Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Comparison of glenohumeral and scapulothoracic kinematics between fastballs and curveballs during baseball pitching.

Shoulder injuries are common in baseball pitchers and primarily involve the glenohumeral joint. Past analyses have examined shoulder biomechanics during different pitch types simply as the motion of the upper arm relative to the thorax. In this study, glenohumeral and scapulothoracic kinematics were compared between fastballs and curveballs at key timepoints throughout a pitch. Upper extremity kinematics of thirteen collegiate pitchers were collected during fastball and curveball pitches with motion capture. A linear model approach was utilised to estimate scapular kinematics based on measurable humerothoracic motion. Glenohumeral kinematics were computed from the scapular and humeral motion data. Comparisons of scapulothoracic and glenohumeral kinematic variables at times of maximum glenohumeral external rotation, ball release, and maximum glenohumeral internal rotation between pitch types were made using paired t-tests with Benjamini-Hochberg corrections. There were no significant differences in glenohumeral kinematics. Fastballs elicited significantly less scapulothoracic internal rotation and more posterior tilt at maximum glenohumeral external rotation. Fastballs produced significantly less scapulothoracic internal rotation and anterior tilt at maximum glenohumeral internal rotation. This study provides further evidence that risk of injury to the glenohumeral joint may be consistent between fastballs and curveballs and offers insights into subtle differences in scapular kinematics between pitch types.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Guidelines for Specialized Epilepsy Centers: Executive Summary of the Report of the National Association of Epilepsy Centers Guideline Panel.

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery. The trustworthy consensus-based statements (TCBS) process produces unbiased, scientifically valid guidelines through a transparent process that incorporates available evidence and expert opinion. A systematic literature search returned 5937 relevant studies from which 197 articles were retained for data extraction. A panel of 41 stakeholders with diverse expertise evaluated this evidence and drafted recommendations following the TCBS process. The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings in major topic areas including epilepsy monitoring unit care, surgery, neuroimaging, neuropsychology, genetics, and outpatient care. Recommendations were informed by the evidence review and reflect the consensus of a broad panel of expert opinions.

Flexible, scalable, high channel count stereo-electrode for recording in the human brain.

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on an innovative, customizable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents an advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology.

Specific afterdischarge properties can enhance the clinical utility of electrical stimulation mapping during intracranial monitoring.

OBJECTIVE: Extraoperative electrical cortical stimulation (ECS) facilitates defining the seizure onset zone (SOZ) and eloquent cortex. The clinical relevance of stimulation-induced afterdischarges (ADs) is not well defined. METHODS: Fifty-five patients who underwent intracranial electroencephalogram evaluations with ECS were retrospectively identified. ADs were identified in these recordings and categorized by pattern, location, and association with stimulation-induced seizures. RESULTS: ADs were generated in 1774/9285 (19%) trials. Rhythmic spikes and irregular ADs within the stimulated bipolar contact pair were predictive of location within the SOZ compared to non-epileptogenic/non-irritative cortex (rhythmic spikes OR 2.24, p = 0.0098; irregular OR 1.39; p = 0.013). ADs immediately preceding stimulated seizures occurred at lower stimulation intensity thresholds compared to other stimulations (mean 2.94 ± 0.28 mA vs. 4.16 ± 0.05 mA respectively; p = 0.0068). CONCLUSIONS: Changes in AD properties can provide clinically relevant data in extraoperative stimulation mapping. SIGNIFICANCE: Although not exclusive to the SOZ, the generation of rhythmic spikes may suggest that a stimulation location is within the SOZ, while decreased stimulation intensity thresholds eliciting ADs may alert clinicians to a heightened probability of seizure generation with subsequent stimulation.

The role of the motor thalamus in deep brain stimulation for essential tremor.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.

A week in the life of the human brain: stable states punctuated by chaotic transitions.

Many important neurocognitive states, such as performing natural activities and fluctuations of arousal, shift over minutes-to-hours in the real-world. We harnessed 3-12 days of continuous multi-electrode intracranial recordings in twenty humans during natural behavior (socializing, using digital devices, sleeping, etc.) to study real-world neurodynamics. Applying deep learning with dynamical systems approaches revealed that brain networks formed consistent stable states that predicted behavior and physiology. Changes in behavior were associated with bursts of rapid neural fluctuations where brain networks chaotically explored many configurations before settling into new states. These trajectories traversed an hourglass-shaped structure anchored around a set of networks that slowly tracked levels of outward awareness related to wake-sleep stages, and a central attractor corresponding to default mode network activation. These findings indicate ways our brains use rapid, chaotic transitions that coalesce into neurocognitive states slowly fluctuating around a stabilizing central equilibrium to balance flexibility and stability during real-world behavior.

