Widespread ripples synchronize human cortical activity during sleep, waking, and memory recall.

Declarative memory encoding, consolidation, and retrieval require the integration of elements encoded in widespread cortical locations. The mechanism whereby such "binding" of different components of mental events into unified representations occurs is unknown. The "binding-by-synchrony" theory proposes that distributed encoding areas are bound by synchronous oscillations enabling enhanced communication. However, evidence for such oscillations is sparse. Brief high-frequency oscillations ("ripples") occur in the hippocampus and cortex and help organize memory recall and consolidation. Here, using intracranial recordings in humans, we report that these ∼70-ms-duration, 90-Hz ripples often couple (within ±500 ms), co-occur (≥ 25-ms overlap), and, crucially, phase-lock (have consistent phase lags) between widely distributed focal cortical locations during both sleep and waking, even between hemispheres. Cortical ripple co-occurrence is facilitated through activation across multiple sites, and phase locking increases with more cortical sites corippling. Ripples in all cortical areas co-occur with hippocampal ripples but do not phase-lock with them, further suggesting that cortico-cortical synchrony is mediated by cortico-cortical connections. Ripple phase lags vary across sleep nights, consistent with participation in different networks. During waking, we show that hippocampo-cortical and cortico-cortical coripples increase preceding successful delayed memory recall, when binding between the cue and response is essential. Ripples increase and phase-modulate unit firing, and coripples increase high-frequency correlations between areas, suggesting synchronized unit spiking facilitating information exchange. co-occurrence, phase synchrony, and high-frequency correlation are maintained with little decrement over very long distances (25 cm). Hippocampo-cortico-cortical coripples appear to possess the essential properties necessary to support binding by synchrony during memory retrieval and perhaps generally in cognition.

Impact of white matter networks on risk for memory decline following resection versus ablation in temporal lobe epilepsy.

BACKGROUND: With expanding neurosurgical options in epilepsy, it is important to characterise each options' risk for postoperative cognitive decline. Here, we characterise how patients' preoperative white matter (WM) networks relates to postoperative memory changes following different epilepsy surgeries. METHODS: Eighty-nine patients with temporal lobe epilepsy with T1-weighted and diffusion-weighted imaging as well as preoperative and postoperative verbal memory scores (prose recall) underwent either anterior temporal lobectomy (ATL: n=38) or stereotactic laser amygdalohippocampotomy (SLAH; n=51). We computed laterality indices (ie, asymmetry) for volume of the hippocampus and fractional anisotropy (FA) of two deep WM tracts (uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF)). RESULTS: Preoperatively, left-lateralised FA of the ILF was associated with higher prose recall (p<0.01). This pattern was not observed for the UF or hippocampus (ps>0.05). Postoperatively, right-lateralised FA of the UF was associated with less decline following left ATL (p<0.05) but not left SLAH (p>0.05), while right-lateralised hippocampal asymmetry was associated with less decline following both left ATL and SLAH (ps<0.05). After accounting for preoperative memory score, age of onset and hippocampal asymmetry, the association between UF and memory decline in left ATL remained significant (p<0.01). CONCLUSIONS: Asymmetry of the hippocampus is an important predictor of risk for memory decline following both surgeries. However, asymmetry of UF integrity, which is only severed during ATL, is an important predictor of memory decline after ATL only. As surgical procedures and pre-surgical mapping evolve, understanding the role of frontal-temporal WM in memory networks could help to guide more targeted surgical approaches to mitigate cognitive decline.

Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

A cost analysis of MR-guided laser interstitial thermal therapy for adult refractory epilepsy.

