Accelerated Transcranial Ultrasound Neuromodulation in Parkinson's Disease: A Pilot Study.

OBJECTIVE: Low-intensity transcranial focused ultrasound (TUS) is a novel method for neuromodulation. We aimed to study the feasibility of stimulating the bilateral primary motor cortices (M1) with accelerated theta-burst TUS (a-tbTUS) on neurophysiologic and clinical outcomes in Parkinson's disease (PD). METHODS: Patients were randomly assigned to receive active or sham a-tbTUS for the first visit and the alternate condition on the second visit, at least 10 days apart. a-tbTUS was administered in three consecutive sonications at 30-minute intervals. We used an accelerated protocol to produce an additive effect of stimulation. Patients were studied in the OFF-medication state. Transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) were used to assess motor cortical excitability before and after TUS. Clinical outcomes after a-tbTUS administration were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III. RESULTS: A total of 20 visits were conducted in 10 PD patients. Compared to the baseline, TMS-elicited MEP amplitudes significantly increased following active but not sham sonication (P = 0.0057). MEP amplitudes were also higher following a-tbTUS than sham sonication (P = 0.0064). There were no statistically significant changes in MDS-UPDRS-III scores with active or sham a-tbTUS. CONCLUSIONS: a-tbTUS increases motor cortex excitability and is a feasible non-invasive neuromodulation strategy in PD. Future studies should determine optimal dosing parameters and the durability of neurophysiologic and clinical outcomes in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Investigation of neurophysiologic and functional connectivity changes following glioma resection using magnetoencephalography.

Background: In patients with glioma, clinical manifestations of neural network disruption include behavioral changes, cognitive decline, and seizures. However, the extent of network recovery following surgery remains unclear. The aim of this study was to characterize the neurophysiologic and functional connectivity changes following glioma surgery using magnetoencephalography (MEG). Methods: Ten patients with newly diagnosed intra-axial brain tumors undergoing surgical resection were enrolled in the study and completed at least two MEG recordings (pre-operative and immediate post-operative). An additional post-operative recording 6-8 weeks following surgery was obtained for six patients. Resting-state MEG recordings from 28 healthy controls were used for network-based comparisons. MEG data processing involved artifact suppression, high-pass filtering, and source localization. Functional connectivity between parcellated brain regions was estimated using coherence values from 116 virtual channels. Statistical analysis involved standard parametric tests. Results: Distinct alterations in spectral power following tumor resection were observed, with at least three frequency bands affected across all study subjects. Tumor location-related changes were observed in specific frequency bands unique to each patient. Recovery of regional functional connectivity occurred following glioma resection, as determined by local coherence normalization. Changes in inter-regional functional connectivity were mapped across the brain, with comparable changes in low to mid gamma-associated functional connectivity noted in four patients. Conclusion: Our findings provide a framework for future studies to examine other network changes in glioma patients. We demonstrate an intrinsic capacity for neural network regeneration in the post-operative setting. Further work should be aimed at correlating neurophysiologic changes with individual patients' clinical outcomes.

Technical and clinical considerations for electroencephalography-based biomarkers for major depressive disorder.

Major depressive disorder (MDD) is a prevalent and debilitating psychiatric disease that leads to substantial loss of quality of life. There has been little progress in developing new MDD therapeutics due to a poor understanding of disease heterogeneity and individuals' responses to treatments. Electroencephalography (EEG) is poised to improve this, owing to the ease of large-scale data collection and the advancement of computational methods to address artifacts. This review summarizes the viability of EEG for developing brain-based biomarkers in MDD. We examine the properties of well-established EEG preprocessing pipelines and consider factors leading to the discovery of sensitive and reliable biomarkers.

Duplication of the internal maxillary artery: Anatomical and clinical considerations.

Duplication of the internal maxillary artery (IMAX) results from a failed regression of either the embryological superficial or deep ring and is reported to be exceedingly rare. We present a patient with this rare anatomical variant who was treated by endovascular technique in the clinical context of an acute oropharyngeal hemorrhage.

