Low-intensity transcranial focused ultrasound (tFUS) is rapidly emerging as a transformative non-invasive brain stimulation (NIBS) modality characterized by high spatial resolution and ability to target deep brain circuits. Unlike electromagnetic techniques such as transcranial magnetic stimulation and transcranial direct current stimulation, which are constrained by centimeter-scale resolution and a depth-focality tradeoff, tFUS leverages mechanical pressure waves to modulate both superficial cortical and deep subcortical structures with millimeter precision. This article discusses recent scientific observations and engineering breakthroughs in the advancement of tFUS for next-generation ultrasonic brain-computer interfaces (uBCIs) and human-machine interfaces. These advancements move beyond open-loop systems and demonstrate closed-loop architectures that incorporate real-time electrophysiological feedback to optimize cognitive variables such as attention, learning, trust, and cooperation in various applications. Other advances in the development of ultrasound sensors for sonomyography to decode muscle activation and functional ultrasound to monitor hemodynamic brain activity are discussed as potential elements in bidirectional uBCIs. Together, these advances position ultrasound as a foundational technology for the development of intelligent, adaptive, and bidirectional neural interfaces that will seamlessly integrate human cognition with next-generation automation and robotic systems.

Background: Both neuromodulation and physical therapy have been shown to mitigate motor and non-motor symptoms of Parkinson’s disease. To date, no studies have examined the integration of transcutaneous auricular vagus nerve stimulation (taVNS) with physical therapy approaches for improving Parkinsonian symptoms. The purpose of this study was to investigate the safety, tolerability, and feasibility of combining taVNS with physical therapy to enhance the therapeutic benefits of exercise as medicine in a clinical setting. Methods: Participants were randomly assigned to receive active or sham bilateral taVNS in combination with PT for 12 visits over 6 weeks. Safety, tolerability, and feasibility outcomes were primary. Secondly, exploratory analyses of changes in cardiovascular and motor function over time were also performed. Results: Overall, taVNS was safe and well-tolerated prior to PT. Cardiovascular analyses suggest that active taVNS may augment HR response to exercise compared to sham. For motor outcomes, both groups showed significant overall improvements; however, no significant between-group differences were found. Conclusions: The preliminary results obtained in this pilot trial confirm that taVNS combined with physical therapy for individuals with PD is safe and feasible. The exploratory cardiovascular and motor findings support the need for larger, adequately powered clinical trials investigating the integration of taVNS into PT and exercise methods for improving PD symptomology. Trial registration: ClinicalTrials.gov NCT05871151.

Decades of physiological and psychological research into human performance and wellness have established a critical role for vagus nerve signaling in peak physical and cognitive performance. We outline models and perspectives that have emerged through neuroscience and psychophysiology studies to elucidate how the vagus nerve governs human performance through its influence on central nervous system functions and autonomic nervous system activity. These functions include the monitoring and regulation of cardio-respiratory activity, emotional responses, inflammation and physical recovery, cognitive control, stress resilience, and team cohesion. We briefly review some useful interventions such as transcutaneous auricular vagus nerve stimulation, heart-rate variability biofeedback, and controlled breathing as accessible tools for enhancing vagal tone, improving executive functioning under pressure, and mitigating fatigue and burnout. We describe how these approaches and their biological underpinnings are rooted by psychological models like the Yerkes-Dodson law and Polyvagal theory to contextualize their effects on athletic performance. These perspectives suppor recent shifts in sports science toward integrating vagal-centered approaches as scalable, evidence-based strategies that can enhance human performance and wellness.

