Microstructure of the sleep eeg in de novo patients with parkinson’s disease: effects of dopamine on the spectral EEG profiles
Brunner H¹, Wetter TC¹, Högl BE², Trenkwalder C¹, Yassouridis A¹, Friess E¹.
1. Max Planck Institute of Psychiatry, Munich/Germany
2. Neurologic Clinic, Innsbruck/Austria

Recent research suggested that deficient uptake or an accelerated breakdown of membrane phospholipids in schizophrenia. Post mortem analysis from schizophrenic brains showed substantial depletions of fatty acids of neuronal membranes and .significantly lower amounts of phosphatidylcholine and phosphatidylethanolamine. Several in vivo NMR-spectroscopy studies in the frontal lobe from schizophrenics demonstrated decreased synthesis and increased breakdown of membrane phospholipids Furthermore, the activity of calcium–independent PLA 2, a key-enzyme in phospholipid metabolism, was elevated in the cortex region of brains from schizophrenic patients. We hypothesize that increased PLA 2 activity may be related to abnormal fatty acid metabolism in schizophrenia.
Herein we tested if the above mentioned membrane alterations affected the structure of neuronal membranes from schizophrenic brains. We investigated the membrane fluidity in isolated synaptosomal/mitochondrial membranes of the frontal cortex and hippocampus from schizophrenic (n=7) and control (n=8) brains. In the frontal cortex schizophrenic patients showed significant higher flexibility of fatty acids in the membrane hydrocarbon core and in the hydrophilic region of phospholipid head groups. No differences were observed in hippocampal membranes.

Our findings of membrane alterations circumscribed into a brain region highly effected in schizophrenia suggest that alterations of brain membrane composition may be related to a frontal lobe dysfunction in schizophrenia.

Hubl D.^1,2, Kleinlogel H.², Frölich L.¹, Weinandi T.¹, Maurer K.¹ , Holstein W. ³, Czekalla J. ³, Dierks T.^1,2
1 Department of Psychiatry and Psychotherapy I Frankfurt/Main, Germany
² University Hospital of Clinical Psychiatry, Bern; Switzerland
³ Medical CNS Division, Lilly Germany, Bad Homburg, Germany
Abstract
Rationale: Olanzapine is an atypical antipsychotic drug charcterized by less severe side effects compared to typical ones. Objectives: We investigated the effect of olanzapine on electrical brain activity (Quantitative EEG and cognitive potentials) in healthy subjects. Methods: A vigilance controlled 19 channel EEG and event related potentials (ERP) in an auditory odd-ball paradigm were recorded before and after (3 h, 6 h, 9 h) application of either a single dose of placebo or olanzapine (2.5 mg and 5 mg) in 10 healthy subjects. QEEG was analysed by spectral analysis and evaluated in 9 frequency bands. For the P300 component in the odd ball ERP the amplitude and latency was analysed. Statistical effects were tested by a repeated measurement ANOVA with three factors. Results: The amplitude of the activity in the theta-band increased most significant 6 h after the 2.5 mg application of olanzapine. A pronounced decrease of alpha 2 activity 6 and especially 9 h after olanzapine application could be observed. In most beta frequency bands, and most significant in the beta 4 band, a dose dependent decrease of the activity beginning 6 h after drug application was demonstrated. Significant interactions could be observed between electrode location and frequency band in a 3 factor analysis for the delta band (increase parieto-occipital), in the alpha 2 band (decrease central and occipital) and for beta 2 band (increase frontal). There were no significant changes in P300 amplitude or latency after drug application. Conclusion: QEEG alterations induced by olanzapine were similar to findings in other atypical antipsychotic drugs, like clozapine. The increase of theta-activity is comparable to the frequency distribution observed for thymoleptics or sedative antipsychotica, whereas the decrease of beta activity in olanzapine is not characteristic for these drugs. There were no clear signs for increased cerebral excitability after single dose application of 2.5 and 5 mg olanzapine in healthy controls.

Kalisch R, Elbel G-K, Gössl C, Czisch M, Auer DP
Max-Planck-Institute for Pschiatry, 80804 München, Germany
phMRI is a new tool for studying drug effects on brain activity. The BOLD (blood oxygenation level dependent) contrast is based on changes in blood oxygenation following changes in brain metabolism but is also influenced by stemic cardiovascular and respiratory variables. We evaluated if systemic effects on BOLD can be separated from specific cerebral drug effects.
In 3 ventilated rats unter isoflurane anesthesia, temperature, resp. gases, blood pressure (BP), herart rate, EEG, and ECG were measured during MR scans (7T, SEEPI). Each animal received i.v. saline after 10 min, 50 mg/kg of the anxiogenic pentylenetetrazole (PTZ) after 20 min and 1 mg/kg diazepam after 30 min. For data analysis, the BOLD time courses were detrended with the end-tidal CO₂ and BP curves.
The positive PTZ response became smaller after detrending (obviously, a concomitant BP rise artificially enhanced the BOLD increase). The consecutive diazepam-induced BOLD decrease emerged stronger after detrending (systemic influences tended to mask the cerebral drug effect).
The separation of systemic and specific cerebral drug effects is especially important for detecting subtle changes in brain activity induced by anxiogenic and anxiolytic substances.

