[Subjective experience and neuronal integration in the brain: do we need a first-person neuroscience?]. / Subjektives Erleben und neuronale Integration im Gehirn: Benötigen wir eine Erste-Person-Neurowissenschaft?

Unlike other medical disciplines psychiatry can be characterized by the special importance of subjective experience. Since subjective experience is tied to First-Person-Perspective and investigation of the brain is possible only in Third-Person-Perspective, the question how subjective experience can be linked to neuronal processes is raised in psychiatry. We suggest a novel methodological approach, First-Person-Neuroscience where subjective experience can be linked directly and systematically to neuronal processes. Due to complexity of the structures and contents of subjective experience, localization in specific brain regions seems inappropriate. Instead, the interplay and coordination of neuronal activity across several brain regions, so-called neuronal integration, should be considered in First-Person-Neuroscience. This is illustrated by two principles of neuronal integration, top-down modulation and reciprocal modulation, whose abnormal function can be related to subjective experience of patients with catatonia and depression. It is concluded that First-Person-Neuroscience can contribute to reveal abnormal brain function in psychiatric disorders and ultimately to development of diagnostic and therapeutic markers.

Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology.

Catatonia was originally described as a psychomotor syndrome in the 19th century by Kahlbaum including motor, affective and behavioral symptoms. Later, at the beginning of the 20th century, catatonia was rather considered as the motoric manifestation of schizophrenia. Accordingly, neuropathological research focused predominantly on those neuroanatomical substrates, i.e. the basal ganglia being primarily involved in the generation of movements. Even though some authors observed minor alterations in the basal ganglia, consistent findings in these subcortical structures could not be obtained. Since neuroleptics can induce catatonic-like symptoms i.e. neuroleptic malignant syndrome (NMS), there has been a recent re-emergence in clinical and scientific interest in catatonia. However, exact psychopathological and pathophysiological characterization of both NMS and catatonia remains unclear.Clinically, catatonia and NMS show more or less similar motor symptoms i.e. akinesia. These may be accounted for by dysregulation in cortical-subcortical circuits between motor/premotor cortex and basal ganglia i.e. the so-called "motor loop". While in NMS the "motor loop" may be dysregulated by neuroleptic blockade of subcortical striatal D-2 receptors one may rather assume cortical gaba-ergic alteration in catatonia. The premotor/motor cortex and consecutively the "motor loop" may be dysregulated by gaba-ergic abnormalities in orbitofrontal cortex. Gaba-ergic cortical dysfunction may account for affective and behavioural abnormalities in catatonia which cannot be observed as such in NMS. Consequently, one may characterize catatonia as a cortical "psychomotor syndrome" while NMS may rather be regarded as subcortical "motor syndrome".

Delayed onset of late movement-related cortical potentials and abnormal response to lorazepam in catatonia.

Catatonia is a psychomotor syndrome with an inability to execute and terminate movements completely, leading consecutively to akinesia and posturing, which both respond almost immediately to benzodiazepines, i.e. gaba-potentiators like lorazepam. However, pathophysiological mechanisms of cortical motor and gaba-ergic dysfunction remain unclear. We therefore investigated movement-related cortical potentials (MRPs) and movement kinematics during a motor task before and after lorazepam. Ten akinetic catatonic patients were compared with 10 psychiatric (similar age, sex, medication, and underlying psychiatric disease but without catatonic syndrome) and 20 healthy controls. MRPs from frontal (F), central (C), and parietal (P) sites were recorded to obtain measures of early and late readiness potential and movement potential. Kinematic measures included parameters for amplitude of movements, peak velocity, average duration of movements, elevation angle, and angle velocity. The motor task consisted in self-initiated extension of the right index finger. All catatonic and psychiatric control patients received intravenous lorazepam (1mg), whereas healthy controls were subjected to a placebo-controlled (10 received lorazepam, 10 received placebo) double-blind study design.Catatonics showed a significantly delayed onset of late readiness and movement potential in central electrodes (Cz, C3) compared with psychiatric and healthy controls. This delayed onset correlated significantly with catatonic motor symptoms and movement duration. Lorazepam led to significantly stronger delays in onset of late readiness potential in left fronto-parietal (F3, C3, P3) electrodes in catatonic patients than in psychiatric and healthy controls. It is concluded that delayed latencies in late MRP components in catatonic patients may reflect their inability to execute and terminate movements completely. Differential and stronger response to lorazepam in catatonia suggests dysfunction in inhibitory control of cortical motor function with increased gaba-ergic sensitivity.

