Effects and safety of transcranial direct current stimulation on multiple health outcomes: an umbrella review of randomized clinical trials.

Transcranial direct current stimulation (tDCS), which delivers a direct current to the brain, emerged as a non-invasive potential therapeutic in treating a range of neurological and neuropsychiatric disorders. However, a comprehensive quantitative evidence synthesis on the effects of tDCS on a broad range of mental illnesses is lacking. Here, we systematically assess the certainty of the effects and safety of tDCS on several health outcomes using an umbrella review of randomized controlled trials (RCTs). The methodological quality of each included original meta-analysis was assessed by the A Measurement Tool for Assessing Systematic Reviews 2 (AMSTAR2), and the certainty of the evidence for each effect was evaluated with Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). We followed an a priori protocol (PROSPERO CRD42023458700). We identified 15 meta-analyses of RCTs (AMSTAR 2; high 3, moderate 3, and low 9) that included 282 original articles, covering 22 unique health endpoints across 22 countries and six continents. From meta-analyses of RCTs supported by very low to high certainty of evidence, it was found that tDCS improved symptoms related to post-stroke, including post-stroke depression scale score (equivalent standardized mean difference [eSMD], 1.61 [95% confidence level, 0.72-2.50]; GRADE=moderate), activities of daily living independence (7.04 [3.41-10.67]; GRADE=high), motor recovery of upper and lower extremity (upper extremity: 0.15 [0.06-0.24], GRADE=high; lower extremity: 0.10 [0.03-0.16], GRADE=high), swallowing performance (GRADE=low), and spasticity (GRADE=moderate). In addition, tDCS had treatment effects on symptoms of several neurological and neuropsychiatric disorders, including obsessive-compulsive disorder (0.81 [0.44-1.18]; GRADE=high), pain in fibromyalgia (GRADE=low), disease of consciousness (GRADE=low), insight score (GRADE=moderate) and working memory (0.34 [0.01-0.67]; GRADE=high) in schizophrenia, migraine-related pain (-1.52 [-2.91 to -0.13]; GRADE=high), attention-deficit/hyperactivity disorder (reduction in overall symptom severity: 0.24 [0.04-0.45], GRADE=low; reduction in inattention: 0.56 [0.02-1.11], GRADE=low; reduction in impulsivity: 0.28 [0.04-0.51], GRADE=low), depression (GRADE=low), cerebellar ataxia (GRADE=low), and pain (GRADE=very low). Importantly, tDCS induced an increased number of reported cases of treatment-emergent mania or hypomania (0.88 [0.62-1.13]; GRADE=moderate). We found varied levels of evidence for the effects of tDCS with multiple neurological and neuropsychiatric conditions, from very low to high certainty of evidence. tDCS was effective for people with stroke, obsessive-compulsive disorder, fibromyalgia, disease of consciousness, schizophrenia, migraine, attention-deficit/hyperactivity disorder, depression, cerebellar ataxia, and pain. Therefore, these findings suggest the benefit of tDCS for several neurological and neuropsychiatric disorders; however, further studies are needed to understand the underlying mechanism and optimize its therapeutic potential.

Lower Serum Calcium Levels Associated with Disrupted Sleep and Rest-Activity Rhythm in Shift Workers.

Vitamin D deficiency is prevalent in many developed countries, and several studies suggest that vitamin D plays an essential role in brain function. A recent study showed that vitamin D deficiency was closely associated with daytime sleepiness and shorter sleep time. The relationshipbetween vitamin D levels and calcium levels is well established, and calcium level regulates slow-wave sleep generation. It is conceivable that the sleep disturbance in vitamin D deficiency may be due to an altered calcium level. Nonetheless, calcium levels, sleep disturbances, and activity rhythms have not been investigated directly. Therefore, we hypothesized that calcium and vitamin D levels might be important in regulating sleep and activity rhythm, and we analyzed the correlation with calcium levels by actigraphy analysis. Interestingly, a negative correlation was found between calcium level and sleep latency, total sleep time, use of sleep medicine, and daytime dysfunction among shift workers. In contrast, non-shift workers showed a negative correlation between the calcium level and the circadian phase. These findings suggest that low serum calcium levels may disrupt sleep-wake control and rest-activity rhythm, even if they are within the normal range.

Aberrant Gamma-Band Oscillations in Mice with Vitamin D Deficiency: Implications on Schizophrenia and its Cognitive Symptoms.

Vitamin D plays an essential role in cognitive functions as well as regulating calcium homeostasis and the immune system. Many epidemiological studies have also shown the close relationship between vitamin D deficiency (VDD) and the risk of schizophrenia. Cortical gamma-band oscillations (GBO) are associated with cognitive functions, such as attention and memory. Patients with schizophrenia show abnormal GBO with increased spontaneous GBO and decreased evoked GBO. However, the direct effect of VDD on GBO remains unknown. Parvalbumin interneurons, which predominantly contribute to the generation of GBO, are surrounded by perineuronal nets (PNN). We sought to investigate the associations among VDD, PNN, and GBO. Here, we injected a viral vector (AAV5-DIO-ChR2-eYFP) into the basal forebrain stereotaxically and implanted electrodes for electroencephalogram (EEG). At baseline, the evoked and spontaneous EEG power at the gamma frequency band was measured in 4-month-old male PV-Cre mice. After six and twenty weeks of vitamin D deficient food administration, the power of GBO was measured in the VDD condition. Next, we injected the chondroitinase ABC (ChABC) enzyme into the frontal cortex to eliminate PNN. We found that the VDD group showed decreased power of both optogenetically- and auditory-evoked GBO, whereas the spontaneous GBO increased. Enzymatic digestion of PNN showed similar changes in GBO. Taken together, we suggest that VDD could result in decreased PNN and, consequently, increase the spontaneous GBO and decrease the evoked GBO, reminiscent of the aberrant GBO in schizophrenia. These results show that VDD might increase the risk of schizophrenia and aggravate the cognitive symptoms of schizophrenia.