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Background and Objectives: Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) motor symptoms. DBS is also associated with postoperative cognitive change in some patients. Previous studies found associations between medial active electrode contacts and overall cognitive decline. Our current aim is to determine the relationship between active electrode contact location and domain-specific cognitive changes., Methods: A single-institution retrospective cohort study was conducted in patients with PD who underwent subthalamic nucleus (STN) DBS from August 05, 2010, to February 22, 2021, and received preoperative and postoperative neuropsychological testing. Standardized norm-referenced test z-scores were categorized into attention, executive function, language, verbal memory, and visuospatial domains. SD change scores were averaged to create domain-specific change scores. We identified anterior commissure/posterior commissure coordinates of active electrode contacts in atlas space. We evaluated differences in active electrode contact location between patients with a domain score decrease of at least 1 SD and less than 1 SD. We performed multiple variable linear regression controlling for age, sex, education, time from surgery to postoperative neuropsychological testing (follow-up duration), disease duration, preoperative unified Parkinson's disease rating scale off medication scores, and preoperative memory scores to determine the relationship between active electrode contact location and domain change., Results: A total of 83 patients (male: n = 60, 72.3%) were included with a mean age of 63.6 ± 8.3 years, median disease duration of 9.0 [6.0, 11.5] years, and median follow-up duration of 8.0 [7.0, 11.0] months. More superior active electrode contact location in the left STN (P = .002) and higher preoperative memory scores (P < .0001) were associated with worsening memory. Active electrode contact location was not associated with change in other domains., Conclusion: In patients with PD who underwent STN DBS, we found an association between superior active electrode contacts in the left STN and verbal memory decline. Our study increases understanding of factors associated with cognitive change after DBS and may help inform postoperative programming., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in 8-12 weeks across all animals, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration. Brain stimulation led to acute increases in cerebrospinal levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF). Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging., Competing Interests: Competing Interests: none

Successful surgical treatment of drug-resistant epilepsy traditionally relies on the identification of seizure onset zones (SOZs). Connectome-based analyses of electrographic data from stereo electroencephalography (SEEG) may empower improved detection of SOZs. Specifically, connectome-based analyses based on the interictal suppression hypothesis posit that when the patient is not having a seizure, SOZs are inhibited by non-SOZs through high inward connectivity and low outward connectivity. However, it is not clear whether there are other motifs that can better identify potential SOZs. Thus, we sought to use unsupervised machine learning to identify network motifs that elucidate SOZs and investigate if there is another motif that outperforms the ISH. Resting-state SEEG data from 81 patients with drug-resistant epilepsy undergoing a pre-surgical evaluation at Vanderbilt University Medical Center were collected. Directed connectivity matrices were computed using the alpha band (8-13 Hz). Principal component analysis (PCA) was performed on each patient's connectivity matrix. Each patient's components were analysed qualitatively to identify common patterns across patients. A quantitative definition was then used to identify the component that most closely matched the observed pattern in each patient. A motif characteristic of the interictal suppression hypothesis (high-inward and low-outward connectivity) was present in all individuals and found to be the most robust motif for identification of SOZs in 64/81 (79%) patients. This principal component demonstrated significant differences in SOZs compared to non-SOZs. While other motifs for identifying SOZs were present in other patients, they differed for each patient, suggesting that seizure networks are patient specific, but the ISH is present in nearly all networks. We discovered that a potentially suppressive motif based on the interictal suppression hypothesis was present in all patients, and it was the most robust motif for SOZs in 79% of patients. Each patient had additional motifs that further characterized SOZs, but these motifs were not common across all patients. This work has the potential to augment clinical identification of SOZs to improve epilepsy treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Epilepsy is a common neurological disorder affecting 1% of the global population. Loss of consciousness in focal impaired awareness seizures (FIASs) and focal-to-bilateral tonic-clonic seizures (FBTCSs) can be devastating, but the mechanisms are not well understood. Although ictal activity and interictal connectivity changes have been noted, the network states of focal aware seizures (FASs), FIASs, and FBTCSs have not been thoroughly evaluated with network measures ictally., Methods: We obtained electrographic data from 74 patients with stereoelectroencephalography (SEEG). Sliding window band power, functional connectivity, and segregation were computed on preictal, ictal, and postictal data. Five-minute epochs of wake, rapid eye movement sleep, and deep sleep were also extracted. Connectivity of subcortical arousal structures was analyzed in a cohort of patients with both SEEG and functional magnetic resonance imaging (fMRI). Given that custom neuromodulation of seizures is predicated on detection of seizure type, a convolutional neural network was used to classify seizure types., Results: We found that in the frontoparietal association cortex, an area associated with consciousness, both consciousness-impairing seizures (FIASs and FBTCSs) and deep sleep had increases in slow wave delta (1-4 Hz) band power. However, when network measures were employed, we found that only FIASs and deep sleep exhibited an increase in delta segregation and a decrease in gamma segregation. Furthermore, we found that only patients with FIASs had reduced subcortical-to-neocortical functional connectivity with fMRI versus controls. Finally, our deep learning network demonstrated an area under the curve of .75 for detecting consciousness-impairing seizures., Significance: This study provides novel insights into ictal network measures in FASs, FIASs, and FBTCSs. Importantly, although both FIASs and FBTCSs result in loss of consciousness, our results suggest that ictal network changes in FIASs uniquely resemble those that occur during deep sleep. Our results may inform novel neuromodulation strategies for preservation of consciousness in epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Non-motor symptoms, including depression and cognitive impairment, are common in essential tremor (ET), but associations between these symptoms and tremor are poorly understood., Methods: A retrospective, single-institution, cohort study evaluated 140 patients with ET undergoing evaluation for deep brain stimulation (DBS) surgery. The Fahn-Tolosa-Marin (FTM) or Washington Heights-Inwood Genetic Study of ET (WHIGET) scale was used to grade tremor. Tremor scores were divided into quartiles. Patients underwent clinical neuropsychological evaluations that included a comprehensive cognitive test battery and Beck Depression Inventory-II (BDI-II). Subgroup analysis was performed with groups who met criteria for depression (BDI-II > 14) or overall cognitive impairment (<9th percentile on at least two dissimilar cognitive tests). Independent samples t-tests were used for continuous variables and chi square tests for categorical variables. Univariable and multivariable regressions were used to determine relationships between tremor and non-motor scores., Results: Tremor quartile was correlated with language domain performance (p = 0.044) but not depression scores. FTM score was associated with BDI-II (β = 0.940, p = 0.010), language (β = -0.936, p = 0.012), and visuospatial domain (β = -0.836, p = 0.025) scores, such that worse tremor was associated with more depression and worse language and visuospatial function. WHIGET score was not associated with any neuropsychological scores on multivariable regression., Conclusion: FTM score was associated with language, visuospatial, and mood symptoms, suggesting a relationship between the severity of these symptom types. Different tremor scores capture different motor symptoms and relationships with nonmotor symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Anterior capsulotomy (AC) is a therapeutic option for patients with severe, treatment-resistant obsessive-compulsive disorder (OCD). The procedure can be performed via multiple techniques, with stereotactic radiosurgery (SRS) gaining popularity because of its minimally invasive nature. The risk-benefit profile of AC performed specifically with SRS has not been well characterized. Therefore, the primary objective of this study was to characterize outcomes following stereotactic radiosurgical AC in OCD patients., Methods: Studies assessing mean Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores before and after stereotactic radiosurgical AC for OCD were included in this analysis. Inverse-variance fixed-effect modeling was used for pooling, and random-effects estimate of the ratio of means and standard mean differences were calculated at 6 months, 12 months, and the last follow-up for Y-BOCS scores, as well as the last follow-up for the Beck Depression Inventory (BDI)/BDI-II scores. A generalized linear mixed model was used to generate fixed- and random-effects models for categorical outcomes. Univariate random-effects meta-regression was used to evaluate associations between postoperative Y-BOCS scores and study covariates. Adverse events were summed across studies. Publication bias was assessed with Begg's test., Results: Eleven studies with 180 patients were eligible for inclusion. The mean Y-BOCS score decreased from 33.28 to 17.45 at the last-follow up (p < 0.001). Sixty percent of patients were classified as responders and 10% as partial responders, 18% experienced remission, and 4% had worsened Y-BOCS scores. The degree of improvement in the Y-BOCS score correlated with time since surgery (p = 0.046). In the random-effects model, the mean BDI at the last follow-up was not significantly different from that preoperatively. However, in an analysis performed with available paired pre- and postoperative BDI/BDI-II scores, there was significant improvement in the BDI/BDI-II scores postoperatively. Adverse events numbered 235, with headaches, weight change, mood changes, worsened depression/anxiety, and apathy occurring most commonly., Conclusions: Stereotactic radiosurgical AC is an effective technique for treating OCD. Its efficacy is similar to that of AC performed via other lesioning techniques.