Connectomic neuromodulation for Alzheimer's disease: A systematic review and meta-analysis of invasive and non-invasive techniques.

Deep brain stimulation (DBS) and non-invasive neuromodulation are currently being investigated for treating network dysfunction in Alzheimer's Disease (AD). However, due to heterogeneity in techniques and targets, the cognitive outcome and brain network connectivity remain unknown. We performed a systematic review, meta-analysis, and normative functional connectivity to determine the cognitive outcome and brain networks of DBS and non-invasive neuromodulation in AD. PubMed, Embase, and Web of Science were searched using three concepts: dementia, brain connectome, and brain stimulation, with filters for English, human studies, and publication dates 1980-2021. Additional records from clinicaltrials.gov were added. Inclusion criteria were AD study with DBS or non-invasive neuromodulation and a cognitive outcome. Exclusion criteria were less than 3-months follow-up, severe dementia, and focused ultrasound intervention. Bias was assessed using Centre for Evidence-Based Medicine levels of evidence. We performed meta-analysis, with subgroup analysis based on type and age at neuromodulation. To determine the patterns of neuromodulation-induced brain network activation, we performed normative functional connectivity using rsfMRI of 1000 healthy subjects. Six studies, with 242 AD patients, met inclusion criteria. On fixed-effect meta-analysis, non-invasive neuromodulation favored baseline, with effect size -0.40(95% [CI], -0.73, -0.06, p = 0.02), while that of DBS was 0.11(95% [CI] -0.34, 0.56, p = 0.63), in favor of DBS. In patients ≥65 years old, DBS improved cognitive outcome, 0.95(95% [CI] 0.31, 1.58, p = 0.004), whereas in patients <65 years old baseline was favored, -0.17(95% [CI] -0.93, 0.58, p = 0.65). Functional connectivity regions were in the default mode (DMN), salience (SN), central executive (CEN) networks, and Papez circuit. The subgenual cingulate and anterior limb of internal capsule (ALIC) showed connectivity to all targets of neuromodulation. This meta-analysis provides level II evidence of a difference in response of AD patients to DBS, based on age at intervention. Brain stimulation in AD may modulate DMN, SN, CEN, and Papez circuit, with the subgenual cingulate and ALIC as potential targets.

Multi-modal investigation of transcranial ultrasound-induced neuroplasticity of the human motor cortex.

INTRODUCTION: There is currently a gap in accessibility to neuromodulation tools that can approximate the efficacy and spatial resolution of invasive methods. Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate cortical and deep brain structures with more focal stimulation compared to existing NIBS modalities. Theta burst TUS (tbTUS, TUS delivered in a theta burst pattern) is a novel repetitive TUS protocol that can induce durable changes in motor cortex excitability, thereby holding promise as a novel neuromodulation tool with durable effects. OBJECTIVE: The aim of the present study was to elucidate the neurophysiologic effects of tbTUS motor cortical excitability, as well on local and global neural oscillations and network connectivity. METHODS: An 80-s train of active or sham tbTUS was delivered to the left motor cortex in 15 healthy subjects. Motor cortical excitability was investigated through transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) using paired-pulse TMS. Magnetoencephalography (MEG) recordings during resting state and an index finger abduction-adduction task were used to assess oscillatory brain responses and network connectivity. The correlations between the changes in neural oscillations and motor cortical excitability were also evaluated. RESULTS: tbTUS to the motor cortex results in a sustained increase in MEP amplitude and decreased SICI, but no change in ICF. MEG spectral power analysis revealed TUS-mediated desynchronization in alpha and beta spectral power. Significant changes in alpha power were detected within the supplementary motor cortex (Right > Left) and changes in beta power within bilateral supplementary motor cortices, right basal ganglia and parietal regions. Coherence analysis revealed increased local connectivity in motor areas. MEP and SICI changes correlated with both local and inter-regional coherence. CONCLUSION: The findings from this study provide novel insights into the neurophysiologic basis of TUS-mediated neuroplasticity and point to the involvement of regions within the motor network in mediating this sustained response. Future studies may further characterize the durability of TUS-mediated neuroplasticity and its clinical applications as a neuromodulation strategy for neurological and psychiatric disorders.