Right lower prefronto-parietal cortical dysfunction in akinetic catatonia: a combined study of neuropsychology and regional cerebral blood flow.

BACKGROUND: Catatonia is a psychomotor syndrome that can be characterized by behavioural, affective and motor abnormalities. In order to reveal further underlying pathophysiological mechanisms of psychomotor disturbances in catatonia we investigated neuropsychological function and regional cerebral perfusion (r-CBF) in a combined study. METHODS: Ten catatonic patients were investigated with Tc-99mECD brain SPECT and compared with 10 psychiatric (similar age, sex, medication and underlying psychiatric diagnosis but without catatonic syndrome) and 20 healthy controls. Neuropsychological measures included tests for general intelligence, attention, executive functions and right parietal visual-spatial abilities. Correlational analyses were performed between neuropsychological measures, catatonic symptoms and r-CBF. RESULTS: Catatonic patients showed a significant decrease of r-CBF in right lower and middle prefrontal and parietal cortex compared with psychiatric and healthy controls as well as significantly poorer performance in visual-spatial abilities associated with right parietal function. Correlational analysis revealed significant correlations between visual-spatial abilities and right parietal r-CBF only in psychiatric and healthy controls but not in catatonic patients. In contrast, attentional measures correlated significantly with motor symptoms, visual-spatial abilities and right parietal r-CBF in catatonia only but not in psychiatric or in healthy controls. CONCLUSION: Findings are preliminary but suggest right lower prefronto-parietal cortical dysfunction in catatonia, which may be closely related to psychomotor disturbances.

Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding.

OBJECTIVES: Catatonia is a psychomotor syndrome with concomittant akinesia and anxiety which both respond almost immediately to benzodiazepines such as lorazepam. The benzodiazepine receptor distribution was therefore investigated in akinetic catatonia with single photon emission tomography (SPECT) using iodine-123-iomazenil ((123) I Iomazenil). METHODS: Ten akinetic catatonic patients, 10 psychiatric controls (similar age, sex, medication, and underlying psychiatric diagnosis but without catatonic syndrome), and 20 healthy controls were investigated with SPECT 2 hours after injection of (123) I Iomazenil. To exclude potential effects of cerebral perfusion (r-CBF) r-CBF was additionally investigated with Tc-99mECD SPECT. RESULTS: Catatonic patients showed significantly lower iomazenil binding and altered right-left relations in the left sensorimotor cortex compared with psychiatric (p<0.001) and healthy (p<0.001) controls. In addition, there was significantly lower r-CBF in the right lower prefrontal and parietal cortex in catatonia whereas in the left sensorimotor cortex no differences in r-CBF between groups were found. Catatonic motor and affective symptoms showed significant correlations (p<0.05) with benzodiazepine binding in the left sensorimotor cortex as well as with right parietal r-CBF. CONCLUSIONS: Reduced iomazenil binding suggests decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia. In addition to reduced GABA-A receptor density in the left sensorimotor cortex the parietal cortex seems to be involved in pathophysiology of catatonic symptoms. It is concluded that, considering results from correlation analyses, both emotional and motor symptoms in catatonia seem to be closely related to left sensorimotor and right parietal alterations.

Impairment in visual-spatial function in catatonia: a neuropsychological investigation.

Catatonia is a psychomotor syndrome with motor and behavioral abnormalities which may be due to alterations in fronto-parietal cortical function. We therefore investigated neuropsychological tasks (attention, executive, visual-spatial, working memory) associated with frontal and parietal cortical function. Thirteen catatonic patients, diagnosed as catatonic according to criteria by Rosebush and Bush, were compared with 13 psychiatric non-catatonic controls (matched with regard to underlying psychiatric diagnosis, age, sex, and medication), and 13 age- and sex-matched healthy controls. Catatonics showed significantly poorer performances and different neuropsychological intercorrelation patterns in visual spatial object perception (VOSPobject) than psychiatric and healthy controls. In addition, we found significant correlations between catatonic symptoms, visual-spatial abilities, and attentional measures (i.e., d2, CWI). Catatonia was characterized by specific visual-spatial deficits which are related to attentional abilities and right parietal cortical function. The data suggest attentional-motor and fronto-parietal dysfunction in catatonia, a conclusion which should be considered as preliminary, however, due to the small sample size.

