Advances in Technical Aspects of Deep Brain Stimulation Surgery.

BACKGROUND: Deep brain stimulation has become an established technology for the treatment of patients with a wide variety of conditions, including movement disorders, psychiatric disorders, epilepsy, and pain. Surgery for implantation of DBS devices has enhanced our understanding of human physiology, which in turn has led to advances in DBS technology. Our group has previously published on these advances, proposed future developments, and examined evolving indications for DBS. SUMMARY: The crucial roles of structural MR imaging pre-, intra-, and post-DBS procedure in target visualization and confirmation of targeting are described, with discussion of new MR sequences and higher field strength MRI enabling direct visualization of brain targets. The incorporation of functional and connectivity imaging in procedural workup and their contribution to anatomical modelling is reviewed. Various tools for targeting and implanting electrodes, including frame-based, frameless, and robot-assisted, are surveyed, and their pros and cons are described. Updates on brain atlases and various software used for planning target coordinates and trajectories are presented. The pros and cons of asleep versus awake surgery are discussed. The role and value of microelectrode recording and local field potentials are described, as well as the role of intraoperative stimulation. Technical aspects of novel electrode designs and implantable pulse generators are presented and compared.

A human prefrontal-subthalamic circuit for cognitive control.

The subthalamic nucleus is a key site controlling motor function in humans. Deep brain stimulation of the subthalamic nucleus can improve movements in patients with Parkinson's disease; however, for unclear reasons, it can also have cognitive effects. Here, we show that the human subthalamic nucleus is monosynaptically connected with cognitive brain areas such as the prefrontal cortex. Single neurons and field potentials in the subthalamic nucleus are modulated during cognitive processing and are coherent with 4-Hz oscillations in medial prefrontal cortex. These data predict that low-frequency deep brain stimulation may alleviate cognitive deficits in Parkinson's disease patients. In line with this idea, we found that novel 4-Hz deep brain stimulation of the subthalamic nucleus improved cognitive performance. These data support a role for the human hyperdirect pathway in cognitive control, which could have relevance for brain-stimulation therapies aimed at cognitive symptoms of human brain disease.awx300media15660002226001.

Infantile cranial fasciitis: case-based review and operative technique.

BACKGROUND: Cranial fasciitis (CF) is an uncommon benign primary lesion of the skull that typically affects the pediatric age group. Due to the rarity of CF, no prospective studies exist. Earliest description of this condition dates to 1980. The limited scientific and clinical literature regarding CF is dominated by case reports. For these reasons, questions pertaining to the true incidence, genetic risk factors, prognosis, and long-term outcome remain unanswered. DISCUSSION: Clinically, CF presents as a firm, painless, growing scalp mass that is typically not considered in the differential diagnosis. Preoperative pathognomonic signs and symptoms are absent, and imaging features are often nonspecific. Treatment is typically through complete surgical resection, at which time histopathological examination confirms the diagnosis of CF. Reconstruction of the skull defect in the child is critical. Autograft techniques help maintain a rigid construct that integrates with the native skull while preserving its continued ability to grow. Generally, a good outcome is observed with complete resection. EXEMPLARY CASE: We report a case of CF in an infant with emphasis on operative nuances and early follow-up results. CONCLUSION: CF is a rare fibroproliferative disease that has a poorly defined incidence and long-term follow-up. Due to its locally invasive nature and nonspecific presentation, CF is often difficult to differentiate from malignancies and infections. Complete surgical resection is the best approach for diagnosis and cure. Its occult clinical presentation often allows it to achieve considerable growth, leaving a sizeable skull defect following resection. Since CF presents in the pediatric population, allograft reconstruction is preferred over titanium mesh or other synthetic materials to allow osseous integration and continued uninterrupted skull growth.

Novel technique for trialing peripheral nerve stimulation: ultrasonography-guided StimuCath trial.