Idiopathic Parkinson's disease and chronic pain in the era of deep brain stimulation: a systematic review and meta-analysis.

OBJECTIVE: Pain is the most common nonmotor symptom of Parkinson's disease (PD) and is often undertreated. Deep brain stimulation (DBS) effectively mitigates the motor symptoms of this multisystem neurodegenerative disease; however, its therapeutic effect on nonmotor symptoms, especially pain, remains inconclusive. While there is a critical need to help this large PD patient population, guidelines for managing this significant disease burden are absent. Herein, the authors systematically reviewed the literature and conducted a meta-analysis to study the influence of traditional (subthalamic nucleus [STN] and globus pallidus internus [GPi]) DBS on chronic pain in patients with PD. METHODS: The authors performed a systematic review of the literature and a meta-analysis following PRISMA guidelines. Risk of bias was assessed using the levels of evidence established by the Oxford Centre for Evidence-Based Medicine. Inclusion criteria were articles written in English, published in a peer-reviewed scholarly journal, and about studies conducting an intervention for PD-related pain in no fewer than 5 subjects. RESULTS: Twenty-six studies were identified and included in this meta-analysis. Significant interstudy heterogeneity was detected (Cochran's Q test p < 0.05), supporting the use of the random-effects model. The random-effects model estimated the effect size of DBS for the treatment of idiopathic pain as 1.31 (95% CI 0.84-1.79). The DBS-on intervention improved pain scores by 40% as compared to the control state (preoperative baseline or DBS off). CONCLUSIONS: The results indicated that traditional STN and GPi DBS can have a favorable impact on pain control and improve pain scores by 40% from baseline in PD patients experiencing chronic pain. Further trials are needed to identify the subtype of PD patients whose pain benefits from DBS and to identify the mechanisms by which DBS improves pain in PD patients.

Where Are We with Deep Brain Stimulation? A Review of Scientific Publications and Ongoing Research.

BACKGROUND: Deep brain stimulation (DBS) is a neuromodulatory technique that delivers adjustable electrical stimuli to brain targets to relieve symptoms associated with dysregulated neural circuitry. Over the last several decades, DBS has been applied to a number of conditions, including motor, pain, mood, and cognitive disorders. An assessment of the body of work in this field is warranted to determine where we have been, define the current state of the field, and chart a path toward the future. OBJECTIVE: The aim of the study was to assess the state of DBS-related research by analyzing the DBS literature as well as active studies sponsored by the National Institutes of Health (NIH) or German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]). METHODS: Peer-reviewed DBS publications were extracted from PubMed. Active NIH-funded DBS projects were extracted from the RePORT database and active DFG projects from the German Research Foundation database. Records were analyzed using custom-developed algorithms to generate a detailed overview of past and present DBS-related research. Specifically, records were categorized by publication year, journal, language, country of origin, contributing authors, disorder, brain target, study design, and topic. Expected project duration and costs were also provided for active studies. RESULTS: In total, 8,974 publications, 172 active NIH-funded projects, and 34 active DFG projects were identified. Records spanned 52 different disorders across 31 distinct brain targets and showed a recent shift toward studies examining conditions other than movement disorders. Most published works involved human research (80.6% of published studies), of which 10.2% were identified as clinical trials. Increasingly, studies focused on imaging or electrophysiological changes associated with DBS (69.8% NIH-active and 70.6% DFG-active vs. 25.8% published) or developing new stimulation techniques and adaptive technologies (37.8% NIH-active and 17.6% DFG-active vs. 6.5% published). CONCLUSIONS: This overview of past and present DBS-related studies provides insight into the status of DBS research and what we can anticipate in the future concerning new indications, improved/novel target selection and stimulation paradigms, closed-loop technology, and a better understanding of the mechanisms of action of DBS.

