Responsive deep brain stimulation guided by ventral striatal electrophysiology of obsession durably ameliorates compulsion.

Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD.

Dynamic neural representations of memory and space during human ambulatory navigation.

Our ability to recall memories of personal experiences is an essential part of daily life. These episodic memories often involve movement through space and thus require continuous encoding of one's position relative to the surrounding environment. The medial temporal lobe (MTL) is thought to be critically involved, based on studies in freely moving rodents and stationary humans. However, it remains unclear if and how the MTL represents both space and memory especially during physical navigation, given challenges associated with deep brain recordings in humans during movement. We recorded intracranial electroencephalographic (iEEG) activity while participants completed an ambulatory spatial memory task within an immersive virtual reality environment. MTL theta activity was modulated by successful memory retrieval or spatial positions within the environment, depending on dynamically changing behavioral goals. Altogether, these results demonstrate how human MTL oscillations can represent both memory and space in a temporally flexible manner during freely moving navigation.

A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5-9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.

Transcranial focused ultrasound selectively increases perfusion and modulates functional connectivity of deep brain regions in humans.

Background: Low intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively. Objective/Hypothesis: We sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region. Methods: In this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC). Results: tFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity. Conclusion: We demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

Mobile cognition: imaging the human brain in the 'real world'.

Cognitive neuroscience studies in humans have enabled decades of impactful discoveries but have primarily been limited to recording the brain activity of immobile participants in a laboratory setting. In recent years, advances in neuroimaging technologies have enabled recordings of human brain activity to be obtained during freely moving behaviours in the real world. Here, we propose that these mobile neuroimaging methods can provide unique insights into the neural mechanisms of human cognition and contribute to the development of novel treatments for neurological and psychiatric disorders. We further discuss the challenges associated with studying naturalistic human behaviours in complex real-world settings as well as strategies for overcoming them. We conclude that mobile neuroimaging methods have the potential to bring about a new era of cognitive neuroscience in which neural mechanisms can be studied with increased ecological validity and with the ability to address questions about natural behaviour and cognitive processes in humans engaged in dynamic real-world experiences.

A wearable platform for closed-loop stimulation and recording of single-neuron and local field potential activity in freely moving humans.

Advances in technologies that can record and stimulate deep brain activity in humans have led to impactful discoveries within the field of neuroscience and contributed to the development of novel therapies for neurological and psychiatric disorders. Further progress, however, has been hindered by device limitations in that recording of single-neuron activity during freely moving behaviors in humans has not been possible. Additionally, implantable neurostimulation devices, currently approved for human use, have limited stimulation programmability and restricted full-duplex bidirectional capability. In this study, we developed a wearable bidirectional closed-loop neuromodulation system (Neuro-stack) and used it to record single-neuron and local field potential activity during stationary and ambulatory behavior in humans. Together with a highly flexible and customizable stimulation capability, the Neuro-stack provides an opportunity to investigate the neurophysiological basis of disease, develop improved responsive neuromodulation therapies, explore brain function during naturalistic behaviors in humans and, consequently, bridge decades of neuroscientific findings across species.

Ethical commitments, principles, and practices guiding intracranial neuroscientific research in humans.

Leveraging firsthand experience, BRAIN-funded investigators conducting intracranial human neuroscience research propose two fundamental ethical commitments: (1) maintaining the integrity of clinical care and (2) ensuring voluntariness. Principles, practices, and uncertainties related to these commitments are offered for future investigation.

Corrigendum: Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

[This corrects the article DOI: 10.3389/fnhum.2021.644593.].

Promises and challenges of human computational ethology.

The movements an organism makes provide insights into its internal states and motives. This principle is the foundation of the new field of computational ethology, which links rich automatic measurements of natural behaviors to motivational states and neural activity. Computational ethology has proven transformative for animal behavioral neuroscience. This success raises the question of whether rich automatic measurements of behavior can similarly drive progress in human neuroscience and psychology. New technologies for capturing and analyzing complex behaviors in real and virtual environments enable us to probe the human brain during naturalistic dynamic interactions with the environment that so far were beyond experimental investigation. Inspired by nonhuman computational ethology, we explore how these new tools can be used to test important questions in human neuroscience. We argue that application of this methodology will help human neuroscience and psychology extend limited behavioral measurements such as reaction time and accuracy, permit novel insights into how the human brain produces behavior, and ultimately reduce the growing measurement gap between human and animal neuroscience.

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.

Boundary-anchored neural mechanisms of location-encoding for self and others.