Hippocampal barques and their manifestation as 14&6 Hz positive spikes during sleep.

OBJECTIVE: This study investigates variations in hippocampal barque occurrence during sleep and compares findings to respective variations of their scalp manifestation as 14&6/sec positive spikes. METHODS: From 11 epilepsy patients, 12 non-epileptogenic hippocampi with barques were identified for this study. Using the first seizure-free whole-night sleep stereo-encephalography (sEEG) recording, we performed sleep staging and measured the occurrence of barques and 14&6/sec positive spikes variants. RESULTS: Hippocampal barques (total count: 9,183; mean count per record: 765.2 ± 251.2) occurred predominantly during non-rapid eye movement (NREM) II sleep (total: 5,744; mean: 478.6 ± 176.1; 62.2 ± 6.0%) and slow-wave sleep (SWS) (total: 2,950; mean: 245.83 ± 92.9; 32.0 ± 6.2%), with rare to occasional occurrence in NREM I (total: 85; mean: 7.0 ± 2.8; 0.9 ± 0.4%), rapid eye movement (REM) (total: 153; mean: 12.75 ± 4.0; 1.7 ± 0.6) and wakefulness (total: 251; mean: 20.9 ± 6.3; 2.9 ± 0.9%). Barque rate increased during SWS (mean: 2.7 ± 1.0 per min) compared to NREM II (2.2 ± 1.0 per min) and other states (wakefulness: 0.1 ± 0.0 per min; NREM I: 0.3 ± 0.1 per min; REM: 0.1 ± 0.0 per min). The 14&6/sec positive spikes variant (total count: 2,406; mean: 343.7 ± 106.7) was present in NREM II (total: 2,059; mean: 249.1 ± 100.2, 84.9 ± 3.6%) and SWS (total: 347; mean: 49.5 ± 12.8, 15.0 ± 3.6%) stages, and absent from the rest of sleep and wakefulness. While all 14&6/sec positive spikes correlated with barques, only 44.7 ± 6.1% of barques manifested as 14&6/sec positive spikes. CONCLUSIONS: Hippocampal barques are predominant in NREM II and SWS, and tend to increase their presence during SWS. Their scalp manifestation as 14&6/sec positive spikes is confounded by wakefulness, REM and NREM I stages, and "masked" by the co-occurrence of NREM II and SWS slow waves, and overlapping reactive micro-arousal elements. SIGNIFICANCE: Our study highlighted the overnight profile of hippocampal barques, in relation to the respective profile of their scalp manifestation, the 14&6/sec positive spikes variant.

Epilepsy Surgery for Cognitive Improvement in Epileptic Encephalopathy.

Epileptic encephalopathies are defined by the presence of frequent epileptiform activity that causes neurodevelopmental slowing or regression. Here, we review evidence that epilepsy surgery improves neurodevelopment in children with epileptic encephalopathies. We describe an example patient with epileptic encephalopathy without drug refractory seizures, who underwent successful diagnostic and therapeutic surgeries. In patients with epileptic encephalopathy, cognitive improvement alone is a sufficient indication to recommend surgical intervention in experienced centers.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

Speech induces spatiotemporal and frequency specific subthalamic-cortical spike-phase coupling events.

Speaking evokes modulation of neuronal activity in the subthalamic nucleus (STN), a basal ganglia node that receives both mono- and polysynaptic inputs from cortex and subcortex. Indeed, speech provides a rich context for exploring interactions within human cortical-basal ganglia circuits, but direct intracranial recordings are rare. Here, we synchronously recorded electrocorticographic signals in the cortex and single units in the STN while participants performed a syllable repetition task during deep brain stimulation (DBS) surgery. STN neurons exhibited transient spike-phase coupling with frequency and spatiotemporal specificity. Theta and alpha spike-phase coupling was prominent in the superior temporal gyrus and supramarginal gyrus during speech production. Beta spike-phase coupling was prominent in some STN neurons during baseline but rebounded after speech termination in a separate population. Thus, STN-cortical interactions are coordinated via transient bursts of behavior-specific synchronization that involves multiple neuronal populations and timescales, suggesting mechanisms for auditory-sensorimotor integration during speech production.

Developmental changes in functional connectivity between the prefrontal cortex and amygdala following fear extinction.