Single-Trajectory Multiple-Target Deep Brain Stimulation for Parkinsonian Mobility and Cognition.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES: The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS: We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS: NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P < 0.01) and increased low- and high-frequency power and functional connectivity. Volume of tissue activated in the left NBM was associated with stable cognition (P < 0.05). CONCLUSIONS: Simultaneous GPi and NBM stimulation is safe and improves motor complications. NBM stimulation altered neuroimaging biomarkers but without lasting cognitive improvement. © 2021 International Parkinson and Movement Disorder Society.

A Network-Based Approach to Glioma Surgery: Insights from Functional Neurosurgery.

The evaluation and manipulation of structural and functional networks, which has been integral to advancing functional neurosurgery, is beginning to transcend classical subspecialty boundaries. Notably, its application in neuro-oncologic surgery has stimulated an exciting paradigm shift from the traditional localizationist approach, which is lacking in nuance and optimization. This manuscript reviews the existing literature and explores how structural and functional connectivity analyses have been leveraged to revolutionize and individualize pre-operative tumor evaluation and surgical planning. We describe how this novel approach may improve cognitive and neurologic preservation after surgery and attenuate tumor spread. Furthermore, we demonstrate how connectivity analysis combined with neuromodulation techniques can be employed to induce post-operative neuroplasticity and personalize neurorehabilitation. While the landscape of functional neuro-oncology is still evolving and requires further study to encourage more widespread adoption, this functional approach can transform the practice of neuro-oncologic surgery and improve the care and outcomes of patients with intra-axial tumors.

Deep brain stimulation: is it time to change gears by closing the loop?

Objective.Adaptive deep brain stimulation (aDBS) is a form of invasive stimulation that was conceived to overcome the technical limitations of traditional DBS, which delivers continuous stimulation of the target structure without considering patients' symptoms or status in real-time. Instead, aDBS delivers on-demand, contingency-based stimulation. So far, aDBS has been tested in several neurological conditions, and will be soon extensively studied to translate it into clinical practice. However, an exhaustive description of technical aspects is still missing.Approach.in this topical review, we summarize the knowledge about the current (and future) aDBS approach and control algorithms to deliver the stimulation, as reference for a deeper undestending of aDBS model.Main results.We discuss the conceptual and functional model of aDBS, which is based on the sensing module (that assesses the feedback variable), the control module (which interpretes the variable and elaborates the new stimulation parameters), and the stimulation module (that controls the delivery of stimulation), considering both the historical perspective and the state-of-the-art of available biomarkers.Significance.aDBS modulates neuronal circuits based on clinically relevant biofeedback signals in real-time. First developed in the mid-2000s, many groups have worked on improving closed-loop DBS technology. The field is now at a point in conducting large-scale randomized clinical trials to translate aDBS into clinical practice. As we move towards implanting brain-computer interfaces in patients, it will be important to understand the technical aspects of aDBS.

Neuromodulatory treatments for psychiatric disease: A comprehensive survey of the clinical trial landscape.

BACKGROUND: Numerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions. OBJECTIVE/HYPOTHESIS: We sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field. METHODS: ClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source. RESULTS: From 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased. CONCLUSION(S): These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field.

Clinical perspectives of adaptive deep brain stimulation.

BACKGROUND: The application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients' changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models. OBJECTIVE: To review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors. FINDINGS: while aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging. CONCLUSIONS: While aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising.

Trends in Clinical Trials for Spinal Cord Stimulation.

