vegetative alterations and these
metabolites. He suggested a close
relationship between catatonia and alterations in posterior hypothalamic
nuclei. Recent investigations of the
dopamine metabolite homovanillic acid in the plasma of 32 acute catatonic
patients showed increased levels in the acute catatonic state (Northoff et al.
1996), particularly in those responding well to lorazepam (Northoff et al.
1995b). Accordingly the dopamine agonist apomorphine exerted no therapeutic
effect at all in acute catatonic patients (Starkstein et al. 1996). Instead one
would rather expect therapeutic efficiacy of dopamine-antagonists like
neuroleptics. However neuroleptics such as haloperidol may
rather induce a catatonia i.e. so-called "neuroleptic-induced
catatonia" (Fricchione 2000). Involvement of the striatal
dopaminergic system especially of D-2 receptors in catatonia does therefore
remain controversial. No systematic studies investigating D-2 receptors in
catatonia have been reported so far.
In contrast
to catatonia dopamine is the major transmitter affected in PD. Several studies
showed decreased striatal D2-receptor binding in patients with PD.
In summary
exact involvement of the dopaminergic system in catatonia remains unclear. In
contrast PD can be characterized by reduction of striatal D-2 receptors.
3.7.3. Glutamat. The glutamatergic system, in particular the
NMDA-receptors, may be involved in catatonia as well. Some catatonic patients
being non-responsive to lorazepam have been treated successfully with the
NMDA-antagonist amantadine. Therapeutic
recovery occurred rather gradually and delayed (Northoff et al. 1997, 1999c).
Such gradual and delayed improvement suggests that NMDA-receptors may be
involved only secondarily in catatonia whereas GABA-A receptors seem to be
primarily altered. However such an assumption remains rather speculative since
neither the NMDA-receptors nor their interactions with GABA-A receptors have
been investigated in catatonia.
In PD a
modulation of glutamatergic-mediated cortico-striatal pathway by
NMDA-antagonists has been suggested as a model for explanation of therapeutic
efficiacy of amantadine/memantine (Merriol et al. 1999). Alternatively
modulation of glutamatergic pathways within basal ganglia themselves i.e.
between subthalamic nuclei and internal pallidum has been discussed.
In summary
both catatonia and PD may be characterized by glutamatergic abnormalities
especially in NMDA-receptors. Amantadine as a NMDA antagonist is therapeutially
effective in both diseases and may modulate glutamatergic-mediated cortical and
subcortical connectivity.
3.7.4. Serotonine. The serotoninergic system has been assumed to
be involved in catatonia. Atypical neuroleptics which have serotoninergic
properties may induce catatonic features (Caroll 2000). Therefore it has been
hypothesized that catatonia may be characterized by a dysequilibrium in the
serotoninergic system with up-regulated 5-HT1a receptors and down-regulated
5-HT2a receptors (Carroll 2000). However no investigation of
the serotoninergic system in catatonia have been reported so far so that
this hypothesis remains speculative.
Similar to
catatonia the serotoninergic system may be involved in PD which may be related
with dopaminergic abnormalities.
In summary
the serotoninergic system seems to be involved in both catatonia and PD. This
may reflect secondary modulation by another primarily altered transmitter
system i.e. GABA in catatonia and Dopamine in PD.
4. PATHOPHYSIOLOGICAL
HYPOTHESIS
The present
hypothesis focuses predominantly similarities and differences between PD and
catatonia with respect to the distinct kinds of modulation. Similar to the
presentation of data (see part 3) various and subtle aspects of pathophysiology
especially in PD will therefore not be discussed in detail. In addition the
present hypothesis primarily focuses on catatonic responders to lorazepam. This
is important to mention since responders and non-responders may be
characterized by distinct underlying pathophysiological mechanisms (Northoff et
al. 1995b, 1998, Ungvari et al. 1999). Instead of giving an overview about the
pathophysiology in its entirety the focus will be rather put on the distinct
kinds of modulation.
4.1. Pathophysiology
of motor symptoms
4.1.1. Deficit in "Execution" of
movements: Akinesia. Both
catatonia and PD can be characterized by akinesia which may be related with
functional alterations in the so-called "direct" "motor
loop". The "motor loop" includes connections from MC/SMA to
putamen, from putamen to internal pallidum, and from there via mediodorsal
thalamic nuclei back to MC/SMA (Masterman and Cummings 1997). Decrease in
striatal dopamine leads to down-regulation of the "direct"
"motor loop" (exclusion of external pallidum) and concurrent
"up-regulation" of the "indirect" "motor loop"
(inclusion of external pallidum) resulting in a netto-effect of decreased
activity in premotor/motor cortex.
