Malek Bajbouj

Association of a functional BDNF polymorphism and anxiety-related personality traits

RationaleConverging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. Recently, it was shown that the Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. The association to anxiety-related traits has not been investigated so far.MethodsWe tested a total of 343 unrelated subjects of German descent (171 male, 172 female, age: 39.0±14.6 years) who were carefully screened for psychiatric health. The self-ratable State–Trait Anxiety Inventory (STAI), which allows anxiety to be quantified as a comparatively stable personality trait, and the NEO-Five Factor Inventory (NEO-FFI) was applied.ResultsIn the trait-related anxiety score, a significant (F=3.2, df=2, p<0.042) effect of the genotype was observed with higher levels of trait anxiety in Val/Val (35.0±7.4) compared to Val/Met (33.4±6.5) and Met/Met (32.0±4.6) genotypes. The NEO neuroticism scores were also higher in Val/Val (29.5±7.0) than in Val/Met (28.4±6.5) or Met/Met (26.8±5.8) genotype, but not at a significant rate.ConclusionsOur findings support the hypothesis that anxiety- and depression-related personality traits are associated with the BDNF polymorphism although the explained variance is low.

Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing

BACKGROUND A common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude. METHODS The P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated. RESULTS We observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients. CONCLUSIONS The association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine.

Talking about Emotion: Prosody and Skin Conductance Indicate Emotion Regulation

Talking about emotion and putting feelings into words has been hypothesized to regulate emotion in psychotherapy as well as in everyday conversation. However, the exact dynamics of how different strategies of verbalization regulate emotion and how these strategies are reflected in characteristics of the voice has received little scientific attention. In the present study, we showed emotional pictures to 30 participants and asked them to verbally admit or deny an emotional experience or a neutral fact concerning the picture in a simulated conversation. We used a 2 × 2 factorial design manipulating the focus (on emotion or facts) as well as the congruency (admitting or denying) of the verbal expression. Analyses of skin conductance response (SCR) and voice during the verbalization conditions revealed a main effect of the factor focus. SCR and pitch of the voice were lower during emotion compared to fact verbalization, indicating lower autonomic arousal. In contradiction to these physiological parameters, participants reported that fact verbalization was more effective in down-regulating their emotion than emotion verbalization. These subjective ratings, however, were in line with voice parameters associated with emotional valence. That is, voice intensity showed that fact verbalization reduced negative valence more than emotion verbalization. In sum, the results of our study provide evidence that emotion verbalization as compared to fact verbalization is an effective emotion regulation strategy. Moreover, based on the results of our study we propose that different verbalization strategies influence valence and arousal aspects of emotion selectively.

Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia.

Attention deficits have been consistently described in schizophrenia. Functional neuroimaging and electrophysiological studies have focused on anterior cingulate cortex (ACC) dysfunction as a possible mediator. However, recent basic research has suggested that the effect of attention is also observed as a relative amplification of activity in modality-associated cortical areas. In the present study, the question was addressed whether an amplification deficit is seen in the auditory cortex of schizophrenic patients during an attention-requiring choice reaction task. Twenty-one drug-free schizophrenic patients and 21 age- and sex-matched healthy controls were studied (32-channel EEG). The underlying generators of the event-related N1 component were separated in neuroanatomic space using a minimum-norm (LORETA) and a multiple dipole (BESA) approach. Both methods revealed activation in the primary auditory cortex (peak latency approximately 100 ms) and in the area of the ACC (peak latency approximately 130 ms). In addition, the adapted multiple dipole model also showed a temporal-radial source activation in nonprimary auditory areas (peak latency approximately 140 ms). In schizophrenic patients, significant activation deficits were found in the ACC as well as in the left nonprimary auditory areas that differentially correlated with negative and positive symptoms. The results suggest that (1) the source in the nonprimary auditory cortex is detected only with a multiple dipole approach and (2) that the N1 generators in the ACC and in the nonprimary auditory cortex are dysfunctional in schizophrenia. This would be in line with the notion that attention deficits in schizophrenia involve an extended cortical network.

