Emergency management of pediatric epileptic seizures in non-hospital settings in Japan.

OBJECTIVE: To assess the current management of pediatric epileptic seizures in non-hospital settings and the efficacy of early therapeutic intervention with rescue medication in Japan. METHODS: This descriptive cross-sectional study was based on an online survey of caregivers of pediatric patients with epilepsy. The survey consisted of questions regarding seizure frequency and symptoms, the use of rescue medication, and emergency medical care. Statistical analyses were performed to evaluate the association between the time to rescue medication administration and seizure resolution. RESULTS: Responses were obtained from 1147 caregivers of pediatric patients with epilepsy. Of the patients described in the study, 98.5 % had been prescribed anti-seizure medication, 95.3 % had more than a few seizures per year, and 90.3 % used rescue medication. The time to seizure resolution was significantly reduced when rescue medication was administered early. Overall, 28.4 % of the patients required emergency transport to hospital, which increased disruption to the lives of caregivers, who returned to their normal activities after an average of 17.2 h. CONCLUSION: Emergency transport of patients places a significant burden on caregivers. Earlier administration of rescue medications is associated with a reduction in the need for emergency room visits, which reduces the burden on the patient as well as the caregiver.

Neural Correlates of Optimal Deep Brain Stimulation for Cervical Dystonia.

A total of 15 individuals with cervical dystonia and good outcome after pallidal deep brain stimulation underwent resting-state functional magnetic resonance imaging under three conditions: stimulation using a priori clinically determined optimal settings (ON-Op), non-optimal settings (ON-NOp), and stimulation off (OFF). ON-Op > OFF and ON-Op > ON-NOp were both associated with significant deactivation within sensorimotor cortex (changes not seen with ON-NOp > OFF). Brain responses to stimulation were related to individual long-term clinical improvement (R = 0.73, R2 = 0.53, p = 0.001). The relationship was consistent when this model included four additional patients with generalized or truncal dystonia. These findings highlight the potential for immediate imaging-based biomarkers of clinical efficacy. ANN NEUROL 2022;92:418-424.

Spinal Cord Stimulation for Parkinson's Disease: A Systematic Review and Meta-Analysis of Pain and Motor Outcomes.

BACKGROUND: Spinal cord stimulation (SCS) has been investigated as a potential therapeutic option for managing refractory symptoms in patients with Parkinson's disease (PD). OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of SCS in PD. METHOD: A comprehensive literature search was conducted on PubMed and Web of Science to identify SCS studies reporting Unified Parkinson Disease Rating Scale-III (UPDRS-III) or Visual Analogue Scale (VAS) score changes in PD cohorts with at least 3 patients and a follow-up period of at least 1 month. Treatment effect was measured as the mean change in outcome scores and analyzed using an inverse variance random-effects model. The risk of bias was assessed using the Newcastle-Ottawa Scale and funnel plots. RESULTS: A total of 11 studies comprising 76 patients were included. Nine studies involving 72 patients reported an estimated decrease of 4.43 points (95% confidence interval [CI]: 2.11; 6.75, p < 0.01) in UPDRS-III score, equivalent to a 14% reduction. The axial subscores in 48 patients decreased by 2.35 points (95% CI: 1.26; 3.45, p < 0.01, 20% reduction). The pooled effect size of five studies on back and leg pain VAS scores was calculated as 4.38 (95% CI: 2.67; 6.09, p < 0.001), equivalent to a 59% reduction. CONCLUSIONS: Our analysis suggests that SCS may provide significant motor and pain benefits for patients with PD, although the results should be interpreted with caution due to several potential limitations including study heterogeneity, open-label designs, small sample sizes, and the possibility of publication bias. Further research using larger sample sizes and placebo-/sham-controlled designs is needed to confirm effectiveness.

Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

Deep brain stimulation targets in epilepsy: Systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus.

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and meta-analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

Neuromodulation for Pain: A Comprehensive Survey and Systematic Review of Clinical Trials and Connectomic Analysis of Brain Targets.

BACKGROUND: Chronic pain is a debilitating condition that imposes a tremendous burden on health-care systems around the world. While frontline treatments for chronic pain involve pharmacological and psychological approaches, neuromodulation can be considered for treatment-resistant cases. Neuromodulatory approaches for pain are diverse in both modality and target and their mechanism of action is incompletely understood. OBJECTIVES: The objectives of this study were to (i) understand the current landscape of pain neuromodulation research through a comprehensive survey of past and current registered clinical trials (ii) investigate the network underpinnings of these neuromodulatory treatments by performing a connectomic mapping analysis of cortical and subcortical brain targets that have been stimulated for pain relief. METHODS: A search for clinical trials involving pain neuromodulation was conducted using 2 major trial databases (ClinicalTrials.gov and the International Clinical Trials Registry Platform). Trials were categorized by variables and analyzed to gain an overview of the contemporary research landscape. Additionally, a connectomic mapping analysis was performed to investigate the network connectivity patterns of analgesic brain stimulation targets using a normative connectome based on a functional magnetic resonance imaging dataset. RESULTS: In total, 487 relevant clinical trials were identified. Noninvasive cortical stimulation and spinal cord stimulation trials represented 49.3 and 43.7% of this count, respectively, while deep brain stimulation trials accounted for <3%. The mapping analysis revealed that superficial target connectomics overlapped with deep target connectomics, suggesting a common pain network across the targets. CONCLUSIONS: Research for pain neuromodulation is a rapidly growing field. Our connectomic network analysis reinforced existing knowledge of the pain matrix, identifying both well-described hubs and more obscure structures. Further studies are needed to decode the circuits underlying pain relief and determine the most effective targets for neuromodulatory treatment.

