Immediate and long-term electrophysiological biomarkers of antidepressant-like behavioral effects after subanesthetic ketamine and medial prefrontal cortex deep brain stimulation treatment.

Introduction: Both ketamine (KET) and medial prefrontal cortex (mPFC) deep brain stimulation (DBS) are emerging therapies for treatment-resistant depression, yet our understanding of their electrophysiological mechanisms and biomarkers is incomplete. This study investigates aperiodic and periodic spectral parameters, and the signal complexity measure sample entropy, within mPFC local field potentials (LFP) in a chronic corticosterone (CORT) depression model after ketamine and/or mPFC DBS. Methods: Male rats were intraperitoneally administered CORT or vehicle for 21 days. Over the last 7 days, animals receiving CORT were treated with mPFC DBS, KET, both, or neither; then tested across an array of behavioral tasks for 9 days. Results: We found that the depression-like behavioral and weight effects of CORT correlated with a decrease in aperiodic-adjusted theta power (5-10 Hz) and an increase in sample entropy during the administration phase, and an increase in theta peak frequency and a decrease in the aperiodic exponent once the depression-like phenotype had been induced. The remission-like behavioral effects of ketamine alone correlated with a post-treatment increase in the offset and exponent, and decrease in sample entropy, both immediately and up to eight days post-treatment. The remission-like behavioral effects of mPFC DBS alone correlated with an immediate decrease in sample entropy, an immediate and sustained increase in low gamma (20-50 Hz) peak width and aperiodic offset, and sustained improvements in cognitive function. Failure to fully induce remission-like behavior in the combinatorial treatment group correlated with a failure to suppress an increase in sample entropy immediately after treatment. Conclusion: Our findings therefore support the potential of periodic theta parameters as biomarkers of depression-severity; and periodic low gamma parameters and cognitive measures as biomarkers of mPFC DBS treatment efficacy. They also support sample entropy and the aperiodic spectral parameters as potential cross-modal biomarkers of depression severity and the therapeutic efficacy of mPFC DBS and/or ketamine. Study of these biomarkers is important as objective measures of disease severity and predictive measures of therapeutic efficacy can be used to personalize care and promote the translatability of research across studies, modalities, and species.

Theta-frequency medial septal nucleus deep brain stimulation increases neurovascular activity in MK-801-treated mice.

Introduction: Deep brain stimulation (DBS) has shown remarkable success treating neurological and psychiatric disorders including Parkinson's disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder. DBS is now being explored to improve cognitive and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e., schizophrenia). While DBS for movement disorders generally involves high-frequency (>100 Hz) stimulation, there is evidence that low-frequency stimulation may have beneficial and persisting effects when applied to cognitive brain networks. Methods: In this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice. Results: Imaging from a sagittal plane across a variety of brain regions within and outside of the septohippocampal circuit, we find that MSN theta-frequency (7.7 Hz) DBS increases hippocampal cerebral blood volume (CBV) during and after stimulation. This effect was not present using standard high-frequency stimulation parameters [i.e., gamma (100 Hz)]. Discussion: These results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in a way that continues beyond the period of electrical stimulation.

Neuromodulation of Eating Disorders: A Review of Underlying Neural Network Activity and Neuromodulatory Treatments.

Eating disorders are a group of psychiatric conditions that involve pathological relationships between patients and food. The most prolific of these disorders are anorexia nervosa, bulimia nervosa, and binge eating disorder. The current standard of care involves psychotherapy, pharmacotherapy, and the management of comorbid conditions, with nutritional rehabilitation reserved for severe cases of anorexia nervosa. Unfortunately, many patients often fail to respond, leaving a concerning treatment gap between the current and requisite treatments for eating disorders. To better understand the neurobiology underlying these eating disorders, investigations have been undertaken to characterize the activity of various neural networks, primarily those activated during tasks of executive inhibition, reward processing, and self-reference. Various neuromodulatory techniques have been proposed to stimulate these networks with the goal of improving patients' BMI and mental health. The aim of this review is to compile a comprehensive summarization of the current literature regarding the underlying neural connectivity of anorexia nervosa, bulimia nervosa, and binge eating disorder as well as the numerous neuromodulatory modalities that have been investigated. Importantly, we aimed to summarize the most significant clinical trials to date as well as to provide an updated assessment of the role of deep brain stimulation, summarizing numerous recently published clinical studies that have greatly contributed to the literature. In this review, we found therapeutic evidence for transcranial magnetic stimulation and transcranial direct current stimulation in treating individuals suffering from anorexia nervosa, bulimia nervosa, and binge eating disorder. We also found significant evidence for the role of deep brain stimulation, particularly as an escalatory therapy option for the those who failed standard therapy. Finally, we hope to provide promising directions for future clinical investigations.