Objective: Subthalamic nucleus (STN) and globus pallidus internus (GPI) deep brain stimulation (DBS) effectively treat motor symptoms in Parkinson's disease (PD) but may be associated with cognitive and psychiatric changes in some patients. Evaluation of changes in cognitive and psychiatric symptoms following DBS is complicated by changes in these symptoms that occur as part of the natural disease course. The aim of this study was to evaluate whether electrode position was associated with changes in neurocognitive symptoms in patients who underwent STN and GPI DBS., Methods: A single-institution retrospective cohort study was conducted on patients with PD who underwent DBS from 2008 to 2019. Cognitive and psychiatric outcomes included Beck Depression Inventory II (BDI-II) score, presence of impulsive-compulsive behavior (ICB), Mini-Mental State Examination (MMSE) score, and overall cognitive status grade determined by comprehensive neuropsychology testing (normal, mild impairment, moderate impairment, and dementia). Pre- and postoperative comparisons were performed using a Wilcoxon signed-rank test or paired t-test. Patients with and without cognitive decline were compared using a Mann-Whitney U-test or unpaired t-test. A chi-square test was used for categorical comparisons., Results: One hundred thirty patients were included (mean age 62.5 ± 7.9 years). At a mean postoperative follow-up from DBS of 13.0 ± 12.7 (range 6-66) months, there was an improvement in ICB (26.3% preoperatively vs 15.0% postoperatively, p = 0.017), but a decline in MMSE score (28.6 ± 1.6 vs 27.6 ± 2.0, p < 0.001) and overall cognitive status (normal: 66.2% vs 39.2%; mild: 12.3% vs 17.7%; moderate: 21.5% vs 33.1%; dementia: 0.0% vs 10.0%; p < 0.001). Patients undergoing STN DBS had a worse decline in overall cognitive status than patients who underwent GPI DBS (p = 0.006). Postoperative cognitive decline was associated with a more medial electrode position only for patients who underwent STN DBS., Conclusions: Cognitive change was observed in some patients with PD who underwent both GPI and STN DBS, likely due partly to underlying disease progression. Compared with GPI DBS, STN DBS was associated with a greater likelihood of cognitive decline. In STN but not GPI DBS, cognitive decline was associated with medialized electrode position, suggesting modulation of nonmotor STN divisions may contribute to cognitive changes following STN DBS.

