Centromedian region thalamic responsive neurostimulation mitigates idiopathic generalized and multifocal epilepsy with focal to bilateral tonic-clonic seizures.

OBJECTIVE: Although >30% of epilepsy patients have drug-resistant epilepsy (DRE), typically those with generalized or multifocal disease have not traditionally been considered surgical candidates. Responsive neurostimulation (RNS) of the centromedian (CM) region of the thalamus now appears to be a promising therapeutic option for this patient population. We present outcomes following CM RNS for 13 patients with idiopathic generalized epilepsy (IGE) and eight with multifocal onsets that rapidly generalize to bilateral tonic-clonic (focal to bilateral tonic-clonic [FBTC]) seizures. METHODS: A retrospective review of all patients undergoing bilateral CM RNS by the senior author through July 2022 were reviewed. Electrodes were localized and volumes of tissue activation were modeled in Lead-DBS. Changes in patient seizure frequency were extracted from electronic medical records. RESULTS: Twenty-one patients with DRE underwent bilateral CM RNS implantation. For 17 patients with at least 1 year of postimplantation follow-up, average seizure reduction from preoperative baseline was 82.6% (SD = 19.0%, median = 91.7%), with 18% of patients Engel class 1, 29% Engel class 2, 53% Engel class 3, and 0% Engel class 4. There was a trend for average seizure reduction to be greater for patients with nonlesional FBTC seizures than for other patients. For patients achieving at least Engel class 3 outcome, median time to worthwhile seizure reduction was 203.5 days (interquartile range = 110.5-343.75 days). Patients with IGE with myoclonic seizures had a significantly shorter time to worthwhile seizure reduction than other patients. The surgical targeting strategy evolved after the first four subjects to achieve greater anatomic accuracy. SIGNIFICANCE: Patients with both primary and rapidly generalized epilepsy who underwent CM RNS experienced substantial seizure relief. Subsets of these patient populations may particularly benefit from CM RNS. The refinement of lead targeting, tuning of RNS system parameters, and patient selection are ongoing areas of investigation.

The Experience of Survivors of Firearm Suicide Attempts: A Retrospective Case Series.

Objective: We sought to identify people who survived firearm suicide attempts to describe the acute stressors, substance use, and mental health conditions related to the attempt. Background: Most firearm deaths in the United States are the result of suicide. Because firearm suicide attempts have a case fatality rate of approximately 90%, little is known about the precipitating factors that lead to firearm suicide attempts. Methods: We conducted a retrospective case series of patients admitted to a large hospital system between 2000 and 2019 who survived intentional, self-inflicted gunshot wounds to the head. Through the electronic medical record, we collected information about acute stressors, substance use, and mental health diagnoses before or at the time of the suicide attempt. Results: Thirty-four patients were included in the study cohort. Patients were predominantly White (74%) and male (88%), with a mean age of 44 (range, 14-82). Nineteen (56%) patients were acutely intoxicated with alcohol upon hospitalization and 17 (50%) patients had a positive urine drug screen. Acute stressors involving interpersonal relationships (53%), work/school (32%), and legal disputes (18%), among others, were documented in 82% of patients. Most patients (65%) had been diagnosed with depression before their index hospitalization. Most patients were discharged to an acute rehabilitation center (41%) or an inpatient psychiatric facility (41%). Conclusions: Acute stress and alcohol intoxication were common in this cohort of patients who attempted suicide using firearms. These data offer an ability to learn from the experience of survivors of firearm suicide attempts, a rare population.

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

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

Spontaneous rupture of an arachnoid cyst in an adult: illustrative case.

BACKGROUND: Arachnoid cysts are common intracranial mass lesions frequently discovered as incidental findings on radiographic imaging. It is routine practice to monitor these lesions as a large majority remain stable. Although traumatic cyst rupture is a known risk, it is rare for patients to present with spontaneous rupture. OBSERVATIONS: The authors report the case of a 32-year-old patient who required emergent neurosurgical intervention for spontaneous rupture of a left hemispheric arachnoid cyst. LESSONS: Patients with ruptured arachnoid cysts can present with vague, nonspecific symptoms that may delay diagnosis. If not diagnosed and treated promptly, arachnoid cyst rupture can progress to a neurosurgical emergency as the subdural collection may cause extensive mass effect and even cerebral herniation.

Human genetics and molecular genomics of Chiari malformation type 1.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation.

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

Accurate Deep Brain Stimulation Lead Placement Concurrent With Research Electrocorticography.

