Theta-burst direct electrical stimulation remodels human brain networks.

Theta-burst stimulation (TBS), a patterned brain stimulation technique that mimics rhythmic bursts of 3-8 Hz endogenous brain rhythms, has emerged as a promising therapeutic approach for treating a wide range of brain disorders, though the neural mechanism of TBS action remains poorly understood. We investigated the neural effects of TBS using intracranial EEG (iEEG) in 10 pre-surgical epilepsy participants undergoing intracranial monitoring. Here we show that individual bursts of direct electrical TBS at 29 frontal and temporal sites evoked strong neural responses spanning broad cortical regions. These responses exhibited dynamic local field potential voltage changes over the course of stimulation presentations, including either increasing or decreasing responses, suggestive of short-term plasticity. Stronger stimulation augmented the mean TBS response amplitude and spread with more recording sites demonstrating short-term plasticity. TBS responses were stimulation site-specific with stronger TBS responses observed in regions with strong baseline stimulation effective (cortico-cortical evoked potentials) and functional (low frequency phase locking) connectivity. Further, we could use these measures to predict stable and varying (e.g. short-term plasticity) TBS response locations. Future work may integrate pre-treatment connectivity alongside other biophysical factors to personalize stimulation parameters, thereby optimizing induction of neuroplasticity within disease-relevant brain networks.

Role of Prefrontal Cortex Circuitry in Maintaining Social Homeostasis.

Homeostasis is a fundamental concept in biology and ensures the stability of life by maintaining the constancy of physiological processes. Recent years have witnessed a surge in research interest in these physiological processes, with a growing focus on understanding the mechanisms underlying social homeostasis. This shift in focus underscores our increasing understanding of the importance of social interactions and their impact on individual well-being. In this review, we explore the interconnected research across 3 primary categories: understanding the neural mechanisms influencing set points, defining contemporary factors that can disrupt social homeostasis, and identifying the potential contributions of social homeostatic failure in the development of psychiatric diseases. We also delve into the role of the prefrontal cortex and its circuitry in regulating social behavior, decision-making processes, and the manifestation of neuropsychiatric disorders, such as depression and anxiety. Finally, we examine the influence of more recent factors such as growing social media exposure and the COVID-19 pandemic on mental health, highlighting their disruptive effects. We also identify gaps in current literature through the analysis of research trends and propose future research directions to advance our understanding of social homeostasis, with implications for mental health interventions.

Semantic encoding during language comprehension at single-cell resolution.

From sequences of speech sounds1,2 or letters3, humans can extract rich and nuanced meaning through language. This capacity is essential for human communication. Yet, despite a growing understanding of the brain areas that support linguistic and semantic processing4-12, the derivation of linguistic meaning in neural tissue at the cellular level and over the timescale of action potentials remains largely unknown. Here we recorded from single cells in the left language-dominant prefrontal cortex as participants listened to semantically diverse sentences and naturalistic stories. By tracking their activities during natural speech processing, we discover a fine-scale cortical representation of semantic information by individual neurons. These neurons responded selectively to specific word meanings and reliably distinguished words from nonwords. Moreover, rather than responding to the words as fixed memory representations, their activities were highly dynamic, reflecting the words' meanings based on their specific sentence contexts and independent of their phonetic form. Collectively, we show how these cell ensembles accurately predicted the broad semantic categories of the words as they were heard in real time during speech and how they tracked the sentences in which they appeared. We also show how they encoded the hierarchical structure of these meaning representations and how these representations mapped onto the cell population. Together, these findings reveal a finely detailed cortical organization of semantic representations at the neuron scale in humans and begin to illuminate the cellular-level processing of meaning during language comprehension.

Sensate immediate breast reconstruction.

As breast cancer therapies and associated oncologic outcomes continue to improve, greater attention has been placed on quality-of-life issues after breast cancer and breast cancer risk-reducing treatments. The loss of sensation that typically occurs after mastectomy can have significant negative psychological, sexual, and functional impact on patients after surgery. Further, injury of nerves not only leads to numbness, but can also cause chronic neuropathic pain, which can be very debilitating to affected patients. In order to minimize these impacts, there is expanding uptake of surgical approaches that preserve nerves at the time of mastectomy and reconstruct injured nerves either during mastectomy or during delayed reconstruction. These advances have been facilitated by anatomic studies investigating different variants of intercostal anatomy and better understanding the course of the nerves innervating the mastectomy skin and nipple-areolar complex (NAC). With improved knowledge of the intercostal nerve anatomy, surgeons are able to carefully preserve nerves at the time of mastectomy, thus improving sensory outcomes. Additionally, nerve reconstruction techniques have advanced, particularly with newer nerve allograft technologies, which allows for nerve reconstruction to be done both at the time of mastectomy, as well as in a delayed fashion. The focus of this article is to describe the current state of sensory preservation and immediate reinnervation at the time of mastectomy and the advances that have allowed for these new approaches.

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.

Single-neuronal elements of speech production in humans.

