Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study.

BACKGROUND: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. MATERIALS AND METHODS: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. RESULTS: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. CONCLUSION: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics.

Psychotic (delusional) depression and suicidal attempts: a systematic review and meta-analysis.

OBJECTIVE: It still remains unclear whether psychotic features increase the risk of suicidal attempts in major depressive disorder. Thus, we attempted, through a systematic review coupled with a meta-analysis, to elucidate further whether unipolar psychotic depression (PMD) compared to non-PMD presents higher levels of suicidal attempts. METHOD: A systematic search was conducted in PubMed, EMBASE, PsycINFO as well as in various databases of the so-called gray literature for all studies providing data on suicidal attempts in PMD compared to non-PMD, and the results were then subjected to meta-analysis. RESULTS: Twenty studies met our inclusion criteria, including in total 1,275 PMD patients and 5,761 non-PMD patients. An elevated risk for suicide attempt for PMD compared to non-PMD patients was found: The total (lifetime) fixed-effects pooled OR was 2.11 (95% CI: 1.81-2.47), and the fixed-effects pooled OR of the five studies of the acute phase of the disorder was 1.93 (95% CI: 1.33-2.80). This elevated risk of suicidal attempt for PMD patients remained stable across all age groups of adult patients. CONCLUSION: Despite data inconsistency and clinical heterogeneity, this systematic review and meta-analysis showed that patients with PMD are at a two-fold higher risk, both during lifetime and in acute phase, of committing a suicidal attempt than patients with non-PMD.

Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. RESULTS: In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. CONCLUSIONS: As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial.

Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation.

Association of serum BDNF levels with hippocampal volumes in first psychotic episode drug-naive schizophrenic patients.

Evidence suggests that hippocampal volumetric abnormalities are present in first-episode schizophrenia. The hippocampus contains the highest brain levels of neurotrophic factors, which are major determinants of neuronal plasticity. Brain-derived neurotrophic factor (BDNF) influences neuronal survival, differentiation, synaptogenesis, and maintenance and is also correlated with neuronal activation in the hippocampus. BDNF is also involved in the development and modulation of dopaminergic-related systems. Alterations of serum BDNF levels have been shown in a number of studies with first episode patients with schizophrenia, probably reflecting an association between BDNF and the pathogenesis of the disorder. In the present study we investigated the correlation between serum BDNF levels and hippocampal volumes in a sample of first episode drug-naïve patients with schizophrenia (FEP) and healthy control subjects. We found that hippocampal volume (HV) was decreased in FEP patients. Corrected right HV of FEP patients were significantly smaller compared to corrected right HVs of healthy subjects. The serum BDNF levels in the sample of FEP patients was significantly reduced compared to the healthy subjects. A significant positive association was found between serum BDNF and the corrected right HV in the group of patients such that the smaller the HV, the more reduced the serum BDNF levels. (Pearson r=0.452, p=0.045). Our findings indicate that low serum BDNF levels are associated with reduction in HV at the onset of schizophrenia and may further support the theory of a neuroprogressive-neurotoxic reaction associated with the onset of psychosis.

Association of serum brain-derived neurotrophic factor and duration of untreated psychosis in first-episode patients with schizophrenia.

BACKGROUND/AIMS: The brain-derived neurotrophic factor (BDNF) levels in serum and the central nervous system are altered in patients with schizophrenia, suggesting that changes in the expression of BDNF might contribute to the disease pathophysiology. Long duration of untreated psychosis (DUP) has been associated with poorer prognosis in patients with schizophrenia. Such a relationship of untreated psychosis to outcome may indicate a neurodegenerative process and may have important implications for understanding the pathophysiology of schizophrenia. METHODS: In this study, we investigated the association between serum BDNF levels and DUP in a sample of drug-naïve patients in their first episode of schizophrenia (FEP). We investigated serum BDNF levels in a sample of 37 drug-naïve FEP patients and 21 matched healthy subjects. RESULTS: The serum BDNF level in the sample of FEP was significantly reduced compared to the healthy subjects (18.87 +/- 8.23 vs. 29.2 +/- 7.73 ng/ml, t = 4.76, d.f. = 57, p = 0.01). A negative correlation was found between serum BDNF levels and DUP in the group of patients (r = -0.346, p = 0.036). CONCLUSIONS: Our findings indicate that low serum BDNF levels at the onset of schizophrenia were associated with a long DUP and this could reflect an acute neurodegenerative reaction during the untreated phase of psychosis.

