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Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.
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BACKGROUND: Alzheimer's disease's (AD) prevalence is projected to increase as the population ages and current treatments are minimally effective. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates into the cerebral cortex, stimulates the mitochondrial respiratory chain, and increases cerebral blood flow. Preliminary data suggests t-PBM may be efficacious in improving cognition in people with early AD and amnestic mild cognitive impairment (aMCI). METHODS: In this randomized, double-blind, placebo-controlled study with aMCI and early AD participants, we will test the efficacy, safety, and impact on cognition of 24 sessions of t-PBM delivered over 8 weeks. Brain mechanisms of t-PBM in this population will be explored by testing whether the baseline tau burden (measured with 18F-MK6240), or changes in mitochondrial function over 8 weeks (assessed with 31P-MRSI), moderates the changes observed in cognitive functions after t-PBM therapy. We will also use changes in the fMRI Blood-Oxygenation-Level-Dependent (BOLD) signal after a single treatment to demonstrate t-PBM-dependent increases in prefrontal cortex blood flow. CONCLUSION: This study will test whether t-PBM, a low-cost, accessible, and user-friendly intervention, has the potential to improve cognition and function in an aMCI and early AD population.
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PURPOSE: The cerebellum is an intricate neural structure that orchestrates various cognitive and behavioral functions. In recent years, there has been an increasing interest in neuromodulation of the cerebellum with transcranial magnetic stimulation (TMS) for therapeutic and basic science applications. Theta burst stimulation (TBS) is an efficient and powerful TMS protocol that is able to induce longer-lasting effects with shorter stimulation times compared with traditional TMS. Parameters for cerebellar TBS are traditionally framed in the bounds of TBS to the cerebral cortex, even when the 2 have distinct histologic, anatomical, and functional characteristics. Tolerability limits have not been systematically explored in the literature for this specific application. Therefore, we aimed to determine the stimulation parameters that have been used for cerebellar. TBS to date and evaluate adverse events and adverse effects related to stimulation parameters. METHODS: We used PubMed to perform a critical review of the literature based on a systematic review of original research studies published between September 2008 and November 2019 that reported on cerebellar TBS. We recovered information from these publications and communication with authors about the stimulation parameters used and the occurrence of adverse events. FINDINGS: We identified 61 research articles on interventions of TBS to the cerebellum. These articles described 3176 active sessions of cerebellar TBS in 1203 individuals, including healthy participants and patients with various neurologic conditions, including brain injuries. Some studies used substantial doses (eg, pulse intensity and number of pulses) in short periods. No serious adverse events were reported. The specific number of patients who experienced adverse events was established for 48 studies. The risk of an adverse event in this population (n = 885) was 4.1%. Adverse events consisted mostly of discomfort attributable to involuntary muscle contractions. Authors used a variety of methods for calculating stimulation dosages, ranging from the long-established reference of electromyography of a hand muscle to techniques that atone for some of the differences between cerebrum and cerebellum. IMPLICATIONS: No serious adverse events have been reported for cerebellar TBS. There is no substantial evidence of a tolerable maximal-efficacy stimulation dose in humans. There is no assurance of equivalence in the translation of cortical excitability and stimulation intensities from the cerebral cortex to cerebellar regions. Further research for the stimulation dose in cerebellar TBS is warranted, along with consistent report of adverse events. © 2020 Elsevier HS Journals, Inc.