Humans are capable of generating extraordinarily diverse articulatory movement combinations to produce meaningful speech. This ability to orchestrate specific phonetic sequences, and their syllabification and inflection over subsecond timescales allows us to produce thousands of word sounds and is a core component of language1,2. The fundamental cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh-density Neuropixels recordings capable of sampling across the cortical column in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events before utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also accurately predicted the phonetic, syllabic and morphological components of upcoming words and showed a temporally ordered dynamic. Collectively, we show how these mixtures of cells are broadly organized along the cortical column and how their activity patterns transition from articulation planning to production. We also demonstrate how these cells reliably track the detailed composition of consonant and vowel sounds during perception and how they distinguish processes specifically related to speaking from those related to listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and demonstrate a cellular process that can support the production of speech.

Co-occurring ripple oscillations facilitate neuronal interactions between cortical locations in humans.

How the human cortex integrates ("binds") information encoded by spatially distributed neurons remains largely unknown. One hypothesis suggests that synchronous bursts of high-frequency oscillations ("ripples") contribute to binding by facilitating integration of neuronal firing across different cortical locations. While studies have demonstrated that ripples modulate local activity in the cortex, it is not known whether their co-occurrence coordinates neural firing across larger distances. We tested this hypothesis using local field-potentials and single-unit firing from four 96-channel microelectrode arrays in the supragranular cortex of 3 patients. Neurons in co-rippling locations showed increased short-latency co-firing, prediction of each other's firing, and co-participation in neural assemblies. Effects were similar for putative pyramidal and interneurons, during non-rapid eye movement sleep and waking, in temporal and Rolandic cortices, and at distances up to 16 mm (the longest tested). Increased co-prediction during co-ripples was maintained when firing-rate changes were equated, indicating that it was not secondary to non-oscillatory activation. Co-rippling enhanced prediction was strongly modulated by ripple phase, supporting the most common posited mechanism for binding-by-synchrony. Co-ripple enhanced prediction is reciprocal, synergistic with local upstates, and further enhanced when multiple sites co-ripple, supporting re-entrant facilitation. Together, these results support the hypothesis that trans-cortical co-occurring ripples increase the integration of neuronal firing of neurons in different cortical locations and do so in part through phase-modulation rather than unstructured activation.

Sensory Outcomes after Neurotization in Nipple-sparing Mastectomy and Implant-based Breast Reconstruction.

Background: Mastectomy and breast reconstruction techniques continue to evolve to optimize aesthetic and reconstructive outcomes. However, the loss of sensation after mastectomy remains a major limitation. This article describes our evolution of a novel approach that we first described in 2019, combining recent advances in breast oncologic, reconstructive, and peripheral nerve surgery to optimize sensory outcomes. Methods: Nipple-sparing mastectomy was performed in all patients and involved preservation of lateral intercostal nerves when anatomy was favorable. When nerves could not be preserved without compromising oncologic safety, nipple-areolar complex neurotization was performed using allograft or intercostal autograft from a transected T3, T4, or T5, lateral intercostal nerve to identified subareolar nerve targets. Immediate, prepectoral, direct-to-implant reconstruction was then performed. Acroval one-point moving and one-point static pressure thresholds established baseline sensibility values, which were then repeated at multiple time points postoperatively. Results: Outcomes from 47 women (79 breasts) were assessed prospectively. Mean follow-up was 9.2 months (range 6-14 months). At 6 months postoperatively, over 80% of patients had good-to-excellent one-point moving as well as one-point static sensibility scores averaged across all areas tested. None of the patients developed persistent dysesthesia or clinical evidence of neuroma. Conclusions: This study represents the largest series reported to date of sensibility outcomes after nipple-sparing mastectomy and implant reconstruction with concurrent neurotization. Sensibility results show that this approach allows for preservation of high degrees of breast and nipple-areolar complex sensation in most patients.

DREDge: robust motion correction for high-density extracellular recordings across species.

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

Benefits of sharing neurophysiology data from the BRAIN Initiative Research Opportunities in Humans Consortium.

Sharing human brain data can yield scientific benefits, but because of various disincentives, only a fraction of these data is currently shared. We profile three successful data-sharing experiences from the NIH BRAIN Initiative Research Opportunities in Humans (ROH) Consortium and demonstrate benefits to data producers and to users.

Anatomic Anomalies of the Nerves Treated during Headache Surgery.

Background: Headache surgery is a well-established, viable option for patients with chronic head pain/migraines refractory to conventional treatment modalities. These operations involve any number of seven primary nerves. In the occipital region, the surgical targets are the greater, lesser, and third occipital nerves. In the temporal region, they are the auriculotemporal and zygomaticotemporal nerves. In the forehead, the supraorbital and supratrochlear are targeted. The typical anatomic courses of these nerves are well established and documented in clinical and cadaveric studies. However, variations of this "typical" anatomy are quite common and relatively poorly understood. Headache surgeons should be aware of these common anomalies, as they may alter treatment in several meaningful ways. Methods: In this article, we describe the experience of five established headache surgeons encompassing over 4000 cases with respect to the most common anomalies of the nerves typically addressed during headache surgery. Descriptions of anomalous nerve courses and suggestions for management are offered. Results: Anomalies of all seven nerves addressed during headache operations occur with a frequency ranging from 2% to 50%, depending on anomaly type and nerve location. Variations of the temporal and occipital nerves are most common, whereas anomalies of the frontal nerves are relatively less common. Management includes broader dissection and/or transection of accessory injured nerves combined with strategies to reduce neuroma formation such as targeted reinnervation or regenerative peripheral nerve interfaces. Conclusions: Understanding these myriad nerve anomalies is essential to any headache surgeon. Implications are relevant to preoperative planning, intraoperative dissection, and postoperative management.