Table 2 Pathophysiological Hypothesis for distinct symptoms in catatonia and ParkinsonŚs
|
|
Catatonia |
Parkinson |
|
|
Motor symptoms |
Akinesia |
- Cortico-cortical - Gaba-ergic |
- Subcortico-cortical - Dopaminergic |
|
Starting problems |
- Top- down-regulation of SMA/MC |
- Deficit in SMA/MC in relation to altered bottom-up modulation |
|
|
Posturing |
- Right orbitofrontal - Right posterior parietal |
- |
|
|
Rigidity |
- Top-down modulation of striatal D-2 receptors |
- Deficit in striatal D-2 receptors |
|
|
Behavioral symptoms |
Motor anosognosia |
- Network between ventrolateral, dorsolateral and parietal cortex |
- |
|
Mutism and Stupor |
- Anterior cingulate and medial prefrontal cortex |
- |
|
|
Preservative-compulsive behavior |
- Concomittant dysfunction in dorso- and ventrolateral prefrontal cortex |
- |
|
|
Affective symptoms |
Anxieties |
- Medial orbitofrontal cortex - Dysbalance between medial and lateral prefrontal cortical pathway |
- |
|
Inability to control anxieties |
- Dysfunctional relation between medial and lateral orbitofrontal cortex |
- |
|
|
Depression |
- |
- Anterior cingulate |
|
|
Therapeutic agents |
GABA (lorazepam) |
- Gaba-ergic mediated neuronal inhibition in medial orbitofrontal cortex - Modulation of functional and behavioral inhibition |
- |
|
NMDA (Amantadine) |
- Down-regulation of glutamatergic-mediated overexcitation in prefrontal and orbitofrontal-parietal pathways |
- Down-regulation of glutamatergic-mediated overexcitation in subcortical pathways |
|
|
Dopamin |
- Top-down modulation of striatal D-2 receptors predisposing for neuroleptic-induced catatonia |
- Compensation for striatal D-2 receptor deficit with "normalization" of "bottom-up modulation" |
|
In contrast
to PD functional imaging studies during performance of movements yielded no
alterations in SMA and MC in catatonia. However effective connectivity ranging
from orbitofrontal cortex to premotor/motor cortex was significantly reduced
during emotional-motor stimulation in catatonic patients. Premotor/motor
cortical function does remain apparentely intact during isolated motor
stimulation whereas it seems to become dysregulated during emotional
stimulation via cortico-cortical connectivity in orbitofrontal/prefrontal
cortex. Consequently the "motor loop" itself seems to remain intact
in catatonia whereas it is dysregulated by orbitofrontal and prefrontal cortex
via "cortico-cortical i.e. horizontal modulation".
In summary
akinesia is closely related to down-regulation of the "motor loop".
This down-regulation may be caused either by dopamine and subcortical-cortical
"bottom-up modulation", as in PD, or by GABA and
"cortico-cortical i.e. horizontal modulation" with consecutive "top-down
modulation", as in catatonia.
4.1.2. Deficits in "Initiation" of
movements: Starting problems. Parkinsonian patients could be characterized by deficits in initiation
which may be considered as one essential component of the "willed action
system".
Movements have to be planned and a
strategy has to be made in order to get an idea what kind of movement shall be
performed which may be closely related to lateral orbitofrontal cortical
function (Deecke 1996). This aspect will be referred to as
"Plan/Strategy" of movements in the further course of the manusript.
There must be an idea of how to move including a decision to perform a movement
which can be initiated either internally (i.e.voluntary) or rather externally
(i.e. involuntary). Internally initiated movements can be considered as willed
movement/actions which may be subserved by a so-called "willed action
system" involving the dorsolateral prefrontal cortex (DLPFC), the anterior
cingulate, the anterior supplementary motor area (SMA), and fronto-striatal
circuits (Jahanshahi et al. 1995, Jahanshahi and Frith 1998, 494, 517-9; Deecke
1996). This aspect will be referred to as "Initiation" in the further
course of the manuscript. Once a movement is initiated it can be executed which
probably is closely related to function of posterior SMA and the motor cortex
(Deecke 1996, Jahanshahi and Frith 1998) which will be referred to as
"Execution" in the further course of the manuscript. The executed
movement can be characterized by dynamic and kinematic properties. Dynamic
properties refer to force and velocity of the movements which may be encoded
primarily in neurons of the motor cortex (Dettmers et al. 1995). Fronto-mesial
structures such as the SMA as well as the putamen and the ventrolateral
thalamus may be important for coding of temporal properties i.e. the 'timing'
of movements (Deecke 1996, Jahanshahi and Frith 1998, 493). Kinematic
properties describe spatial characteristics of movements such as angles, etc.
