Sergei Mechtcheriakov

A widespread distinct pattern of cerebral atrophy in patients with alcohol addiction revealed by voxel-based morphometry

Background: Patients with alcohol addiction show a number of transient or persistent neurological and psychiatric deficits. The complexity of these brain alterations suggests that several brain areas are involved, although the definition of the brain alteration patterns is not yet accomplished. Aim: To determine brain atrophy patterns in patients with alcohol dependence. Methods: Voxel-based morphometry (VBM) of grey matter (GM) and white matter (WM) was performed in 22 patients with alcohol dependence and in 22 healthy controls matched for age and sex. Results: In patients with alcohol dependence, VBM of GM revealed a significant decrease in density (p<0.001) in the precentral gyrus, middle frontal gyrus, insular cortex, dorsal hippocampus, anterior thalamus and cerebellum compared with controls. Reduced density of WM was found in the periventricular area, pons and cerebellar pedunculi in patients with alcohol addiction. Conclusions: Our findings provide evidence that alcohol addiction is associated with altered density of GM and WM of specific brain regions. This supports the assumption that alcohol dependence is associated with both local GM dysfunction and altered brain connectivity. Also, VBM is an effective tool for in vivo investigation of cerebral atrophy in patients with alcohol addiction.

Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease☆

Alzheimers disease (AD) is a progressive neurodegenerative disorder with characteristic neuropathological changes of the brain. Great efforts have been undertaken to determine the progression of the disease and to monitor therapeutic interventions. Especially, the analysis of blood plasma had yielded incongruent results. Recently, Ray et al. (Nat. Med. 13, 2007, 1359f) identified changes of 18 signaling proteins leading to an accuracy of 90% in the diagnosis of AD. The aim of the present study was to examine 16 of these signaling proteins by quantitative Searchlight multiplex ELISA in order to determine their sensitivity and specificity in our plasma samples from AD, mild cognitive impairment (MCI), depression with and without cognitive impairment and healthy subjects. Quantitative analysis revealed an increased concentration in Biocoll isolated plasma of 5 out of these 16 proteins in MCI and AD patients compared to healthy subjects: EGF, GDNF and MIP1δ (in AD), MIP4 (in MCI) and RANTES (in MCI and AD). ROC analysis predicted a sensitivity of 65-75% and a specificity of 52-63% when comparing healthy controls versus MCI or AD. Depression without any significant cognitive deficits did not cause any significant changes. Depressed patients with significant cognitive impairment were not different from MCI patients. In conclusion, we detected a number of altered proteins that may be related to a disease specific pathophysiology. However, the overall expression pattern of plasma proteins could not be established as a biomarker to differentiate MCI from AD or from depression.

No benefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, single centre, randomised, double blind, sham controlled “add on” trial

Repetitive transcranial magnetic stimulation (rTMS) has been reported to demonstrate slight effects in the treatment of depression. Hence, a novel bilateral versus unilateral and sham stimulation design was applied to further assess rTMS’ antidepressant effects. Forty one medication free patients with major depression, admitted to a psychiatric unit specialising in affective disorders, were consecutively randomised into 3 groups. Group A1 (n = 12) received unilateral active stimulation consisting of high frequency (hf) rTMS over the left dorsolateral prefrontal cortex (LDLPC) and subsequent sham low frequency (lf) rTMS over the right dorsolateral prefrontal cortex (RDLPC). Group A2 (n = 13) received simultaneous bilateral active stimulation consisting of hf-rTMS over the LDLPC and lf-rTMS over the RDLPC. Group C (n = 13) received bilateral sham stimulation. Stimulation was performed on 10 consecutive workdays. All patients received antidepressant medication on the first day of stimulation, which was continued during and after the stimulation period. As no significant difference in antidepressant outcome between group A1 and A2 was found, the two groups were pooled. The time course of the outcome variables Hamilton depression rating scale (HDRS21) and Beck depression inventory (days 0, 7, 14, 28) by repeated measures analysis of variance revealed no significant group differences (in terms of a group by time interaction), whereas there was a significant effect of time on all three outcome variables in all groups. The results suggest that rTMS as an “add on” strategy, applied in a unilateral and a bilateral stimulation paradigm, does not exert an additional antidepressant effect.