OBJECTIVE: MR-guided laser interstitial thermal therapy (LITT) is used increasingly for refractory epilepsy. The goal of this investigation is to directly compare cost and short-term adverse outcomes for adult refractory epilepsy treated with temporal lobectomy and LITT, as well as to identify risk factors for increased costs and adverse outcomes. METHODS: The National Inpatient Sample (NIS) was queried for patients who received LITT between 2012 and 2019. Patients with adult refractory epilepsy were identified. Multivariable mixed-effects models were used to analyze predictors of cost, length of stay (LOS), and complications. RESULTS: LITT was associated with reduced LOS and overall cost relative to temporal lobectomy, with a statistical trend toward lower incidence of postoperative complications. High-volume surgical epilepsy centers had lower LOS overall. Longer LOS was a significant driver of increased cost for LITT, and higher comorbidity was associated with non-routine discharge. SIGNIFICANCE: LITT is an affordable alternative to temporal lobectomy for adult refractory epilepsy with an insignificant reduction in inpatient complications. Patients may benefit from expanded access to this treatment modality for both its reduced LOS and lower cost.

Investigating Deep Brain Stimulation of the Habenula: A Review of Clinical Studies.

OBJECTIVES: The aim of this study was to examine the current scientific literature on deep brain stimulation (DBS) targeting the habenula for the treatment of neuropsychiatric disorders including schizophrenia, major depressive disorder, and obsessive-compulsive disorder (OCD). MATERIALS AND METHODS: Two authors performed independent data base searches using the PubMed, Cochrane, PsycINFO, and Web of Science search engines. The data bases were searched for the query ("deep brain stimulation" and "habenula"). The inclusion criteria involved screening for human clinical trials written in English and published from 2007 to 2020. From the eligible studies, data were collected on the mean age, sex, number of patients included, and disorder treated. Patient outcomes of each study were summarized. RESULTS: The search yielded six studies, which included 11 patients in the final analysis. Treated conditions included refractory depression, bipolar disorder, OCD, schizophrenia, and major depressive disorder. Patients with bipolar disorder unmedicated for at least two months had smaller habenula volumes than healthy controls. High-frequency stimulation of the lateral habenula attenuated the rise of serotonin in the dorsal raphe nucleus for treating depression. Bilateral habenula DBS and patient OCD symptoms were reduced and maintained at one-year follow up. Low- and high-frequency stimulation DBS can simulate input paths to the lateral habenula to treat addiction, including cocaine addiction. More data are needed to draw conclusions as to the impact of DBS for schizophrenia and obesity. CONCLUSIONS: The habenula is a novel target that could aid in reducing neuropsychiatric symptoms and should be considered in circuit-specific investigation of neuromodulation for psychiatric disorders. More information needs to be gathered and assessed before this treatment is fully approved for treatment of neuropsychiatric conditions.

Microscale Physiological Events on the Human Cortical Surface.

Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their "intermediate" microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit.

Neurosurgical Treatments for Cancer Pain.

Cancer-related pain is a uniquely challenging entity for treating practitioners for a variety of reasons, including its often severe and medically refractory nature, the emotional and social circumstances surrounding the disease process, and the frequently associated limited life expectancy.

History of Women in Neurosurgery (WINS).

In 2020, the Women in Neurosurgery (WINS) organization, a joint section of the AANS and Congress of Neurological Surgeons, celebrated 30 years since its inception. In this paper, the authors explore the history of WINS from its beginnings through its evolution over the past three decades. The achievements of the group are highlighted, as well as the broader achievements of the women in the neurosurgical community over this time period.

Three Cases of Trigeminal Neuralgia with Radiographic Absence of Meckel's Cave.

Trigeminal neuralgia (TN) is a debilitating but treatable disease. Classic TN has referable vascular compression of the trigeminal nerve, but rarely secondary sources of anatomic compression will present, including vascular malformations, aneurysms, or tumors. Understanding the etiology of the patients' symptoms leads to targeted treatment. Three patients presented with symptoms consistent with TN: shooting, paroxysmal pains in the distribution of the trigeminal nerve. However, imaging revealed no vascular conflict at the root entry zone of the trigeminal nerve. Instead, on the affected side Meckel's cave was absent. No other compressive mass lesion was identified. In all three cases, patients were offered both Gamma Knife Radiosurgery and surgical decompression of Meckel's cave. All 3 patients elected to proceed with stereotactic radiation and reported improvement in pain. Many cases of classic TN can be explained by neurovascular conflict at the trigeminal root entry zone, but secondary sources of compression or restriction along the nerve can result in similar symptomology. In this case series, an absent or hypoplastic ipsilateral Meckel's cave may have produced symptoms consistent with TN. Imaging with fine cuts through Meckel's cave is an important diagnostic tool.