Oscillatory activity in the local field potential (LFP) is thought to be a marker of cognitive processes. To understand how it differentiates tasks and brain areas in humans, we recorded LFPs in 15 adults with intracranial depth electrodes, as they performed visual-spatial and shape working memory tasks. Stimulus appearance produced widespread, broad-band activation, including in occipital, parietal, temporal, insular, and prefrontal cortex, and the amygdala and hippocampus. Occipital cortex was characterized by most elevated power in the high-gamma (100-150 Hz) range during the visual stimulus presentation. The most consistent feature of the delay period was a systematic pattern of modulation in the beta frequency (16-40 Hz), which included a decrease in power of variable timing across areas, and rebound during the delay period. These results reveal the widespread nature of oscillatory activity across a broad brain network and region-specific signatures of oscillatory processes associated with visual working memory., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD), but disparities exist in access to DBS along gender, racial, and socioeconomic lines., Summary: Women are underrepresented in clinical trials and less likely to undergo DBS compared to their male counterparts. Racial and ethnic minorities are also less likely to undergo DBS procedures, even when controlling for disease severity and other demographic factors. These disparities can have significant impacts on patients' access to care, quality of life, and ability to manage their debilitating movement disorders., Key Messages: Addressing these disparities requires increasing patient awareness and education, minimizing barriers to equitable access, and implementing diversity and inclusion initiatives within the healthcare system. In this systematic review, we first review literature discussing gender, racial, and socioeconomic disparities in DBS access and then propose several patient, provider, community, and national-level interventions to improve DBS access for all populations., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Despite the known benefits of deep brain stimulation (DBS), the cost of the procedure can limit access and can vary widely. Our aim was to conduct a systematic review of the reported costs associated with DBS, as well as the variability in reporting cost-associated factors to ultimately increase patient access to this therapy., Methods: A systematic review of the literature for cost of DBS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase databases were queried. Olsen & Associates (OANDA) was used to convert all reported rates to USD. Cost was corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022., Results: Twenty-six articles on the cost of DBS surgery from 2001 to 2021 were included. The median number of patients across studies was 193, the mean reported age was 60.5 ± 5.6 years, and median female prevalence was 38.9%. The inflation- and currency-adjusted mean cost of the DBS device was USD 21,496.07 ± USD 8,944.16, the cost of surgery alone was USD 14,685.22 ± USD 8,479.66, the total cost of surgery was USD 40,942.85 ± USD 17,987.43, and the total cost of treatment until 1 year of follow-up was USD 47,632.27 ± USD 23,067.08. There were no differences in costs observed across surgical indication or country., Conclusion: Our report describes the large variation in DBS costs and the manner of reporting costs. The current lack of standardization impedes productive discourse as comparisons are hindered by both geographic and chronological variations. Emphasis should be put on standardized reporting and analysis of reimbursement costs to better assess the variability of DBS-associated costs in order to make this procedure more cost-effective and address areas for improvement to increase patient access to DBS., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Deep brain stimulation (DBS) is commonly performed with patients awake to perform intraoperative microelectrode recordings and/or macrostimulation testing to guide final electrode placement. Supplemental information from atlas-based databases derived from prior patient data and visualised as efficacy heat maps transformed and overlaid onto preoperative MRIs can be used to guide preoperative target planning and intraoperative final positioning. Our quantitative analysis of intraoperative testing and corresponding changes made to final electrode positioning aims to highlight the value of intraoperative neurophysiological testing paired with image-based data to optimise final electrode positioning in a large patient cohort., Methods: Data from 451 patients with movement disorders treated with 822 individual DBS leads at a single institution from 2011 to 2021 were included. Atlas-based data was used to guide surgical targeting. Intraoperative testing data and coordinate data were retrospectively obtained from a large patient database. Medical records were reviewed to obtain active contact usage and neurologist-defined outcomes at 1 year., Results: Microelectrode recording firing profiles differ per track, per target and inform the locations where macrostimulation testing is performed. Macrostimulation performance correlates with the final electrode track chosen. Centroids of atlas-based efficacy heat maps per target were close in proximity to and may predict active contact usage at 1 year. Overall, patient outcomes at 1 year were improved for patients with better macrostimulation response., Conclusions: Atlas-based imaging data is beneficial for target planning and intraoperative guidance, and in conjunction with intraoperative neurophysiological testing during awake DBS can be used to individualize and optimise final electrode positioning, resulting in favourable outcomes., Competing Interests: Competing interests: Some of the technology described in this article has been licensed by Vanderbilt University to FHC, Inc. which distributes it under the name WayPoint Navigator. BD receives royalties for this license. PK has a fiduciary relationship with NeuroTargeting, LLC, but has not received financial compensation in the 5 years prior to this article., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Cognitive impairment is the most frequent non-motor symptom in Parkinson's disease and is associated with deficits in a number of cognitive functions including working memory. However, the pathophysiology of Parkinson's disease cognitive impairment is poorly understood. Beta oscillations have previously been shown to play an important role in cognitive functions including working memory encoding. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits increases the spectral power of beta oscillations and results in Parkinson's disease motor symptoms. Analogous changes in parallel cognitive CSTC circuits involving the caudate and dorsolateral prefrontal cortex (DLPFC) may contribute to Parkinson's disease cognitive impairment. The objective of our study is to evaluate whether changes in beta oscillations in the caudate and DLPFC contribute to cognitive impairment in Parkinson's disease patients. To investigate this, we used local field potential recordings during deep brain stimulation surgery in 15 patients with Parkinson's disease. Local field potentials were recorded from DLPFC and caudate at rest and during a working memory task. We examined changes in beta oscillatory power during the working memory task as well as the relationship of beta oscillatory activity to preoperative cognitive status, as determined from neuropsychological testing results. We additionally conducted exploratory analyses on the relationship between cognitive impairment and task-based changes in spectral power in additional frequency bands. Spectral power of beta oscillations decreased in both DLPFC and caudate during working memory encoding and increased in these structures during feedback. Subjects with cognitive impairment had smaller decreases in caudate and DLPFC beta oscillatory power during encoding. In our exploratory analysis, we found that similar differences occurred in alpha frequencies in caudate and theta and alpha in DLPFC. Our findings suggest that oscillatory power changes in cognitive CSTC circuits may contribute to cognitive symptoms in patients with Parkinson's disease. These findings may inform the future development of novel neuromodulatory treatments for cognitive impairment in Parkinson's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Essential tremor (ET) and Parkinson's disease (PD) are the most common tremor disorders and are common indications for deep brain stimulation (DBS). In some patients, PD and ET symptoms overlap and diagnosis can be challenging based on clinical criteria alone. The objective of this study was to identify structural brain differences between PD and ET DBS patients to help differentiate these disorders and improve our understanding of the different brain regions involved in these pathologic processes., Methods: We included ET and PD patients scheduled to undergo DBS surgery in this observational study. Patients underwent 3T brain MRI while under general anesthesia as part of their procedure. Cortical thicknesses and subcortical volumes were quantified from T1-weighted images using automated multi-atlas segmentation. We used logistic regression analysis to identify brain regions associated with diagnosis of ET or PD., Results: 149 ET and 265 PD patients were included. Smaller volumes in the pallidum and thalamus and reduced thickness in the anterior orbital gyrus, lateral orbital gyrus, and medial precentral gyrus were associated with greater odds of ET diagnosis. Conversely, reduced volumes in the caudate, amygdala, putamen, and basal forebrain, and reduced thickness in the orbital part of the inferior frontal gyrus, supramarginal gyrus, and posterior cingulate were associated with greater odds of PD diagnosis., Conclusions: These findings identify structural brain differences between PD and ET patients. These results expand our understanding of the different brain regions involved in these disorders and suggest that structural MRI may help to differentiate patients with these two disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Why are people with focal epilepsy not continuously having seizures? Previous neuronal signalling work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is a high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure-onset zones have increased inward connectivity that could be associated with interictal suppression of seizure activity. Accordingly, we hypothesize that seizure-onset zones are actively suppressed by the rest of the brain network during interictal states. Full testing of this hypothesis would require collaboration across multiple domains of neuroscience. We focused on partially testing this hypothesis at the electrographic network level within 81 individuals with drug-resistant focal epilepsy undergoing presurgical evaluation. We used intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, early propagation and non-involved zones. We then used diffusion imaging to acquire estimates of white-matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, we generated a resting-state classification model to assist clinicians in detecting seizure-onset and propagation zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and early propagation zones demonstrate markedly increased inwards connectivity and decreased outwards connectivity using both resting-state (one-way ANOVA, P-value = 3.13 × 10-13) and neurostimulation analyses to evaluate evoked responses (one-way ANOVA, P-value = 2.5 × 10-3). When controlling for the distance between regions, the difference between inwards and outwards connectivity remained stable up to 80 mm between brain connections (two-way repeated measures ANOVA, group effect P-value of 2.6 × 10-12). Structure-function coupling analyses revealed that seizure-onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue (two-way repeated measures ANOVA, interaction effect P-value of 9.76 × 10-21). Using these observations, our support vector classification models achieved a maximum held-out testing set accuracy of 92.0 ± 2.2% to classify early propagation and seizure-onset zones. These results suggest that seizure-onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure-onset zones. These findings have implications for the identification of seizure-onset zones using only brief electrographic recordings to reduce patient morbidity and augment the presurgical evaluation of drug-resistant epilepsy. Further testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative and neuromodulation approaches to improve surgical success rates in those suffering from drug-resistant focal epilepsy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Acetylcholine is a critical modulatory neurotransmitter for cognitive function. Cholinergic drugs improve cognitive performance and enhance neuronal activity in the sensory and association cortices. An alternative means of improving cognitive function is through the use of deep brain stimulation. Prior animal studies have demonstrated that stimulation of the nucleus basalis of Meynert through DBS improves cognitive performance on a visual working memory task to the same degree as cholinesterase inhibitors. Additionally, unlike current pharmacological treatments for neurocognitive disorders, DBS does not lose efficacy over time and adverse effects are rare. These findings suggest that DBS may be a promising alternative for treating cognitive impairments in neurodegenerative disorders such as Alzheimer's disease. Thus, further research and human trials should be considered to assess the potential of DBS as a therapeutic treatment for these disorders.