OBJECTIVE Peripheral nerve stimulation (PNS) has been used for the treatment of neuropathic pain for many decades. Despite the specific indications for PNS, clinicians often have difficulty screening for candidates likely to have a good or fair outcome. Given the expense of a permanent implant, most insurance companies will not pay for the implant without a successful PNS trial. And since PNS has only recently been approved by the US Food and Drug Administration, many insurance companies will not pay for a conventional trial of PNS. The objective of this study is to describe a short low-cost method for trialing and screening patients for peripheral nerve stimulator implantation. Additionally, this study demonstrates the long-term efficacy of PNS in the treatment of chronic neuropathic pain and the relative effectiveness of this novel screening method. METHODS The records of all patients who had undergone trialing and implantation of a PNS system for chronic refractory pain at the authors' institution over a 1-year period (August 1, 2012-July 31, 2013) were examined in this retrospective case series. The search revealed 17 patients, 13 who had undergone a novel in-office ultrasonography-guided StimuCath screening technique and 4 who had undergone a traditional week-long screening procedure. All 17 patients experienced a successful PNS trial and proceeded to permanent PNS system implantation. Patients were followed up for a mean duration of 3.0 years. Visual analog scale (VAS) pain scores were used to assess pain relief in the short-term (< 6 weeks), at 1 year, and at the last follow-up. Final outcome was also characterized as good, fair, poor, or bad. RESULTS Of these 17 patients, 10 were still using their stimulator at the last follow-up, with 8 of them obtaining good relief (classified as ≥ 50% pain relief, with an average 81% reduction in the VAS score) and 2 patients attaining fair relief (< 50% relief but still using stimulation therapy). Among the remaining 7 patients, the stimulator had been explanted in 4 and there had been no relief in 3. Excluding explanted cases, follow-up ranged from 14 to 46 months, with an average of 36 months. Patients with good or fair relief had experienced pain prior to implantation for an average of 5.1 years (range 1.8-15.2 years). A longer duration of pain trended toward a poorer outcome (bad outcome 7.6 years vs good outcome 4.1 years, p = 0.03). Seven (54%) of the 13 patients with the shorter trial experienced a good or fair outcome with an average 79% reduction in the VAS score; however, all 4 of the bad outcome cases came from this group. Three (75%) of the 4 patients with the longer trial experienced a good or fair outcome at the last follow-up, with an average 54% reduction in the VAS score. There was no difference between the trialing methods and the proportion of favorable (good or fair) outcomes (p = 0.71). CONCLUSIONS Short, ultrasonography-guided StimuCath trials were feasible in screening patients for permanent implantation of PNS, with efficacy similar to the traditional week-long screening noted at the 3-year follow-up.

Improvement in Hearing Loss Following Posterior Fossa Arachnoid Cyst Fenestration: A Case Study.

Arachnoid cysts are abnormal intradural collections of cerebrospinal fluid. For posterior fossa arachnoid cysts (PFACs), symptoms vary greatly, often relating to cranial nerve impingement and/or hydrocephalus. Literature on long-term symptomatic and radiographic follow-up of PFACs is lacking. This case study describes a 32-year-old man who presented with headaches and left-sided hearing loss and was found to have a large left-sided cerebellopontine angle arachnoid cyst with syrinx and ventriculomegaly. After PFAC fenestration and excision, his headaches resolved and his hearing markedly improved. At the one-year postoperative evaluation, symptom improvement persisted, and MRI demonstrated a stable decreased cyst and near-complete resolution of his syrinx.

Speech, voice, and language outcomes following deep brain stimulation: A systematic review.