Charting the road forward in psychiatric neurosurgery: proceedings of the 2016 American Society for Stereotactic and Functional Neurosurgery workshop on neuromodulation for psychiatric disorders.

OBJECTIVE: Refractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain stimulation (DBS)-based therapies for depression and obsessive-compulsive disorder (OCD). Results from recent pivotal trials of these therapies, however, did not demonstrate the degree of efficacy expected from previous smaller trials. To discuss next steps, neurosurgeons, neurologists, psychiatrists and representatives from industry convened a workshop sponsored by the American Society for Stereotactic and Functional Neurosurgery in Chicago, Illinois, in June of 2016. DESIGN: Here we summarise the proceedings of the workshop. Participants discussed a number of issues of importance to the community. First, we discussed how to interpret results from the recent pivotal trials of DBS for OCD and depression. We then reviewed what can be learnt from lesions and closed-loop neurostimulation. Subsequently, representatives from the National Institutes of Health, the Food and Drug Administration and industry discussed their views on neuromodulation for psychiatric disorders. In particular, these third parties discussed their criteria for moving forward with new trials. Finally, we discussed the best way of confirming safety and efficacy of these therapies, including registries and clinical trial design. We close by discussing next steps in the journey to new neuromodulatory therapies for these devastating illnesses. CONCLUSION: Interest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.

Deep brain stimulation for intractable neuropathic facial pain.

OBJECTIVE Deep brain stimulation (DBS) is a well-established, evidence-based therapy with FDA approval for Parkinson's disease and essential tremor. Despite the early successful use of DBS to target the sensory thalamus for intractable facial pain, subsequent studies pursuing various chronic pain syndromes reported variable efficacy, keeping DBS for pain as an investigational and "off-label" use. The authors report promising results for a contemporary series of patients with intractable facial pain who were treated with DBS. METHODS Pain outcomes for 7 consecutive patients with unilateral, intractable facial pain undergoing DBS of the ventral posteromedial nucleus of the thalamus (VPM) and the periaqueductal gray (PAG) were retrospectively reviewed. Pain was assessed preoperatively and at multiple postoperative time points using the visual analog scale (VAS), the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), and the Pain Disability Index (PDI). RESULTS VAS scores significantly decreased from a mean ± SD of 9.0 ± 1.3 preoperatively to 2.6 ± 1.5 at 1 year postoperatively (p = 0.001). PDI scores decreased from a mean total of 48.5 to 28.5 (p = 0.01). SF-MPQ-2 scores decreased from a mean of 4.6 to 2.4 (p = 0.03). Notably, several patients did not experience maximum improvement until 6-9 months postoperatively, correlating with repeated programming adjustments. CONCLUSIONS DBS of the VPM and PAG is a potential therapeutic option for patients suffering from severe, intractable facial pain refractory to other interventions. Improved efficacy may be observed over time with close follow-up and active DBS programming adjustments.

Deep Brain Stimulation for Status Dystonicus: A Case Series and Review of the Literature.

