Search

OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson’s disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection. METHODS The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 μsec for STN; 3.3 V and 90 μsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared. RESULTS VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex. CONCLUSIONS On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

Deep brain stimulation has been extensively studied as a therapeutic option for treatment-resistant depression (TRD). DBS across different targets is associated with on average 60% response rates in previously refractory chronically depressed patients. However, response rates vary greatly between patients and between studies and often require extensive trial-and-error optimizations of stimulation parameters. Emerging evidence from tractography imaging suggests that targeting combinations of white matter tracts, rather than specific grey matter regions, is necessary for meaningful antidepressant response to DBS. In this article, we review efficacy of various DBS targets for TRD, which networks are involved in their therapeutic effects, and how we can use this information to improve targeting and programing of DBS for individual patients. We will also highlight how to integrate these DBS network findings into developing adaptive stimulation and optimal trial designs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01270-3.

A central goal of neuroscience is to advance knowledge of the molecular basis of human brain function. Most molecular studies of the human brain have been performed using tissue from postmortem brain donors rather than living people. The assumption underlying this practice – which had never been rigorously tested prior to this report – is that the postmortem human brain is an appropriate proxy for the living human brain at the molecular level. Here, this assumption is thoroughly challenged for the first time by comparing human prefrontal cortex gene expression between 275 living samples and 243 postmortem samples. Vast differences in gene expression were found between the living and postmortem human brain. Expression levels differed significantly for nearly 80% of genes, and this finding was not a consequence of any potential technical or biological confounders of the gene expression data. Postmortem brain gene expression signatures of Alzheimer’s disease, schizophrenia, Parkinson’s disease, bipolar disorder, and autism spectrum disorder were shown to be inaccurate representations of disease processes occurring in the living brain. In light of these findings, the use of postmortem tissue as a proxy for living tissue in human brain research should be reconsidered. To advance knowledge of the molecular basis of human brain function, the study of tissue from living people should be prioritized.

Objective A recently introduced Spinal Cord Stimulation (SCS) system operates at 10 kHz, faster than conventional SCS systems, resulting in significantly more power delivered to tissues. Using a SCS heat phantom and bioheat multi-physics model, we characterized tissue temperature increases by this 10 kHz system. We also evaluated its Implanted Pulse Generator (IPG) output compliance and the role of impedance in temperature increases. Materials and methods The 10 kHz SCS system output was characterized under resistive loads (1-10 KΩ). Separately, fiber optic temperature probes quantified temperature increases (ΔTs) around the SCS lead in specially developed heat phantoms. The role of stimulation Level (1-7; ideal pulse peak-to-peak of 1-7mA) was considered, specifically in the context of stimulation current Root Mean Square (RMS). Data from the heat phantom were verified with the SCS heat-transfer models. A custom high-bandwidth stimulator provided 10 kHz pulses and sinusoidal stimulation for control experiments. Results The 10 kHz SCS system delivers 10 kHz biphasic pulses (30-20-30 μs). Voltage compliance was 15.6V. Even below voltage compliance, IPG bandwidth attenuated pulse waveform, limiting applied RMS. Temperature increased supralinearly with stimulation Level in a manner predicted by applied RMS. ΔT increases with Level and impedance until stimulator compliance was reached. Therefore, IPG bandwidth and compliance dampen peak heating. Nonetheless, temperature increases predicted by bioheat multi-physic models (ΔT = 0.64°C and 1.42°C respectively at Level 4 and 7 at the cervical segment; ΔT = 0.68°C and 1.72°C respectively at Level 4 and 7 at the thoracic spinal cord)-within ranges previously reported to effect neurophysiology. Conclusions Heating of spinal tissues by this 10 kHz SCS system theoretically increases quickly with stimulation level and load impedance, while dampened by IPG pulse bandwidth and voltage compliance limitations. If validated in vivo as a mechanism of kHz SCS, bioheat models informed by IPG limitations allow prediction and optimization of temperature changes.

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.