BACKGROUND: Deep brain stimulation (DBS) reliably ameliorates cardinal motor symptoms in Parkinson's disease (PD) and essential tremor (ET). However, the effects of DBS on speech, voice and language have been inconsistent and have not been examined comprehensively in a single study. OBJECTIVE: We conducted a systematic analysis of literature by reviewing studies that examined the effects of DBS on speech, voice and language in PD and ET. METHODS: A total of 675 publications were retrieved from PubMed, Embase, CINHAL, Web of Science, Cochrane Library and Scopus databases. Based on our selection criteria, 90 papers were included in our analysis. The selected publications were categorized into four subcategories: Fluency, Word production, Articulation and phonology and Voice quality. RESULTS: The results suggested a long-term decline in verbal fluency, with more studies reporting deficits in phonemic fluency than semantic fluency following DBS. Additionally, high frequency stimulation, left-sided and bilateral DBS were associated with worse verbal fluency outcomes. Naming improved in the short-term following DBS-ON compared to DBS-OFF, with no long-term differences between the two conditions. Bilateral and low-frequency DBS demonstrated a relative improvement for phonation and articulation. Nonetheless, long-term DBS exacerbated phonation and articulation deficits. The effect of DBS on voice was highly variable, with both improvements and deterioration in different measures of voice. CONCLUSION: This was the first study that aimed to combine the outcome of speech, voice, and language following DBS in a single systematic review. The findings revealed a heterogeneous pattern of results for speech, voice, and language across DBS studies, and provided directions for future studies.

Symptomatic and Radiographic Improvement Following Surgery for Posterior Fossa Arachnoid Cysts: Meta-Analysis and Literature Review.

OBJECTIVE: Arachnoid cysts are benign, intradural collections of cerebrospinal fluid that are often asymptomatic but, in rare instances, will grow and may cause symptoms. When these are in the posterior fossa, the symptomatology greatly ranges, and the indications for surgery are not well defined. The objective of this study is to examine radiographic and symptomatic outcomes following surgery for posterior fossa arachnoid cysts (PFAC). METHODS: A literature review was performed utilizing PubMed for all studies involving ≥ 5 patients with PFACs who underwent surgery. A single-arm meta-analysis was performed to assess the postoperative radiographic improvement. Given the heterogeneous variety of presenting symptoms, these were not conducive to meta-analyses but the outcomes are reported in detail. RESULTS: Nine publications with 67 patients met inclusion criteria. Excision/fenestration was the most common operation (n=60). Less common included CP shunts (n=2), concurrent excision/fenestration and ETV (n=4), and one patient who underwent concurrent VP/CP shunts. This literature review revealed improvement of headache in 90% of patients; 88% with cerebellar symptoms; 92% with nausea/emesis; 78% with hearing loss; 60% with tinnitus; and 91% with vision deficits. Meta-analysis of seven studies reporting postoperative radiographic size demonstrated that 75% of people experienced decreased PFAC size (Effect Size: 0.75, 95% CI: 0.50-0.94). CONCLUSIONS: Although there is a high rate of radiographic improvement for PFAC surgery, there is a wide variety of presenting symptoms with differing postoperative improvement rates. This study reinforces the importance of preoperative counseling regarding symptomatic outcomes for PFAC surgery, with supporting statistical analysis but limited by the sample sizes available.

KETAMINE: Neural- and network-level changes.

Ketamine is a widely used clinical drug that has several functional and clinical applications, including its use as an anaesthetic, analgesic, anti-depressive, anti-suicidal agent, among others. Among its diverse behavioral effects, it influences short-term memory and induces psychedelic effects. At the neural level across different brain areas, it modulates neural firing rates, neural tuning, brain oscillations, and modularity, while promoting hypersynchrony and random connectivity between neurons. In our recent studies we demonstrated that topical application of ketamine on the visual cortex alters neural tuning and promotes vigorous connectivity between neurons by decreasing their firing variability. Here, we begin with a brief review of the literature, followed by results from our lab, where we synthesize a dendritic model of neural tuning and network changes following ketamine application. This model has potential implications for focused modulation of cortical networks in clinical settings. Finally, we identify current gaps in research and suggest directions for future studies, particularly emphasizing the need for more animal experiments to establish a platform for effective translation and synergistic therapies combining ketamine with other protocols such as training and adaptation. In summary, investigating ketamine's broader systemic effects, not only provides deeper insight into cognitive functions and consciousness but also paves the way to advance therapies for neuropsychiatric disorders.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization. Reward outcome representations across wide-spread regions follow a sequential order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We further highlight the role of the anterior insula in generalizing between reward prediction error and risk prediction error codes. Together our results emphasize the importance of neural dynamics for understanding value-based decisions under uncertainty.

