Hakuei Fujiyama

Research suggests that changes in functional connectivity contribute to age-related declines in response inhibition. Through a double-blind crossover study, we investigated the effects of dual-site beta transcranial alternating current stimulation (tACS) over the right inferior frontal gyrus (rIFG) and pre-supplementary motor area (preSMA) on functional connectivity measured with electroencephalography and response inhibition (stop-signal task performance) in 15 older (aged 61-79 years) and 18 young (aged 18-34 years) adults. Two tACS conditions were administered in separate sessions: in-phase tACS, where electrical currents delivered to rIFG and preSMA had a 0° phase difference, and anti-phase tACS, where currents had a 180° phase difference. Resting-state beta band rIFG-preSMA connectivity significantly increased after in-phase tACS for older and young adults, and decreased after anti-phase tACS for older adults. This shows that tACS can modulate rIFG-preSMA connectivity in a phase-specific manner in the aging brain. However, response inhibition significantly improved after both in- and anti-phase tACS for young and older adults, indicating that inhibitory performance might not be directly regulated by resting-state rIFG-preSMA phase connectivity.

Posttraumatic stress disorder (PTSD) and chronic pain (CP) are highly co-occurring conditions, characterised by poor treatment outcomes and shared mechanisms that exacerbate symptom severity and functional impairment. This randomised, waitlist-controlled trial evaluated the efficacy of a six-week heart rate variability biofeedback (HRVBF) intervention in improving concurrent symptoms of PTSD and CP. Data of 73 Australian participants (mean age: 42.2; 14 male, 59 female), meeting clinical criteria for both conditions, were analysed following either six weeks of HRVBF or waitlist control. Symptom changes were assessed using validated psychometric measures. The HRVBF group demonstrated significant reductions in PTSD symptoms, with a 24.3 % decrease in PTSD Checklist total scores (d = −0.02) and improvement across all symptom clusters, compared to no significant change in the waitlist group. Similarly, trauma-related distress (Impact of Events Scale) decreased by 18.9 % (d = 0.03) post-intervention. Pain interference (Brief Pain Inventory – short form) improved significantly (24.9 % reduction; d = 0.19), whereas reductions in pain intensity and pain disability did not differ significantly between groups. These results highlight the potential of HRVBF as an effective intervention for co-occurring PTSD and CP.

Individuals who face difficulties with voluntary movement experience considerable challenges in performing everyday tasks, significantly compromising their sense of autonomy. Transcranial alternating current stimulation (tACS) holds promise in modulating sensorimotor beta oscillations, which underscore voluntary movement. However, the exact effect of beta tACS on oscillatory power is still largely elusive. This study aimed to examine the effect of different intensities of beta tACS (20 Hz) on both resting-state and event-related sensorimotor oscillations. Twenty-one healthy young adults (13 female; mean age 24.30 ± 4.84 years) received four separate 20 min sessions of tACS at different intensities (sham, 0.5 mA, 1.0 mA, or 1.5 mA, peak-to-peak), targeting the left primary motor cortex during rest. Electroencephalography (EEG) was recorded before and after stimulation, during both resting state and a self-paced right index finger button press task. Changes in sensorimotor beta power (13–30 Hz) were analyzed. For the resting-state, none of the real stimulation intensities induced significant changes in beta power relative to sham. For event-related activity, we observed intensity-dependent changes in bilateral broadband power (4–90 Hz): during movement preparation, 1.0 mA stimulation increased power; during movement termination, 0.5 mA stimulation decreased power while 1.0 mA and 1.5 mA stimulation induced comparable increases in power. While none of the stimulation intensities induced changes in broadband power during movement execution, 1.0 mA stimulation shifted participants’ peak beta frequency toward the tACS frequency. Interestingly, changes in power during movement preparation and execution following 1.0 mA stimulation were negatively associated with participants’ pre-tACS peak beta frequency. Together, these findings contribute to our understanding of the sensorimotor response to beta tACS, as well as the effect of stimulation intensity on tACS-induced neuromodulation, which has important implications for research and clinical settings.

Objective
Tremor is one of the most common motor symptoms of Parkinson’s disease (PD), with adverse effects on daily functioning and quality of life. This study investigated the effects of concurrent intermittent theta-burst stimulation and gamma frequency transcranial alternating current stimulation (iTBS-γ-tACS) on neuroplasticity in the motor cortex and resting tremor severity in individuals with tremor-dominant PD.

Methods
Eighteen individuals (mean age 66.8 ± 10.0 years, 6 females) with tremor-dominant PD attended two sessions, one involving iTBS-γ-tACSreal (real iTBS and real tACS), and the other involving iTBS-γ-tACSsham (real iTBS and sham tACS). Measures of neuroplasticity (corticospinal excitability and intracortical inhibition) and tremor severity were measured before and after iTBS-γ-tACS.

Results
Corticospinal excitability in the target muscle increased significantly after iTBS-γ-tACSreal, but not iTBS-γ-tACSsham. Intracortical inhibition and tremor severity were not significantly modulated by either stimulation condition.

Conclusions
iTBS-γ-tACSreal, but not iTBS-γ-tACSsham, elicited long-term potentiation-like neuroplastic changes in the target muscle.