This systematic review assessed design characteristics and reporting quality of published randomized clinical trials of spinal cord stimulation (SCS) for treatment of pain in adults and adolescents. The study protocol was registered with PROSPERO (CRD42018090412). Relevant articles were identified by searching the following databases through December 31, 2018: MEDLINE, Embase, WikiStim, The Cochrane Database of Systematic Reviews, and The Cochrane Central Register of Controlled Trials. Forty-six studies were included. Eighty-seven percent of articles identified a pain-related primary outcome. Secondary outcomes included physical functioning, health-related quality of life, and reductions in opioid use. Nineteen of the 46 studies prespecified adverse events as an outcome, with 4 assessing them as a primary outcome. Eleven studies stated that they blinded participants. Of these, only 5 were assessed as being adequately blinded. The number of participants enrolled was generally low (median 38) and study durations were short (median 12 weeks), particularly in studies of angina. Fifteen studies employed an intention-to-treat analysis, of which only seven specified a method to accommodate missing data. Review of these studies identified deficiencies in both reporting and methodology. The review's findings suggest areas for improving the design of future studies and increasing transparency of reporting. Perspective This article presents a systematic review of research methods and reporting quality of randomized clinical trials of SCS for the treatment of various pain complaints. The review identifies deficiencies in both methodology and reporting, which may inform the design of future studies and improve reporting standards.

Supplemental Digital Content is Available in the Text., Spinal cord stimulation (SCS) is an interventional nonpharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). Although randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, nonspecific effects of treatment variables (eg, paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations. To address these challenges, 3 professional societies (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, Institute of Neuromodulation, and International Neuromodulation Society) convened a meeting to develop consensus recommendations on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain. This article summarizes the results of this meeting. Highlights of our recommendations include disclosing all funding source and potential conflicts; incorporating mechanistic objectives when possible; avoiding noninferiority designs without internal demonstration of assay sensitivity; achieving and documenting double-blinding whenever possible; documenting investigator and site experience; keeping all information provided to patients balanced with respect to expectation of benefit; disclosing all information provided to patients, including verbal scripts; using placebo/sham controls when possible; capturing a complete set of outcome assessments; accounting for ancillary pharmacologic and nonpharmacologic treatments in a clear manner; providing a complete description of intended and actual programming interactions; making a prospective ascertainment of SCS-specific safety outcomes; training patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and providing transparent and complete reporting of results according to applicable reporting guidelines.

Excessive brain iron deposition is involved in Parkinson's disease (PD) pathogenesis. However, the correlation of iron accumulation in various brain nuclei is not well-established in different stages of the disease. This cross-sectional study aims to evaluate quantitative susceptibility mapping (QSM) as an imaging technique to measure brain iron accumulation in PD patients in different stages compared to healthy controls.Ninety-six PD patients grouped by their Hoehn and Yahr (HY) stages and 31 healthy controls were included in this analysis. The magnetic susceptibility values of the substantia nigra (SN), red nucleus (RN), caudate, putamen, and globus pallidus were obtained and compared.Iron level was increased in the SN of PD patients in all stages versus controls (p .001), with no significant difference within stages. Iron in the RN was significantly increased in stage II versus controls (p = .013) and combined stages III and IV versus controls (p .001). The iron levels in caudate, putamen, and globus pallidus were not different between any groups.Our data suggest iron accumulation occurs early in the disease course and only in the SN and RN of these patients. This is a large cross-sectional study of brain iron deposition in PD patients according to HY staging. Prospective studies are warranted to further validate QSM as a method to follow brain iron, which could serve as a disease biomarker and a therapeutic target.

Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer’s Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.One-Sentence SummaryCharacterizing the genetic regulation of chromatin accessibility and gene expression in human microglia refines molecular mechanisms of Alzheimer’s disease risk loci.

OBJECTIVEThe objective of this study was to investigate the relationship between iron and white matter connectivity in the subthalamic nucleus (STN) in patients undergoing deep brain stimulation (DBS) of the STN for treatment of Parkinson’s disease.METHODSNine Parkinson’s disease patients underwent preoperative 3T MRI imaging which included acquisition of T1-weighted anatomical images along with diffusion tensor imaging (DTI) and quantitative susceptibility mapping (QSM). MR tractography was performed for the seed voxels located within the STN, and the correlations between normalized QSM values and the STN’s connectivity to a set of a priori chosen regions of interest were assessed.RESULTSA strong negative correlation was found between STN connectivity and QSM intensity for the thalamus, premotor, motor, and sensory regions, while a strong positive correlation was found for frontal, putamen, and brain stem areas.CONCLUSIONSQuantitative susceptibility mapping not only accurately delineates the STN borders but is also able to provide functional information about the STN functional subdivisions. The observed iron-to-connectivity correlation patterns may aid in planning DBS surgery to avoid unwanted side effects associated with DBS.

