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The ability to remember what happened where and when constitutes the basic fabric of our memories and who we are. Forming and recalling memories depends on detecting novelty, building associations to prior knowledge, and dynamically retrieving context-relevant information. Previous studies have scrutinized the neural machinery for individual components of recognition or associative memory under laboratory conditions, such as recalling elements from arbitrary lists of words or pictures. In this study, we implemented a well-known card-matching game that integrates multiple components of memory formation together in a naturalistic setting to investigate the dynamic neural processes underlying complex natural human memory. We recorded intracranial field potentials from 1,750 depth or subdural electrodes implanted in 20 patients with pharmacologically-intractable epilepsy while they were performing the task. We leveraged generalized linear models to simultaneously assess the relative contribution of neural responses to distinct task components. Neural activity in the gamma frequency band signaled novelty and graded degrees of familiarity, represented the strength and outcome of associative recall, and finally reflected visual feedback on a trial-by-trial basis. The large-scale data and models enable dissociating and at the same time dynamically tracing the different cognitive components during fast, complex, and natural human memory behaviors.SignificanceDifferent aspects of memory like recognition, association, and recall have often been studied in isolation under laboratory conditions. Here we implemented a task that naturally integrates recognition, association, and retrieval, mimicking real-world memory experiences. Recording invasive intracranial field potentials from the human brain, this study shows that neural activity in the gamma frequency band in neocortical areas in temporal and frontal cortex reflects temporally overlapping yet computationally dissociable mental processes during dynamic memory formation.

Background and ObjectivesWhile somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.MethodsWe performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.ResultsSomatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in theSVILgene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown ofSVILvia the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found thatSVILregulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway.DiscussionWe propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants inSVILresult in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

Cognitive control involves flexibly combining multiple sensory inputs with task-dependent goals during decision making. Several tasks have been proposed to examine cognitive control, including Stroop, Eriksen-Flanker, and the Multi-source interference task. Because these tasks have been studied independently, it remains unclear whether the neural signatures of cognitive control reflect abstract control mechanisms or specific combinations of sensory and behavioral aspects of each task. To address this question, here we recorded invasive neurophysiological signals from 16 subjects and directly compared the three tasks against each other. Neural activity patterns in the theta and high-gamma frequency bands differed between incongruent and congruent conditions, revealing strong modulation by conflicting task demands. These neural signals were specific to each task, generalizing within a task but not across tasks. These results highlight the complex interplay between sensory inputs, motor outputs, and task demands and argue against a universal and abstract representation of conflict.

Background and ObjectivesTo assess the scope of surgical epilepsy exposure and training among fellows in Epilepsy and Clinical Neurophysiology (CNP) fellowship programs in the United States. Characteristics associated with increased fellow involvement in epilepsy surgery were evaluated.MethodsA 10-question multiple-choice survey was designed to characterize individual fellowship programs, epilepsy surgery programs, trainee involvement, and assessment of trainee performance. The survey was distributed to program directors of adult Epilepsy and CNP-EEG track fellowships between November 2021 and April 2022. Epilepsy surgery procedures included resective approaches, neurostimulation modalities, and palliative interventions approved for drug-resistant epilepsy. Associations between categorical variables were evaluated using the Fisher exact test.ResultsThere were 37 responses from a total of 72 survey recipients (51% response rate). The majority (68%) of surgical programs performed >30 surgical procedures per year. The range of procedures was overall similar across programs. At most programs, fellows were personally involved in 1–10 (49%) or 11–30 (46%) surgical procedures per year. Institutions with >50 surgical cases/year were more likely to expose fellows to >10 cases/y compared with institutions with volumes ≤50 per year (77% vs 33%,p= 0.017). Fellows had the greatest involvement in presurgical planning with more variable involvement in perioperative and postoperative activities. Competency in surgical management was primarily investigated through faculty assessments (97%), whereas oral (46%) and written (30%) assessments were less frequently used.DiscussionHigh-volume epilepsy surgery centers provide trainees with increased exposure despite also having more fellowship positions. There is variability in surgical epilepsy exposure, trainee involvement, and performance evaluation metrics between institutions. We identify specific areas that programs may focus on to improve fellow competency in the surgical management of epilepsy.

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer’s disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD., Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .

