Hakuei Fujiyama

Objective
Neurofibromatosis type 1 (NF1) is a genetic disorder associated with cognitive and behavioral deficits. In NF1, decreased neurofibromin levels attenuate hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) activity, thereby increasing inhibitory interneuron activity and decreasing synaptic plasticity. Lamotrigine, an HCN1-agonist, rescued this electrophysiological phenotype in an NF1 mouse model. We investigated whether lamotrigine can alter cortical inhibition and plasticity in adolescents with NF1 using transcranial magnetic stimulation (TMS).

Methods
We performed an explorative analysis of secondary outcomes in the NF1-EXCEL trial (Clinicaltrials.gov identifier NCT02256124). Thirty-one adolescents with NF1 were randomized to either receive lamotrigine or a placebo. Using TMS, cortical inhibition was assessed with short-interval intracortical inhibition (SICI) and cortical plasticity with paired associative stimulation (PAS) at baseline and after 10 weeks of intervention.

Results
Lamotrigine did not affect baseline cortical excitability. Additionally, no significant effects on either SICI or PAS responses were found after lamotrigine treatment in adolescents with NF1. Finally, lamotrigine did not affect pre-PAS single-pulse cortical excitability measures.

Conclusion
10-week lamotrigine treatment does not alter cortical inhibition and plasticity in adolescents with NF1.

Significance
While limited by a small sample size, our study indicates that lamotrigine cannot consistently modulate SICI or PAS in adolescents with NF1, suggesting limited potential for treating the underlying pathophysiological mechanisms.

Mounting evidence suggests that transcranial alternating current stimulation can enhance response inhibition, a cognitive process crucial for sustained effort and decision-making. However, most studies have focused on within-session effects, with limited investigation into the effects of repeated applications, which are crucial for clinical applications. We examined the effects of repeated bifocal transcranial alternating current stimulation targeting the right inferior frontal gyrus and pre-supplementary motor area on response inhibition, functional connectivity, and simulated driving performance. Thirty young adults (18-35 yr) received either a sham or transcranial alternating current stimulation (20 Hz, 20 min) across 5 sessions over 2 wk. Resting-state electroencephalography assessed functional connectivity between the pre-supplementary motor area and right inferior frontal gyrus at baseline, the final transcranial alternating current stimulation session, and the 7-d follow-up. Response inhibition was measured using a stop-signal task, and driving performance was assessed before and after the intervention. The results showed significant improvements in functional connectivity in the transcranial alternating current stimulation group between sessions, though response inhibition and driving braking performance remained unchanged. However, while not the targeted behavior, general driving performance potentially improved following bifocal transcranial alternating current stimulation, with participants maintaining stable driving behavior alongside increased spare attentional capacity. These findings suggest that repeated bifocal transcranial alternating current stimulation may enhance cortical connectivity and related cognitive-motor processes, supporting its potential for clinical applications.

Concurrent application of transcranial alternating current stimulation over distant cortical regions has been shown to modulate functional connectivity between stimulated regions; however, the precise mechanisms remain unclear. Here, we investigated how bifocal transcranial alternating current stimulation applied over the bilateral primary sensorimotor cortices modulates connectivity between the left and right primary motor cortices (M1). Using a cross-over sham-controlled triple-blind design, 37 (27 female, age: 18 to 37 yrs) healthy participants received transcranial alternating current stimulation (1.0 mA, 20 Hz, 20 min) over the bilateral sensorimotor cortices. Before and after transcranial alternating current stimulation, functional connectivity between the left and right M1s was assessed using imaginary coherence measured via resting-state electroencephalography and interhemispheric inhibition via dual-site transcranial magnetic stimulation protocol. Additionally, manual dexterity was assessed using the Purdue pegboard task. While imaginary coherence remained unchanged after stimulation, beta (20 Hz) power decreased during the transcranial alternating current stimulation session. Bifocal transcranial alternating current stimulation but not sham strengthened interhemispheric inhibition between the left and right M1s and improved bimanual assembly performance. These results suggest that improvement in bimanual performance may be explained by modulation in interhemispheric inhibition, rather than by coupling in the oscillatory activity. As functional connectivity underlies many clinical symptoms in neurological and psychiatric disorders, these findings are invaluable in developing noninvasive therapeutic interventions that target neural networks to alleviate symptoms.