Developing Predictive Models to Anticipate Shunt Complications in 33,248 Pediatric Patients with Shunted Hydrocephalus Utilizing Machine Learning.

INTRODUCTION: Hydrocephalus is a common pediatric neurosurgical pathology, typically treated with a ventricular shunt, yet approximately 30% of patients experience shunt failure within the first year after surgery. As a result, the objective of the present study was to validate a predictive model of pediatric shunt complications with data retrieved from the Healthcare Cost and Utilization Project (HCUP) National Readmissions Database (NRD). METHODS: The HCUP NRD was queried from 2016 to 2017 for pediatric patients undergoing shunt placement using ICD-10 codes. Comorbidities present upon initial admission resulting in shunt placement, Johns Hopkins Adjusted Clinical Groups (JHACG) frailty-defining criteria, and Major Diagnostic Category (MDC) at admission classifications were obtained. The database was divided into training (n = 19,948), validation (n = 6,650), and testing (n = 6,650) datasets. Multivariable analysis was performed to identify significant predictors of shunt complications which were used to develop logistic regression models. Post hoc receiver operating characteristic (ROC) curves were created. RESULTS: A total of 33,248 pediatric patients aged 6.9 ± 5.7 years were included. Number of diagnoses during primary admission (OR: 1.05, 95% CI: 1.04-1.07) and initial neurological admission diagnoses (OR: 3.83, 95% CI: 3.33-4.42) positively correlated with shunt complications. Female sex (OR: 0.87, 95% CI: 0.76-0.99) and elective admissions (OR: 0.62, 95% CI: 0.53-0.72) negatively correlated with shunt complications. ROC curve for the regression model utilizing all significant predictors of readmission demonstrated area under the curve of 0.733, suggesting these factors are possible predictors of shunt complications in pediatric hydrocephalus. CONCLUSION: Efficacious and safe treatment of pediatric hydrocephalus is of paramount importance. Our machine learning algorithm delineated possible variables predictive of shunt complications with good predictive value.

Deep Brain Stimulation beyond the Clinic: Navigating the Future of Parkinson's and Alzheimer's Disease Therapy.

Deep brain stimulation (DBS) is a surgical procedure that uses electrical neuromodulation to target specific regions of the brain, showing potential in the treatment of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Despite similarities in disease pathology, DBS is currently only approved for use in PD patients, with limited literature on its effectiveness in AD. While DBS has shown promise in ameliorating brain circuits in PD, further research is needed to determine the optimal parameters for DBS and address any potential side effects. This review emphasizes the need for foundational and clinical research on DBS in different brain regions to treat AD and recommends the development of a classification system for adverse effects. Furthermore, this review suggests the use of either a low-frequency system (LFS) or high-frequency system (HFS) depending on the specific symptoms of the patient for both PD and AD.

Aberrant functional connectivity between reward and inhibitory control networks in pre-adolescent binge eating disorder.

BACKGROUND: Behavioral features of binge eating disorder (BED) suggest abnormalities in reward and inhibitory control. Studies of adult populations suggest functional abnormalities in reward and inhibitory control networks. Despite behavioral markers often developing in children, the neurobiology of pediatric BED remains unstudied. METHODS: 58 pre-adolescent children (aged 9-10-years) with BED (mBMI = 25.05; s.d. = 5.40) and 66 age, BMI and developmentally matched control children (mBMI = 25.78; s.d. = 0.33) were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development (ABCD) Study. We investigated group differences in resting-state functional MRI functional connectivity (FC) within and between reward and inhibitory control networks. A seed-based approach was employed to assess nodes in the reward [orbitofrontal cortex (OFC), nucleus accumbens, amygdala] and inhibitory control [dorsolateral prefrontal cortex, anterior cingulate cortex (ACC)] networks via hypothesis-driven seed-to-seed analyses, and secondary seed-to-voxel analyses. RESULTS: Findings revealed reduced FC between the dlPFC and amygdala, and between the ACC and OFC in pre-adolescent children with BED, relative to controls. These findings indicating aberrant connectivity between nodes of inhibitory control and reward networks were corroborated by the whole-brain FC analyses. CONCLUSIONS: Early-onset BED may be characterized by diffuse abnormalities in the functional synergy between reward and cognitive control networks, without perturbations within reward and inhibitory control networks, respectively. The decreased capacity to regulate a reward-driven pursuit of hedonic foods, which is characteristic of BED, may in part, rest on this dysconnectivity between reward and inhibitory control networks.