which may be encoded by neurons in parietal cortex (area 5, 39, 40) (Kalaska et
al. 1996, Jeannerod 1997, 57-8, 72-3). Finally the movement must be terminated
which will be referred to as "Termination" implying postural change
with on-line monitoring 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 related to the ability of
"Initiation". Parkinsonian patients do show indeed severe deficits
internal initiation while they are well able to execute them once they have
overcome their initiation problems. Consequently PD may be characterized by
disturbance in the "willed action system" with problems in the
voluntary generation of movements by itself (Jahanshahi and Frith 1998).
In contrast
to PD catatonia cannot be characterized by primary alterations in the
"willed action system" since both "Initiation" and function of SMA seem to remain more or less intact in these
patients. Therefore voluntary generation and
"initiation" implying that the "willed action system"
itself remains basically intact. Instead the "willed action
system" becomes dysregulated by cortico-cortical connectivity so that it
only appears as if there is a deficit in "Initiation" in catatonia.
In summary
"initiation" as part of the "willed action system" is
disturbed in PD clinically accounting for starting problems. Whereas in
catatonia the intact functioning "willed action system" becomes
dysregulated by cortico-cortical modulation resulting in motor similarity
between catatonic and parkinsonic patients.
4.1.3. Deficit in "Termination" of
movements: Posturing. In order to terminate a movement on-line of monitoring of the spatial
position of the respective movement is necessarily required.
Neuropsychologically such on-line monitoring may be subserved by visuo-spatial
attention as closely related to function of the right posterior parietal
cortex.
The posterior parietal cortex has
been shown to be specifically involved in location and direction of the spatial
position of movements and limbs in relation to intrapersonal space of the body
(Roland et al. 1980, Colby and Duhamal 1996, Anderson 1999). On the basis of
spatial attention with a redirection to extrapersonal or sensory space
movements will be selected in orientation on the respective spatial context.
Providing the spatial frame of reference, the posterior inferior parietal
cortex, as in contrast to the posterior superior parietal cortex, is
specifically involved in abstract spatial processing and exploration (Karnath 1999).
As such the right posterior inferior parietal cortex may provide the
intrapersonal "spatial frame of reference of the body necessary for the
conscious organization of movements thus making spatial codes available for
prefrontal cortical representation" (Vallar 1999; p.45). In addition to
spatial monitoring the posterior inferior parietal cortex seems to be
specifically involved in early initiation of movements (Castiello 1999,
Desmurget et al. 1999, Mattingley et al. 1998, Snyder et al. 1997, Driver and
Mattingley 1998) which, in the present context, may be interpreted as a
specific relationship between "initiation of Termination" and posterior inferior parietal
cortical function. Consequently posterior inferior parietal cortical function
may provide the linkage between spatial registration as "internal spatial
monitoring" and "initiation of Termination" as necessarily
required for postural change and consecutive "execution of
Termination".
In
catatonia alterations in right parietal cortical function were found in
neuropsychology and SPECT. Neuropsychologically catatonic patients showed
deficits in visuo-spatial abilities correlating with attentional function.
SPECT results revealed decreased r-CBF in right parietal cortex and abnormal
correlations with visuo-spatial abilities. Involvement of right posterior
parietal cortex in pathophysiology of catatonia is further supported by
consideration of anatomo-functional parcellation in this region. Distinct areas
respresenting eye movements, arm movements and head movements,
may be distinguished within posterior parietal cortex (Colby and Duhamel 1996,
Anderson 1999). Such distinct representational areas for eyes, head, and arm
coincide with clinical observations that posturing in catatonia can occur in
eyes, arms, and/or head. Posturing of eyes may be reflected in staring,
posturing of head is reflected in "psychic pillow", and posturing of
arm is the classical type of posturing (see above). All three kinds of
posturing can occur simultaneously but they may also dissociate from each other
so that, for example, patients may show only the "psychic pillow"
without staring and posturing of limbs. It is therefore postulated that such a
clinical dissociation between these three kinds of posturing may have its
physiological origin in anatomo-functional parcellation in posterior parietal
cortex.
