Non-invasive brain stimulation in research and therapy

Abstract

Since the introduction of transcranial magnetic stimulation (TMS) almost four decades ago, non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to study brain-behaviour relationships in healthy and impaired states with unprecedented precision. Various NIBS techniques, including TMS, transcranial direct current stimulation (tDCS), and emerging methods such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) are employed in both research and clinical settings. TMS has gained regulatory approval for treating conditions like major depressive disorder and migraine, while tDCS is showing efficacy in enhancing cognitive functions in various populations. This collection of articles examines key studies, including the modulation of cognitive-motor functions, optimization of light stimulation for Alzheimer’s therapy, and effects on risk-taking behaviour in violent offenders. Notably, the findings suggest that NIBS can effectively influence executive functions and decision-making processes. They highlight the integration of NIBS with neuroimaging techniques, the importance of personalized targeting, and the potential for combined therapeutic approaches. Future directions include addressing methodological challenges and leveraging artificial intelligence to refine treatment protocols. Collectively, these advancements position NIBS as a transformative tool in both neuroscience research and clinical practice, offering new avenues for understanding and treating complex neuropsychiatric conditions.

Since the introduction of transcranial magnetic stimulation (TMS) by Barker et al.¹ in 1985, non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to study brain-behaviour relationships in healthy and impaired states with unprecedented precision. Various types of NIBS techniques, each with its unique mechanism of action, are employed in both research and clinical settings. Transcranial magnetic stimulation (TMS) utilizes magnetic fields to induce electrical currents in specific brain regions, allowing researchers to modulate neural activity with increasing precision. Conversely, transcranial direct current stimulation (tDCS) delivers low electrical currents through scalp electrodes, influencing cortical excitability. Other techniques, such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS), offer alternative approaches to modulating brain activity through rhythmic or stochastic stimulation patterns. NIBS techniques represent a rapidly advancing field with profound ramifications for neuroscience research and therapy, alongside their application in psychiatric and neurological disorders².

NIBS holds significant promise as a therapeutic intervention tool since it affords us the unique opportunity to ‘modulate’ any reachable brain circuits linked with the ‘symptoms’ of neuropsychiatric disorders. Use of TMS has already obtained regulatory approval as a therapeutic tool for major depressive disorder, migraine with aura, obsessive–compulsive disorder and nicotine use disorder³. By selectively modulating cortical excitability and influencing network plasticity, NIBS offers a unique opportunity to elucidate the biological mechanisms underlying neuropsychiatric conditions such as schizophrenia, Alzheimer’s disease, and neurodevelopmental disorders⁴. Additionally, there is evidence of efficacy of TMS to enhance motor recovery following stroke⁵, improving seizure control in epilepsy⁶, alleviating motor symptoms in Parkinson’s disease⁷, treating cerebellar ataxias⁸, and managing chronic pain⁹ and tinnitus¹⁰. Among psychiatric disorders, TMS was found to significantly improve symptoms of generalized anxiety disorder¹¹ and use of tDCS resulted in significantly improved attention and working memory in patients with schizophrenia¹¹. Such evidence regarding the therapeutic efficacy of NIBS has also been reported in pediatric populations^12–14.

In addition to being a therapeutic intervention tool, the use of NIBS techniques over the last three decades is reshaping our understanding of the brain-behaviour relationship. For instance, the effects of TMS on language functions, perception, movements, and action production have achieved robust replications across many different laboratories¹⁵. The integration of NIBS with neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), allows for real-time monitoring of neural responses and mapping brain connectivity with improved targeting of stimulation sites. Recent developments in NIBS technology have expanded its potential applications and efficacy.

Furthermore, such innovative combination of TMS and EEG (TMS-EEG) offers an exciting potential of biomarker discovery in neuropsychiatric disorders⁴. Advances in stimulation protocols, such as personalized targeting based on neuroimaging data and optimization of stimulation parameters, have improved treatment outcomes. Moreover, the integration of NIBS with other therapeutic modalities, such as cognitive-behavioural therapy¹⁶ and pharmacotherapy¹⁷, holds promise for synergistic effects in treating psychiatric disorders.

Articles in this collection showcase the use of NIBS in research and therapy.

It is unclear how the primary motor cortex (M1) participates in cognitive-motor and sensory-motor functions. Rizvi et al.¹⁸ investigated the effects of tDCS over the M1 on cognitive-motor and sensory-motor functions. Sixty-four healthy participants underwent either real or sham tDCS while performing standardized robotic tasks. Results showed that real tDCS improved decision-making and inhibitory control during motor tasks and enhanced bimanual coordination but had no effect on visuomotor skills or proprioception. This suggests that augmenting M1 activity with tDCS can influence cognitive and sensory functions in specific task contexts.