Clinico-physiological correlates of Parkinson's disease from multi-resolution basal ganglia recordings.

Parkinson's disease (PD) has been associated with pathological neural activity within the basal ganglia. Herein, we analyzed resting-state single-neuron and local field potential (LFP) activities from people with PD who underwent awake deep brain stimulation surgery of the subthalamic nucleus (STN; n = 125) or globus pallidus internus (GPi; n = 44), and correlated rate-based and oscillatory features with UPDRSIII off-medication subscores. Rate-based single-neuron features did not correlate with PD symptoms. STN single-neuron and LFP low-beta (12-21 Hz) power and burst dynamics showed modest correlations with bradykinesia and rigidity severity, while STN spiketrain theta (4-8 Hz) power correlated modestly with tremor severity. GPi low- and high-beta (21-30 Hz) power and burst dynamics correlated moderately with bradykinesia and axial symptom severity. These findings suggest that elevated single-neuron and LFP oscillations may be linked to symptoms, though modest correlations imply that the pathophysiology of PD may extend beyond resting-state beta oscillations.

Correlation of silent brain infarcts and leukoaraiosis in middle-aged ischemic stroke patients: a retrospective study.

Background: Cerebrovascular diseases of the brain are usually defined by transient ischemic attacks and strokes. However, they can also cause brain injuries without neurological events. Silent brain infarcts (SBI) and leukoaraiosis are symptoms of both vascular and neurological abnormalities. This study aims to investigate the association between SBI, leukoaraiosis, and middle-aged patients with ischemic stroke. Methods: A single-center retrospective study of 50 middle-aged, ischemic stroke patients were studied from November 2022 and May 2023. The patients were divided into two groups based on the presence or absence of leukoaraiosis. History taking, physical examination, brain CT scan, and MRI were all part of the diagnostic process. Metabolic syndrome (MetS) was also assessed through various factors. The statistical analysis included descriptive statistics, logistic regression analysis, and chi-square test. Results: Out of the cohort comprising 50 patients, characterized by a mean age of 52.26 years (SD 5.29), 32 were male, constituting 64% of the sample. Among these patients, 26 individuals exhibited leukoaraiosis, with 17 of them (65.4%) also presenting with SBI. Moreover, within this cohort, 22 patients were diagnosed with MetS, representing 84.6% of those affected. The Multivariate logistic regression analysis showed a strong and independent association between leukoaraiosis and SBI. Individuals with leukoaraiosis were nearly five times more likely to have SBI compared to those without leukoaraiosis. Conclusion: The study highlights leukoaraiosis as a significant risk factor for SBI, alongside MetS. Advanced imaging techniques have facilitated their detection, revealing a higher prevalence among stroke patients, particularly associated with age and hypertension. Further research is needed to fully understand their complex relationship and develop better management strategies for cerebrovascular diseases, ultimately improving patient outcomes.

Effects of Very Low- and High-Frequency Subthalamic Stimulation on Motor Cortical Oscillations During Rhythmic Lower-Limb Movements in Parkinson's Disease Patients.