The amygdala and prefrontal cortex (PFC) undergo dramatic changes in structure, function, and regional connectivity in early life, ultimately stabilizing in early adulthood. Pathways between these two structures underlie many forms of emotional learning, including the extinction of conditioned fear. Here we sought to characterize changes in extinction-related medial PFC (mPFC) â†’ amygdala functional connectivity across development that might explain adolescent impairments in extinction. The retrograde tracer Fluorogold was infused into the amygdala of postnatal day (P)22-23 (juvenile), P31-32 (adolescent), or ≥ P69 (adult) rats, which were then exposed to fear conditioning and extinction training. Brains were collected following extinction or context exposure and processed for expression of pMAPK (as a marker of learning-dependent plasticity) in prelimbic (PL) and infralimbic (IL) amygdala-projecting neurons. Consistent with previous findings, amygdala-projecting mPFC neurons were located primarily in layers (L)II/III and V of the mPFC. We noted that mPFC LII/III projected predominantly to the ipsilateral basolateral amygdala, whereas LV projected bilaterally and targeted multiple amygdalar nuclei. Extinction was not associated with changes in extinction-related plasticity in the PL-amygdala pathways in any age group. No changes were seen in LII/III of the IL, but extinction-related plasticity in LV amygdala-projecting IL neurons decreased linearly across development. These findings suggest that extinction-related functional connectivity between the IL and the amygdala undergoes fundamental changes across development that may contribute to alterations in fear suppression across development.

Invasive neurophysiology and whole brain connectomics for neural decoding in patients with brain implants.

Brain computer interfaces (BCI) provide unprecedented spatiotemporal precision that will enable significant expansion in how numerous brain disorders are treated. Decoding dynamic patient states from brain signals with machine learning is required to leverage this precision, but a standardized framework for identifying and advancing novel clinical BCI approaches does not exist. Here, we developed a platform that integrates brain signal decoding with connectomics and demonstrate its utility across 123 hours of invasively recorded brain data from 73 neurosurgical patients treated for movement disorders, depression and epilepsy. First, we introduce connectomics-informed movement decoders that generalize across cohorts with Parkinson's disease and epilepsy from the US, Europe and China. Next, we reveal network targets for emotion decoding in left prefrontal and cingulate circuits in DBS patients with major depression. Finally, we showcase opportunities to improve seizure detection in responsive neurostimulation for epilepsy. Our platform provides rapid, high-accuracy decoding for precision medicine approaches that can dynamically adapt neuromodulation therapies in response to the individual needs of patients.

Differential cortical network engagement during states of un/consciousness in humans.

What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs. non-arousable unconsciousness (propofol-induced general anesthesia). Information integration and complex processing we`re reduced, while variability increased in any type of unconscious state. These changes were more pronounced during anesthesia than sleep and involved different cortical engagement. During sleep, changes were mostly uniformly distributed across the brain, whereas during anesthesia, the prefrontal cortex was the most disrupted, suggesting that the lack of arousability during anesthesia results not from just altered overall physiology but from a disconnection between the prefrontal and other brain areas. These findings provide direct evidence for different neural dynamics during loss of consciousness compared with loss of arousability.

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Modified Neuropixels probes for recording human neurophysiology in the operating room.

Neuropixels are silicon-based electrophysiology-recording probes with high channel count and recording-site density. These probes offer a turnkey platform for measuring neural activity with single-cell resolution and at a scale that is beyond the capabilities of current clinically approved devices. Our team demonstrated the first-in-human use of these probes during resection surgery for epilepsy or tumors and deep brain stimulation electrode placement in patients with Parkinson's disease. Here, we provide a better understanding of the capabilities and challenges of using Neuropixels as a research tool to study human neurophysiology, with the hope that this information may inform future efforts toward regulatory approval of Neuropixels probes as research devices. In perioperative procedures, the major concerns are the initial sterility of the device, maintaining a sterile field during surgery, having multiple referencing and grounding schemes available to de-noise recordings (if necessary), protecting the silicon probe from accidental contact before insertion and obtaining high-quality action potential and local field potential recordings. The research team ensures that the device is fully operational while coordinating with the surgical team to remove sources of electrical noise that could otherwise substantially affect the signals recorded by the sensitive hardware. Prior preparation using the equipment and training in human clinical research and working in operating rooms maximize effective communication within and between the teams, ensuring high recording quality and minimizing the time added to the surgery. The perioperative procedure requires ~4 h, and the entire protocol requires multiple weeks.

A Transcriptomic Comparative Study of Cranial Vasculature.

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls.