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.

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.

Finding healing where it hurts.

In 2021, Cell Press together with Cell Signaling Technology held the second installment of the Rising Black Scientist Award (RBSA) Essay Contest meant to support talented and motivated young Black scientists on their journey. Charleese Williams and Elle Lett won the 2021 RBSA undergraduate and post-graduate scholars, respectively (https://www.cell.com/cell/issue?pii=S0092-8674(21)X0003-7). In recognition of the excellence of this year's submissions, we at Med are honored to also highlight the unique story of Jay Gill, which strongly resonates with the journal's mission to improve global health.

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.].

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.

Temporally restricted dopaminergic control of reward-conditioned movements.

Midbrain dopamine (DA) neurons encode both reward- and movement-related events and are implicated in disorders of reward processing as well as movement. Consequently, disentangling the contribution of DA neurons in reinforcing versus generating movements is challenging and has led to lasting controversy. In this study, we dissociated these functions by parametrically varying the timing of optogenetic manipulations in a Pavlovian conditioning task and examining the influence on anticipatory licking before reward delivery. Inhibiting both ventral tegmental area and substantia nigra pars compacta DA neurons in the post-reward period had a significantly greater behavioral effect than inhibition in the pre-reward period of the task. Furthermore, the contribution of DA neurons to behavior decreased linearly as a function of elapsed time after reward. Together, the results indicate a temporally restricted role of DA neurons primarily related to reinforcing stimulus-reward associations and suggest that directly generating movements is a comparatively less important function.

It's the thought that counts: examining the task-dependent effects of transcranial direct current stimulation on executive function.

BACKGROUND: Prior investigations employing transcranial direct current stimulation (tDCS) have shown that stimulation can elicit subsequent improvement on tests of various cognitive abilities, including working memory. While stimulation parameters such as intensity and duration are known to determine the effects of tDCS, the degree to which stimulation effects are influenced by the nature of cognitive activities during stimulation remains unclear. OBJECTIVE/HYPOTHESIS: To determine whether manipulating the working memory load of a task performed during stimulation would modulate tDCS-induced enhancement of performance on a different, related measure after stimulation. METHODS: In two separate but closely related sham-controlled experiments, two groups of healthy subjects underwent anodal tDCS (2 mA) of the left dorsolateral prefrontal cortex (DLPFC) for 20 min. In Experiment 1, subjects (n = 11) trained on a letter 3Back task during stimulation. In Experiment 2 subjects (n = 11) trained on a letter 1Back task, which resembled the 3Back task but featured a lower working memory load. In both experiments, before and after stimulation, subjects completed an adjusting Paced Auditory Serial Addition Task (A-PASAT). Both the experimenter and subjects were blind to stimulation conditions in both experiments. RESULTS: Subjects were both faster and more accurate on the A-PASAT task after receiving real tDCS paired with 3Back training (Experiment1) compared to sham+3Back, real+1Back, and sham+1Back conditions. CONCLUSIONS: The cognitive demands of a task performed during tDCS can influence the effects of tDCS on post-stimulation performance. This finding has direct relevance to the use of tDCS as an investigative tool in cognitive neuroscience and as a therapy.

Rational genomics I: antisense open reading frames and codon bias in short-chain oxido reductase enzymes and the evolution of the genetic code.

The short-chain oxidoreductase (SCOR) family of enzymes includes over 6000 members, extending from bacteria and archaea to humans. Nucleic acid sequence analysis reveals that significant numbers of these genes are remarkably free of stopcodons in reading frames other than the coding frame, including those on the antisense strand. The genes from this subset also use almost entirely the GC-rich half of the 64 codons. Analysis of a million hypothetical genes having random nucleotide composition shows that the percentage of SCOR genes having multiple open reading frames exceeds random by a factor of as much as 1 x 10(6). Nevertheless, screening the content of the SWISS-PROT TrEMBL database reveals that 15% of all genes contain multiple open reading frames. The SCOR genes having multiple open reading frames and a GC-rich coding bias exhibit a similar GC bias in the nucleotide triple composition of their DNA. This bias is not correlated with the GC content of the species in which the SCOR genes are found. One possible explanation for the conservation of multiple open reading frames and extreme bias in nucleic acid composition in the family of Rossman folds is that the primordial member of this family was encoded early using only very stable GC-rich DNA and that evolution proceeded with extremely limited introduction of any codons having two or more adenine or thymine nucleotides. These and other data suggest that the SCOR family of enzymes may even have diverged from a common ancestor before most of the AT-rich half of the genetic code was fully defined.