BACKGROUND: Status dystonicus (SD) is a rare and potentially life-threatening complication of primary or secondary dystonia, characterized by acute worsening of dystonic movements. There is no consensus regarding optimal treatment, which may be medical and/or surgical. METHODS: We present our experience with pallidal deep brain stimulation (DBS) in 5 DYT1-positive patients with SD and provide a review of the literature to examine optimal management. RESULTS: Of the 5 patients treated with pallidal DBS, all experienced postoperative resolution of their dystonic crisis within a range of 1-21 days. Long-term follow-up resulted in 1 patient returning to preoperative baseline, 3 patients improving from baseline, and 1 patient making a complete recovery. Of the 28 SD patients (including our 5 patients) reported in the literature who were treated with DBS or ablative surgery, 26 experienced cessation of their dystonic crisis with a return to baseline function and, in most cases, clinical improvement. CONCLUSION: DBS is an effective therapeutic modality for the treatment of SD. In addition to the long-term benefits of stimulation, early and aggressive treatment may improve the overall outcome.

Acoustic and language-specific sources for phonemic abstraction from speech.

Spoken language comprehension requires abstraction of linguistic information from speech, but the interaction between auditory and linguistic processing of speech remains poorly understood. Here, we investigate the nature of this abstraction using neural responses recorded intracranially while participants listened to conversational English speech. Capitalizing on multiple, language-specific patterns where phonological and acoustic information diverge, we demonstrate the causal efficacy of the phoneme as a unit of analysis and dissociate the unique contributions of phonemic and spectrographic information to neural responses. Quantitive higher-order response models also reveal that unique contributions of phonological information are carried in the covariance structure of the stimulus-response relationship. This suggests that linguistic abstraction is shaped by neurobiological mechanisms that involve integration across multiple spectro-temporal features and prior phonological information. These results link speech acoustics to phonology and morphosyntax, substantiating predictions about abstractness in linguistic theory and providing evidence for the acoustic features that support that abstraction.

Barriers to neurosurgery for medical students: a national study focused on the intersectionality of gender and race.

OBJECTIVE: Despite 51.2% of medical school graduates being female, only 29.8% of neurosurgery residency applicants are female. Furthermore, only 12.6% of neurosurgery applicants identify as underrepresented in medicine (URM). Evaluating the entry barriers for female and URM students is crucial in promoting the equity and diversity of the neurosurgical workforce. The objective of this study was to evaluate barriers to neurosurgery for medical students while considering the interaction between gender and race. METHODS: A Qualtrics survey was distributed widely to US medical students, assessing 14 factors of hesitancy toward neurosurgery. Likert scale responses, representing statement agreeability, converted to numeric values on a 7-point scale were analyzed by Mann-Whitney U-test and ANOVA comparisons with Bonferroni correction. RESULTS: Of 540 respondents, 68.7% were female and 22.6% were URM. There were 22.6% male non-URM, 7.4% male URM, 53.5% female non-URM, and 15.2% female URM respondents. The predominant reasons for hesitancy toward neurosurgery included work/life integration, length of training, competitiveness of residency position, and perceived malignancy of the field. Females were more hesitant toward neurosurgery due to maternity/paternity needs (p = 0.005), the absence of seeing people like them in the field (p < 0.001), and opportunities to pursue health equity work (p < 0.001). Females were more likely to have difficulties finding a mentor in neurosurgery who represented their identities (p = 0.017). URM students were more hesitant toward neurosurgery due to not seeing people like them in the field (p < 0.001). Subanalysis revealed that when students were stratified by both gender and URM status, there were more reasons for hesitancy toward neurosurgery that had significant differences between groups (male URM, male non-URM, female URM, and female non-URM students), suggesting the importance of intersectionality in this analysis. CONCLUSIONS: The authors highlight the implications of gender and racial diversity in the neurosurgical workforce on medical student interest and recruitment. Their findings suggest the importance of actively working to address these barriers, including 1) maternity/paternity policy reevaluation, standardization, and dissemination; and 2) actively providing resources for the creation of mentorship relationships for both women and URM students in an effort to create a workforce that aligns with the changing demographics of medical graduates to continue to improve diversity in neurosurgery.

Intraoperative application and early experience with novel high-resolution, high-channel-count thin-film electrodes for human microelectrocorticography.