Vagus nerve stimulation for depression: efficacy and safety in a European study

BACKGROUND Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

Evidence for Impaired Cortical Inhibition in Patients with Unipolar Major Depression

BACKGROUND Several lines of evidence suggest that central cortical inhibitory mechanisms, especially associated with gamma-aminobutyric acid (GABA) neurotransmission, may play a role in the pathophysiology of major depression. Transcranial magnetic stimulation is a useful tool for investigating central cortical inhibitory mechanisms associated with GABAergic neurotransmission in psychiatric and neurological disorders. METHODS By means of transcranial magnetic stimulation, different parameters of cortical excitability, including motor threshold, the cortical silent period, and intracortical inhibition/facilitation, were investigated in 20 medication-free depressed patients and 20 age- and gender-matched healthy volunteers. RESULTS Silent period and intracortical inhibition were reduced in depressed patients, consistent with a reduced GABAergic tone. Moreover, patients showed a significant hemispheric asymmetry in motor threshold. CONCLUSIONS This study provides evidence of reduced GABAergic tone and motor threshold asymmetry in patients with major depression.

Two-year outcome of vagus nerve stimulation in treatment-resistant depression.

One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms. Some of the previous studies of vagus nerve stimulation (VNS) have suggested antidepressant effects. Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant reduction (P ≤ 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score, the primary outcome measure. After 2 years, 53.1% (26/49) of the patients fulfilled the response criteria (≥50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scores ≤ 10). The proportion of patients who fulfilled the remission criteria remained constant as the duration of VNS treatment increased. Voice alteration, cough, and pain were the most frequently reported adverse effects. Two patients committed suicide during the study; no other deaths were reported. No statistically significant differences were seen in the number of concomitant antidepressant medications. The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression.

GABA in the insula — a predictor of the neural response to interoceptive awareness

The insula has been identified as a key region involved in interoceptive awareness. Whilst imaging studies have investigated the neural activation patterns in this region involved in intero- and exteroceptive awareness, the underlying biochemical mechanisms still remain unclear. In order to investigate these, a well-established fMRI task targeting interoceptive awareness (heartbeat counting) and exteroceptive awareness (tone counting) was combined with magnetic resonance spectroscopy (MRS). Controlling for physiological noise, neural activity in the insula during intero- and exteroceptive awareness was confirmed in an independent data sample using the same fMRI design. Focussing on MRS values from the left insula and combining them with neural activity during intero- and exteroceptive awareness in the same healthy individuals, we demonstrated that GABA concentration in a region highly involved in interoceptive processing is correlated with neural responses to interoceptive stimuli, as opposed to exteroceptive stimuli. In addition, both GABA and interoceptive signal changes in the insula predicted the degree of depressed affect, as measured by the Beck Hopelessness Scale. On the one hand, the association between GABA concentration and neural activity during interoceptive awareness provides novel insight into the biochemical underpinnings of insula function and interoception. On the other, through the additional association of both GABA and neural activity during interoception with depressed affect, these data also bear potentially important implications for psychiatric disorders like depression and anxiety, where GABAergic deficits, altered insula function and abnormal affect coincide.

Antidepressant electroconvulsive therapy: Mechanism of action, recent advances and limitations

A considerable number of depressive patients do not respond to or remit during pharmacotherapeutical or psychotherapeutical interventions resulting in an increasing interest in non-pharmacological strategies to treat affective disorders. Electroconvulsive therapy (ECT) dates back to the beginning of modern biologic psychiatry and ongoing research has successfully improved efficacy in addition to safety while reducing side effects. Double-blind, randomized, controlled trials have shown powerful interactions between electrode placement (right unilateral, bifrontal, bitemporal) and dosage (relative to seizure threshold) in the efficacy and side effects of ECT. This review aims to summarize current research data on the mechanism of action, efficacy, and recent advances in ECT technique.

Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders

Significance Electroconvulsive therapy is controversial: How does a major electrical discharge over half the brain result in recovery in disorders such as refractory major depression and manic depression, which are apparently different diseases? We find local but not general brain anatomy changes following electroconvulsive therapy that are differently distributed in each disease, and the areas affected are those implicated as abnormal in each disorder. An interaction between electroconvulsive therapy and specific pathology appears to be responsible for the therapeutic effect. Our results have implications for other electrically based brain treatments, such as deep brain stimulation and transcranial magnetic stimulation. There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders stemming from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to a “barbaric” form of placebo effect. Here we show differential, highly specific, spatially distributed effects of ECT on regional brain structure in two populations: patients with unipolar or bipolar disorder. Unipolar and bipolar disorders respond differentially to ECT and the associated local brain-volume changes, which occur in areas previously associated with these diseases, correlate with symptom severity and the therapeutic effect. Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.