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.

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.

Co-occurring ripple oscillations facilitate neuronal interactions between cortical locations in humans.

Synchronous bursts of high frequency oscillations ('ripples') are hypothesized to contribute to binding by facilitating integration of neuronal firing across cortical locations. We tested this hypothesis using local field-potentials and single-unit firing from four 96-channel microelectrode arrays in supragranular cortex of 3 patients. Neurons in co-rippling locations showed increased short-latency co-firing, prediction of each-other's firing, and co-participation in neural assemblies. Effects were similar for putative pyramidal and interneurons, during NREM sleep and waking, in temporal and Rolandic cortices, and at distances up to 16mm. Increased co-prediction during co-ripples was maintained when firing-rate changes were equated, and were strongly modulated by ripple phase. Co-ripple enhanced prediction is reciprocal, synergistic with local upstates, and further enhanced when multiple sites co-ripple. Together, these results support the hypothesis that trans-cortical co-ripples increase the integration of neuronal firing of neurons in different cortical locations, and do so in part through phase-modulation rather than unstructured activation.

ROBUST ONLINE MULTIBAND DRIFT ESTIMATION IN ELECTROPHYSIOLOGY DATA.

High-density electrophysiology probes have opened new possibilities for systems neuroscience in human and non-human animals, but probe motion poses a challenge for downstream analyses, particularly in human recordings. We improve on the state of the art for tracking this motion with four major contributions. First, we extend previous decentralized methods to use multiband information, leveraging the local field potential (LFP) in addition to spikes. Second, we show that the LFP-based approach enables registration at sub-second temporal resolution. Third, we introduce an efficient online motion tracking algorithm, enabling the method to scale up to longer and higher-resolution recordings, and possibly facilitating real-time applications. Finally, we improve the robustness of the approach by introducing a structure-aware objective and simple methods for adaptive parameter selection. Together, these advances enable fully automated scalable registration of challenging datasets from human and mouse.

Congenitally Fused Cervical Spine Is Associated With Adjacent-Level Degeneration in the Absence of Cervical Spine Surgery.

BACKGROUND: Cervical fusion surgery is associated with adjacent-level degeneration, but surgical and technical factors are difficult to dissociate from the mechanical effects of the fusion itself. OBJECTIVE: To determine the effect of fusion on adjacent-level degeneration in unoperated patients using a cohort of patients with congenitally fused cervical vertebrae. METHODS: We identified 96 patients with incidental single-level cervical congenital fusion on computed tomography imaging. We compared these patients to an age-matched control cohort of 80 patients without congenital fusion. We quantified adjacent-level degeneration through direct measurements of intervertebral disk parameters as well as the validated Kellgren & Lawrence classification scale for cervical disk degeneration. Ordinal logistic regression and 2-way analysis of variance testing were performed to correlate extent of degeneration with the congenitally fused segment. RESULTS: Nine hundred fifty-five motion segments were analyzed. The numbers of patients with C2-3, C3-4, C4-5, C5-6, and C6-7 congenitally fused segments were 47, 11, 11, 17, and 9, respectively. We found that patients with congenital fusion at C4-C5 and C5-C6 had a significantly greater extent of degeneration at adjacent levels compared with the degree of degeneration at the same levels in control patients and in patients with congenital fusion at other cervical levels, even while controlling for expected degeneration and age. CONCLUSION: Taken together, our data suggest that congenitally fused cervical spinal segments at C4-C5 and C5-C6 are associated with adjacent-level degeneration independent of fixation instrumentation. This study design removes surgical factors that might contribute to adjacent-level degeneration.

Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology.

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine's antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine's NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.

Natural language processing models reveal neural dynamics of human conversation.

Human verbal communication requires a rapid interplay between speech planning, production, and comprehension. These processes are subserved by local and long-range neural dynamics across widely distributed brain areas. How linguistic information is precisely represented during natural conversation or what shared neural processes are involved, however, remain largely unknown. Here we used intracranial neural recordings in participants engaged in free dialogue and employed deep learning natural language processing models to find a striking similarity not only between neural-to-artificial network activities but also between how linguistic information is encoded in brain during production and comprehension. Collectively, neural activity patterns that encoded linguistic information were closely aligned to those reflecting speaker-listener transitions and were reduced after word utterance or when no conversation was held. They were also observed across distinct mesoscopic areas and frequency bands during production and comprehension, suggesting that these signals reflected the hierarchically structured information being conveyed during dialogue. Together, these findings suggest that linguistic information is encoded in the brain through similar neural representations during both speaking and listening, and start to reveal the distributed neural dynamics subserving human communication.