Objective: Despite advances in the treatment of psychiatric diseases, currently available therapies do not provide sufficient and durable relief for as many as 30-40% of patients. Neuromodulation, including deep brain stimulation (DBS), has emerged as a potential therapy for persistent disabling disease, however it has not yet gained widespread adoption. In 2016, the American Society for Stereotactic and Functional Neurosurgery (ASSFN) convened a meeting with leaders in the field to discuss a roadmap for the path forward. A follow-up meeting in 2022 aimed to review the current state of the field and to identify critical barriers and milestones for progress., Design: The ASSFN convened a meeting on June 3, 2022 in Atlanta, Georgia and included leaders from the fields of neurology, neurosurgery, and psychiatry along with colleagues from industry, government, ethics, and law. The goal was to review the current state of the field, assess for advances or setbacks in the interim six years, and suggest a future path forward. The participants focused on five areas of interest: interdisciplinary engagement, regulatory pathways and trial design, disease biomarkers, ethics of psychiatric surgery, and resource allocation/prioritization. The proceedings are summarized here., Conclusion: The field of surgical psychiatry has made significant progress since our last expert meeting. Although weakness and threats to the development of novel surgical therapies exist, the identified strengths and opportunities promise to move the field through methodically rigorous and biologically-based approaches. The experts agree that ethics, law, patient engagement, and multidisciplinary teams will be critical to any potential growth in this area., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Sarah Bick receives funding from the Neurosurgery Research and Career Development Program (K12 NS080223) and consulting honoraria from Varian Medical Systems. Rafael Carbunaru owns stock options and is an employee of Boston Scientific, a manufacturer of DBS devices. Jennifer Chandler receives funding from CIHR (Canadian Institutes of Health Research) through the ERANET-Neuron program. Binith Cheeran owns stock options and is an employee of Abbott, a manufacturer of DBS devices. Rachel Davis receives consulting honoraria from Medtronic and speaker fees from Baylor for an OCD conference. Darin Dougherty's research has been funded by the International OCD Foundation, Brain and Behavior Research Foundation, National Institute of Mental Health, Tiny Blue Dot Foundation and Medtronic; he has received honoraria and consultation fees from Medtronic, Sage, and Celanese and has equity in Neurable, Innercosmos, and Intrinsic Powers. Ashley Feinsinger receives funding from the NIH (RF1MH121373 and UH3NS103442), received honoraria for her work on the NIH Neuroethics Workgroup, she is on an advisory board of Vivani Medical Products (Orion Early Feasibility Study), and she is on the data safety monitoring board of R01 MH122431. Kelly Foote reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Medtronic (donation of closed-loop DBS devices) outside the submitted work; and grants from Medtronic, Boston Scientific, and Functional Neuromodulation outside the submitted work. Wayne Goodman receives funding from NIH (UH3NS100459), the McNair Foundation, and Biohaven. WG receives royalties from Nview, LLC and OCDscales, LLC as well as consulting honoraria from Biohaven. Aysegul Gunduz receives investigational device donations from Medtronic under the NIH BRAIN Public-Private Partnership agreements, and her research is funded by NIH grants UH3NS095553, R01NS096008, UH3NS119844. Casey Halpern has patents related to sensing and brain stimulation for the treatment of neuropsychiatric disorders, and he works as a consultant for Boston Scientific Neuromodulation and Insightec. Brian Kopell has received consulting honoraria from Abbott and Medtronic. Cynthia Kubu receives grant funding from the NIH (5RO1MH114853, 5RC1NS068086, 3RF1MH123407-01S1) and participates on the data safety monitoring boards for studies investigating the use of DBS for pain (UHS3 BRIAN/UH3 HEAL, 3UH3NS113661). She is the president of the Society for Clinical Neuropsychology. Sarah Lisanby receives funding from the NIMH (1ZIAMH002955) and has a role on the Scientific Advisory Boards of the Aalto University School of Science and the German Center for Brain Stimulation. Cameron McIntyre is a paid consultant for Boston Scientific Neuromodulation, receives royalties from Hologram Consultants, Neuros Medical, Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, BrainDynamics, CereGate, Autonomic Technologies, Cardionomic, Enspire DBS. Michael Okun serves as Medical Advisor for the Parkinson's Foundation, and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. Michael Okun's research is supported by: NIHR01 NR014852, R01NS096008, UH3NS119844, U01NS119562. Michael Okun is PI of the NIH R25NS108939 Training Grant. Michael Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). Nader Pouratian receives research funding from NIH (R24 MH114796, UH3 NS103442, UH3 NS103549, R01 NS097782, UH3 NS113661, R01 GM135420, RF1 MH121373), consulting/presentation honoraria from Abbott, Sensoria Therapeutics, Boston Scientific, and BrainLab. Nader Pouratian is on an advisory board at Abbott Laboratories and has leadership positions in the Congress of Neurological Surgeons and American Society of Stereotactic and Functional Neurosurgery. Robert Raike owns stock options and is an employee of Medtronic, a manufacturer of DBS devices. Patricio Riva-Posse has received honoraria for consulting for Janssen Pharmaceuticals, Abbott Neuromodulation, and LivaNova. Sameer Sheth received funding from the McNair Foundation for this work. SS receives consulting honoraria from Boston Scientific, Neuropace, Zimmer Biomet, and Koh Young. Nora Vanegas-Arroyave receives research funding from NIH and the Michael J. Fox foundation. Alik Widge has received honoraria for consulting for Abbott, he has received device donations from Medtronic, and he has unlicensed patents in the area of deep brain stimulation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In drug-resistant temporal lobe epilepsy, automated tools for seizure onset zone (SOZ) localization that use brief interictal recordings could supplement presurgical evaluations and improve care. Thus, the authors sought to localize SOZs by training a multichannel convolutional neural network on stereoelectroencephalography (SEEG) cortico-cortical evoked potentials., Methods: The authors performed single-pulse electrical stimulation in 10 drug-resistant temporal lobe epilepsy patients implanted with SEEG. Using 500,000 unique poststimulation SEEG epochs, the authors trained a multichannel 1-dimensional convolutional neural network to determine whether an SOZ had been stimulated., Results: SOZs were classified with mean sensitivity of 78.1% and specificity of 74.6% according to leave-one-patient-out testing. To achieve maximum accuracy, the model required a 0- to 350-msec poststimulation time period. Post hoc analysis revealed that the model accurately classified unilateral versus bilateral mesial temporal lobe seizure onset, as well as neocortical SOZs., Conclusions: This was the first demonstration, to the authors' knowledge, that a deep learning framework can be used to accurately classify SOZs with single-pulse electrical stimulation-evoked responses. These findings suggest that accurate classification of SOZs relies on a complex temporal evolution of evoked responses within 350 msec of stimulation. Validation in a larger data set could provide a practical clinical tool for the presurgical evaluation of drug-resistant epilepsy.