Development of new therapeutic approaches and strategies for common neuropsychiatric disorders, including Major Depressive Disorder, anxiety disorders, and Post-Traumatic Stress Disorder, represent a significant global health challenge. Recent research indicates that emotional dysregulation and persistent inflammation are closely linked and serve as key pathophysiological features of these conditions. Emotional dysregulation is mechanistically coupled to locus coeruleus and norepinephrine (LC-NE) or noradrenergic system activity. Stemming from chronic stress, persistently elevated activity of the LC-NE system leads to hypervigilance, anxious states, and depressed mood. Concurrently, these symptoms are marked by systemic inflammation as indicated by elevated pro-inflammatory cytokines, and central neuroinflammation indicated by microglial activation in brain regions and networks involved in mood regulation and emotional control. In turn, chronic inflammation increases sympathetic tone and LC-NE activity resulting in a vortex of psychoneuroimmunological dysfunction that worsens mental health. Transcutaneous auricular vagus nerve stimulation (taVNS) in a non-invasive neuromodulation method uniquely positioned to address both noradrenergic dysfunction and chronic inflammation in neuropsychiatric applications. Evidence spanning the past decade demonstrates taVNS works via two complementary mechanisms. An ascending pathway engages vagal afferents projecting to the LC-NE system in the brain stem, which has been shown to modulate cortical arousal, cognitive function, mood, and stress responses. Through descending circuits, taVNS also modulates the cholinergic anti-inflammatory pathway to suppress the production of pro-inflammatory cytokines like TNF-α and IL-6 mitigating poor health outcomes caused by inflammation. By enhancing both central brain function and peripheral immune responses, taVNS has shown significant potential for recalibrating perturbed affective-cognitive processing. The present article describes and discusses recent evidence suggesting that taVNS offers a promising network-based paradigm for restoring psychoneuroimmunological homeostasis in common neuropsychiatric conditions.

Substantial diagnostic and therapeutic advances have been made in medicine to address breast cancer. There remain unmet needs to translate solutions for addressing insomnia and mental health concerns in breast cancer patients. In this open-label, pilot clinical trial, we evaluated the safety and efficacy of nightly, bilateral, transcutaneous auricular vagus nerve stimulation (taVNS) on insomnia and mental health outcomes in breast cancer patients across a two-week treatment period. Our results demonstrate that noninvasive vagus nerve stimulation can significantly reduce insomnia severity, improve sleep quality, decrease sleep onset latency, and enhance sleep efficiency. Treatment with taVNS also significantly reduced the number of nightly awakenings, cancer-related fatigue, and depression scores while increasing heart rate variability. These observations demonstrate that auricular vagus nerve stimulation holds promise for improving sleep quality and mental health in patients diagnosed with breast cancer. Future investigations aimed at more thoroughly investigating the safety profile and clinical impacts of taVNS on the quality of life in patients with breast cancer are warranted. ClinicalTrials.gov Identifier: NCT06006299 23/08/2023.

Recent advances in manufacturing of flexible and conformable microelectronics have opened opportunities for health monitoring and disease treatment. Other material engineering advances, such as the development of conductive, skin-like hydrogels, liquid metals, electric textiles, and piezoelectric films provide safe and comfortable means of interfacing with the human body. Together, these advances have enabled the design and engineering of bioelectronic devices with integrated multimodal sensing and stimulation capabilities to be worn nearly anywhere on the body. Of particular interest here, the external ear (auricle) offers a unique opportunity to design scalable bioelectronic devices with a high degree of usability and familiarity given the broad use of headphones. This review article discusses recent design and engineering advances in the development of auricular bioelectronic devices capable of physiological and biochemical sensing, cognitive monitoring, targeted neuromodulation, and control for human-computer interactions. Stemming from this scalable foundation, there will be increased growth and competition in research and engineering to advance auricular bioelectronics. This activity will lead to increased adoption of these smart headphone-style devices by patients and consumers for tracking health, treating medical conditions, and enhancing human-computer interactions.