It may be
hypothesized that the deficit in right parietal visuo-spatial attention in
catatonic patients leads to an inability in "initiation of
Termination". The spatial position of the ongoing movement can no longer
be registrated in an appropriate way resulting in an
impossibility to initiate the terminating movement. This may result in
an inability of "execution of Termination" with a consecutive
blockade in postural change which clinically is reflected in posturing.
Assumption of relation between posturing and right parietal cortical
dysfunction is supported by electrophysiological findings during termination
(Pfennig et al. 2001, Pfennig 2001). Furthermore patients with lesions in right
parietal 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
with isolated lesions in right parietal cortex as, for example, neglect showing
the following differences: (i) patients with neglect do not show posturing;
(ii) unlike patients with neglect catatonic patients do neither deny the
existence of limbs or parts of their body nor overlook these body parts in
relation to the environment so that they do not strike with these body parts
against walls, doors, etc.; (iii) patients with neglect do show attentional
deficits whereas in catatonic patients no such deficits could be found; (iv)
patients with neglect do often show sensory deficits which cannot be observed
in catatonia; (v) unlike patients with neglect catatonic patients do not show a
right-left pattern with respect to their symptoms i.e. posturing; (vi) unlike
patients with neglect catatonic patients do not suffer from alterations in
peripersonal and extrapersonal space (as reflected in successfull
ball-experiments; Northoff et al. 1995) whereas they may be characterized by
alterations in personal space being unable to locate the position of his/her
own limbs in relation to the rest of the body. Since personal and
peri/extrapersonal space may be subserved by distinct neural networks (Galatti
et al. 1999) distinction between both kinds of spaces may not only be
phenomenologically relevant but physiologically as well. Hence catatonia cannot
be compared with neglect as an attentional disorder so that posturing cannot be
accounted for by disturbances in attention which is further supported by
neuropsychological findings showing no specific alterations in attentional
measures (see above).
Other
disorders related with right posterior parietal cortical dysfunction must be
distinguished from catatonia as well. Patients with Balint Syndrome show
symptoms like an inability to fixate objects and an optic ataxia which both
cannot be observed in catatonia. Since Balint Syndrome and especially optic
ataxia indicate involvement of right posterior superior parietal cortex
differences between catatonia and Balint syndrome do further underline the
particular importance of the right posterior inferior parietal cortex in
catatonia.
In contrast
to catatonia parkinsonian patients do neither show posturing nor alterations in
right parietal cortex.
In summary
catatonia can be characterized by specific deficits in "initiation of termination"
while PD show rather deficits in "initiation of
execution" implying functional dissociation between both diseases with
respect to initiation of movements. Whereas the deficit in "initiation of
termination" seems to be related with dysfunction in right posterior
inferior parietal cortex lack of "initiation of execution" seems to
be accounted for by functional deficits in SMA.
4.1.4. Alteration in tonus of movements:
Cogwheel rigidity and flexibilitas cerea. Parkinsonian patients could be characterized by
muscular hypertonus with a so-called "cogwheel rigidity" which may be
accounted for by a deficit in striatal D2-receptors and consecutive
dyscoordination of activity in internal pallidum.
Catatonic
patients may show muscular hypertonus but without "cogwheel rigidity"
– instead they show a smooth kind of rigidity a so-called flexibilitas cerea.
Since there is no primary i.e. direct deficit of striatal D-2-receptors in
catatonia dyscoordination of the internal pallidum may be not as strong as in PD
implying that there may be some kind of smooth musuclar hypertonus without
cogwheel rigidity. Assumption of discrete down-regulation of striatal D-2
receptors may be supported by symptomatic overlap between catatonia and
neuroleptic malignant syndrome, possibility of "neuroleptic-induced
catatonia", and central role of striatum in animals models of catatonia
(see Caroll 2000).
Origin of down-regulation in striatal D-2 receptors in catatonia remains
however unclear.
Down-regulation of striatal D2-receptors may be related with cortical
alterations: Orbitofrontal cortical alterations may lead to down-regulation in
D2-receptors in caudate via "top-down modulation" within the
"orbitofrontal cortical loop" (see Figure 4). Or striatal D-2
receptors may be top-down modulated within the "motor loop" which by
itself may be dysregulated by cortico-cortical connectivity. However due to
lack of specific investigation of basal ganglia in catatonia both assumption
remain speculative.