Bilateral Focused Ultrasound Thalamotomy for Essential Tremor (BEST-FUS Phase 2 Trial).

BACKGROUND: In patients with medically refractory essential tremor, unilateral magnetic resonance-guided focused ultrasound thalamotomy can improve contralateral tremor. However, this procedure does not address ipsilateral symptoms. OBJECTIVE: The objective of the current study was to determine whether bilateral thalamotomies can be performed with an acceptable safety profile where benefits outweigh adverse effects. METHODS: We conducted a prospective, single-arm, single-blinded phase 2 trial of second-side magnetic resonance-guided focused ultrasound thalamotomy in patients with essential tremor. Patients were followed for 3 months. The primary outcome was the change in quality of life relative to baseline, as well as the answer to the question "Given what you know now, would you treat the second side again?". Secondary outcomes included tremor, gait, speech, and adverse effects. RESULTS: Ten patients were analyzed. The study met both primary outcomes, with the intervention resulting in clinically significant improvement in quality of life at 3 months (mean Quality of Life in Essential Tremor score difference, 19.7; 95%CI, 8.0-31.4; P = 0.004) and all patients reporting that they would elect to receive the second-side treatment again. Tremor significantly improved in all patients. Seven experienced mild adverse effects, including 2 with transient gait impairment and a fall, 1 with dysarthria and dysphagia, and 1 with mild dysphagia persisting at 3 months. CONCLUSIONS: Staged bilateral magnetic resonance-guided focused ultrasound thalamotomy can be performed with a reasonable safety profile similar to that seen with unilateral thalamotomy and improves the tremor and quality of life of patients with essential tremor. Longer-term follow-up and continued accrual in the phase 3 trial will be required to validate these findings. © 2021 International Parkinson and Movement Disorder Society.

Blood oxygen level-dependent (BOLD) response patterns with thalamic deep brain stimulation in patients with medically refractory epilepsy.

OBJECTIVE: Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) has shown promise as a treatment for medically refractory epilepsy. To better understand the mechanism of this intervention, we used functional magnetic resonance imaging (fMRI) to map the acute blood oxygen level-dependent (BOLD) response pattern to thalamic DBS in fully implanted patients with epilepsy. METHODS: Two patients with epilepsy implanted with bilateral ANT-DBS devices underwent four fMRI acquisitions each, during which active left-sided monopolar stimulation was delivered in a 30-s DBS-ON/OFF cycling paradigm. Each fMRI acquisition featured left-sided stimulation of a different electrode contact to vary the locus of stimulation within the thalamus and to map the brain regions modulated as a function of different contact selection. To determine the extent of peri-electrode stimulation and the engagement of local structures during each fMRI acquisition, volume of tissue activated (VTA) modeling was also performed. RESULTS: Marked changes in the pattern of BOLD response were produced with thalamic stimulation, which varied with the locus of the active contact in each patient. BOLD response patterns to stimulation that directly engaged at least 5% of the anterior nuclear group by volume were characterized by changes in the bilateral putamen, thalamus, and posterior cingulate cortex, ipsilateral middle cingulate cortex and precuneus, and contralateral medial prefrontal and anterior cingulate. SIGNIFICANCE: The differential BOLD response patterns associated with varying thalamic DBS parameters provide mechanistic insights and highlight the possibilities of fMRI biomarkers of optimizing stimulation in patients with epilepsy.

A case of cervicogenic headache caused by C5 nerve root derived shwannoma: Case report.

Introduction We report a case of cervicogenic headache caused by an intradural extramedullary tumor of the middle cervical spine, which has not previously been reported. Case presentation The patient was a 73-year-old male who visited a physician for a chief complaint of pain from the left lower jaw to the auricle and occipital region. The headache was induced with retroflexion of the neck. On cervical magnetic resonance imaging, an intradural extramedullary tumor was noted on the left side at the C4/5 level. The intradural tumor, which arose from the C5 nerve root, was excised and the pain was resolved. The pathological diagnosis was schwannoma. Conclusion Previously reported cases of spinal cord tumor-induced cervicogenic headache were due to upper cervical spinal tumors. This is the first report that a middle-lower cervical intradural extramedullary tumor caused cervicogenic headache.