Objective: Temporal lobe epilepsy (TLE) is one of the most common causes of medically refractory focal epilepsy. Anterior temporal lobectomy (ATL) leads to improved seizure control in patients with medically refractory TLE. Various auras are associated with TLE; however, the relationships between aura type and outcome after ATL are poorly understood. Our objective was to investigate the associations among clinical features, aura type, and seizure outcome after ATL., Methods: The records of patients who underwent ATL between 1993 and 2016 at a single institution (N = 174) were retrospectively reviewed. Demographic and clinical variables were compared among aura types using analysis of variance and logistic regression analysis. A multiple regression analysis was conducted to determine whether aura type predicted seizure outcome after ATL., Results: Mesial temporal sclerosis (MTS) on magnetic resonance imaging inversely correlated with cephalic auras (P = 0.0090). Affective auras (P = 0.014) and somatosensory auras (P = 0.021) were correlated with findings of MTS on pathology, whereas this finding was inversely correlated with the presence of auditory auras (P = 0.0056). On multiple regression analysis, predictors of worse seizure outcome after ATL were cephalic auras (P = 0.0048), gustatory auras (P = 0.029), visual auras (P = 0.049), and tonic-clonic seizures (P = 0.047). Fewer preoperative antiepileptic medications (P = 0.0032), and presence of multiple auras (P = 0.011) were associated with better outcome., Conclusions: Cephalic auras, gustatory auras, and visual auras were associated with worse seizure outcome after ATL., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Our aim is to review several recent landmark studies discussing the application of advanced neuroimaging to guide target selection in deep brain stimulation (DBS) for psychiatric disorders., Materials and Methods: We performed a PubMed literature search of articles related to psychiatric neurosurgery, DBS, diffusion tensor imaging, probabilistic tractography, functional magnetic resonance imaging (MRI), and blood oxygen level-dependent activation. Relevant articles were included in the review., Results: Recent advances in neuroimaging, namely the use of diffusion tensor imaging, probabilistic tractography, functional MRI, and positron emission tomography have provided higher resolution depictions of structural and functional connectivity between regions of interest. Applying these imaging modalities to DBS has increased understanding of the mechanism of action of DBS from the single structure to network level, allowed for new DBS targets to be discovered, and allowed for individualized DBS targeting for psychiatric indications., Conclusions: Advanced neuroimaging techniques may be especially important to guide personalized DBS targeting in psychiatric disorders such as treatment-resistant depression and obsessive-compulsive disorder where symptom profiles and underlying disordered circuitry are more heterogeneous. These articles suggest that advanced imaging can help to further individualize and optimize DBS, a promising next step in improving its efficacy., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