In summary
rigidity may be related to alterations in internal pallidum as induced by
down-regulation of striatal D-2 receptors. Abnormal modulation of D-2 receptors
may be due to alterations in either subcortical-subcortical connectivity, as in
PD, or abnormal cortico-cortical connectivity with consecutive "horizontal
modulation" and concurrent cortico-subcortical "top-down
modulation", as it may be the case in catatonia.
4.2. Pathophysiology
of behavioral symptoms
4.2.1. Deficit in on-line monitoring: Motor
anosognosia. Subjective
experience in catatonic patients could be characterized by unawareness of
posturing and movement disturbances in general whereas parkinsonian patients
were well aware of their motor deficits. This raises the question for
difference between catatonic and parkinsonian patients with respect to
"internal monitoring" of the movement. It should be noted that
catatonic patients showed an unawareness only with
respect to their motor disturbances since they were well aware or even
hyperaware of emotional alterations excluding the possibility of a deficit in
general awareness.
Awareness of movements is closely
related to the ability of on-line monitoring as an "internal
monitoring" which by itself does necessarily require generation of an
"internal model" of the respective movement. According to Miall and
Wolpert (1996), distinct kinds of models can be distinguished (see Figure 2).
There is a causal representation of the motor apparatus which can be described
as a "Forward dynamic model". The model of the behavior and the
environment can be called "Forward output model". Finally an
"Inverse model" can be assumed where the causal flow of the motor
system is inverted by representing the causal events that produced the
respective motor state (for more detailed discussion see Miall and Wolpert
1996).
Figure 2: "Forward model" of physiological motor control in catatonia and Parkinson's
The figure shows the
"forward model" as established by Miall and Wolpert (1996)
supplemented by the distinct aspects of movements
"Plan"/"Strategy", "Initiation",
"Execution". In addition distinct processes involved in
"Termination" of movements, feedback, "estimated spatial
position", "initiation and execution of Termination" are
included. In orientation on the model by Miall and Wolpert (1996)
"predicted" and "actual state" are compared with each other
necessarily presupposing the estimation of the actual spatial position. Both
estimation of spatial position and comparison between actual and predicted
state seem to be disturbed in catatonia as indicated by quadrats with crosses
leading consecutively to alterations in "initiation and execution of
Termination" finally resulting in posturing as the most bizarre symptom in
catatonia. Parkinson's in contrast may rather be characterized by deficit in
"Initiation" leading to difficulties in "Execution"
whereas, unlike in catatonia, estimation of spatial position and comparison
between acutal and predicted spatial state remain intact by themselves.
Note that there is double
dissociation between catatonia and Parkinson's with regard to feedforward and
feedback: Feedback is disturbed in catatonia while feedforward seems to be
preserved by itself whereas in Parkinson's feedforward is disturbed with
feedback remaining intact.
"Internal
monitoring" of movements could itself be either "implicit" or
"explicit". Following Jeannerod (1997) only certain aspects of
movements are internally monitored in an "explicit" mode of
processing. "Plan/Strategy" and to some extent "Initiation"
are accessible to consciousness and can be characterized by "explicit
internal monitoring". In contrast "Execution" itself is not
accessible to consciousness and can be related only with "implicit
internal monitoring" (Jeannerod 1997). Accordingly Jeannerod distinguishes
between an "implicit" "How system" and an
"explicit" "Who system" of movements/action the former
being responsible for "Execution" whereas the latter includes "Plan/Strategy"
and "Initiation".
Empirically
such an assumption is further supported by a study from Grafton et al. (1995)
investigating whether persons were conscious or non-conscious of a particular
order of sequences of movements they performed - consciousness of the order of
sequence necessarily presupposing an "explicit internal monitoring"
of "Plan/Strategy". Subjects showing consciousness of the order of
sequence could be characterized by activation in right dorsolateral prefrontal
cortex (Area 9), right posterior parietal cortex (Area 40), and right premotor
cortex (Area 6) compared to those subjects who were unconscious. Increasing
demand of "explicit internal monitoring", as induced by mirror
experiments, lead to activation in right lateral dorsolateral prefrontal cortex
(Area 9 and 46) and right posterior parietal cortex (Area 40) (Fink et al.
1999).
Following distinction between "implicit" and "explicit" internal monitoring an analogous hypothesis shall be developped for "Termination". &