Human operators of remote and semi-autonomous systems must have a high level of executive function to safely and efficiently conduct operations. These operators face unique cognitive challenges when monitoring and controlling robotic machines, such as vehicles, drones, and construction equipment. The development of safe and experienced human operators of remote machines requires structured training and credentialing programs. This review critically evaluates the potential for incorporating neurotechnology into remote systems operator training and work to enhance human-machine interactions, performance, and safety. Recent evidence demonstrating that different noninvasive neuromodulation and neurofeedback methods can improve critical executive functions such as attention, learning, memory, and cognitive control is reviewed. We further describe how these approaches can be used to improve training outcomes, as well as teleoperator vigilance and decision-making. We also describe how neuromodulation can help remote operators during complex or high-risk tasks by mitigating impulsive decision-making and cognitive errors. While our review advocates for incorporating neurotechnology into remote operator training programs, continued research is required to evaluate the how these approaches will impact industrial safety and workforce readiness.

Parkinson’s Disease (PD) is a prevalent, progressive neurodegenerative disease with motor and non-motor symptoms. Vagus Nerve Stimulation (VNS) has emerged as a potential therapeutic approach for PD, but published research on this topic varies widely. This scoping review maps existing literature on VNS for PD, highlighting stimulation methods, operational parameters, safety profiles, neurophysiological mechanisms, and clinical outcomes in human and animal models. Online databases were used to identify 788 papers published between 2013 and 2023, from which 17 publications on invasive and non-invasive VNS in PD were selected. Studies showed high variability in VNS parameters and study design. Evidence in animal models and human subjects suggests potential neurophysiological effects on PD-related pathology and motor function improvements. However, significant gaps in the literature remain. Future research should include rigorous reporting of study design, standardization of stimulation parameters, and larger sample sizes to ultimately facilitate translation of VNS into clinical practice.

The rapid growth of the drone industry, particularly in the use of small unmanned aerial systems (sUAS) and unmanned aerial vehicles (UAVs), requires the development of advanced training protocols for remote pilots. Remote pilots must develop a combination of technical and cognitive skills to manage the complexities of modern drone operations. This paper explores the integration of neurotechnology, specifically auricular vagus nerve stimulation (aVNS), as a method to enhance remote pilot training and performance. The scientific literature shows aVNS can safely improve cognitive functions such as attention, learning, and memory. It has also been shown useful to manage stress responses. For safe and efficient sUAS/UAV operation, it is essential for pilots to maintain high levels of vigilance and decision-making under pressure. By modulating sympathetic stress and cortical arousal, aVNS can prime cognitive faculties before training, help maintain focus during training and improve stress recovery post-training. Furthermore, aVNS has demonstrated the potential to enhance multitasking and cognitive control. This may help remote pilots during complex sUAS operations by potentially reducing the risk of impulsive decision-making or cognitive errors. This paper advocates for the inclusion of aVNS in remote pilot training programs by proposing that it can provide significant benefits in improving cognitive readiness, skill and knowledge acquisition, as well as operational safety and efficiency. Future research should focus on optimizing aVNS protocols for drone pilots while assessing long-term benefits to industrial safety and workforce readiness in real-world scenarios.

Response inhibition in humans is important to avoid undesirable behavioral action consequences. Neuroimaging and lesion studies point to a locus of inhibitory control in the right inferior frontal gyrus (rIFG). Electrophysiology studies have implicated a downstream event-related potential from rIFG, the fronto-central P300, as a putative neural marker of the success and timing of inhibition over behavioral responses. However, it remains to be established whether rIFG effectively drives inhibition and which aspect of P300 activity uniquely indexes inhibitory control-ERP timing or amplitude. Here, we dissect the connection between rIFG and P300 for inhibition by using transcranial-focused ultrasound (tFUS) to target rIFG of human subjects while they performed a Stop-Signal task. By applying tFUS simultaneously with different task events, we found behavioral inhibition was improved, but only when applied to rIFG simultaneously with a 'stop' signal. Improved inhibition through tFUS to rIFG was indexed by faster stopping times that aligned with significantly shorter N200/P300 onset latencies. In contrast, P300 amplitude was modulated during tFUS across all groups without a paired change in behavior. Using tFUS, we provide evidence for a causal connection between anatomy, behavior, and electrophysiology underlying response inhibition.

Physical exercise is known to improve mental health. Athletes can experience unique physical and emotional stressors, which can deteriorate mental health and cognitive function. Training apathy can lead to cognitive dissonance and further degrade performance by promoting maladaptive, avoidance coping strategies. Introduction of psychosocial and training variables, such as those used in CrossFit (CF) and other community-based fitness programs with strong peer support have been shown to help reduce training apathy and negative affect. Here, we explored whether addition of psychophysiological variation, experienced as "hunger for air" during underwater breath-hold exercises, could provide unique mental health benefits for athletes. We studied the influence of CF and Deep End Fitness (DEF), a community-based underwater fitness program, on several outcome measures of mental health and emotional well-being in volunteer athletes. We observed a significant reduction in stress scores of both the control CF training group and the experimental DEF group. We found that DEF produced a significant improvement in positive affect while CF training did not. Further supportive of our hypothesis that the psychological and biological stressors experienced in underwater, breath-hold training cause positive adaptive changes and benefits, DEF training uniquely increased problem-based coping. While our observations demonstrate both CF and DEF training can improve mental health in athletes, DEF produced additional, unique benefits to positive coping and attitudes of athletes. Future studies should further evaluate the broader benefits of community-based, underwater training programs on psychological and physiological health in athletes and the public.

Rehabilitation approaches for individuals with neurologic conditions have increasingly shifted toward promoting neuroplasticity for enhanced recovery and restoration of function. This review focuses on exercise strategies and non-invasive neuromodulation techniques that target neuroplasticity, including transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and peripheral nerve stimulation (PNS). We have chosen to focus on non-invasive neuromodulation techniques due to their greater potential for integration into routine clinical practice. We explore and discuss the application of these interventional strategies in four neurological conditions that are frequently encountered in rehabilitation settings: Parkinson's Disease (PD), Traumatic Brain Injury (TBI), stroke, and Spinal Cord Injury (SCI). Additionally, we discuss the potential benefits of combining non-invasive neuromodulation with rehabilitation, which has shown promise in accelerating recovery. Our review identifies studies that demonstrate enhanced recovery through combined exercise and non-invasive neuromodulation in the selected patient populations. We primarily focus on the motor aspects of rehabilitation, but also briefly address non-motor impacts of these conditions. Additionally, we identify the gaps in current literature and barriers to implementation of combined approaches into clinical practice. We highlight areas needing further research and suggest avenues for future investigation, aiming to enhance the personalization of the unique neuroplastic responses associated with each condition. This review serves as a resource for rehabilitation professionals and researchers seeking a comprehensive understanding of neuroplastic exercise interventions and non-invasive neuromodulation techniques tailored for specific diseases and diagnoses.

Focused ultrasound is a novel brain stimulation modality that combines the noninvasiveness of repetitive transcranial magnetic stimulation and the precision of deep brain stimulation. In this review, the authors examine low-intensity focused ultrasound for brain mapping and neuromodulation. They also discuss high-intensity focused ultrasound, which is used for incisionless surgeries, such as capsulotomies for obsessive-compulsive disorder. Future potential applications of focused ultrasound are also presented.

BACKGROUND:Autism spectrum disorder (ASD) is associated with anxiety and sleep problems. We investigated transdermal electrical neuromodulation (TEN) of the cervical nerves in the neck as a safe, effective, comfortable and non-pharmacological therapy for decreasing anxiety and enhancing sleep quality in ASD. METHODS:In this blinded, sham-controlled study, seven adolescents and young adults with high-functioning ASD underwent five consecutive treatment days, one day of the sham followed by four days of subthreshold TEN for 20 min. Anxiety-provoking cognitive tasks were performed after the sham/TEN. Measures of autonomic nervous system activity, including saliva α-amylase and cortisol, electrodermal activity, and heart rate variability, were collected from six participants. RESULTS:Self-rated and caretaker-rated measures of anxiety were significantly improved with TEN treatment as compared to the sham, with effect sizes ranging from medium to large depending on the rating scale. Sleep scores from caretaker questionnaires also improved, but not significantly. Performance on two of the three anxiety-provoking cognitive tasks and heart rate variability significantly improved with TEN stimulation as compared to the sham. Four of the seven (57%) participants were responders, defined as a ≥ 30% improvement in self-reported anxiety. Salivary α-amylase decreased with more TEN sessions and decreased from the beginning to the end of the session on TEN days for responders. TEN was well-tolerated without significant adverse events. CONCLUSIONS:This study provides preliminary evidence that TEN is well-tolerated in individuals with ASD and can improve anxiety.