We present an experimental protocol to record neuronal activity during intermittent stimulation of nucleus basalis (NB), as macaque monkeys perform cognitive tasks. This protocol includes implantation of electrodes and generator devices to deliver electrical stimulation to NB using multiple approaches in monkeys. Direct stimulation of NB avoids peripheral cholinergic side effects, optimizes timing, and activates non-cholinergic projection neurons. We describe electrode preparation, surgery, and implantation for direct evaluation of how stimulation affects monkeys' behavior and neuronal activity. For complete details on the use and execution of this profile, please refer to Qi et al. (2021)., Competing Interests: The authors have received stimulator devices from Boston Scientific through a Materials Transfer Agreement., (© 2022 The Authors.)

Objective: Obsessive-compulsive disorder (OCD) is among the most debilitating and medically refractory psychiatric disorders. While cingulotomy is an anatomically targeted neurosurgical treatment that has shown significant promise in treating OCD-related symptoms, the precise underlying neuroanatomical basis for its beneficial effects has remained poorly understood. Therefore, the authors sought to determine whether lesion location is related to responder status following cingulotomy., Methods: The authors reviewed the records of 18 patients who had undergone cingulotomy. Responders were defined as patients who had at least a 35% improvement in the Yale-Brown Obsessive Compulsive Scale (YBOCS) score. The authors traced the lesion sites on T1-weighted MRI scans and used an anatomical registration matrix generated by the imaging software FreeSurfer to superimpose these lesions onto a template brain. Lesion placement was compared between responders and nonresponders. The placement of lesions relative to various anatomical regions was also compared., Results: A decrease in postoperative YBOCS score was significantly correlated with more superiorly placed lesions (decrease -0.52, p = 0.0012). While all lesions were centered within 6 mm of the cingulate sulcus, responder lesions were placed more superiorly and posteriorly along the cingulate sulcus (1-way ANOVA, p = 0.003). The proportions of the cingulum bundle, cingulate gyrus, and paracingulate cortex affected by the lesions were the same between responders and nonresponders. However, all responders had lesions covering a larger subregion of Brodmann area (BA) 32. In particular, responder lesions covered a significantly greater proportion of the posterior BA32 (1-way ANOVA, p = 0.0064)., Conclusions: Lesions in patients responsive to cingulotomy tended to be located more superiorly and posteriorly and share greater coverage of a posterior subregion of BA32 than lesions in patients not responsive to this treatment.