ObjectiveInterictal discharges (IIDs) and high frequency oscillations (HFOs) are neurophysiologic biomarkers of epilepsy. In this study, we use custom poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) microelectrodes to better understand their microscale dynamics.MethodsElectrodes with spatial resolution down to 50µm were used to record intraoperatively in 30 subjects. For IIDs, putative spatiotemporal paths were generated by peak-tracking, followed by clustering. For HFOs, repeating patterns were elucidated by clustering similar time windows. Fast events, consistent with multi-unit activity (MUA), were covaried with either IIDs or HFOs.ResultsIIDs seen across the entire array were detected in 93% of subjects. Local IIDs, observed across ConclusionsOverall, these data suggest micro-domains of irritable cortex that form part of an underlying pathologic architecture that contributes to the seizure network.SignificanceMicroelectrodes in cases of human epilepsy can reveal dynamics that are not seen by conventional electrocorticography and point to new possibilities for their use in the diagnosis and treatment of epilepsy.HighlightsPEDOT:PSS microelectrodes with at least 50µm spatial resolution uniquely reveal spatiotemporal patterns of markers of epilepsyHigh spatiotemporal resolution allows interictal discharges to be tracked and reveal cortical domains involved in microseizuresHigh frequency oscillations detected by microelectrodes demonstrate localized clustering on the cortical surface

The biophysical properties of neurons are the foundation for computation in the brain. Neuronal size is a key determinant of single neuron input–output features and varies substantially across species1–3. However, it is unknown whether different species adapt neuronal properties to conserve how single neurons process information4–7. Here we characterize layer 5 cortical pyramidal neurons across 10 mammalian species to identify the allometric relationships that govern how neuronal biophysics change with cell size. In 9 of the 10 species, we observe conserved rules that control the conductance of voltage-gated potassium and HCN channels. Species with larger neurons, and therefore a decreased surface-to-volume ratio, exhibit higher membrane ionic conductances. This relationship produces a conserved conductance per unit brain volume. These size-dependent rules result in large but predictable changes in somatic and dendritic integrative properties. Human neurons do not follow these allometric relationships, exhibiting much lower voltage-gated potassium and HCN conductances. Together, our results in layer 5 neurons identify conserved evolutionary principles for neuronal biophysics in mammals as well as notable features of the human cortex. Analyses of layer 5 cortical pyramidal neurons in 10 mammalian species show that human neurons are distinct in that they do not follow the expected allometric relationship between neuron size and membrane conductance.

The ability to regulate emotions in the service of meeting ongoing goals and task demands is a key aspect of adaptive human behavior in our volatile social world. Consequently, difficulties in processing and responding to emotional stimuli underlie many psychiatric diseases ranging from depression to anxiety, the common thread being effects on behavior. Behavior, which is made up of shifting, difficult to measure hidden states such as attention and emotion reactivity, is a product of integrating external input and latent mental processes. Directly measuring, and differentiating, separable hidden cognitive, emotional, and attentional states contributing to emotion conflict resolution, however, is challenging, particularly when only using task-relevant behavioral measures such as reaction time. State-space representations are a powerful method for investigating hidden states underlying complex systems. Using state-space modeling of behavior, we identified relevant hidden cognitive states and predicted behavior in a standardized emotion regulation task. After identifying and validating models which best fit the behavior and narrowing our focus to one model, we used targeted intracranial stimulation of the emotion regulation-relevant neurocircuitry, including prefrontal structures and the amygdala, to causally modulate separable states. Finally, we focused on this one validated state-space model to perform real-time, bidirectional closed-loop adaptive stimulation in a subset of participants. These approaches enable an improved understanding of how to sample and understand emotional processing in a way which could be leveraged in neuromodulatory therapy for disorders of emotional regulation.

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

Objective Atypical meningioma (AM) patients often undergo gross total resection (GTR) at the time of presentation, but subsequent prognosis and optimal management remain unclear. We sought to define the long-term recurrence rate of AMs after GTR, along with factors predicting recurrence, including postoperative radiation. Methods We performed a retrospective review of 108 AMs after GTR at our institution from 1993 to 2004. Recurrence risk factors were analyzed using multivariate Cox regression. Results There were 600 patient-years of imaging follow-up on 48 men and 60 women. Of 108 tumors, 30 (28%) recurred 3 to 144 months after GTR (mean, 36 months). Actuarial tumor recurrence rates were 7% (1 year), 41% (5 years), and 48% (10 years). Of 108 patients, 8 received postoperative radiation without recurrence (P = 0.1). Multivariate analysis including age, sex, postoperative radiation, tumor location, MIB-1 labeling index, and 6 atypical-defining histological features identified recurrence-predicting factors: older age (hazard ratio, 1.6/decade; P = 0.01), sheeting (hazard ratio, 2.2; P = 0.025), and prominent nucleoli (hazard ratio, 2.1; P = 0.034). Recursive partitioning identified a subset, men with mitoses and prominent nucleoli, with 70% recurrence (n = 14). All patients with recurrences received radiation, and 22 of 30 patients underwent craniotomies (average, 2.7 craniotomies per patient with recurrence; range, 1-7 craniotomies). Only 1 of 22 re-resected meningiomas underwent malignant transformation. Of 30 patients with recurrence, 10 experienced tumor-induced mortality an average of 7 years after recurrence (range, 1-14 years). Conclusion After GTR without postoperative radiation, AMs have a high recurrence rate. Most recurrences occurred within 5 years after resection. Recurrences caused numerous reoperations per patient and shortened survival. Our finding suggesting lower recurrence rates in patients undergoing immediate postoperative radiation should be investigated in larger, prospective series.