Transcranial electrical stimulation (tES) has garnered significant attention as a non-invasive neuromodulation technique with promising therapeutic potential for various neurological and neuropsychiatric conditions. However, considerable variability in response to tES both between and within-individuals is a prevailing issue. This review explored recent advancements in optimising tES through individualised protocols that consider individual head anatomy, neural oscillatory activities and dynamic changes in the neurophysiology of the stimulated brain. Real-time monitoring and closed-loop systems allow adaptive adjustments of stimulation parameters in response to ongoing brain activity, which holds promise for enhancing tES effectiveness and overcoming the challenge of inter-session response variability. Overall, the reviewed literature highlights the emerging trend towards individualised tES protocols as a means to unlock the full potential of tES in research and clinical use. While promising, further research is warranted to establish standardised methodologies and validate the efficacy of individually tailored tES protocols to realise its full potential.

The persistence of posttraumatic stress symptoms (PTSS) can be debilitating. However, many people experiencing such symptoms may not qualify for or may not seek treatment. Potentially contributing to ongoing residual symptoms of PTSS is emotion dysregulation. Meanwhile, the research area of mindfulness and compassion has grown to imply emotion regulation as one of its underlying mechanisms; yet, its influence on emotion regulation in PTSS cohort is unknown. Here, we explored the potential effectiveness of an 8-week Compassion-oriented and Mindfulness-based Exposure Therapy (CoMET) for individuals with PTSS using a waitlist control design. A total of 28 individuals (27 females, age range = 18–39 years) participated in the study (17 CoMET; 11 waitlist control). Following CoMET, participants reported significant decreases in PTSS severity (from clinical to non-clinical levels), emotion dysregulation and experiential avoidance, as well as significant increases in mindfulness, self-compassion and quality of life. Electroencephalogram-based brain network connectivity analysis revealed an increase in alpha-band connectivity following CoMET in a network that includes the amygdala, suggesting that CoMET successfully induced changes in functional connectivity between brain regions that play a crucial role in emotion regulation. In sum, the current study demonstrated promising intervention outcomes of CoMET in effectively alleviating the symptoms of PTSS via enhanced emotion regulation.

The efficacy of transcranial alternating current stimulation (tACS) is thought to be brain state-dependent, such that tACS during task performance would be hypothesised to offer greater potential for improving performance compared to tACS at rest. However, to date, no empirical study has tested this postulation. The current study compared the effects of dual-site beta tACS applied during a stop signal task (online) to the effects of the same tACS protocol applied prior to the task (offline) and a sham control stimulation in 53 young, healthy adults (32 female; 18–35 yrs). The right inferior frontal gyrus (rIFG) and centre (midline) of the pre-supplementary motor area (preSMA), which are thought to play critical roles in action cancellation, were simultaneously stimulated, sending phase-synchronised stimulation for 15 min with the aim of increasing functional connectivity. The offline group showed significant within-group improvement in response inhibition without showing overt task-related changes in functional connectivity measured with EEG connectivity analysis, suggesting offline tACS is efficacious in inducing behavioural changes potentially via a post-stimulation early plasticity mechanism. In contrast, neither the online nor sham group showed significant improvements in response inhibition. However, EEG connectivity analysis revealed significantly increased task-related functional connectivity following online stimulation and a medium effect size observed in correlation analyses suggested that an increase in functional connectivity in the beta band at rest was potentially associated with an improvement in response inhibition. Overall, the results indicate that both online and offline dual-site beta tACS can be beneficial in improving inhibitory control via distinct underlying mechanisms.

Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.

Changes in both brain structure and neurophysiological function regulating homotopic as well as heterotopic interhemispheric interactions (IHIs) are assumed to be responsible for the bimanual performance deficits in older adults. However, how the structural and functional networks regulating bimanual performance decline in older adults, as well as the interplay between brain structure and function remain largely unclear. Using a dual-site transcranial magnetic stimulation paradigm, we examined the age-related changes in the interhemispheric effects from the dorsolateral prefrontal cortex and dorsal premotor cortex onto the contralateral primary motor cortex (M1) during the preparation of a complex bimanual coordination task in human. Structural properties of these interactions were assessed with diffusion-based fiber tractography. Compared with young adults, older adults showed performance declines in the more difficult bimanual conditions, less optimal brain white matter (WM) microstructure, and a decreased ability to regulate the interaction between dorsolateral prefrontal cortex and M1. Importantly, we found that WM microstructure, neurophysiological function, and bimanual performance were interrelated in older adults, whereas only the task-related changes in IHI predicted bimanual performance in young adults. These results reflect unique interactions between structure and function in the aging brain, such that declines in WM microstructural organization likely lead to dysfunctional regulation of IHI, ultimately accounting for bimanual performance deficits.