BACKGROUND: Standard high-frequency deep brain stimulation (HF-DBS) at the subthalamic nucleus (STN) is less effective for lower-limb motor dysfunctions in Parkinson's disease (PD) patients. However, the effects of very low frequency (VLF; 4 Hz)-DBS on lower-limb movement and motor cortical oscillations have not been compared. OBJECTIVE: To compare the effects of VLF-DBS and HF-DBS at the STN on a lower-limb pedaling motor task and motor cortical oscillations in patients with PD and with and without freezing of gait (FOG). METHODS: Thirteen PD patients with bilateral STN-DBS performed a cue-triggered lower-limb pedaling motor task with electroencephalography (EEG) in OFF-DBS, VLF-DBS (4 Hz), and HF-DBS (120-175 Hz) states. We performed spectral analysis on the preparatory signals and compared GO-cue-triggered theta and movement-related beta oscillations over motor cortical regions across DBS conditions in PD patients and subgroups (PDFOG-and PDFOG+). RESULTS: Both VLF-DBS and HF-DBS decreased the linear speed of the pedaling task in PD, and HF-DBS decreased speed in both PDFOG-and PDFOG+. Preparatory theta and beta activities were increased with both stimulation frequencies. Both DBS frequencies increased motor cortical theta activity during pedaling movement in PD patients, but this increase was only observed in the PDFOG + group. Beta activity was not significantly different from OFF-DBS at either frequency regardless of FOG status. CONCLUSION: Results suggest that VL and HF DBS may induce similar effects on lower-limb kinematics by impairing movement speed and modulating motor cortical oscillations in the lower frequency band.

Appraising systematic reviews: a comprehensive guide to ensuring validity and reliability.

Systematic reviews play a crucial role in evidence-based practices as they consolidate research findings to inform decision-making. However, it is essential to assess the quality of systematic reviews to prevent biased or inaccurate conclusions. This paper underscores the importance of adhering to recognized guidelines, such as the PRISMA statement and Cochrane Handbook. These recommendations advocate for systematic approaches and emphasize the documentation of critical components, including the search strategy and study selection. A thorough evaluation of methodologies, research quality, and overall evidence strength is essential during the appraisal process. Identifying potential sources of bias and review limitations, such as selective reporting or trial heterogeneity, is facilitated by tools like the Cochrane Risk of Bias and the AMSTAR 2 checklist. The assessment of included studies emphasizes formulating clear research questions and employing appropriate search strategies to construct robust reviews. Relevance and bias reduction are ensured through meticulous selection of inclusion and exclusion criteria. Accurate data synthesis, including appropriate data extraction and analysis, is necessary for drawing reliable conclusions. Meta-analysis, a statistical method for aggregating trial findings, improves the precision of treatment impact estimates. Systematic reviews should consider crucial factors such as addressing biases, disclosing conflicts of interest, and acknowledging review and methodological limitations. This paper aims to enhance the reliability of systematic reviews, ultimately improving decision-making in healthcare, public policy, and other domains. It provides academics, practitioners, and policymakers with a comprehensive understanding of the evaluation process, empowering them to make well-informed decisions based on robust data.

Deep brain stimulation for chronic pain: a systematic review and meta-analysis.

Background: Deep brain stimulation (DBS) has shown promise in effectively treating chronic pain. This study aimed to assess the efficacy of DBS in this context. Methods: We conducted a systematic literature search using PubMed, Scopus, and Web of Science, following the PRISMA guidelines. A well-constructed search strategy was utilized. Our literature search identified two groups of subjects: one group underwent DBS specifically for chronic pain treatment (DBS-P), while the second group received DBS for other indications (DBS-O), such as Parkinson's disease or dystonia, with pain perception investigated as a secondary outcome in this population. Meta-analysis was performed using R version 4.2.3 software. Heterogeneity was assessed using the tau^2 and I^2 indices, and Cochran's Q-test was conducted. Results: The analysis included 966 patients in 43 original research studies with chronic pain who underwent DBS (340 for DBS-P and 625 for DBS-O). Subgroup analysis revealed that DBS-P exhibited a significant effect on chronic pain relief, with a standardized mean difference (SMD) of 1.65 and a 95% confidence interval (CI) of [1.31; 2.00]. Significant heterogeneity was observed among the studies, with an I^2 value of 85.8%. However, no significant difference was found between DBS-P and DBS-O subgroups. Subgroup analyses based on study design, age, pain diseases, and brain targets demonstrated varying levels of evidence for the effectiveness of DBS across different subgroups. Additionally, meta-regression analyses showed no significant relationship between age or pain duration and DBS effectiveness for chronic pain. Conclusion: These findings significantly contribute to the expanding body of knowledge regarding the utility of DBS in the management of chronic pain. The study underscores the importance of conducting further research to enhance treatment outcomes and elucidate patient-specific factors that are associated with treatment response. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=428442, identifier CRD42023428442.