Pattern of brain atrophy in elderly patients with depression revealed by voxel-based morphometry

In this study, we explored to what extent brain abnormalities can be identified in specific brain structures of patients suffering from late onset depression. We examined the structural difference in regional gray and white matter volume between 14 community-dwelling patients suffering from geriatric depression and 20 age-matched non-depressed normal subjects by voxel-based morphometry (VBM) based on magnetic resonance imaging. All subjects also underwent an extensive neuropsychological assessment. Compared with control subjects, patients with depression were impaired in measures of verbal and visual memory, construction, executive ability, and information-processing speed. VBM of gray matter revealed a significant decrease of volume in the right rostral hippocampus, in the right amygdala and in the medial orbito-frontal cortex (gyrus rectus) bilaterally. In the correlation analysis of gray matter volume with the score of the geriatric depression scale, we observed a negative correlation with the medial orbito-frontal cortex (gyrus rectus) bilaterally. There were no differences in white matter volumes between patients with depression and healthy control subjects. The most important limitation of this study was sample size. A larger sample size may have improved detection of changes not reaching significance. Furthermore, our results may not be generalizable across depression severity or to hospitalized patients. The findings are consistent with our hypothesis that depression in the elderly is associated with local gray matter dysfunction.

Olfactory functions and volumetric measures of orbitofrontal and limbic regions in schizophrenia.

OBJECTIVE Olfactory deficits in schizophrenia patients have been suggested to reflect medial temporal and/or prefrontal brain abnormalities. In this study, we examined the relationship between different olfactory functions and volumes of the hippocampus-amygdala complex (HAC) and the orbitofrontal brain region using magnetic resonance imaging (MRI). METHODS Thirty-three young men with schizophrenia (DSM-IV) and 40 healthy controls performed unirhinal olfactory assessment including the main olfactory functions (threshold, discrimination, and identification), and odor judgements (intensity, edibility, familiarity, and pleasantness). Volumes of regions in the medial temporal lobe (hippocampus and amygdala) and the prefrontal region (orbitofrontal gray and white matter) were measured on MRI scans. RESULTS Compared with controls, patients showed bilaterally impaired thresholds, quality discrimination and identification, as well as edibility judgements. Olfactory deficits were not attributable to smoking, premorbid intelligence, or impaired thresholds. Relative to controls, patients had bilateral reduced hippocampus and amygdala volumes. In patients, smaller hippocampus volumes were associated with poorer olfactory discrimination ability. CONCLUSIONS Olfactory deficits in schizophrenia appear to be associated with morphometric abnormalities in the medial temporal rather than the orbitofrontal region (OFR). These results indicate that olfactory quality discrimination deficits are related to structural hippocampus abnormalities. Future studies of genetic and behavioral high-risk samples seem warranted.

Chemical shift magnetic resonance spectroscopy of cingulate grey matter in patients with minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is frequently diagnosed in patients with liver cirrhosis who do not show overt clinical cirrhosis-associated neurological deficits. This condition manifests primarily with visuo-motor and attention deficits. We studied the association between visuo-motor deficits and magnetic resonance spectroscopic parameters in cingulate grey matter and white matter of centrum semiovale in patients with liver cirrhosis. The data revealed an increase in the glutamate–glutamine/creatine ratio and a decrease in choline/creatine and inositol/creatine ratios in patients with liver cirrhosis. The analysis of the data showed that cirrhosis-associated deterioration of the visuo-motor function significantly correlates with a decrease in the choline/creatine ratio and an increase in N-acetylaspartate/choline in cingulate grey matter but not in the neighbouring white matter. Furthermore, the increase in the glutamate–glutamine/creatine ratio correlated significantly with the increase in the N-acetylaspartate/creatine ratio. These data suggest an association between altered choline, glutamate-glutamine and NAA metabolism in cingulate grey matter and symptoms of MHE, and underline the importance of differentiation between grey and white matter in magnetic resonance spectroscopic studies on patients with cirrhosis-associated brain dysfunction.