Purpose: To identify MR spectroscopic changes in the rat hippocampus following proton radiosurgery. Methods and Materials: A group of 12 rats were treated with Bragg peak proton beam irradiation involving the right hippocampus. Single doses of 30 CGE, 50 CGE, 70 CGE, 90 CGE were delivered to groups of 3 animals using single fraction technique. Animals were imaged using a standard 3 T GE Signa MRI at 4 months following treatment. An untreated animal was also studied. A 3″ surface coil was employed to obtain T1 weighted coronal pre- and post-gadolinium images (TR 600 and TE 30) and dual echo T2 weighted coronal images (TR 3000, TE 30/90). Volumetric analysis with custom software was done to evaluate areas of increased signal on T2 weighted images and the development of hydrocephalus was examined. Animals were sacrificed and specimens of the treated hippocampus were harvested for High Resolution Magic Angle Spinning MR Spectroscopy (HRMAS) followed by histopathology of the tissue samples. Peak values of choline, creatine, N-acetyl aspartate and lipids were evaluated and compared. Results: Peak tissue injury occurred in the surviving 90 CGE animal by both T2 weighted and post-gadolinium imaging. Gadolinium enhancement was seen in decreasing volumes of tissue at dosage levels from 90 to 50 CGE. Hydrocephalus was seen on the untreated side in the 90 CGE animal likely because of mass effect, while it was seen in small degrees in the side of treatment in the 70 and 50 CGE animals. Histopathology showed changes at 90 and 70 CGE, but not at 50 or 30 CGE at this time point using H and E stains. HRMAS showed spectroscopic changes in the surviving 90 and 70 CGE animals but not in the 50 and 30 CGE animals. Statistical significance was not reached because of the small sample size. Conclusions: Following single dose proton radiosurgery of rat hippocampus, HRMAS is able to identify metabolic changes induced by radiation. Studies built on these principles may help develop non-invasive MR spectroscopic methods to distinguish radiation changes from tumor recurrence.

Recording neural activity during neurosurgical interventions is an invaluable tool for both improving patient outcomes and advancing our understanding of neural mechanisms and organization. However, increasing clinical electrodes' signal-to-noise and spatial specificity requires overcoming substantial physical barriers due to the compromised metal electrochemical interface properties. The electrochemical properties of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) based interfaces surpass those of current clinical electrocorticography electrodes. Here, robust fabrication process of PEDOT:PSS microelectrode arrays is demonstrated for safe and high fidelity intraoperative monitoring of human brain. PEDOT:PSS microelectrodes measure significant differential neural modulation under various clinically relevant conditions. This study reports the first evoked (stimulus-locked) cognitive activity with changes in amplitude across pial surface distances as small as 400 µm, potentially enabling basic neurophysiology studies at the scale of neural micro-circuitry.

Surgical interventions for the treatment of psychiatric disease have a long history. Before the availability of effective psychotropic drugs, the widespread practice of psychosurgery reached a dramatic peak in the mid 20th century, with the notorious era of the Freeman lobotomy. The practice of psychosurgery continued on a much smaller scale for medically-refractory psychiatric patients, continuing to develop with a concept of minimalism out of the school of stereotaxy in neurosurgery. The modern era of psychosurgery has established four procedures with extensive experience supporting their indications and efficacies in properly selected patients. All of modern intracranial psychosurgery is stereotactic in nature, though historically interventions have been lesion-based. More recently, the idea of psychosurgery has been met with renewed enthusiasm, favoring DBS to avoid the historic dependence on lesioning. While there are some advantages to DBS over ablative methods, it is important to keep in mind that the two modalities are neither functionally nor clinically equivalent. Furthermore, while DBS is a new and experimental modality with unproven long-term effects, there is extensive experience with lesioning that supports its benefit for carefully selected psychiatric patients. Furthermore, the theoretical and practical aspects of each modality, warrant continued consideration and research to determine their optimal roles in psychosurgical practice. However, it is clear that ablative methods play an important role in the surgical management of severe, intractable psychiatric disease today and will likely continue to do so in the future.