Thienel R, Bender S, Oades RD, Dittmann-Balcar A, Rao ML¹, Schall U²
Biological Psychiatry and Biopsychology Research Group, Clinic for Psychiatry and Psychotherapy and Clinic for Child and Adolescent Psychiatry, University of Essen
¹ Clinic for Psychiatry and Psychotherapy, University of Bonn
² Discipline for Psychiatry & Centre for Mental Health Studies, Newcastle, Australia 
Auditory gating was investigated in 46 first to third episode patients (mean age = 29.13 (SD=12.23)) diagnosed with schizophrenia (DSM-IV). Additional measures were clinical ratings (Positive and Negative Symptom Scale, PANSS), a neuropsychological test (Tower of London Test, TOL) assessing executive functions known to be mediated by the prefrontal lobe, as well as the dopamine D₂-receptor-occupancy. Twenty-nine patients with a mean age of 27.9 (SD=11.31) were followed-up for one year.
The auditory gating measure was the frontocentral difference wave of non-target minus target P3 evoked potentials in a 100 ms prepulse condition recorded in a go/no go auditory discrimination task (prepulse-induced non-target positivity or PINTP; Bender et al., 1999).
At therapy onset, patients show significant PINTP reduction compared to 27 healthy controls. Over one year, patients' PINTP increase was significantly associated with improved clinical ratings (ie. PANSS factor: difficulty in abstract thinking, conceptual disorganisation, lack of spontaneity, and flow of conversation) and better Tower of London performance. Dopamine D₂-receptor occupancy, assessed in the course of neuroleptic treatment, was significantly correlated with PINTP increase. These findings indicate that neuroleptic D₂-receptor blockade is associated with improved fronto-temporal brain processing in the course of treatment.
(Supported by the Deutsche Forschungsgemeinschaft Scha 628/4-1).

Wigger A
Max Planck Institute of Psychiatry, 80804 München, Germany
Two Wistar rat lines, bred for either high (HAB) or low (LAB) anxiety-related behaviour on the elevated plus-maze, were recently established as a novel psychopathological animal model. Beside stable line-specific differences in anxiety-related and stress-coping behaviours in various test paradigms, HAB/LAB-rats also differ in neuroendocrine parameters related to inborn emotionality. Similar to human patients suffering from psychiatric diseases, the HPA axis response to exposure to an emotional stressor was enhanced in HAB compared to LAB rats. Further, both mRNA expression (in situ hybridisation) and release (in vivo microdialysis) of arginine-8-vasopressin – a main ACTH secretagogue - are elevated in the paraventricular nucleus of HABs, indicating that endogenous, centrally released vasopressin is critically involved. In contrast, intrahypothalamic release and mRNA expression of oxytocin did not differ between HABs and LABs. The anxiety-related behaviour on the elevated plus-maze as well as the coping strategy in the forced swim test were differentially influenced by pharmacological treatment in both rat lines. Firstly, anxiolytic treatment with diazepam was more effective in HAB rats. Secondly, in HABs also antidepressive treatment with paroxetine showed a more pronounced effect on the coping strategy during forced swimming than in LABs (Keck et al.). These results validate our animal model as appropriate for subsequent studies focussing on mechanisms underlying pathological emotionality and emotionality-dependent responses to both anxiolytic and antidepressive drugs.
Studies on the developmental and genetic basis of the line-specific differences use a cross-fostering and cross-mating protocol, respectively. Nursing of neonate HAB or LAB offspring by foster mothers of the other line (cross-fostering) failed to reveal any differences between control and cross-fostered HAB and LAB rats, indicating that there is no line-specific difference in maternal behaviour or offspring "education". In contrast, mating of HAB females with LAB males and vice versa (cross-breeding) resulted in intermediate F1- and F2-generations displaying intermediate anxiety-related behaviours, indicating a genetic determination of the differing emotionality in both lines. Thus, the HAB/LAB rats offer a unique model for further molecular-biological studies on the genetic basis of emotionality including emotionality-dependent drug responses. Results from such studies might provide further insights into the aetiology of psychiatric diseases and potentially lead to improved therapeutic strategies.