Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial.

OBJECTIVE: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials. METHODS: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1). RESULTS: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm. CONCLUSION: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.

Antidepressant effects of ketamine and ECT: A pilot comparison.

BACKGROUND: To compare the antidepressant effects and cognitive adverse effects of intravenous ketamine infusion and Electro-convulsive therapy (ECT) in persons with severe depressive episodes. METHODS: This assessor-blinded randomized control trial included 25 patients (either sex; 18-65 years) meeting ICD-10 criteria for severe depression (bipolar or unipolar). Patients received either ECT (n = 13) or intravenous infusions of ketamine hydrochloride (0.5 mg/kg over 45 min; n = 12) for six alternate day sessions over a period of two weeks. Severity of depression was assessed at baseline and on every alternate day of intervention using the Hamilton Depression Rating Scale (HDRS) and self-reported Beck Depression Inventory (BDI). RESULTS: Baseline socio-demographic and clinical variables including HDRS (ECT: 25.15±6.58; Ketamine: 23.33±4.05, p = 0.418) and BDI (ECT: 37.07±6.58; Ketamine: 33.33±9.29; p = 0.254) were comparable. Repeated-measures analysis of variance revealed that ECT patients showed significantly greater reduction in HDRS (group*time interaction effect; F = 4.79; p<0.001) and BDI scores (group*time interaction effect; F = 3.83; p<0.01). ECT patients had higher response rate than ketamine patients [HDRS: ECT- 13/13(100%) vs ketamine- 8/12 (66.70%); p = 0.04]. This was true for remission as well [ECT- 12/13(92.30%) vs ketamine- 6/12(50%), p = 0.030; both HDRS and BDI]. Performance on Digit Symbol Substitution Test (as part of the Battery for ECT-Related Cognitive Deficits scale) significantly improved in ketamine patients (p = 0.02) while that in ECT patients worsened non significantly (p = 0.30). LIMITATIONS: Relatively small sample size; higher proportion of dropouts in the Ketamine arm. CONCLUSION: This study favoured ECT over ketamine for a better efficacy over six treatment sessions in severe depression. The results need to be replicated in larger studies. TRIAL REGISTRATION: CTRI/2019/09/021184.

Investigational and Therapeutic Applications of Transcranial Magnetic Stimulation in Schizophrenia.

PURPOSE OF REVIEW: This current review summarizes the investigational and therapeutic applications of transcranial magnetic stimulation (TMS) in schizophrenia. RECENT FINDINGS: Fairly consistent findings of an impaired cortical excitation-inhibition balance, cortical plasticity, and motor resonance have been reported in schizophrenia. Cortical connectivity impairments have also been demonstrated in motor and prefrontal brain regions. In terms of treatment, the best support is for 1-Hz TMS to the left temporoparietal cortex for the short-term treatment of persistent auditory hallucinations. High-frequency TMS to the left prefrontal cortex improves negative and cognitive symptoms, but with inconsistent and small effects. TMS combined with diverse brain mapping techniques and clinical evaluation can unravel critical brain-behavior relationships relevant to schizophrenia. These provide critical support to the conceptualization of schizophrenia as a connectopathy with anomalous cortical plasticity. Adaptive modulation of these aberrant brain networks in a neuroscience-informed manner drives short-term therapeutic gains in difficult-to-treat symptoms of schizophrenia.

Motor cortical plasticity in schizophrenia: A meta-analysis of Transcranial Magnetic Stimulation - Electromyography studies.

BACKGROUND: Several lines of investigations converge upon aberrant synaptic plasticity as a potential pathophysiological characteristic of schizophrenia. In vivo experiments using neuromodulatory perturbation techniques like Transcranial Magnetic and Direct Current Stimulation (TMS & tDCS) have been increasingly used to measure 'motor cortical plasticity' in schizophrenia. A systematic quantification of cortical plasticity and its moderators in schizophrenia is however lacking. METHOD: The PubMed/MEDLINE database was searched for studies up to December 31st, 2017 that examined case-control experiments comparing neuromodulation following single-session of TMS or tDCS. The primary outcome was the standardized mean difference for differential changes in motor evoked potential (MEP) amplitudes measured with single-pulse TMS (MEP Δ) between patients and healthy subjects following TMS or tDCS. After examining heterogeneity, meta-analyses were performed using fixed effects models. RESULTS: A total of 16 datasets comparing cortical plasticity (MEP Δ) between 189 schizophrenia patients and 187 healthy controls were included in the meta-analysis. Patients demonstrated diminished MEP Δ with effect sizes (Cohen's d) ranging from 0.66 (LTP-like plasticity) to 0.68 (LTD-like plasticity). Heterosynaptic plasticity studies demonstrated a greater effect size (0.79) compared to homosynaptic plasticity studies (0.62), though not significant (P = 0.43). Clinical, perturbation protocol- and measurement-related factors, and study quality did not significantly moderate the aberrant plasticity demonstrated in schizophrenia. CONCLUSIONS: Schizophrenia patients demonstrate diminished LTP- and LTD-like motor cortical plasticity, which is not influenced by the various clinical and experimental protocol related confounders. These consistent findings should encourage the use of perturbation-based biomarkers to characterize illness trajectories and treatment response.