Everyday tasks in social settings require humans to encode neural representations of not only their own spatial location, but also the location of other individuals within an environment. At present, the vast majority of what is known about neural representations of space for self and others stems from research in rodents and other non-human animals1-3. However, it is largely unknown how the human brain represents the location of others, and how aspects of human cognition may affect these location-encoding mechanisms. To address these questions, we examined individuals with chronically implanted electrodes while they carried out real-world spatial navigation and observation tasks. We report boundary-anchored neural representations in the medial temporal lobe that are modulated by one's own as well as another individual's spatial location. These representations depend on one's momentary cognitive state, and are strengthened when encoding of location is of higher behavioural relevance. Together, these results provide evidence for a common encoding mechanism in the human brain that represents the location of oneself and others in shared environments, and shed new light on the neural mechanisms that underlie spatial navigation and awareness of others in real-world scenarios.

Stimulation of the right entorhinal white matter enhances visual memory encoding in humans.

BACKGROUND: While deep brain stimulation has been successful in treating movement disorders, such as in Parkinson's disease, its potential application in alleviating memory disorders is inconclusive. OBJECTIVE/HYPOTHESIS: We investigated the role of the location of the stimulating electrode on memory improvement and hypothesized that entorhinal white versus gray matter stimulation would have differential effects on memory. METHODS: Intracranial electrical stimulation was applied to the entorhinal area of twenty-two participants with already implanted electrodes as they completed visual memory tasks. RESULTS: We found that stimulation of right entorhinal white matter during learning had a beneficial effect on subsequent memory, while stimulation of adjacent gray matter or left-sided stimulation was ineffective. This finding was consistent across three different visually guided memory tasks. CONCLUSIONS: Our results highlight the importance of precise stimulation site on modulation of human hippocampal-dependent memory and suggest that stimulation of afferent input into the right hippocampus may be an especially promising target for enhancement of visual memory.

Wireless Programmable Recording and Stimulation of Deep Brain Activity in Freely Moving Humans.

Uncovering the neural mechanisms underlying human natural ambulatory behavior is a major challenge for neuroscience. Current commercially available implantable devices that allow for recording and stimulation of deep brain activity in humans can provide invaluable intrinsic brain signals but are not inherently designed for research and thus lack flexible control and integration with wearable sensors. We developed a mobile deep brain recording and stimulation (Mo-DBRS) platform that enables wireless and programmable intracranial electroencephalographic recording and electrical stimulation integrated and synchronized with virtual reality/augmented reality (VR/AR) and wearables capable of external measurements (e.g., motion capture, heart rate, skin conductance, respiration, eye tracking, and scalp EEG). When used in freely moving humans with implanted neural devices, this platform is adaptable to ecologically valid environments conducive to elucidating the neural mechanisms underlying naturalistic behaviors and to the development of viable therapies for neurologic and psychiatric disorders.

Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology.

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.

A Novel Mobile Tool (Somatomap) to Assess Body Image Perception Pilot Tested With Fashion Models and Nonmodels: Cross-Sectional Study.

BACKGROUND: Distorted perception of one's body and appearance, in general, is a core feature of several psychiatric disorders including anorexia nervosa and body dysmorphic disorder and is operative to varying degrees in nonclinical populations. Yet, body image perception is challenging to assess, given its subjective nature and variety of manifestations. The currently available methods have several limitations including restricted ability to assess perceptions of specific body areas. To address these limitations, we created Somatomap, a mobile tool that enables individuals to visually represent their perception of body-part sizes and shapes as well as areas of body concerns and record the emotional valence of concerns. OBJECTIVE: This study aimed to develop and pilot test the feasibility of a novel mobile tool for assessing 2D and 3D body image perception. METHODS: We developed a mobile 2D tool consisting of a manikin figure on which participants outline areas of body concern and indicate the nature, intensity, and emotional valence of the concern. We also developed a mobile 3D tool consisting of an avatar on which participants select individual body parts and use sliders to manipulate their size and shape. The tool was pilot tested on 103 women: 65 professional fashion models, a group disproportionately exposed to their own visual appearance, and 38 nonmodels from the general population. Acceptability was assessed via a usability rating scale. To identify areas of body concern in 2D, topographical body maps were created by combining assessments across individuals. Statistical body maps of group differences in body concern were subsequently calculated using the formula for proportional z-score. To identify areas of body concern in 3D, participants' subjective estimates from the 3D avatar were compared to corresponding measurements of their actual body parts. Discrepancy scores were calculated based on the difference between the perceived and actual body parts and evaluated using multivariate analysis of covariance. RESULTS: Statistical body maps revealed different areas of body concern between models (more frequently about thighs and buttocks) and nonmodels (more frequently about abdomen/waist). Models were more accurate at estimating their overall body size, whereas nonmodels tended to underestimate the size of individual body parts, showing greater discrepancy scores for bust, biceps, waist, hips, and calves but not shoulders and thighs. Models and nonmodels reported high ease-of-use scores (8.4/10 and 8.5/10, respectively), and the resulting 3D avatar closely resembled their actual body (72.7% and 75.2%, respectively). CONCLUSIONS: These pilot results suggest that Somatomap is feasible to use and offers new opportunities for assessment of body image perception in mobile settings. Although further testing is needed to determine the applicability of this approach to other populations, Somatomap provides unique insight into how humans perceive and represent the visual characteristics of their body.