ABSTRACTThe dorsal anterior cingulate cortex (dACC) operates as an integrator of bottom-up and top-down signals and is implicated in both cognitive control and emotional processing. The dACC is believed to be causally involved in switching between attention networks, and previous work has linked it to cognitive performance, concentration, relaxation, and emotional distraction. The present study was designed to evaluate the feasibility of influencing default mode network (DMN) activity and emotional attention by targeting and modulating the dACC with transcranial focused ultrasound (tFUS). Subjects were divided into two groups, one receiving MR-neuronavigated tFUS to the dACC and the other an identical, but inactive tFUS sham. Subjects performed a modified version of the Erikson flanker paradigm using fear and neutral faces as emotional background distractors. Our observations demonstrate that tFUS can be targeted to the human dACC to produce effects consistent with those expected from relaxed contention, including significantly reduced reaction time slowing due to emotional distractors, and an increase in parasympathetic markers of the HRV. These results suggest that tFUS altered emotional processing and enhanced sustained attention, perhaps by facilitating reduced attentional engagement with emotional distractors and reduced need for attention switching evidenced by significant effects on event related potentials (ERPs), reduced alpha suppression, and modulation of delta and theta EEG activity. We conclude that the dACC represents a viable neuroanatomical target for tFUS in order to modulate DMN activity, including emotional attention, conflict resolution, and cognitive control. These effects of dACC-targeted tFUS may prove useful for treating certain mental health disorders known to involve perturbed DMN activity, such as depression and anxiety.

•We examined transcranial ultrasound (TUS) as a potential depression intervention.•Depression scores did not change differentially for TUS/Placebo, but trait worry decreased in the Active TUS Condition and increased in the Placebo Condition.•Those in TUS Active Condition had an increase in global affect over the course of the study.

Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood. Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.

The dorsal anterior cingulate cortex (dACC) operates as an integrator of bottom-up and top-down signals and is implicated in both cognitive control and emotional processing. The dACC is believed to be causally involved in switching between attention networks, and previous work has linked it to cognitive performance, concentration, relaxation, and emotional distraction. The present study was designed to evaluate the feasibility of influencing default mode network (DMN) activity and emotional attention by targeting and modulating the dACC with transcranial focused ultrasound (tFUS). Subjects were divided into two groups, one receiving MR-neuronavigated tFUS to the dACC and the other an identical, but inactive tFUS sham. Subjects performed a modified version of the Erikson flanker paradigm using fear and neutral faces as emotional background distractors. Our observations demonstrate that tFUS can be targeted to the human dACC to produce effects consistent with those expected from relaxed contention, including significantly reduced reaction time slowing due to emotional distractors, and an increase in parasympathetic markers of the HRV. These results suggest that tFUS altered emotional processing and enhanced sustained attention, perhaps by facilitating reduced attentional engagement with emotional distractors and reduced need for attention switching evidenced by significant effects on event related potentials (ERPs), reduced alpha suppression, and modulation of delta and theta EEG activity. We conclude that the dACC represents a viable neuroanatomical target for tFUS in order to modulate DMN activity, including emotional attention, conflict resolution, and cognitive control. These effects of dACC-targeted tFUS may prove useful for treating certain mental health disorders known to involve perturbed DMN activity, such as depression and anxiety.