Sex differences in regional gray matter density in pre-adolescent binge eating disorder: a voxel-based morphometry study.

BACKGROUND: Binge eating disorder (BED) is a pernicious psychiatric disorder which is linked with broad medical and psychiatric morbidity, and obesity. While BED may be characterized by altered cortical morphometry, no evidence to date examined possible sex-differences in regional gray matter characteristics among those with BED. This is especially important to consider in children, where BED symptoms often emerge coincident with rapid gray matter maturation. METHODS: Pre-adolescent, 9-10-year old boys (N = 38) and girls (N = 33) with BED were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development Study. We investigated sex differences in gray matter density (GMD) via voxel-based morphometry. Control sex differences were also assessed in age and body mass index and developmentally matched control children (boys N = 36; girls N = 38). Among children with BED, we additionally assessed the association between dorsolateral prefrontal (dlPFC) GMD and parent-reported behavioral approach and inhibition tendencies. RESULTS: Girls with BED uniquely demonstrate diffuse clusters of greater GMD (p < 0.05, Threshold Free Cluster Enhancement corrected) in the (i) left dlPFC (p = 0.003), (ii) bilateral dmPFC (p = 0.004), (iii) bilateral primary motor and somatosensory cortex (p = 0.0003) and (iv) bilateral precuneus (p = 0.007). Brain-behavioral associations suggest a unique negative correlation between GMD in the left dlPFC and behavioral approach tendencies among girls with BED. CONCLUSIONS: Early-onset BED may be characterized by regional sex differences in terms of its underlying gray matter morphometry.

Subthreshold repetitive transcranial magnetic stimulation suppresses ketamine-induced poly population spikes in rat sensorimotor cortex.

Cortical oscillations within or across brain regions play fundamental roles in sensory, motor, and memory functions. It can be altered by neuromodulations such as repetitive transcranial magnetic stimulation (rTMS) and pharmacological manipulations such as ketamine. However, the neurobiological basis of the effects of rTMS and ketamine, as well as their interactions, on cortical oscillations is not understood. In this study, we developed and applied a rodent model that enabled simultaneous rTMS treatment, pharmacological manipulations, and invasive electrophysiological recordings, which is difficult in humans. Specifically, a miniaturized C-shaped coil was designed and fabricated to deliver focal subthreshold rTMS above the primary somatosensory (S1) and motor (M1) cortex in rats. Multi-electrode arrays (MEA) were implanted to record local field potentials (LFPs) and single unit activities. A novel form of synchronized activities, poly population spikes (PPS), was discovered as the biomarker of ketamine in LFPs. Brief subthreshold rTMS effectively and reversibly suppressed PPS while increasing the firing rates of single unit activities. These results suggest that ketamine and rTMS have convergent but opposing effects on cortical oscillations and circuits. This highly robust phenomenon has important implications to understanding the neurobiological mechanisms of rTMS and ketamine as well as developing new therapeutic strategies involving both neuromodulation and pharmacological agents.

Neuromodulation of OCD: A review of invasive and non-invasive methods.

Early research into neural correlates of obsessive compulsive disorder (OCD) has focused on individual components, several network-based models have emerged from more recent data on dysfunction within brain networks, including the the lateral orbitofrontal cortex (lOFC)-ventromedial caudate, limbic, salience, and default mode networks. Moreover, the interplay between multiple brain networks has been increasingly recognized. As the understanding of the neural circuitry underlying the pathophysiology of OCD continues to evolve, so will too our ability to specifically target these networks using invasive and noninvasive methods. This review discusses the rationale for and theory behind neuromodulation in the treatment of OCD.

Pathophysiological Mechanisms Underlying Idiopathic Normal Pressure Hydrocephalus: A Review of Recent Insights.

The pathophysiologic mechanisms underpinning idiopathic normal pressure hydrocephalus (iNPH), a clinically diagnosed dementia-causing disorder, continue to be explored. An increasing body of evidence implicates multiple systems in the pathogenesis of this condition, though a unifying causative etiology remains elusive. Increased knowledge of the aberrations involved has shed light on the iNPH phenotype and has helped to guide prognostication for treatment with cerebrospinal fluid diversion. In this review, we highlight the central role of the cerebrovasculature in pathogenesis, from hydrocephalus formation to cerebral blood flow derangements, blood-brain barrier breakdown, and glymphatic pathway dysfunction. We offer potential avenues for increasing our understanding of how this disease occurs.

Frequency-specific medial septal nucleus deep brain stimulation improves spatial memory in MK-801-treated male rats.