Background and purpose Quantitative susceptibility mapping (QSM) of the brain has become highly reproducible and has applications in an expanding array of diseases. To translate QSM from bench to bedside, it is important to automate its reconstruction immediately after data acquisition. In this work, a server system that automatically reconstructs QSM and exchange images with the scanner using the DICOM standard is demonstrated using a multi-site, multi-vendor reproducibility study and a large, single-site, multi-scanner image quality review study in a clinical environment. Methods A single healthy subject was scanned with a 3D multi-echo gradient echo sequence at nine sites around the world using scanners from three manufacturers. A high-resolution (HiRes, .5 × .5 × 1 mm3 reconstructed) and standard-resolution (StdRes, .5 × .5 × 3 mm3 ) protocol was performed. ROI analysis of various white matter and gray matter regions was performed to investigate reproducibility across sites. At one institution, a retrospective multi-scanner image quality review was carried out of all clinical QSM images acquired consecutively in 1 month. Results Reconstruction times using a GPU were 29 ± 22 seconds (StdRes) and 55 ± 39 seconds (HiRes). ROI standard deviation across sites was below 24 ppb (StdRes) and 17 ppb (HiRes). Correlations between ROI averages across sites were on average .92 (StdRes) and .96 (HiRes). Image quality review of 873 consecutive patients revealed diagnostic or excellent image quality in 96% of patients. Conclusion Online QSM reconstruction for a variety of sites and scanner platforms with low cross-site ROI standard deviation is demonstrated. Image quality review revealed diagnostic or excellent image quality in 96% of 873 patients.

BACKGROUND AND PURPOSE: The objective ofthis study was to demonstrate a global cerebrospinal fluid (CSF) method for a consistent and automated zero referencing of brain quantitative susceptibility mapping (QSM). METHODS: Whole brain CSF mask was automatically segmented by thresholding the gradient echo transverse relaxation [Formula: see text] map, and regularization was employed to enforce uniform susceptibility distribution within the CSF volume in the field-to-susceptibility inversion. This global CSF regularization method was compared with a prior ventricular CSF regularization. Both reconstruction methods were compared in a repeatability study of 12 healthy subjects using t-test on susceptibility measurements, and in patient studies of 17 multiple sclerosis (MS) and 10 Parkinson’s disease (PD) patients using Wilcoxon rank-sum test on radiological scores. RESULTS: In scan-rescan experiments, global CSF regularization provided more consistent CSF volume as well as higher repeatability of QSM measurements than ventricular CSF regularization with a smaller bias: –2.7 parts per billion (ppb) versus –0.13 ppb (t-test p

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.

OBJECTIVE The objective of this study was to evaluate clinical features and response to deep brain stimulation (DBS) in G2019S LRRK2-Parkinson disease (LRRK2-PD) and idiopathic PD (IPD). METHODS The authors conducted a clinic-based cohort study of PD patients recruited from the Mount Sinai Beth Israel Genetics database of PD studies. The cohort included 87 participants with LRRK2-PD (13 who underwent DBS) and 14 DBS participants with IPD enrolled between 2009 and 2017. The baseline clinical features, including motor ratings and levodopa-equivalent daily dose (LEDD), were compared among LRRK2-PD patients with and without DBS, between LRRK2-PD with DBS and IPD with DBS, and between LRRK2-PD with subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) DBS. Longitudinal motor scores (Unified Parkinson’s Disease Rating Scale–part III) and medication usage were also assessed pre- and postoperatively. RESULTS Compared to LRRK2-PD without DBS (n = 74), the LRRK2-PD with DBS cohort (n = 13) had a significantly younger age of onset, longer disease duration, were more likely to have dyskinesia, and were less likely to experience hand tremor at disease onset. LRRK2-PD participants were also more likely to be referred for surgery because of severe dyskinesia (11/13 [85%] vs 6/14 [43%], p = 0.04) and were less likely to be referred for medically refractory tremor (0/13 [0%] vs 6/14 [43%], p = 0.02) than were IPD patients. Among LRRK2-PD patients, both STN-DBS and GPi-DBS targets were effective, although the sample size was small for both groups. There were no revisions or adverse effects reported in the GPi-DBS group, while 2 of the LRRK2-PD participants who underwent STN-DBS required revisions and a third reported depression as a stimulation-related side effect. Medication reduction favored the STN group. CONCLUSIONS The LRRK2-PD cohort referred for DBS had a slightly different profile, including earlier age of onset and dyskinesia. Both the STN and GPi DBS targets were effective in symptom suppression. Patients with G2019S LRRK2 PD were well-suited for DBS therapy and had favorable motor outcomes regardless of the DBS target. LRRK2-DBS patients had longer disease durations and tended to have more dyskinesia. Dyskinesia commonly served as the trigger for DBS surgical candidacy. Medication-refractory tremor was not a common indication for surgery in the LRRK2 cohort.