Catatonia as a psychomotor syndrome: a rating scale and extrapyramidal motor symptoms.

BACKGROUND: Catatonia was first described by Kahlbaum as a psychomotor disease with motor, behavioral, and affective symptoms. In keeping with this concept, we developed a rating scale for catatonia (Northoff Catatonia Scale [NCS]) with three different categories of symptoms (i.e., motor, behavioral, affective). Furthermore, the question of the relationship among catatonic symptoms, extrapyramidal motor symptoms, and neuroleptics was addressed in the present study. METHOD: 34 acute catatonic patients and 68 age-, sex-, diagnosis-, and medication-matched psychiatric control subjects were investigated on days 0, 1, 3, 7, and 21 with the NCS, with other already validated catatonia rating scales by Rosebush, Bush (BFCRS), and Rogers (MRS), as well as with scales for hypokinetic (SEPS) and dyskinetic (AIMS) extrapyramidal motor features. Validity and reliability of the new scale, factor analysis, correlational analysis, and differences between catatonic patients and psychiatric control subjects were statistically calculated. RESULTS: NCS showed high validity (i.e., significant positive correlations [p <0.0001] with the other scales, significant differences between catatonic and control subjects), high intra-and interrater reliabilities (r = 0.80-0.96), and high affective subscores. Factor analysis revealed four factors best characterized as affective, hypoactive, hyperactive, and behavioral. Catatonic scores in NCS correlated significantly with AIMS on day 0 and SEPS on days 7 and 21. There were no significant differences in catatonic (i.e., NCS, MRS, BFCRS) and extrapyramidal (i.e., AIMS, SEPS) scores between neuroleptically treated and untreated catatonic subjects. CONCLUSIONS: The following conclusions were drawn: (1) the NCS has to be considered as a valid and reliable rating instrument for catatonia; (2) catatonia can be characterized by psychomotor symptoms encompassing motor, affective, and behavioral alterations; and (3) extrapyramidal hyperkinesias like dyskinesias are apparently closely related to catatonic symptoms which, in general, seem to be relatively independent of previous neuroleptic medication.

Glutamatergic dysfunction in catatonia? Successful treatment of three acute akinetic catatonic patients with the NMDA antagonist amantadine.

Therapeutic efficiacy of the NMDA antagonist amantadine is reported in three acute neuroleptic free akinetic catatonic patients. Intravenous infusion of amantadine led to the resolution of catatonic symptoms and considerable reductions of scores in various motor scales (Simpson Angus scale for extrapyramidal side effects (SEPS), the abnormal involuntary movement scale (AIMS), Rogers catatonia and schizophrenia scales). The therapeutic effect of amantadine showed a characteristic temporal pattern with most pronounced effects four to six hours after administration and recurrence of catatonic symptoms by 24 hours later, at least partially. Such a temporal pattern of therapeutic efficacy and decreasing efficacy occurred in all three patients on all days. The results suggest the central importance of glutamatergic dysfunction in catatonic syndrome.

Increase of serum creatine phosphokinase in catatonia: an investigation in 32 acute catatonic patients.

We investigated serum creatine phosphokinase (CPK) and associated parkinsonic (SEPS) and dyskinetic (AIMS) movements in 32 hospital admitted acute catatonic patients. Thirty-two (N = 24 without neuroleptics on admission) catatonic patients were compared with 32 non-catatonic dyskinetic psychiatric patients, 32 non-catatonic non-dyskinetic psychiatric patients and 32 healthy controls. CPK was significantly higher (P = 0.015) in catatonics (mean 255.75, S.D. +/- 226.54) than in healthy controls (38.6, +/- 27.4) and non-catatonic non-dyskinetic psychiatric patients (57.1, +/- 120.8) whereas there was no significant difference between catatonics and non-catatonic dyskinetic psychiatric patients (453.4, +/- 128.5). There were significantly positive correlations between CPK and AIMS, as well as significantly negative correlations between CPK and SEPS, in all three groups. Our results suggest that increased serum CPK in catatonia may be related to occurrence of dyskinetic movements. Furthermore, we were able to distinguish a parkinsonic (low CPK, low AIMS, high SEPS) and a dyskinetic (high CPK, high AIMS, low SEPS) subtype in catatonia.