BACKGROUND: Spinal cord stimulation (SCS) is a neuromodulation technology widely used in the treatment of intractable chronic pain syndromes. SCS is now being applied more broadly as a possible therapy for a range of indications, including neurological, cardiac, and gastrointestinal disorders. Ongoing research in this field is critical in order to gain further insights into the mechanisms of SCS, determine its role in new indications, and refine programming techniques for the optimization of therapeutic outcomes. OBJECTIVE: To assess the state of SCS-related human research by cataloging and summarizing clinical trials that have been recently completed or are currently underway in this field. METHODS: A search was conducted for clinical trials pertaining to SCS using the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing SCS-related research. Specifically, trials were categorized by intervention, trial start date, study completion status, clinical phase, projected subject enrollment, condition, country of origin, device manufacturer, funding source, and study topic. RESULTS: In total, 212 relevant clinical trials were identified. 175 trials (82.5%) involved invasive SCS, while the remaining 37 trials (17.5%) used noninvasive forms of spinal stimulation. Most trials examined the efficacy of SCS for chronic pain syndromes or new indications, while others assessed different stimulation parameters. The studies spanned >27 different disorders, with almost 20% of trials pertaining to conditions other than chronic pain syndromes. The majority of SCS trials were US-based (55.7% of studies), but many countries (e.g., Belgium and UK) are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 2:1. Emphasizing the need to optimize therapeutic outcomes of SCS, one-quarter of trials predominantly focused on the assessment of alternative stimulation parameters such as burst or high-frequency stimulation. CONCLUSIONS: A large number of clinical trials of SCS are underway. Improvements in the treatment of pain and novel indications for SCS constitute the majority of studies. This overview of SCS-related clinical trials provides a window into future new indications, novel stimulation techniques, and a heightened understanding of the mechanisms of action.

Bio-Heat Model of Kilohertz-Frequency Deep Brain Stimulation Increases Brain Tissue Temperature.

OBJECTIVES: Early clinical trials suggest that deep brain stimulation at kilohertz frequencies (10 kHz-DBS) may be effective in improving motor symptoms in patients with movement disorders. The 10 kHz-DBS can deliver significantly more power in tissue compared to conventional frequency DBS, reflecting increased pulse compression (duty cycle). We hypothesize that 10 kHz-DBS modulates neuronal function through moderate local tissue heating, analogous to kilohertz spinal cord stimulation (10 kHz-SCS). To establish the role of tissue heating in 10 kHz-DBS (30 µs, 10 kHz, at intensities of 3-7 mApeak ), a decisive first step is to characterize the range of temperature changes during clinical kHz-DBS protocols. MATERIALS AND METHODS: We developed a high-resolution magnetic resonance imaging-derived DBS model incorporating joule-heat coupled bio-heat multi-physics to establish the role of tissue heating. Volume of tissue activated (VTA) under assumptions of activating function (for 130 Hz) or heating (for 10 kHz) based neuromodulation are contrasted. RESULTS: DBS waveform power (waveform RMS) determined joule heating at the deep brain tissues. Peak heating was supralinearly dependent on stimulation RMS. The 10 kHz-DBS stimulation with 2.3 to 5.4 mARMS (corresponding to 3 to 7 mApeak ) produced 0.10 to 1.38°C heating at the subthalamic nucleus (STN) target under standard tissue parameters. Maximum temperature increases were predicted inside the electrode encapsulation layer (enCAP) with 2.3 to 5.4 mARMS producing 0.13 to 1.87°C under standard tissue parameters. Tissue parameter analysis predicted STN heating was especially sensitive (ranging from 0.44 to 1.35°C at 3.8 mARMS ) to decreasing enCAP electrical conductivity and decreasing STN thermal conductivity. CONCLUSIONS: Subject to validation with in vivo measurements, neuromodulation through a heating mechanism of action by 10 kHz-DBS can indicate novel therapeutic pathways and strategies for dose optimization.

Clinical trials for deep brain stimulation: Current state of affairs.

BACKGROUND: Deep brain stimulation (DBS) is a surgical neuromodulation procedure with a historically wide range of possible therapeutic indications, including movement disorders, neuropsychiatric conditions, and cognitive disorders. Ongoing research in this field is critical to gain further insights into the mechanisms of DBS, to discover novel brain targets for new and existing indications, and to refine targeting and post-operative programming techniques for the optimization of therapeutic outcomes. OBJECTIVE: To update on the state of DBS-related clinical human research by cataloging and summarizing clinical trials that have been completed or are currently ongoing in this field worldwide. METHODS: A search was conducted for clinical trials pertaining to DBS, currently listed on the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing DBS-related research. Specifically, trials were categorized by trial start date, study completion status, clinical phase, projected subject enrollment, disorder, brain target, country of origin, device manufacturer, funding source, and study topic. RESULTS: In total, 384 relevant clinical trials were identified. The trials spanned 28 different disorders across 26 distinct brain targets, with almost 40% of trials being for conditions other than movement disorders. The majority of DBS trials have been US-based (41.9% of studies) but many countries are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 3:1. Emphasizing the need to better understand the mechanism of action of DBS, one-third of the studies predominantly focus on imaging or electrophysiological changes associated with DBS. CONCLUSIONS: This overview of current DBS-related clinical trials provides insight into the status of DBS research and what we can anticipate in the future concerning new brain targets, indications, techniques, and developing a better understanding of the mechanisms of action of DBS.

Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner.

Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested this hypothesis in two ways. First, adult mice were intravenously inoculated with Salmonella typhimurium, resulting in sepsis. Second, newborn mouse pups were intranasally infected with reovirus (serotype 3 Dearing), which induced encephalitis. In both mouse models, wild-type Lrrk2 expression was protective and showed a sex effect, with female Lrrk2-deficient animals not controlling infection as well as males. Mice expressing Lrrk2 carrying the Parkinson's disease-linked p.G2019S mutation controlled infection better, with reduced bacterial growth and longer animal survival during sepsis. This gain-of-function effect conferred by the p.G2019S mutation was mediated by myeloid cells and was abolished in animals expressing a kinase-dead Lrrk2 variant, p.D1994S. Mouse pups with reovirus-induced encephalitis that expressed the p.G2019S Lrrk2 mutation showed increased mortality despite lower viral titers. The p.G2019S mutant Lrrk2 augmented immune cell chemotaxis and generated more reactive oxygen species during virulent infection. Reovirus-infected brains from mice expressing the p.G2019S mutant Lrrk2 contained higher concentrations of α-synuclein. Animals expressing one or two p.D1994S Lrrk2 alleles showed lower mortality from reovirus-induced encephalitis. Thus, Lrrk2 alleles may alter the course of microbial infections by modulating inflammation, and this may be dependent on the sex and genotype of the host as well as the type of pathogen.

Empathy in Autism Spectrum Disorder.

Empathy is an essential component of human social life. It requires the ability to understand another's mental state and respond with an appropriate emotion or action. Individuals with autism spectrum disorder (ASD) have been described to exhibit atypical empathic responses which limit communication and social interactions. This review highlights the clinical characteristics and mechanisms underlying empathy in ASD by summarizing 61 peer-reviewed articles. Studies characterized empathic differences due to sex, age, intelligence, and disorder severity and provided valuable insights into the roles that genetics, neural networks, and sensory processing have in eliciting empathy. This knowledge will lead to improved diagnostics and therapies to improve social cognition, emotional recognition, and the empathic response in patients with ASD.

Characterizing the effects of deep brain stimulation with magnetoencephalography: A review.

BACKGROUND: Deep brain stimulation (DBS) is an important form of neuromodulation that is being applied to patients with motor, mood, or cognitive circuit disorders. Despite the efficacy and widespread use of DBS, the precise mechanisms by which it works remain unknown. Over the last decade, magnetoencephalography (MEG) has become an important functional neuroimaging technique used to study DBS. OBJECTIVE: This review summarizes the literature related to the use of MEG to characterize the effects of DBS. METHODS: Peer reviewed literature on DBS-MEG was obtained by searching the publicly accessible literature databases available on PubMed. The abstracts of all reports were scanned and publications which combined DBS-MEG in human subjects were selected for review. RESULTS: A total of 32 publications met the selection criteria, and included studies which applied DBS for Parkinson's disease, dystonia, chronic pain, phantom limb pain, cluster headache, and epilepsy. DBS-MEG studies provided valuable insights into network connectivity, pathological coupling, and the modulatory effects of DBS. CONCLUSIONS: As DBS-MEG research continues to develop, we can expect to gain a better understanding of diverse pathophysiological networks and their response to DBS. This knowledge will improve treatment efficacy, reduce side-effects, reveal optimal surgical targets, and advance the development of closed-loop neuromodulation.