Several reasons why ketamine as a neuroplastic agent may have failed to prevent postoperative delirium: Implications for future protocols.

Ketamine exerts anti-inflammatory, neuroprotective and neuroplastic activity, therefore it may counteract the neurotoxic processes underlying postoperative delirium. However, the majority of studies in this field failed. We identified several pharmacological reasons why these studies may have failed, together with suggestions of how to remediate them. Among them, the interaction with intravenous general anesthetics exerting the opposite effect on GABA interneurons than ketamine may be of principal importance. We suggest biomarkers which may elucidate the influence of this interaction on the different steps of neuroplastic pathways. We hypothesize that administering ketamine before or after general anesthesia could both prevent the interactions and strengthen the effect of ketamine by timing surgery within the climax of ketamine-induced neuroplastic changes or by stabilizing AMPA receptors. It is vital to deal with these questions because the protocols of ongoing studies are based again on the administration of ketamine during general anesthesia (the major identified pitfall).

The effect of low-frequency rTMS on auditory hallucinations, EEG source localization and functional connectivity in schizophrenia.

BACKGROUND: Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) diminishes auditory hallucinations (AHs). The aims of our study were a) to assess the efficacy of LF-rTMS in a randomized, sham-controlled double-blind alignment, b) to identify the electrophysiological changes accompanying the LF-rTMS, and c) to identify the influence of LF-rTMS on brain functional connectivity (FC). METHODS: Nineteen schizophrenia patients with antipsychotic-resistant AHs were randomized to either active (n = 10) or sham (n = 9) LF-rTMS administered over the left temporo-parietal region for ten days. The clinical effect was assessed by the Auditory Hallucination Rating Scale (AHRS). The localization of the differences in electrical activity was identified by standardized low resolution brain electromagnetic tomography (sLORETA) and FC was measured by lagged phase synchronization. RESULTS: AHRS scores were significantly improved for patients receiving active rTMS compared to the sham (median reduction: 40 % vs 12 %; p = 0.01). sLORETA revealed a decrease of alpha-2, beta-1,-2 bands in the left hemisphere in the active group. Active rTMS led to a decrease of the lagged phase connectivity in beta bands originating in areas close to the site of stimulation, and to a prevailing increase of alpha-2 FC. No significant differences in current density or FC were observed in the sham group. LIMITATIONS: Limitations to our study included the small group sizes, and the disability of LORETA to assess subcortical neuronal activity. CONCLUSIONS: LF-rTMS attenuated AHs and induced a decrease of higher frequency bands on the left hemisphere. The FC changes support the assumption that LF-rTMS is linked to the modulation of cortico-cortical coupling.

Relapse in schizophrenia: Definitively not a bolt from the blue.

Detailed study of the period before schizophrenic relapse when early warning signs (EWS) are present is crucial to effective pre-emptive strategies. To investigate the temporal properties of EWS self-reported weekly via a telemedicine system. EWS history was obtained for 61 relapses resulting in hospitalization involving 51 patients with schizophrenia. Up to 20 weeks of EWS history per case were evaluated using a non-parametric bootstrap test and generalized mixed-effects model to test the significance and homogeneity of the findings. A statistically significant increase in EWS sum score was detectable 5 weeks before hospitalization. However, analysis of EWS dynamics revealed a gradual, monotonic increase in EWS score across during the 8 weeks before a relapse. The findings-in contrast to earlier studies-suggest that relapse is preceded by a lengthy period during which pathophysiological processes unfold; these changes are reflected in subjective EWS.

Altered Neural Correlate of the Self-Agency Experience in First-Episode Schizophrenia-Spectrum Patients: An fMRI Study.

BACKGROUND: The phenomenology of the clinical symptoms indicates that disturbance of the sense of self be a core marker of schizophrenia. AIMS: To compare neural activity related to the self/other-agency judgment in patients with first-episode schizophrenia-spectrum disorders (FES, n = 35) and healthy controls (HC, n = 35). METHOD: A functional magnetic resonance imaging (fMRI) using motor task with temporal distortion of the visual feedback was employed. A task-related functional connectivity was analyzed with the use of independent component analysis (ICA). RESULTS: (1) During self-agency experience, FES showed a deficit in cortical activation in medial frontal gyrus (BA 10) and posterior cingulate gyrus, (BA 31; P < .05, Family-Wise Error [FWE] corrected). (2) Pooled-sample task-related ICA revealed that the self/other-agency judgment was dependent upon anti-correlated default mode and central-executive networks (DMN/CEN) dynamic switching. This antagonistic mechanism was substantially impaired in FES during the task. DISCUSSION: During self-agency experience, FES demonstrate deficit in engagement of cortical midline structures along with substantial attenuation of anti-correlated DMN/CEN activity underlying normal self/other-agency discriminative processes.