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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Patients with medically refractory temporal lobe epilepsy (TLE) are candidates for neuromodulation procedures. While vagus nerve stimulation (VNS) was historically the procedure of choice for this condition, the responsive neurostimulation system (RNS) has come into favor for its more targeted approach. While both VNS and RNS have been reported as efficacious treatments for TLE, the outcomes of these 2 procedures have not been directly compared. This study aims to compare outcomes following VNS versus RNS for TLE., Methods: We retrospectively reviewed the records of all patients with TLE who underwent VNS or RNS placement at our institution from 2003 to 2018. The primary outcome was change in seizure frequency. Other outcomes included Engel score, change in anti-epileptic medications, and complications., Results: Twenty-three patients met inclusion criteria; 11 underwent VNS and 12 underwent RNS. At baseline, the 2 groups were statistically similar regarding age at surgery, epilepsy duration, and preoperative seizure frequency. At last follow-up, both groups displayed reduced seizure frequency (mean reduction of 46.3% for the VNS group and 58.1% for the RNS group, p = 0.49). Responder rate, Engel score, and change in medications were statistically similar between groups. Compared to 0.0% of the VNS group, 13.3% of the RNS group experienced infection requiring re-operation., Conclusion: Despite their different mechanisms, VNS and RNS resulted in similar response rates for patients with TLE. We suggest that VNS should not be excluded as a treatment for patients with medically refractory TLE who are not candidates for resective or ablative procedures., (© 2020 S. Karger AG, Basel.)

Neuromodulation is a promising treatment modality for disorders of learning and memory, offering the possibility of precise alteration of disordered neural circuits. Studies to date have failed to identify an optimal target and stimulation paradigm. Six epilepsy patients with depth electrodes implanted for seizure localization participated in our study. We recorded local field potentials from implanted electrodes while subjects participated in an associative learning task requiring them to learn an association between presented images and a button press. Three subjects participated in stimulation sessions during which caudate or putamen stimulation was delivered for some images during feedback after correct responses. Caudate stimulation enhanced learning. Both caudate and dorsolateral prefrontal cortex demonstrated a beta power increase during the feedback period of the learning task that was greater following correct than incorrect trials. In dorsolateral prefrontal cortex, this difference increased with learning and persisted beyond the end of the feedback period. Caudate stimulation was associated with increased dorsolateral prefrontal cortex beta power following feedback. These findings suggest that temporally specific caudate stimulation is a promising neuromodulation strategy to improve learning in disorders of learning and memory., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Foramen ovale electrodes (FOEs) are a minimally invasive method to localize mesial temporal seizures in cases in which noninvasive methods are inconclusive. The objective of this study was to identify factors predicting the ability of FOEs to yield a diagnosis in order to determine optimal candidates for this procedure., Methods: All cases of diagnostic investigations performed with FOEs at the authors' institution between 2005 and 2017 were reviewed. FOE investigation was defined as diagnostic if it led to a treatment decision. Demographic and clinical variables for diagnostic and nondiagnostic investigations were compared using a Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables., Results: Ninety-three patients underwent investigations performed with FOEs during the study period and were included in the study. FOE investigation was diagnostic in 75.3% of cases. Of patients who underwent anterior temporal lobectomy following diagnostic FOE evaluation, 75.9% were Engel class I at last follow-up (average 40.1 months). When the diagnostic and nondiagnostic FOE groups were compared, patients who had diagnostic investigations were more likely to be male (57.1% male vs 26.1% in the nondiagnostic group, p = 0.015). They were also more likely to have temporal lesions on preoperative MRI (p = 0.018)., Conclusions: FOEs are a useful, minimally invasive diagnostic modality resulting in a treatment decision in 75% of cases. Male patients and patients with temporal lesions on MRI may be most likely to benefit from FOE investigation.

Background: Trigeminal neuralgia (TN) increases in prevalence with age. Although microvascular decompression (MVD) is the most effective long-term operative treatment for TN, its use in older patient populations has been debated due to its invasive nature. Recent studies have demonstrated safety of MVD in older patients; however, efficacy data are more limited., Objective: To determine the relationship between age and pain outcomes following MVD for TN., Methods: Subjects underwent MVD for TN at our institution between 1/1/2004 and 12/31/2013, had typical TN, and demonstrated neurovascular compression on preoperative imaging. We performed a retrospective case series study by reviewing the electronic medical records and performing phone interviews to determine long-term outcomes. We divided patients into 2 groups for analysis, under 60 and 60 yr of age and older., Results: One hundred twenty-four subjects were included in the study, 82 under 60, and 42 60 yr of age and older. The average length of follow-up was 42.4 mo. Patients in the older age group had average pain score of 1.57 at most recent follow-up, while for the younger age group it was 2.18 (P = .0084). Multiple regression analysis found that older age, male gender, and preoperative medication responsiveness were significantly correlated with lower long-term pain scores, while V2 dermatome involvement was correlated with higher long-term pain scores., Conclusion: Patients 60 yr of age and older have significantly better long-term pain outcomes following MVD than younger patients.