Deep brain stimulation for substance use disorder: a systematic review and meta-analysis.

Objective: Substance use disorder (SUD) is a significant public health issue with a high mortality rate. Deep brain stimulation (DBS) has shown promising results in treating SUD in certain cases. In this study, we conducted a meta-analysis to evaluate the efficacy of DBS in the treatment of SUD and reduction of relapse rates. Methods: We performed a thorough and methodical search of the existing scientific literature, adhering to the PRISMA guidelines, to identify 16 original studies that fulfilled our inclusion criteria. We used the evidence levels recommended by the Oxford Centre for Evidence-Based Medicine to assess bias. The R version 4.2.3 software was utilized to calculate the mean effect size. We estimated study heterogeneity by employing tau2 and I2 indices and conducting Cochran's Q test. Results: The results showed that DBS treatment resulted in a significant improvement in the clinical SUD scales of patients, with an average improvement of 59.6%. The observed relapse rate was 8%. The meta-analysis estimated a mean effect size of 55.9 [40.4; 71.4]. Heterogeneity analysis showed a large degree of heterogeneity among the included studies. Subgroup and meta-regression analysis based on age and SUD type suggested that DBS may be more effective for patients above 45 years of age, and for alcohol and opioid addiction compared to nicotine addiction. Conclusion: The current literature suggests that DBS has a moderate effect on SUD symptoms. However, the limited number of studies and small sample size indicate that more research is needed to better understand the factors that influence its effectiveness.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.

Trends and disparities in deep brain stimulation utilization in the United States: a Nationwide Inpatient Sample analysis from 1993 to 2017.

Background: Deep brain stimulation (DBS) is an approved treatment option for Parkinson's Disease (PD), essential tremor (ET), dystonia, obsessive-compulsive disorder and epilepsy in the United States. There are disparities in access to DBS, and clear understanding of the contextual factors driving them is important. Previous studies aimed at understanding these factors have been limited by single indications or small cohort sizes. The aim of this study is to provide an updated and comprehensive analysis of DBS utilization for multiple indications to better understand the factors driving disparities in access. Methods: The United States based National Inpatient Sample (NIS) database was utilized to analyze the surgical volume and trends of procedures based on indication, using relevant ICD codes. Predictors of DBS use were analyzed using a logistic regression model. DBS-implanted patients in each indication were compared based on the patient-, hospital-, and outcome-related variables. Findings: Our analysis of 104,356 DBS discharges from 1993 to 2017 revealed that the most frequent indications for DBS were PD (67%), ET (24%), and dystonia (4%). Although the number of DBS procedures has consistently increased over the years, radiofrequency ablation utilization has significantly decreased to only a few patients per year since 2003. Negative predictors for DBS utilization in PD and ET cohorts included age increase and female sex, while African American status was a negative predictor across all cohorts. Significant differences in patient-, hospital-, and outcome-related variables between DBS indications were also determined. Interpretation: Demographic and socioeconomic-based disparities in DBS use are evident. Although racial disparities are present across all indications, other disparities such as age, sex, wealth, and insurance status are only relevant in certain indications. Funding: This work was supported by Alan & Susan Hudson Cornerstone Chair in Neurosurgery at University Health Network.

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.

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.