BACKGROUND: Few treatments exist for the cognitive symptoms of schizophrenia. Pharmacological agents resulting in glutamate N-methyl-d-aspartate (NMDA) receptor hypofunction, such as MK-801, mimic many of these symptoms and disrupt neural activity. Recent evidence suggests that deep brain stimulation (DBS) of the medial septal nucleus (MSN) can modulate medial prefrontal cortex (mPFC) and hippocampal activity and improve spatial memory. OBJECTIVE: Here, we examine the effects of acute MK-801 administration on oscillatory activity within the septohippocampal circuit and behavior. We also evaluate the potential for MSN stimulation to improve cognitive behavioral measures following MK-801 administration. METHODS: 59 Sprague Dawley male rats received either acute intraperitoneal (IP) saline vehicle injections or MK-801 (0.1 mg/kg). Theta (5-12 Hz), low gamma (30-50 Hz) and high frequency oscillatory (HFO) power were analyzed in the mPFC, MSN, thalamus and hippocampus. Rats underwent MSN theta (7.7 Hz), gamma (100 Hz) or no stimulation during behavioral tasks (Novel object recognition (NOR), elevated plus maze, Barnes maze (BM)). RESULTS: Injection of MK-801 resulted in frequency-specific changes in oscillatory activity, decreasing theta while increasing HFO power. Theta, but not gamma, stimulation enhanced the anxiolytic effects of MK-801 on the elevated plus maze. While MK-801 treated rats exhibited spatial memory deficits on the Barnes maze, those that also received MSN theta, but not gamma, stimulation found the escape hole sooner. CONCLUSIONS: These findings demonstrate that acute MK-801 administration leads to altered neural activity in the septohippocampal circuit and impaired spatial memory. Further, these findings suggest that MSN theta-frequency stimulation improves specific spatial memory deficits and may be a possible treatment for cognitive impairments caused by NMDA hypofunction.

Early life social instability stress causes lasting cognitive decrement and elevated hippocampal stress-related gene expression.

BACKGROUND: Early life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents. METHODS: The current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4). RESULTS: Mice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort. CONCLUSIONS: Ecologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity.

A Review of Medical and Surgical Options for the Treatment of Facial Pain.

Facial pain is a common medical complaint that is easily misdiagnosed. As a result, this pain often goes mistreated. Despite this, there are a variety of pharmacologic, surgical, and neuromodulatory options for the treatment of facial pain. In this review, the authors detail the forms of facial pain and their treatment options. They discuss the common medications used in the first-line treatment of facial pain and the second-line surgical and neuromodulatory options available to patients when pharmacologic options fail.

Electrical devices for visual restoration.

Given the rising number of patients with blindness from macular, optic nerve, and visual pathway disease, there is considerable interest in the potential of electrical stimulation devices to restore vision. Electrical devices for restoration of visual function can be grouped into three categories: (1) visual prostheses whose goal is to bypass damaged areas and directly activate downstream intact portions of the visual pathway; (2) electric field stimulation whose goal is to activate endogenous transcriptional and molecular signaling pathways to promote neuroprotection and neuro-regeneration; and (3) neuromodulation whose stimulation would resuscitate neural circuits vital to coordinating responses to visual input.  In this review, we discuss these three approaches, describe advances made in the different fields, and comment on limitations and potential future directions.

Preexisting Ventricular Shunts Are Associated with Failed Evacuation of Acute Subdural Hematomas: Single-Institution Case Series of Complications and Management Strategies.

BACKGROUND: The effect of ventricular shunts on radiographic outcomes after evacuation of acute subdural hematomas (aSDHs) has not yet been established. We studied a series of patients who had undergone craniotomy for aSDH, exploring a possible relationship between the occurrence of a postoperative extra-axial collection (EAC) and the presence of a ventricular shunt. METHODS: We reviewed all craniotomies for convexity aSDH performed between July 2015 and June 2020. The medical record review included perioperative coagulation studies, platelet counts, and antiplatelet and anticoagulation agent use. Univariate and multivariate analyses were conducted to identify the factors associated with postoperative EACs and reevacuation. RESULTS: A total of 58 patients had undergone craniotomy for aSDHs, including 9 with ventricular shunts. The median age was 67 years (interquartile range, 54-78 years), and 40% of the patients were women. Of the 58 patients, 16 were taking antiplatelet agents, and 6 were taking anticoagulation agents. Ten patients had developed perioperative thrombocytopenia (platelet count, <100,000/µL). Twelve patients had perioperative coagulopathy (international normalized ratio, ≥1.5). A postoperative EAC >10 mm occurred in 17 patients (29.3%). Eight patients (13.8%) had undergone reevacuation. The presence of a shunt and an increasing preoperative aSDH size were independently associated with an EAC >10 mm (P = 0.013 and P = 0.003, respectively). Only the presence of a shunt predicted for the need for reevacuation (P = 0.001). The shunts were explanted (n = 3) or valves were adjusted (n = 3) in all but 3 cases. CONCLUSIONS: We found that a lack of brain reexpansion after aSDH evacuation worsens radiographic outcomes and was more common in patients with shunts. Increasing shunt valve resistance might help prevent the formation of large EACs after aSDH evacuation.