Significance
This is the first study to show iTBS-γ-tACS can induce neuroplasticity in individuals with tremor-dominant PD. Despite no significant changes in tremor severity, future research should explore if targeting neuroplasticity in the cortical representation of the tremor-dominant muscle and/or multi-session administrations of iTBS-γ-tACS can reduce tremor.

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.

Research suggests that changes in functional connectivity contribute to age-related declines in response inhibition. Through a double-blind crossover study, we investigated the effects of dual-site beta transcranial alternating current stimulation (tACS) over the right inferior frontal gyrus (rIFG) and pre-supplementary motor area (preSMA) on functional connectivity measured with electroencephalography and response inhibition (stop-signal task performance) in 15 older (aged 61-79 years) and 18 young (aged 18-34 years) adults. Two tACS conditions were administered in separate sessions: in-phase tACS, where electrical currents delivered to rIFG and preSMA had a 0° phase difference, and anti-phase tACS, where currents had a 180° phase difference. Resting-state beta band rIFG-preSMA connectivity significantly increased after in-phase tACS for older and young adults and decreased after anti-phase tACS for older adults. Response inhibition significantly improved after both in- and anti-phase tACS for young and older adults. These findings suggest that tACS can potentially modulate rIFG-preSMA connectivity in a phase-specific manner in the aging brain, and that inhibitory performance might not be directly regulated by resting-state rIFG-preSMA phase connectivity. Due to the lack of sham control, placebo effects cannot be ruled out. However, the differing neurophysiological effects from in- and anti-phase tACS suggest that rIFG-preSMA resting-state phase connectivity is unlikely to underpin the changes in inhibitory performance. Future studies incorporating a sham control are required to verify these findings.

Abstract
Resting tremor—involuntary and rhythmic shaking that usually occurs in the limbs—is the most common presenting motor symptom in Parkinson’s disease (PD). Tremor is not associated with the severity of dopamine depletion in the basal ganglia, and dopaminergic medication, which is used primarily to target dopamine depletion in the basal ganglia, has limited efficacy in reducing tremor. This suggests that other brain regions might underpin tremor in PD. Intracortical inhibition within the primary motor cortex (M1) has been implicated in tremor: intracortical inhibition in M1 is lower in PD than controls, higher motor cortex GABA is associated with lower tremor severity in PD, and pharmacological increases in GABA activity reduce tremor severity in PD. A combined intermittent theta-burst stimulation (iTBS)—gamma transcranial alternating current stimulation (tACS) protocol has been shown to increase short-interval intracortical inhibition (SICI) in PD. Therefore, in the current study, we examined M1 excitability, SICI, and resting tremor before and after real and sham iTBS-tACS. In a within-subjects design, we tested 19 participants (13 male; mean age 66 years) with idiopathic, tremor-dominant PD OFF medication. M1 excitability increased after real but not sham iTBS-tACS. There was no change in SICI after either real or sham iTBS-tACS. Resting tremor in the extensor carpi radialis showed a trend to increase after sham but not real iTBS, indicating that real iTBS-tACS might have prevented resumption of tremor activity in PD participants OFF medication. These findings provide preliminary evidence that iTBS-tACS induced long-term potentiation-like plasticity in M1 in tremor-dominant PD, which could influence tremor severity. However, further research is needed to examine the time-course of iTBS-tACS-induced changes in M1 excitability and tremor severity. If iTBS-tACS can reduce tremor, it could offer an alternative, or supplementary, treatment to levodopa medication for people with tremor-dominant PD.

Research Category and Technology and Methods
Clinical Research: 10. Transcranial Magnetic Stimulation (TMS)

Cognitive behavioural therapy (CBT) is the first-line non-pharmacological intervention for the most prevalent and co-occurring mental health conditions (anxiety, major depressive, posttraumatic stress, and alcohol use disorders). However, CBT response rates are variable and access is limited by cost, availability, and up-take. Yoga demonstrates efficacy for these conditions and may be more accessible than CBT. However, to better refine personalised healthcare and ensure maximum generalisability to “real-world” presentations, we need methodologically robust randomised controlled trials (RCTs) that compare yoga to appropriate controls, monitor mental health co-occurrences, and examine biomarkers and mechanisms of action alongside outcomes. We present the study protocol for an ongoing, experimenter-masked, parallel-group, non-inferiority design RCT to evaluate the efficacy of 10-week yoga (novel intervention) versus 10-week transdiagnostic CBT (the Unified Protocol; evidence-based active control) for co-occurring anxiety, major depressive, posttraumatic stress, or alcohol use disorders among community-dwelling Australian adults (aged ≥18 years). The protocol is approved by Murdoch University Human Research Ethics Committee. The primary outcome measure is the Kessler Psychological Distress Scale (weeks 0, 11, 23, 35) and power analyses determined a minimum of 67 participants per group are required to assess non-inferiority. Secondary outcomes include a clinician-administered interview, self-reported symptoms, and functional outcomes. Sleep and emotion regulation self-report measures (including ecological momentary assessment) and physiological biomarkers (actigraphy, heart rate variability) will be tested as potential moderators and mediators of outcome. Experimenter-masked analyses will use both intent-to-treat and per-protocol approaches.

Findings will inform evidence-based formal recommendations and policy regarding the implementation of yoga into healthcare and may advance precision medicine.

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.

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.