Henney et al.¹⁹ examined alternative options for entraining 40 Hz brain activity, crucial in Alzheimer’s disease therapy, due to concerns over visible flickering and discomfort associated with stroboscopic flicker. Using heterochromatic flicker based on spectral combinations of blue, cyan, green, lime, amber, and red, the investigators aimed to optimize 40 Hz light stimulation for therapeutic purposes. Results indicated that the choice of colour combinations significantly impacts the steady-state visually evoked potential (SSVEP) response, with combinations involving blue and/or red consistently evoking higher SSVEP. Combining colours from extreme ends of the visual spectrum may offer the best balance between flickering sensation and SSVEP magnitude, encouraging further investigation into the optimal colour combinations for effective neurostimulation.

Kuhn et al.²⁰ conducted a randomized controlled trial to investigate the modulation of risk-taking behavior in a group of violent offenders. Using a double-blind, sham-controlled, cross-over design, the study found that tDCS targeting the dlPFC significantly reduced risky decision-making, as measured by the Balloon Analogue Risk Task, compared to sham stimulation. These findings suggest that dlPFC stimulation can reduce impulsive behavior and improve self-regulation, which may have important implications for managing aggression in criminal populations²¹. The results provide promising insights into the use of NIBS for mitigating risk-related behaviors, potentially offering a therapeutic approach for treating violent offenders.

Hemmerich et al.²² investigated the effect and interaction of cognitive load and high-definition transcranial direct current stimulation (HD-tDCS) on the decrement of executive vigilance. HD—tDCS has a higher spatial precision than conventional tDCS and offers a more precise targeting of the brain region of interest. They manipulated task load (single vs. dual) and applied HD-tDCS over the right posterior parietal cortex (sham vs. active), following the preregistration of their protocol. They observed neither differences in the decrement of executive vigilance between single and dual task, nor any influence of HD-tDCS. However, when compared with previous findings using a triple task, these results suggest that the effect of HD-tDCS on the executive vigilance is present (?) only under high cognitive demand. The authors suggested that task demand is an important factor in considering the efficacy of HD-tDCS intervention on vigilance performance.

Hooyman et al.²³ investigated the possibility of any measurable placebo effect of tDCS on cognitive training and the potential sources of this effect. Three groups of no exposure to tDCS, sham tDCS, and active tDCS performed 20 min of an adapted Corsi Block Tapping Task, which measures visuospatial working memory. The stimulation during the training was applied on the right parietal-left supraorbital montage. They observed improved performance in the tDCS groups (active and sham combined) as compared to no exposure group, suggesting a placebo effect of tDCS. Participants’ tDCS expectations were significantly related to the placebo effect, as they assumed they were receiving active stimulation. This placebo effect shows that the benefits of tDCS on cognitive training can occur even in absence of active stimulation. The authors suggest disentangling this effect from the treatment expectations and potentially leverage them to maximize treatment benefit.

Application of NIBS has been extended to children as well. Nejati et al.²⁴ explored the effects of concurrent stimulation of the left dorsolateral prefrontal cortex and the right ventromedial prefrontal cortex using tRNS on executive functions in children with attention deficit-hyperactivity disorder (ADHD). Eighteen children with ADHD performed tasks measuring various executive functions while receiving both real and sham tRNS in two sessions, spaced a week apart. They observed improved inhibition, working memory, and decision-making under real stimulation, but no change in set-shifting. These findings suggest that simultaneous dlPFC and vmPFC stimulation enhances certain hot and cold executive functions in children with ADHD. Interestingly, the authors argue that simultaneous upregulating of these two prefrontal regions—challenging several tDCS studies—improves executive functions in children with ADHD.

Future directions

In the coming years, NIBS will increasingly focus on improving precision of individualized target selection, minimizing both intra- and inter-individual variability of NIBS responses, resolving concerns regarding the methodological challenges of ‘sham’ NIBS conditions, and clarifying risk/benefit in vulnerable population such as children and adults with neurodevelopmental disorders^25–28. Use of artificial intelligence and computational modelling will have a growing impact on refining treatment protocols to improve precision of selecting ‘personalized’ targets and ‘dosing’. Furthermore, research will continue to explore novel NIBS techniques, such as closed-loop brain stimulation²⁹ and focused ultrasound³⁰ to investigate their therapeutic potential in diverse neurological and psychiatric conditions.

Competing interests

The authors are members of the editorial board of Scientific Reports. The authors have no competing interests to declare.