Motor dysfunction in patients with liver cirrhosis: impairment of handwriting

Motor dysfunction is an important clinical finding in patients with liver cirrhosis and mild forms of hepatic encephalopathy. The mechanisms and clinical appearance of motor impairment in patients with liver cirrhosis are not completely understood. We studied fine motor control in forty four patients with advanced liver cirrhosis (excluding those with hepatic encephalopathy grade II) and 48 healthy controls using a kinematic analysis of standardized handwriting tests. We analysed parameters of velocity, the ability to coordinate and the level of automatisation of handwriting movements. Furthermore, we studied the association between impairment of handwriting and clinical neuro–psychiatric symptoms. As compared with control subjects, patients showed a statistically significant reduction of movement peak velocity in all handwriting tasks as well as a substantial increase of number of velocity inversions per stroke. Using a z–score based assessment we found impairment of handwriting in fourteen out of forty four patients (31.8 %). The deterioration of handwriting was associated with clinical symptoms of motor dysfunction, such as bradykinesia, adiadochokinesia, dysmetria of upper extremities and gait ataxia. This is the first study that quantitatively investigates impairment of handwriting in patients with liver cirrhosis. Our findings suggest the application of kinematic analysis of handwriting for diagnostics of motor dysfunction in patients with mild forms of hepatic encephalopathy.

Tryptophan Metabolism in Post-Withdrawal Alcohol-Dependent Patients

AIMS The aim of the study was to investigate the parameters of tryptophan and phenylalanine metabolism and their associations to immune system activation and to behavioural symptoms during medium-term withdrawal (4-12 weeks of abstinence) in alcohol-dependent patients. METHODS Biochemical assays and clinical assessments at the beginning of treatment (fourth week of alcohol abstinence in average) and prior to the discharge after 8 weeks of treatment. RESULTS Kynurenine to tryptophan ratio (Kyn/Trp) slightly correlated with neopterin levels in early post-withdrawal period (Week 4 of abstinence) but this association disappeared after 12 weeks of abstinence. Phenylalanine and tyrosine concentrations as well as phenylalanine to tyrosine ratio (Phe/Tyr) decreased between Weeks 4 and 12 of abstinence. Kynurenine and Kyn/Trp increased significantly at 12th week of abstinence when compared with the beginning of the study (Week 4 of abstinence). At Week 12, Kyn/Trp significantly correlated with such behavioural symptoms as fatigue, irritability and sleep disturbances. CONCLUSIONS Tryptophan breakdown in early stages may be influenced by the increased activity of indoleamine 2,3-dioxygenase but the increase of Kyn/Trp between Weeks 4 and 12 of abstinence seems to be independent of immune changes and correlates with behavioural symptoms in later stages of the post-withdrawal course. A possible role of kynurenine metabolites in mediation of the increased stress sensibility in post-withdrawal alcohol-dependent patients is discussed.

Schizophrenia and episodic ataxia type 2

The frequent co-occurrence of degenerative cerebellar pathology and schizophrenia, as well as the recently reported increased association rate between autosomal dominant ataxias and major psychosis, strongly suggests the involvement of the cerebellum in the pathophysiology of schizophrenia.1–3 The analysis of associations between psychosis and neurodegenerative diseases may improve our understanding of the pathophysiology of schizophrenia and facilitate the search for susceptibility genes for this disorder.4 To our best knowledge, there have been no previous reports about an association between schizophrenia and the periodic autosomal dominant ataxias, such as episodic ataxia type 1 and type 2 (EA1 and EA2). We present a case of a young man who has been diagnosed with paranoid schizophrenia (ICD-10: F20.0) and episodic ataxia type 2. The patient, a man aged 27 years, was first admitted to our hospital with psychotic symptoms in June 1995. He presented with paranoid delusions and delusions of reference, acoustic hallucinations (commenting voices), formal thought disorder, and behaviour disorganisation, as well as negative symptoms such as blunted affect, poor rapport, and lack of spontaneity. At this time, he was diagnosed as having paranoid schizophrenia (ICD-10: F20.0) and showed a PANSS (positive and negative symptom scale) total score of 137 (fig …