Background and Objectives: The retrolaminar block (RB) is used for truncal analgesia, but its mechanism of neural blockade remains obscure. We sought to learn the pattern of local anesthetic spread after thoracic RB using cadaveric models., Methods: In 8 fresh cadavers, an ultrasound-guided T4 RB was performed with 20 mL of methylene blue 1% and bupivacaine 0.5%. For comparison, an RB at T9 in 1 cadaver and a T4 thoracic paravertebral block in another cadaver were performed. Subsequently, posterior and anterior thoracic dissections were performed to examination where the dye spread., Results: After T4 RB, dye was noted to spread in the ipsilateral retrolaminar plane (all 8 cadavers, median cephalad spread 3.5 cm, caudad spread 10.7 cm, lateral spread 2.5 cm), the contralateral retrolaminar plane (6 cadavers), the paravertebral space (5 cadavers, median of 3 segments, T3-T5), the intercostal space (5 cadavers, median of 3.5 cm laterally), the T4 epidural space (6 cadavers), and the intervertebral foramina (4 cadavers, median of 2 segments, T4-T5). After T9 retrolaminar injection, dye was noted in the ipsilateral retrolaminar plane (5.5 cm cephalad, 13.5 cm caudad, and 2.5 cm lateral), the contralateral retrolaminar plane, and the epidural space. Dye after T4 traditional paravertebral block spread to T1-T6 paravertebral space with 15-cm lateral spread., Conclusions: Injectate spread to the paravertebral space, epidural space, intercostal space, and intervertebral foramina is possible in the RB but is quite variable. In comparison to the thoracic paravertebral block, injectate spread within the paravertebral space is more limited.

The subthalamic nucleus (STN) is a small almond-shaped subcortical structure classically known for its role in motor inhibition through the indirect pathway within the basal ganglia. Little is known about the role of the STN in mediating cognitive functions in humans. Here, we explore the role of the STN in human subjects making decisions under conditions of uncertainty using single-neuron recordings and intermittent deep brain stimulation (DBS) during a financial decision-making task. Intraoperative single-neuronal data from the STN reveals that on high-uncertainty trials, spiking activity encodes the upcoming decision within a brief (500 ms) temporal window during the choice period, prior to the manifestation of the choice. Application of intermittent DBS selectively prior to the choice period alters decisions and biases subject behavior towards conservative wagers., Competing Interests: SP, TH, SS, MM, SB, JY, AF, AW, DD, EE No competing interests declared, MF Senior editor, eLife, (© 2018, Patel et al.)

Objectives: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms in advanced Parkinson's disease. STN DBS may also affect emotion, possibly by impacting a parallel limbic cortico-striatal circuit. The objective of this study was to investigate changes in prefrontal cortical activity related to DBS during an emotion induction task., Materials and Methods: We used near infrared spectroscopy to monitor prefrontal cortex hemodynamic changes during an emotion induction task. Seven DBS patients were tested sequentially in the stimulation-on and stimulation-off states while on dopaminergic medication. Patients watched a series of positive, negative, and neutral videos. The general linear model was used to compare prefrontal oxygenated hemoglobin concentration between DBS states., Results: Deep brain stimulation was correlated with prefrontal oxygenated hemoglobin changes relative to the stimulation off state in response to both positive and negative videos. These changes were specific to emotional stimuli and were not seen during neutral stimuli., Conclusions: These results suggest that STN stimulation influences the prefrontal cortical representation of positive and negative emotion induction., (© 2016 International Neuromodulation Society.)

Background: Herpes simplex virus (HSV) is a common cause of viral encephalitis that can lead to refractory seizures. The primary treatment of HSV encephalitis is with acyclovir; however, surgery sometimes plays a role in obtaining tissue diagnosis or decompression in cases with severe mass effect. We report a unique case in which anterior temporal lobectomy was successfully used to treat refractory status epilepticus in HSV encephalitis., Methods: Case report and review of the literature., Results: We report a case of a 60-year-old man with HSV encephalitis, who presented with seizures originating from the right temporal lobe refractory to maximal medical management. Right anterior temporal lobectomy was performed for the purpose of treatment of refractory status epilepticus and obtaining tissue diagnosis, with ultimate resolution of seizures and excellent functional outcome., Conclusions: We suggest that anterior temporal lobectomy should be considered in cases of HSV encephalitis with refractory status epilepticus with clear unilateral origin.

Hematologic malignancies most commonly spread to the central nervous system via leptomeningeal infiltration. We present a unique case of a woman who presented with a right parietal mass as the initial manifestation of B cell acute lymphocytic leukemia. Because the diagnosis was unclear at the time of presentation she underwent surgical debulking of the mass prior to treatment with chemotherapy. Unfortunately, she relapsed several months after treatment and ultimately entered hospice care. We review the literature surrounding management considerations in patients with intracranial leukemic involvement., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Disorders of learning and memory have a large social and economic impact in today's society. Unfortunately, existing medical treatments have shown limited clinical efficacy or potential for modification of the disease course. Deep brain stimulation is a successful treatment for movement disorders and has shown promise in a variety of other diseases including psychiatric disorders. The authors review the potential of neuromodulation for the treatment of disorders of learning and memory. They briefly discuss learning circuitry and its involvement in Alzheimer disease and traumatic brain injury. They then review the literature supporting various targets for neuromodulation to improve memory in animals and humans. Multiple targets including entorhinal cortex, fornix, nucleus basalis of Meynert, basal ganglia, and pedunculopontine nucleus have shown a promising potential for improving dysfunctional memory by mechanisms such as altering firing patterns in neuronal networks underlying memory and increasing synaptic plasticity and neurogenesis. Significant work remains to be done to translate these findings into durable clinical therapies.