OBJECTIVE: The study objective was to evaluate intraoperative experience with newly developed high-spatial-resolution microelectrode grids composed of poly(3,4-ethylenedioxythiophene) with polystyrene sulfonate (PEDOT:PSS), and those composed of platinum nanorods (PtNRs). METHODS: A cohort of patients who underwent craniotomy for pathological tissue resection and who had high-spatial-resolution microelectrode grids placed intraoperatively were evaluated. Patient demographic and baseline clinical variables as well as relevant microelectrode grid characteristic data were collected. The primary and secondary outcome measures of interest were successful microelectrode grid utilization with usable resting-state or task-related data, and grid-related adverse intraoperative events and/or grid dysfunction. RESULTS: Included in the analysis were 89 cases of patients who underwent a craniotomy for resection of neoplasms (n = 58) or epileptogenic tissue (n = 31). These cases accounted for 94 grids: 58 PEDOT:PSS and 36 PtNR grids. Of these 94 grids, 86 were functional and used successfully to obtain cortical recordings from 82 patients. The mean cortical grid recording duration was 15.3 ± 1.15 minutes. Most recordings in patients were obtained during experimental tasks (n = 52, 58.4%), involving language and sensorimotor testing paradigms, or were obtained passively during resting state (n = 32, 36.0%). There were no intraoperative adverse events related to grid placement. However, there were instances of PtNR grid dysfunction (n = 8) related to damage incurred by suboptimal preoperative sterilization (n = 7) and improper handling (n = 1); intraoperative recordings were not performed. Vaporized peroxide sterilization was the most optimal sterilization method for PtNR grids, providing a significantly greater number of usable channels poststerilization than did steam-based sterilization techniques (median 905.0 [IQR 650.8-935.5] vs 356.0 [IQR 18.0-597.8], p = 0.0031). CONCLUSIONS: High-spatial-resolution microelectrode grids can be readily incorporated into appropriately selected craniotomy cases for clinical and research purposes. Grids are reliable when preoperative handling and sterilization considerations are accounted for. Future investigations should compare the diagnostic utility of these high-resolution grids to commercially available counterparts and assess whether diagnostic discrepancies relate to clinical outcomes.

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma.

Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.

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.

Psychiatric outcomes after temporal lobe surgery in patients with temporal lobe epilepsy and comorbid psychiatric illness: A systematic review and meta-analysis.

BACKGROUND: The currently available evidence is unclear in regard to psychiatric outcomes of temporal lobe epilepsy (TLE) in patients with comorbid psychiatric disorders (PD). AIM: To identify and synthesize psychiatric outcomes in patients with TLE and comorbid psychiatric illnesses before and after TLE surgery. METHODS: Studies were included if participants were adults and/or children with temporal epilepsy and comorbid psychiatric illness. Surgical interventions included focal resection (e.g., lobectomy, selective amygdalohippocampectomy) or stereotactic laser ablation. Included studies reported on pre- and post- surgery data of comorbid psychiatric illness (e.g., mood and anxiety disorders, depression, psychosis, adjustment disorders, non-epileptic seizures, and personality disorders). RESULTS: Ten studies were included in the review. The proportion of patients achieving PD resolution or improvements after surgery varied widely between studies, ranging from 15 % to 57 % at the reported follow-up time. Three studies reported on PD symptom worsening after surgery, with considerable variations of patient proportions across studies. Meta-analysis suggests that 43 % of patients demonstrated improvement and 33 % of patients showed a worsening in psychiatric scores across all studies. Preliminary data from three studies suggest that seizure control may be associated with favourable psychiatric outcomes. CONCLUSION: A considerable proportion of reported TLE patients with comorbid psychiatric illnesses have improvement in their psychiatric symptoms after temporal lobe epilepsy surgery. There is scarcity of detailed outcome reporting including symptom scores, and to date, predictive factors for favourable vs unfavourable outcomes in this patient population are not clear. Further research on the topic is warranted.

White matter network organization predicts memory decline after epilepsy surgery.

The authors have withdrawn their manuscript owing to a substantial change in data analysis and findings/conclusions. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.