The field of neuromodulation, at its essence, aims to apply electrical stimulation to the brain to ameliorate various pathology. Many methods of applying this stimulation exist, including invasive and non-invasive means. In the realm of invasive stimulation, stimulation of the cortex remains one of the earliest techniques investigated, yet one of the most underutilized today. Evidence for the efficacy of direct invasive cortical stimulation continues to mount, especially in recent years. In this chapter we will review the evidence for the use of invasive cortical stimulation as it applies to neuropathic pain, epilepsy, psychiatric disease, movement disorders, tinnitus, and post-stroke recovery, as well explore some potential mechanisms and future directions of the technique.

OBJECTIVE The objective of this study was to investigate the correlation between the quantitative susceptibility mapping (QSM) signal gradient of the subthalamic nucleus (STN) and motor impairment in patients with Parkinson’s disease (PD). METHODS All PD patients who had undergone QSM MRI for presurgical deep brain stimulation (DBS) planning were eligible for inclusion in this study. The entire STN and its three functional subdivisions, as well as the adjacent white matter (WM), were segmented and measured. The QSM value difference between the entire STN and adjacent WM (STN-WM), between the limbic and associative regions of the STN (L-A), and between the associative and motor regions of the STN (A-M) were obtained as measures of gradient and were input into an unsupervised k-means clustering algorithm to automatically categorize the overall boundary distinctness between the STN and adjacent WM and between STN subdivisions (gradient blur [GB] and gradient sharp [GS] groups). Statistical tests were performed to compare clinical and image measurements for discrimination between GB and GS groups. RESULTS Of the 39 study patients, 19 were categorized into the GB group and 20 into the GS group, based on quantitative cluster analysis. The GB group had a significantly higher presurgical off-medication Unified Parkinson’s Disease Rating Scale Part III score (51.289 ± 20.741) than the GS group (38.5 ± 16.028; p = 0.037). The GB group had significantly higher QSM values for the STN and its three subdivisions and adjacent WM than those for the GS group (p < 0.01). The GB group also demonstrated a significantly higher STN-WM gradient in the right STN (p = 0.01). The GB group demonstrated a significantly lower L-A gradient in both the left and the right STN (p < 0.02). CONCLUSIONS Advancing PD with more severe motor impairment leads to more iron deposition in the STN and adjacent WM, as shown in the QSM signal. Loss of the STN inner QSM signal gradient should be considered as an image marker for more severe motor impairment in PD patients.

Background While deep brain stimulation (DBS) is a relatively safe procedure, skin erosion is a commonly reported hardware complication that can threaten the DBS system. Patients with Parkinson disease are especially at risk for this complication due to their autonomic dysregulation and impaired nutrition. Early detection of impending skin erosion allows for intervention that may prevent hardware destruction. Here we report a novel technique to address this complication preemptively. We describe the use of an acellular dermal matrix to prevent skin erosion in 20 patients with Parkinson disease who were treated with DBS and showed signs of impending skin erosion. Methods Twenty patients with signs of impending hardware erosion were identified. An acellular dermal matrix was surgically placed under the at-risk skin overlying the DBS lead. Results None of the 20 patients treated with this technique went on to require further revision surgery or removal of hardware. Conclusions Surgical placement of acellular dermal matrix in patients identified as having impending hardware erosions is a safe and cost-effective way to prevent hardware complications.

ObjectiveRefractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain stimulation (DBS)-based therapies for depression and obsessive–compulsive disorder (OCD). Results from recent pivotal trials of these therapies, however, did not demonstrate the degree of efficacy expected from previous smaller trials. To discuss next steps, neurosurgeons, neurologists, psychiatrists and representatives from industry convened a workshop sponsored by the American Society for Stereotactic and Functional Neurosurgery in Chicago, Illinois, in June of 2016.DesignHere we summarise the proceedings of the workshop. Participants discussed a number of issues of importance to the community. First, we discussed how to interpret results from the recent pivotal trials of DBS for OCD and depression. We then reviewed what can be learnt from lesions and closed-loop neurostimulation. Subsequently, representatives from the National Institutes of Health, the Food and Drug Administration and industry discussed their views on neuromodulation for psychiatric disorders. In particular, these third parties discussed their criteria for moving forward with new trials. Finally, we discussed the best way of confirming safety and efficacy of these therapies, including registries and clinical trial design. We close by discussing next steps in the journey to new neuromodulatory therapies for these devastating illnesses.ConclusionInterest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. Level of Evidence: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951–971.

Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PD-associated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

Objectives Spinal cord stimulation (SCS) is a recognized treatment for chronic pain. This systematic review aims to assess economic evaluations of SCS for the management of all chronic pain conditions, summarize key findings, and assess the quality of studies to inform healthcare resource allocation decisions and future research. Methods Economic evaluations were identified by searching general medical and economic databases complemented with screening of reference lists of identified studies. No restrictions on language or treatment comparators were applied. Relevant data were extracted. The quality of included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results Fourteen studies met the inclusion criteria and were judged to be of acceptable quality. Economic evaluations assessed SCS for the management of refractory angina pectoris, failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), diabetic peripheral neuropathy (DPN), and peripheral arterial disease. Model-based studies typically applied a 2-stage model, i.e. decision tree followed by Markov model. Time horizon varied from 1 year to lifetime. Cost-effectiveness ranged widely from dominant (SCS cost-saving and more effective) to incremental cost-effectiveness ratio of >£100,000 per quality-adjusted life-year. Cost-effectiveness appeared to depend on the time horizon, choice of comparator, and indication. Ten of the studies indicated SCS as cost-saving or cost-effective compared with the alternative strategies. Conclusion The results consistently suggest that SCS is cost-effective when considering a long-term time horizon, particularly for the management of FBSS and CRPS. Further studies are needed to assess the cost-effectiveness of SCS for ischemic pain and DPN.

Impulsivity and compulsivity are prominent non-motor problems in Parkinson's disease (PD). Despite 20 years of research, there is still an ongoing debate as to whether subthalamic deep brain stimulation (STN DBS) for PD exacerbates or improves these symptoms. Here, we review how STN DBS affects clinical symptoms and neurocognitive aspects of impulsivity and compulsivity. When comparing patients post- to pre-surgery, in the majority of studies STN DBS for PD is associated with a decrease in clinically diagnosed impulse-control disorders and disorders of compulsivity. To avoid confounds, such as post-surgical decreases in dopaminergic medication doses, comparisons can also be made between DBS "On" versus "Off" conditions. These experimentally assayed effects of STN DBS with respect to neurocognitive aspects of impulsivity and compulsivity are more mixed. STN DBS improves behavioral flexibility without impairing negative feedback learning, delay discounting, or inhibitory control, as long as stimulation is restricted to the dorsal STN. However, STN DBS may drive impulsive actions when a subject is faced with competing choices. We discuss how motivated responses may be either enhanced or impaired by STN DBS depending on engagement of dorsal or ventral STN-mediated circuits. Future studies should combine structural and functional circuit measures with behavioral testing in PD patients on and off medication and stimulation. A more sophisticated understanding of how to modulate cortico-striatal-thalamo-cortical loops will increase the likelihood that these circuit manipulation techniques can successfully be applied to a wider range of neuropsychiatric disorders.