BACKGROUND: Using electrocorticography for research (R-ECoG) during deep brain stimulation (DBS) surgery has advanced our understanding of human cortical-basal ganglia neurophysiology and mechanisms of therapeutic circuit modulation. The safety of R-ECoG has been established, but potential effects of temporary ECoG strip placement on targeting accuracy have not been reported. OBJECTIVE: To determine whether temporary subdural electrode strip placement during DBS implantation surgery affects lead implantation accuracy. METHODS: Twenty-four consecutive patients enrolled in a prospective database who underwent awake DBS surgery were identified. Ten of 24 subjects participated in R-ECoG. Lead locations were determined after fusing postoperative computed tomography scans into the surgical planning software. The effect of brain shift was quantified using Lead-DBS and analyzed in a mixed-effects model controlling for time interval to postoperative computed tomography. Targeting accuracy was reported as radial and Euclidean distance errors and compared with Mann-Whitney tests. RESULTS: Neither radial error nor Euclidean distance error differed significantly between R-ECoG participants and nonparticipants. Pneumocephalus volume did not differ between the 2 groups, but brain shift was slightly greater with R-ECoG. Pneumocephalus volume correlated with brain shift, but neither of these measures significantly correlated with Euclidean distance error. There were no complications in either group. CONCLUSION: In addition to an excellent general safety profile as has been reported previously, these results suggest that performing R-ECoG during DBS implantation surgery does not affect the accuracy of lead placement.

Racial and Social Determinants of Civilian Gunshot Wounds to the Head.

Objective: To assess the clinical, racial, and social characteristics of victims of Gunshot wounds (GSWs) to the head and assess for associations between these factors and outcomes. Summary Background Data: Previous literature has not focused on the association of race and socioeconomic factors with these specific injuries. Methods: We identified patients with GSWs to the head who presented to 2 urban academic medical centers between 1998 and 2020, and extracted patient-level demographic data, information about the clinical and surgical course, and outcomes at discharge and follow-up. Results: The cohort included 250 patients, 90% (n = 226) of whom were male, with a mean age of 28 years. Forty-five percent were white (n = 112), 19% Black (n = 48), 18% Latinx (n = 45), with 6% "other" (n = 16), and 12% "unknown" (n = 29). The majority of patients presented with assault-related trauma (n = 153, 61%) as compared to self-inflicted injuries (n = 97, 39%). Across the entire cohort, sex, age, race, and median income by ZIP code were not significant predictors of outcome. Victims of assault by GSW to the head were more likely to be age 18 or younger (OR 5.26, P = 0.01), between the ages of 19 and 33 years (OR 4.7, P = 0.001), Black (OR 6.66, P < .001), and Latinx (OR 2.65, P = 0.03). Most patients (n = 155, 63%) had a poor functional outcome (modified Rankin Score 3-6) at discharge. Conclusion: Age, race, and income status were not independent predictors of mortality or functional outcome at discharge in our population. Assault-related GSWs to the head mostly involved young Black or Latinx men of lower socioeconomic status, while self-inflicted injuries were largely seen in older white men.

Direct Visualization of the Dural Puncture Site During Lumbar Spine Surgery Performed Under Spinal Anesthesia: A Case Report.

Spinal anesthesia (SA) has been utilized for lumbar surgical procedures; however, postdural puncture headache (PDPH) and subdural hemorrhage (SDH) are potential consequences. We present the case of a 76-year-old with progressive neurogenic claudication secondary to lumbar spinal stenosis who received SA for a 2-level lumbar posterior decompression. After decompression, the site of dural puncture from a 24-gauge Sprotte spinal needle was identified. Our intraoperative image demonstrates the submillimeter dural defect that can potentially engender complications as significant as PDPH and/or SDH. We recommend searching for, and preemptively sealing, the dural puncture site when SA is used for lumbar spine surgery.

Deep brain stimulation for obsessive-compulsive disorder.

Neurosurgical interventions have been used for decades to treat severe, refractory obsessive-compulsive disorder (OCD). Deep brain stimulation (DBS) is a neurosurgical procedure that is used routinely to treat movement disorders such as Parkinson's disease and essential tremor. Over the past two decades, DBS has been applied to OCD, building on earlier experience with lesional procedures. Promising results led to Humanitarian Device Exemption (HDE) approval of the therapy from the United States Food and Drug Administration in 2009. In this review, the authors describe the development of DBS for OCD, the most recent outcome data, and areas for future research.

Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls.

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of polygenetic risk for schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychotic disorder patients, a measure of premorbid intelligence that is minimally affected by psychosis onset (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide single nucleotide polymorphism (SNP) data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was significantly associated with lower BACS scores (r = -0.17, p = 6.6 × 10-4 at PT = 1 × 10-4), but not with WRAT or EY. Among individuals with psychosis, PRSSCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRSSCZ and WRAT in more than 4500 healthy subjects from the Philadelphia Neurodevelopmental Cohort. The association was again null (p > 0.3, N = 4511), suggesting that different cognitive phenotypes vary in their etiologic relationship with schizophrenia.

Connectivity-based parcellation of the anterior limb of the internal capsule.

The anterior limb of the internal capsule (ALIC) is an important locus of frontal-subcortical fiber tracts involved in cognitive and limbic feedback loops. However, the structural organization of its component fiber tracts remains unclear. Therefore, although the ALIC is a promising target for various neurosurgical procedures for psychiatric disorders, more precise understanding of its organization is required to optimize target localization. Using diffusion tensor imaging (DTI) collected on healthy subjects by the Human Connectome Project (HCP), we generated parcellations of the ALIC by dividing it according to structural connectivity to various frontal regions. We then compared individuals' parcellations to evaluate the ALIC's structural consistency. All 40 included subjects demonstrated a posterior-superior to anterior-inferior axis of tract organization in the ALIC. Nonetheless, subdivisions of the ALIC were found to vary substantially, as voxels in the average parcellation were accurately assigned for a mean of only 66.2% of subjects. There were, however, some loci of consistency, most notably in the region maximally connected to orbitofrontal cortex. These findings clarify the highly variable organization of the ALIC and may represent a tool for patient-specific targeting of neuromodulation. Hum Brain Mapp 38:6107-6117, 2017. © 2017 Wiley Periodicals, Inc.

Evolving Applications, Technological Challenges and Future Opportunities in Neuromodulation: Proceedings of the Fifth Annual Deep Brain Stimulation Think Tank.

The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinson's disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this year's meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice.

Novel gene-brain structure relationships in psychotic disorder revealed using parallel independent component analyses.

BACKGROUND: Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder overlap with regard to symptoms, structural and functional brain abnormalities, and genetic risk factors. Neurobiological pathways connecting genes to clinical phenotypes across the spectrum from schizophrenia to psychotic bipolar disorder remain largely unknown. METHODS: We examined the relationship between structural brain changes and risk alleles across the psychosis spectrum in the multi-site Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) cohort. Regional MRI brain volumes were examined in 389 subjects with a psychotic disorder (139 schizophrenia, 90 schizoaffective disorder, and 160 psychotic bipolar disorder) and 123 healthy controls. 451,701 single-nucleotide polymorphisms were screened and processed using parallel independent component analysis (para-ICA) to assess associations between genes and structural brain abnormalities in probands. RESULTS: 482 subjects were included after quality control (364 individuals with psychotic disorder and 118 healthy controls). Para-ICA identified four genetic components including several risk genes already known to contribute to schizophrenia and bipolar disorder and revealed three structural components that showed overlapping relationships with the disease risk genes across the three psychotic disorders. Functional ontologies representing these gene clusters included physiological pathways involved in brain development, synaptic transmission, and ion channel activity. CONCLUSIONS: Heritable brain structural findings such as reduced cortical thickness and surface area in probands across the psychosis spectrum were associated with somewhat distinct genes related to putative disease pathways implicated in psychotic disorders. This suggests that brain structural alterations might represent discrete psychosis intermediate phenotypes along common neurobiological pathways underlying disease expression across the psychosis spectrum.

Polygenic risk for type 2 diabetes mellitus among individuals with psychosis and their relatives.

BACKGROUND: An elevated prevalence of Type 2 diabetes (T2D) has been observed in people with psychotic disorders and their relatives compared to the general population. It is not known whether this population also has increased genetic risk for T2D. METHODS: Subjects included probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, their first-degree relatives without psychotic disorders, and healthy controls, who participated in the Bipolar Schizophrenia Network for Intermediate Phenotypes study. We constructed sets of polygenic risk scores for T2D (PGRST2D) and schizophrenia (PGRSSCHIZ) using publicly available data from genome-wide association studies. We then explored the correlation of PGRST2D with psychiatric proband or relative status, and with self-reported diabetes. Caucasians and African-Americans were analyzed separately. We also evaluated correlations between PGRSSCHIZ and diabetes mellitus among Caucasian probands and their relatives. RESULTS: In Caucasians, PGRST2D was correlated with self-reported diabetes mellitus within probands, but was not correlated with proband or relative status in the whole sample. In African-Americans, a PGRST2D based on selected risk alleles for T2D in this population did not correlate with proband or relative status. PGRSSCHIZ was not correlated with self-reported diabetes within Caucasian probands. CONCLUSION: Differences in polygenic risk for T2D do not explain the increased prevalence of diabetes mellitus observed in psychosis probands and their relatives.