Oxytocin und die suchterhaltenden Mechanismen der Alkoholabhängigkeit

One of the crucial purposes of treating alcohol-dependent patients is to enhance their ability to stay abstinent after detoxification therapy. Anxiety and stress vulnerability are the main factors provoking alcohol craving and relapse. In the first months of abstinence, alcohol-dependent patients frequently show sleep disturbances, irritability and depression, indicating chronic activation of stress pathways. In addition, the loss of confidence in interpersonal interactions results in social withdrawal and reduced willingness to participate in therapeutic programs.Current research shows that the peptide hormone oxytocin exerts substantial anxiolytic effects and facilitates prosocial behavior. Oxytocin can be safely applied as intranasal preparation. Oxytocin acts by inhibiting the effects of the corticotropin-releasing factor on GABAergic interneurons in the amygdala and paraventricular nucleus of hypothalamus.Recent research strongly suggests that application of oxytocin may beneficially influence the mechanisms of relapse and craving by reduction of anxiety, stress vulnerability and social withdrawal in abstinent alcohol-dependent patients.This article reviews neurobiological mechanisms of oxytocin effects on stress-related pathways and discusses the potential use of oxytocin in the treatment of alcohol addiction.ZusammenfassungEine der größten Herausforderungen in der Behandlung der Alkoholabhängigkeit ist die Aufrechterhaltung der Abstinenzfähigkeit der Patienten nach dem Abschluss der Entzugsbehandlung. Die erhöhte Stressempfindlichkeit und vielfältige Angstsymptome gelten als Hauptfaktoren, die das Alkoholverlangen triggern und Alkoholrückfälle begünstigen können. In den ersten Monaten der Alkoholabstinenz sind bei alkoholabhängigen Patienten häufig Schlafstörungen, erhöhte Reizbarkeit und depressive Verstimmungen als Indikatoren für die Aktivierung von Stressmechanismen zu beobachten. Hinzu kommt die Unsicherheit in den sozialen Interaktionen, die bei Abstinenzversuchen auftritt und oft zu stressassoziierten Erlebnissen führt. Dies resultiert häufig in der Vernachlässigung von sozialen Kontakten und stattdessen zunehmender Bevorzugung des Substanzkonsums sowie in der verminderten Fähigkeit, die für den Therapieerfolg notwendige soziale Interaktion mit dem therapeutischen Umfeld aufrechtzuerhalten.Rezente Studien zeigen, dass das Peptidhormon Oxytocin sich durch eine anxiolytische Wirkung und die Fähigkeit, Stresssymptome abzumildern, auszeichnet. Darüber hinaus entfaltet Oxytocin sog. prosoziale Effekte, welche zu einer verstärkten Hinwendung zu sozialer Interaktion führen. Intranasal lässt es sich zudem leicht und sicher verabreichen.Aus neurobiologischer Sicht entfaltet Oxytocin seine anxiolytische Wirkung durch die Hemmung der Effekte des Corticotropin-releasing Factor (CRF) an GABAergen Interneuronen in Amygdala und Nucleus paraventricularis im Hypothalamus.Somit kann die anxiolytische, stresshemmende und prosoziale Wirkung von Oxytocin für die Vorbeugung der durch Angstsymptomatik, Stressempfindlichkeit und sozialen Rückzug ausgelösten Rückfälle genutzt werden. Die neurobiologischen Grundlagen der Wirkungen von Oxytocin auf Mechanismen der Suchterhaltung bei Alkoholabhängigkeit werden in dieser Übersichtsarbeit im Detail vorgestellt und diskutiert.SummaryOne of the crucial purposes of treating alcohol-dependent patients is to enhance their ability to stay abstinent after detoxification therapy. Anxiety and stress vulnerability are the main factors provoking alcohol craving and relapse. In the first months of abstinence, alcohol-dependent patients frequently show sleep disturbances, irritability and depression, indicating chronic activation of stress pathways. In addition, the loss of confidence in interpersonal interactions results in social withdrawal and reduced willingness to participate in therapeutic programs.Current research shows that the peptide hormone oxytocin exerts substantial anxiolytic effects and facilitates prosocial behavior. Oxytocin can be safely applied as intranasal preparation. Oxytocin acts by inhibiting the effects of the corticotropin-releasing factor on GABAergic interneurons in the amygdala and paraventricular nucleus of hypothalamus.Recent research strongly suggests that application of oxytocin may beneficially influence the mechanisms of relapse and craving by reduction of anxiety, stress vulnerability and social withdrawal in abstinent alcohol-dependent patients.This article reviews neurobiological mechanisms of oxytocin effects on stress-related pathways and discusses the potential use of oxytocin in the treatment of alcohol addiction.