All tissues of the body are innervated by nociceptors with the exception of the neuraxis. Unlike other physiological processes, pain does not emanate from a single specific organ but is a distributed system. There is also no completely objective way to know that pain truly exists nor a single target or location to treat it. Therefore, patient selection and psychological assessment is of the utmost importance in evaluating a patient for a surgical pain-relief procedure. When evaluating a patient with chronic pain and entertaining a surgical option, one practical approach to discriminate the types of procedures available is to divide them in to “Neuromodulation” and “Neuroablation” procedures. Neuroablation is typically a destructive procedure that interrupts afferent input from the nociceptive pathways or selectively ablates the thalamic and cortical areas that mediate perception of painful stimuli. Although the lesions themselves are irreversible, the long term effect on pain perception is often limited to months or years because of the adaptablitiy and plasticity of the nervous system. Neuromodulation on the other hand, seeks to decrease pain by modulating nociceptive input by either pharmacological or electrical means. In this chapter, we examine the neurosurgical procedures to treat pain syndromes.

Object. The Photon Radiosurgery System (PRS) is a miniature x-ray generator that can stereotactically irradiate intracranial tumors by using low-energy photons. Treatment with the PRS typically occurs in conjunction with stereotactic biopsy, thereby providing diagnosis and treatment in one procedure. The authors review the treatment of patients with brain metastases with the aid of the PRS and discuss the indications, advantages, and limitations of this technique. Methods. Clinical characteristics, treatment parameters, neuroimaging-confirmed outcome, and survival were reviewed in all patients with histologically verified brain metastases who were treated with the PRS at the Massachusetts General Hospital between December 1992 and November 2000. Local control of lesions was defined as either stabilization or diminution in the size of the treated tumor as confirmed by Gd-enhanced magnetic resonance imaging. Between December 1992 and November 2000, 72 intracranial metastatic lesions in 60 patients were treated with the PRS. Primary tumors included lung (33 patients), melanoma (15 patients), renal cell (five patients), breast (two patients), esophageal (two patients), colon (one patient), and Merkle cell (one patient) cancers, and malignant fibrous histiocytoma (one patient). Supratentorial metastases were distributed throughout the cerebrum, with only one cerebellar metastasis. The lesions ranged in diameter from 6 to 40 mm and were treated with a minimal peripheral dose of 16 Gy (range 10–20 Gy). At the last follow-up examination (median 6 months), local disease control had been achieved in 48 (81%) of 59 tumors. An actuarial analysis demonstrated that the survival rates at 6 and 12 months were 63 and 34%, respectively. Patients with a single brain metastasis survived a mean of 11 months. Complications included four patients with postoperative seizures, three with symptomatic cerebral edema, two with hemorrhagic events, and three with symptomatic radiation necrosis requiring surgery. Conclusions. Stereotactic interstitial radiosurgery performed using the PRS can obtain local control of cerebral metastases at rates that are comparable to those achieved through open resection and external stereotactic radiosurgery. The major advantage of using the PRS is that effective treatment can be accomplished at the time of stereotactic biopsy.

Inhibitory neuronal activity is critical for the normal functioning of the brain, but is thought to go awry during neurological disorders such as epilepsy. Animal models have suggested both decreased and increased inhibition as possible initiators of epileptic activity, but it is not known if, or how, human inhibitory neurons shape seizures. Here, using large-scale recordings of neocortical single neurons in patients with secondarily generalized tonic-clonic seizures, we show that fast-spiking (FS) inhibitory activity first increases as a seizure spreads across the neocortex, impeding and altering the spatial flow of fast epileptic traveling waves. Unexpectedly, however, FS cells cease firing less than half-way through a seizure. We use biophysically-realistic computational models to show that this cessation is due to FS cells entering depolarization block as a result of extracellular potassium accumulation during the seizure and not because they are inhibited by other inhibitory subtypes. Strikingly, this absence of FS inhibitory activity is accompanied by dramatic increases in local seizure amplitude along with unobstructed traveling waves and is seen during all secondarily generalized seizures examined, independent of etiology or focus. FS cessation also leads to prominent spike-and-wave events, suggesting that FS cell dynamics control the transition between the tonic and clonic phases of these seizures. Thus, it may be possible to curtail human seizures by preventing inhibitory neurons from entering potassium-dependent depolarization block, a novel and potentially powerful therapeutic avenue in treating multiple kinds of epilepsies.