Low Intensity Repetitive Transcranial Magnetic Stimulation Modulates Spontaneous Spiking Activities in Rat Cortex.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique for neuromodulation. Even at low intensities, rTMS can alter the structure and function of neural circuits; yet the underlying mechanism remains unclear. Here we report a new experimental paradigm for studying the effect of low intensity rTMS (LI-rTMS) on single neuron spiking activities in the sensorimotor cortex of anesthetized rats. We designed, built, and tested a miniaturized TMS coil for use on small animals such as rats. The induced electric field in different 3D locations was measured along different directions using a dipole probe. A maximum electric field strength of 2.3 V/m was achieved. LI-rTMS (10 Hz, 3 min) was delivered to the rat primary motor and somatosensory cortices. Single-unit activities were recorded before and after LI-rTMS. Results showed that LI-rTMS increased the spontaneous firing rates of primary motor and somatosensory cortical neurons. Diverse modulatory patterns were observed in different neurons. These results indicated the feasibility of using miniaturized coil in rodents as an experimental platform for evaluating the effect of LI-rTMS on the brain and developing therapeutic strategies for treating neurological disorders.

Gamified Dual-Task Training for Individuals with Parkinson Disease: An Exploratory Study on Feasibility, Safety, and Efficacy.

OBJECTIVES: The feasibility and safety of the use of neurorehabilitation technology (SMARTfit® Trainer system) by physical therapists in implementing a gamified physical-cognitive dual-task training (DTT) paradigm for individuals with Parkinson disease (IWPD) was examined. Additionally, the efficacy of this gamified DTT was compared to physical single-task training (STT), both of which were optimized using physio-motivational factors, on changes in motor and cognitive outcomes, and self-assessed disability in activities of daily living. METHODS: Using a cross-over study design, eight participants with mild-to-moderate idiopathic PD (including one with mild cognitive impairment) completed both training conditions (i.e., gamified DTT and STT). For each training condition, the participants attended 2-3 sessions per week over 8.8 weeks on average, with the total amount of training being equivalent to 24 1 h sessions. A washout period averaging 11.5 weeks was inserted between training conditions. STT consisted of task-oriented training involving the practice of functional tasks, whereas for gamified DTT, the same task-oriented training was implemented simultaneously with varied cognitive games using an interactive training system (SMARTfit®). Both training conditions were optimized through continual adaptation to ensure the use of challenging tasks and to provide autonomy support. Training hours, heart rate, and adverse events were measured to assess the feasibility and safety of the gamified DTT protocol. Motor and cognitive function as well as perceived disability were assessed before and after each training condition. RESULTS: Gamified DTT was feasible and safe for this cohort. Across participants, significant improvements were achieved in more outcome measures after gamified DTT than they were after STT. Individually, participants with specific demographic and clinical characteristics responded differently to the two training conditions. CONCLUSION: Physical therapists' utilization of technology with versatile hardware configurations and customizable software application selections was feasible and safe for implementing a tailor-made intervention and for adapting it in real-time to meet the individualized, evolving training needs of IWPD. Specifically in comparison to optimized STT, there was a preliminary signal of efficacy for gamified DTT in improving motor and cognitive function as well as perceived disability in IWPD.

Large Primary Transethmoidal Encephalocele Presenting in an Adult.

Transethmoidal encephaloceles are rare and most commonly present at birth with congenital abnormalities, cerebrospinal fluid rhinorrhea, or visual symptoms. Here, we report the case of a 43-year-old presenting with longstanding headache, blurry vision, anosmia, and rhinorrhea. Magnetic resonance imaging confirmed a transethmoidal encephalocele. The patient underwent craniotomy for resection of the encephalocele and repair of the cribriform defect. The postoperative course was uneventful, and the patient was discharged home with the resolution of rhinorrhea and headache. This report highlights a rare case of primary transethmoidal encephalocele undiagnosed until adulthood despite longstanding symptoms and successful treatment with resolution of symptoms.