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Quantitative assessments reveal improved neuroscience engagement and learning through outreach.

Lack of resources and exposure to neuroscience in K-12 education has resulted in a limited number of K-12 students pursuing higher education in the field. Meanwhile, the rapid expansion of the field of neuroscience has encouraged many higher educational institutes to offer neuroscience majors. This has opened up the opportunity to engage faculty, as well as graduate and undergraduate students in bringing the most needed knowledge and awareness about neuroscience into K-12 classrooms. However, undergraduate neuroscience curricula have limited formal opportunities to engage in outreach, and few existing programs have assessments to determine their effectiveness. To address these needs, we developed quantitative assessment tools that complement an existing neuroscience outreach program-Project Brainstorm-at the University of California, Los Angeles (UCLA). 29 UCLA undergraduates enrolled in the 2016 and 2017 programs participated in this study, along with 298 K-12 students from local schools across the Los Angeles area. In undergraduate students, we assessed (a) improvement in students' teaching/communication abilities across the course of the outreach program, and (b) confidence in explaining neuroscience topics and interest in pursuing teaching career. In K-12 students, we evaluated (a) knowledge gain in neuroscience topics and (b) interest in pursuing higher education. Overall, Project Brainstorm showed significant improvement in all the above-mentioned categories. The assessment tools and data presented here provide a data-driven approach for optimizing neuroscience outreach programs and can easily be adapted to other outreach programs within neuroscience and in other STEM fields.

Reporting Guidelines and Issues to Consider for Using Intracranial Brain Stimulation in Studies of Human Declarative Memory.

Participants with stimulating and recording electrodes implanted within the brain for clinical evaluation and treatment provide a rare opportunity to unravel the neuronal correlates of human memory, as well as offer potential for modulation of behavior. Recent intracranial stimulation studies of memory have been inconsistent in methodologies employed and reported conclusions, which renders generalizations and construction of a framework impossible. In an effort to unify future study efforts and enable larger meta-analyses we propose in this mini-review a set of guidelines to consider when pursuing intracranial stimulation studies of human declarative memory and summarize details reported by previous relevant studies. We present technical and safety issues to consider when undertaking such studies and a checklist for researchers and clinicians to use for guidance when reporting results, including targeting, placement, and localization of electrodes, behavioral task design, stimulation and electrophysiological recording methods, details of participants, and statistical analyses. We hope that, as research in invasive stimulation of human declarative memory further progresses, these reporting guidelines will aid in setting standards for multicenter studies, in comparison of findings across studies, and in study replications.

Enhancing the Ecological Validity of fMRI Memory Research Using Virtual Reality.

Functional magnetic resonance imaging (fMRI) is a powerful research tool to understand the neural underpinnings of human memory. However, as memory is known to be context-dependent, differences in contexts between naturalistic settings and the MRI scanner environment may potentially confound neuroimaging findings. Virtual reality (VR) provides a unique opportunity to mitigate this issue by allowing memories to be formed and/or retrieved within immersive, navigable, visuospatial contexts. This can enhance the ecological validity of task paradigms, while still ensuring that researchers maintain experimental control over critical aspects of the learning and testing experience. This mini-review surveys the growing body of fMRI studies that have incorporated VR to address critical questions about human memory. These studies have adopted a variety of approaches, including presenting research participants with VR experiences in the scanner, asking participants to retrieve information that they had previously acquired in a VR environment, or identifying neural correlates of behavioral metrics obtained through VR-based tasks performed outside the scanner. Although most such studies to date have focused on spatial or navigational memory, we also discuss the promise of VR in aiding other areas of memory research and facilitating research into clinical disorders.