An evoked auditory response fMRI study of the effects of rTMS on putative AVH pathways in healthy volunteers.

BACKGROUND: Auditory verbal hallucinations (AVH) are the most prevalent symptom in schizophrenia. They are associated with increased activation within the temporoparietal cortices and are refractory to pharmacological and psychological treatment in approximately 25% of patients. Low frequency repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex has been demonstrated to be effective in reducing AVH in some patients, although results have varied. The cortical mechanism by which rTMS exerts its effects remain unknown, although data from the motor system is suggestive of a local cortical inhibitory effect. We explored neuroimaging differences in healthy volunteers between application of a clinically utilized rTMS protocol and a sham rTMS equivalent when undertaking a prosodic auditory task. METHOD: Single-blind placebo controlled fMRI study of 24 healthy volunteers undertaking an auditory temporoparietal activation task, who received either right temporoparietal rTMS or sham RTMS. RESULTS: The main effect of group was bilateral inferior parietal deactivation following real rTMS. An interaction of group and task type showed deactivation during real rTMS in the right superior temporal gyrus (STG), left thalamus, left postcentral gyrus and cerebellum. However, the left parietal lobe showed an increase in activation following right sided real rTMS, but this increase was specific to a non-linguistic, tone-sequence task. CONCLUSION: rTMS does cause local inhibitory effects, not only in the underlying region of application, but also in functionally connected cortical regions. However, there is also a related, task dependent, increase in activation within selected cortical areas in the contralateral hemisphere; these are likely to reflect compensatory mechanisms, and such cortical activation may in some cases contribute to, or retard, some of the therapeutic effects seen with rTMS.

Neuropsychological relationships in paranoid schizophrenia with and without delusional misidentification syndromes. A comparative study.

Delusional misidentification syndromes (DMSs) and schizophrenia are strongly associated, since the former occur predominantly in the context of paranoid schizophrenia. However, the possible underlying neuropsychological relationships between DMSs and paranoid schizophrenia have not been thoroughly investigated. The aim of the present study was to investigate whether DMSs in paranoid schizophrenia are associated with a distinct neuropsychological substrate indicative of differential bilateral frontal and right hemisphere dysfunction. We compared two matched groups of paranoid schizophrenic patients with (N=22) and without (N=22) DMS(s) on a battery of neuropsychological tests assessing mainly frontal and right hemisphere functions. No statistically significant differences were detected between the two groups. Our findings are indicative of a bilateral frontal and right hemisphere dysfunction of equal severity in both DMS and non-DMS patients with paranoid schizophrenia.

Investigation of serum BDNF levels in drug-naive patients with schizophrenia.

The role of brain-derived neurotrophic factor (BDNF) is to promote and modulate the neuronal responses across neurotransmitter systems in the brain. Therefore, abnormal BDNF signaling may be associated with the pathophysiology of schizophrenia. Decreased BDNF levels in the brain and the serum of patients with psychotic disorders have been reported. In the present study, we assessed serum BDNF levels in a group of 14 drug-naive first-episode patients with schizophrenia (FEP), compared to 15 healthy controls. The serum BDNF levels in the sample of FEP patients was significantly reduced compared to normal controls (23.92+/-5.99 ng/ml vs. 30.0+/-8.43 ng/ml, F=5.01, df=1, p=.034). Negative correlations were shown between serum BDNF levels of the patients and the PANSS Positive and Negative subscale scores. Our findings indicate that BDNF levels at the onset of schizophrenia may reflect associated pathophysiological processes as well as the severity of positive and negative psychotic symptoms.