Impulsivity across the psychosis spectrum: Correlates of cortical volume, suicidal history, and social and global function.

Patients with psychotic disorders appear to exhibit greater impulsivity-related behaviors relative to healthy controls. However, the neural underpinning of this impulsivity remains uncertain. Furthermore, it remains unclear how impulsivity might differ or be conserved between psychotic disorder diagnoses in mechanism and manifestation. In this study, self-reported impulsivity, measured by Barratt Impulsiveness Scale (BIS), was compared between 305 controls (HC), 139 patients with schizophrenia (SZ), 100 with schizoaffective disorder (SZA), and 125 with psychotic bipolar disorder (PBP). In each proband group, impulsivity was associated with regional cortical volumes (using FreeSurfer analysis of T1 MRI scans), suicide attempt history, Global Assessment of Functioning (GAF), and Social Functioning Scale (SFS). BIS scores were found to differ significantly between participant groups, with SZA and PBP exhibiting significantly higher impulsivity than SZ, which exhibited significantly higher impulsivity than HC. BIS scores were significantly related to suicide attempt history, and they were inversely associated with GAF, SFS, and bilateral orbitofrontal cortex (OFC) volume in both SZA and PBP, but not SZ. These findings indicate that psychotic disorders, particularly those with prominent affective symptoms, are characterized by elevated self-reported impulsivity measures. Impulsivity's correlations with suicide attempt history, GAF, and SFS suggest that impulsivity may be a mediator of clinical outcome. The observed impulsivity-OFC correlations corroborate the importance of OFC deficits in impulsivity. These correlations' presence in SZA and PBP but not in SZ suggests that impulsivity may have different underlying mechanisms in affective and non-affective psychotic disorders.

Local gyrification index in probands with psychotic disorders and their first-degree relatives.

BACKGROUND: Psychotic disorders are characterized by aberrant neural connectivity. Alterations in gyrification, the pattern and degree of cortical folding, may be related to the early development of connectivity. Past gyrification studies have relatively small sample sizes, yield mixed results for schizophrenia, and are scant for psychotic bipolar and schizoaffective (SZA) disorders and for relatives of these conditions. Here, we examine gyrification in psychotic disorder patients and their first-degree relatives as a possible endophenotype. METHODS: Regional local gyrification index (LGI) values, as measured by FreeSurfer software, were compared between 243 control subjects, 388 psychotic disorder probands, and 300 of their first-degree relatives. For patients, LGI values were examined grouped across psychotic diagnoses and then separately for schizophrenia, SZA, and bipolar disorder. Familiality (heritability) values and correlations with clinical measures were also calculated for regional LGI values. RESULTS: Probands exhibited significant hypogyria compared with control subjects in three brain regions and relatives with Axis II cluster A disorders showed nearly significant hypogyria in these same regions. Local gyrification index values in these locations were significantly heritable and uncorrelated with any clinical measure. Observations of significant hypogyria were most widespread in SZA. CONCLUSIONS: Psychotic disorders appear to be characterized by significant regionally localized hypogyria, particularly in cingulate cortex. This abnormality may be a structural endophenotype marking risk for psychotic illness and it may help elucidate etiological underpinnings of psychotic disorders.

Geographical rural status and health outcomes in pediatric liver transplantation: an analysis of 6 years of national United Network of Organ Sharing Data.

OBJECTIVE: To determine whether children in rural areas have worse health than children in urban areas after liver transplantation (LT). STUDY DESIGN: We used urban influence codes published by the US Department of Agriculture to categorize 3307 pediatric patients undergoing LT in the United Network of Organ Sharing database between 2004 and 2009 as urban or rural. Allograft rejection, patient death, and graft failure were used as primary outcome measures of post-LT health. Pediatric end-stage liver disease/model of end-stage liver disease scores >20 was used to measure worse pre-LT health. RESULTS: In a multivariate analysis, we found greater rates of allograft rejection within 6 months of LT (OR 1.27; 95% CI 1.05-1.53) and a lower occurrence of posttransplantation lymphoproliferative disorder (OR 0.64; 95% CI 0.41-0.99) in patients in rural areas. The difference in allograft rejection was eliminated at 1 year of LT (OR 1.18; 95% CI 0.98-1.42). Rural location did not impact other outcome measures. CONCLUSION: We conclude that rural location makes a negative impact on patient health within the first 6 months of LT by increasing the risk for allograft rejection, although patients in rural areas may have lower rates of developing posttransplantation lymphoproliferative disorder. Long-term adverse health effects were not seen.