Background While transcranial magnetic stimulation (TMS) has been studied for the treatment of psychiatric disorders, emerging evidence supports its use for pain and headache by stimulating either motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC). However, its clinical implementation is hindered due to a lack of consensus in the quality of clinical evidence and treatment recommendation/guideline(s). Thus, working collaboratively, this multinational multidisciplinary expert panel aims to: 1) assess and rate the existing outcome evidence of TMS in various pain/headache conditions; 2) provide TMS treatment recommendation/guidelines for the evaluated conditions and comorbid depression; and 3) assess the cost-effectiveness and technical issues relevant to the long-term clinical implementation of TMS for pain and headache. Methods Seven task groups were formed under the guidance of a 5-member steering committee with four task groups assessing the utilization of TMS in the treatment of Neuropathic Pain (NP), Acute Pain, Primary Headache Disorders, and Posttraumatic Brain Injury related Headaches (PTBI-HA), and remaining three assessing the treatment for both pain and comorbid depression, and the cost-effectiveness and technological issues relevant to the treatment. Results The panel rated the overall level of evidence and recommendability for clinical implementation of TMS as: 1) high and extremely/strongly for both NP and PTBI-HA respectively; 2) moderate for postoperative pain and migraine prevention, and recommendable for migraine prevention. While the use of TMS for treating both pain and depression in one setting is clinically and financially sound, more studies are required to fully assess the long-term benefit of the treatment for the two highly comorbid conditions, especially with neuronavigation. Conclusions After extensive literature review, the panel provided recommendations and treatment guidelines for TMS in managing neuropathic pain and headaches. In addition, the panel also recommended more outcome and cost-effectiveness studies to assess the feasibility of the long-term clinical implementation of the treatment.

Objective To introduce quantitative susceptibility mapping (QSM), a novel magnetic resonance imaging sequence, to the field of neurosurgery. Methods QSM is introduced both in its historical context and by providing a brief overview of the physics behind the technique tailored to a neurosurgical audience. Its application to clinical neurosurgery is then highlighted using case examples. Results QSM offers a quantitative assessment of susceptibility (previously considered as an artifact) via a single, straightforward gradient echo acquisition. QSM differs from standard susceptibility weighted imaging in its ability to both quantify and precisely localize susceptibility effects. Clinical applications of QSM are wide reaching and include precise localization of the deep nuclei for deep brain stimulation electrode placement, differentiation between blood products and calcification within brain lesions, and enhanced sensitivity of cerebral micrometastasis identification. Conclusions We present this diverse range of QSM’s clinical applications to neurosurgical care via case examples. QSM can be obtained in all patients able to undergo magnetic resonance imaging and is easily integratable into busy neuroradiology programs because of its short acquisition time and straightforward, automated offline postprocessing workflow. Clinical integration of QSM may help clinicians better identify and characterize neurosurgical lesions, thereby improving patient care.

Background Deep brain stimulation (DBS) is effective in treating the segmental symptoms of Parkinson's disease (PD) as well as axial symptoms that are levodopa responsive. PD patients on chronic DBS who develop axial symptoms and gait disturbances several years later oftentimes are refractory to high frequency stimulation (HFS). Several studies report benefit produced by low frequency subthalamic nucleus (STN) stimulation in such patients, though the sustainability of the effects has been mixed. Objective To report the clinical outcomes of a series of patients with Parkinson's disease and levodopa responsive axial and gait disturbances who were switched to 60 Hz stimulation within one year of their DBS surgery. Methods A retrospective review of 5 patients, whose severe pre-DBS, levodopa responsive gait disorders worsened on HFS STN-DBS and were subsequently switched to 60 Hz stimulation within 1 year of their surgery. Results The median age of this cohort was 66 years with median disease duration of 14 years. Four of 5 patients' experienced acute worsening of their axial and gait UPDRS III scores on HFS. All patients' gait disorder improved with 60 Hz along with amelioration of their segmental symptoms and reduction of their levodopa induced dyskinesia. The median time on HFS prior to switching to 60 Hz was two months. Stimulation through the ventral contacts was utilized in all patients with relatively modest changes achieved in levodopa equivalent daily dose. Conclusion This case series demonstrates the clinical efficacy of utilizing low frequency (60 Hz) STN stimulation early in the DBS programming course in more advanced PD patients with levodopa responsive gait disturbance and freezing of gait. Activation of a broader stimulation field likely contributed to both axial and segmental symptom improvement while possibly aiding in the reduction of dyskinesia.