Plasma homovanillic acid concentrations in catatonia.

We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans.

[The subjective experience in catatonia: systematic study of 24 catatonic patients]. / Subjektives Erleben in der Katatonie: Systematische Untersuchung bei 24 katatonen Patienten.

Catatonic patients are often not able to communicate their subjective experiences behind their "fassade of immobility." Therefore was retrospectively (3 weeks later) investigated subjective experiences in 24 catatonic patients with a self-assessment-scale especially for catatonia developed by us. Our results showed that catatonic patients subjectively experience less their altered movements but rather cognitive, i.e. ambivalence, or affective, i.e. intense emotions which couldn't be controlled, alterations. According to our results we were able to distinguish an emotive (intense anxiety) from a non-emotive, i.e. cognitive (predominating ambivalence), subtype in catatonia with regard to subjective experience.

Catatonia: short-term response to lorazepam and dopaminergic metabolism.

Therapeutic response to lorazepam and dopaminergic metabolism were investigated in 18 neuroleptically naive acute catatonic patients. They were diagnosed as catatonic according to criteria by Lohr and Rosebush and treated exclusively with lorazepam (2-4 mg) during the first 24 h. Dopaminergic metabolism (plasma HVA, plasma MHPG), anxiety (HAM-A) and parkinsonic/dyskinetic movements (SEPS, AIMS) were measured under standard conditions before initial treatment with lorazepam (day 0) and 24 h after initial treatment (day 1). On day 0 responders to lorazepam treatment (complete remission of catatonic syndrome after 24 h according to Rosebush and Lohr) showed significantly higher (P = 0.004) plasma HVA (130.4 +/- 51.2 pmol/ml; means +/- SD) than non-responders (no remission of catatonic syndrome after 24 h; 73.2 +/- 40.5 pmol/ml; means +/- SD). On day 1 plasma HVA did not differ any more significantly between both groups Clinically, responders showed significantly higher HAM-A (P = 0.025) and AIMS (P = 0.022) scores as well as significantly lower SEPS (P = 0.049) scores than non-responders on day 0. Hence catatonic short-term responders and nonresponders to lorazepam can be distinguished with regard to plasma HVA, anxiety and dyskinetic/parkinsonic movements.

Ball experiments in 32 acute akinetic catatonic patients: deficits of internal initiation and generation of movements.

We undertook ball experiments in 32 akinetic catatonic patients in order to determine specific functional deficits in the motor system in akinetic catatonia. Standardized ball experiments (catching, throwing, stopping, kicking) were conducted in 32 acute akinetic catatonic patients (23 without neuroleptics on admission), diagnosed according to Lohr, Rosebush, and the Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) on days 0 and 21. Additionally, associated psychopathology was evaluated using different scales on days 0 and 21: the Global Assessment Scale, the Brief Psychiatric Rating Scale, the Hamilton-Anxiety Scale, the scale for the assessment of negative symptoms (SANS), and the Simpson scale for extrapyramidal side effects (SEPS). Significantly more patients were able to perform more externally guided tasks (catching, stopping) than internally guided tasks (throwing, kicking). Patients showed significantly more posturing and awkward movements on day 0 than on day 21. There was a significantly positive correlation between hypokinetic extrapyramidal features (SEPS) and negative symptoms with their cognitive alterations (SANS) on day 0. The findings suggest a deficit of internal initiation, as in parkinsonism, as well as a dysfunction in the generation of voluntary movements in akinetic catatonia. We assume an underactivity in the dorsolateral prefrontal cortex and the supplementary motor area with consecutive down-regulation of the cortical-striatal-thalamic circuit, the "motor loop," in catatonia.

The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis.

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-alpha (TNF), lymphotoxin-alpha (LT), and interferon-gamma (IFN-gamma) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.