Successful magnetic resonance-guided focused ultrasound treatment of tremor in patients with a skull density ratio of 0.4 or less.

OBJECTIVE: The use of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor-related disorders and other novel indications has been limited by guidelines advocating treatment of patients with a skull density ratio (SDR) above 0.45 ± 0.05 despite reports of successful outcomes in patients with a low SDR (LSDR). The authors' goal was to retrospectively analyze the sonication strategies, adverse effects, and clinical and imaging outcomes in patients with SDR ≤ 0.4 treated for tremor using MRgFUS. METHODS: Clinical outcomes and adverse effects were assessed at 3 and 12 months after MRgFUS. Outcomes and lesion location, volume, and shape characteristics (elongation and eccentricity) were compared between the SDR groups. RESULTS: A total of 102 consecutive patients were included in the analysis, of whom 39 had SDRs ≤ 0.4. No patient was excluded from treatment because of an LSDR, with the lowest being 0.22. Lesioning temperatures (> 52°C) and therapeutic ablations were achieved in all patients. There were no significant differences in clinical outcome, adverse effects, lesion location, and volume between the high SDR group and the LSDR group. SDR was significantly associated with total energy (rho = -0.459, p < 0.001), heating efficiency (rho = 0.605, p < 0.001), and peak temperature (rho = 0.222, p = 0.025). CONCLUSIONS: The authors' results show that treatment of tremor in patients with an LSDR using MRgFUS is technically possible, leading to a safe and lasting therapeutic effect. Limiting the number of sonications and adjusting the energy and duration to achieve the required temperature early during the treatment are suitable strategies in LSDR patients.

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.

Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers. OBJECTIVE: The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation. METHODS: A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included. RESULTS: A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis. CONCLUSIONS: Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations.

Enhanced Interplay of Neuronal Coherence and Coupling in the Dying Human Brain.

The neurophysiological footprint of brain activity after cardiac arrest and during near-death experience (NDE) is not well understood. Although a hypoactive state of brain activity has been assumed, experimental animal studies have shown increased activity after cardiac arrest, particularly in the gamma-band, resulting from hypercapnia prior to and cessation of cerebral blood flow after cardiac arrest. No study has yet investigated this matter in humans. Here, we present continuous electroencephalography (EEG) recording from a dying human brain, obtained from an 87-year-old patient undergoing cardiac arrest after traumatic subdural hematoma. An increase of absolute power in gamma activity in the narrow and broad bands and a decrease in theta power is seen after suppression of bilateral hemispheric responses. After cardiac arrest, delta, beta, alpha and gamma power were decreased but a higher percentage of relative gamma power was observed when compared to the interictal interval. Cross-frequency coupling revealed modulation of left-hemispheric gamma activity by alpha and theta rhythms across all windows, even after cessation of cerebral blood flow. The strongest coupling is observed for narrow- and broad-band gamma activity by the alpha waves during left-sided suppression and after cardiac arrest. Albeit the influence of neuronal injury and swelling, our data provide the first evidence from the dying human brain in a non-experimental, real-life acute care clinical setting and advocate that the human brain may possess the capability to generate coordinated activity during the near-death period.

Probing responses to deep brain stimulation with functional magnetic resonance imaging.

BACKGROUND: Deep brain stimulation (DBS) is an established treatment for certain movement disorders and has additionally shown promise for various psychiatric, cognitive, and seizure disorders. However, the mechanisms through which stimulation exerts therapeutic effects are incompletely understood. A technique that may help to address this knowledge gap is functional magnetic resonance imaging (fMRI). This is a non-invasive imaging tool which permits the observation of DBS effects in vivo. OBJECTIVE: The objective of this review was to provide a comprehensive overview of studies in which fMRI during active DBS was performed, including studied disorders, stimulated brain regions, experimental designs, and the insights gleaned from stimulation-evoked fMRI responses. METHODS: We conducted a systematic review of published human studies in which fMRI was performed during active stimulation in DBS patients. The search was conducted using PubMED and MEDLINE. RESULTS: The rate of fMRI DBS studies is increasing over time, with 37 studies identified overall. The median number of DBS patients per study was 10 (range = 1-67, interquartile range = 11). Studies examined fMRI responses in various disease cohorts, including Parkinson's disease (24 studies), essential tremor (3 studies), epilepsy (3 studies), obsessive-compulsive disorder (2 studies), pain (2 studies), Tourette syndrome (1 study), major depressive disorder, anorexia, and bipolar disorder (1 study), and dementia with Lewy bodies (1 study). The most commonly stimulated brain region was the subthalamic nucleus (24 studies). Studies showed that DBS modulates large-scale brain networks, and that stimulation-evoked fMRI responses are related to the site of stimulation, stimulation parameters, patient characteristics, and therapeutic outcomes. Finally, a number of studies proposed fMRI-based biomarkers for DBS treatment, highlighting ways in which fMRI could be used to confirm circuit engagement and refine DBS therapy. CONCLUSION: A review of the literature reflects an exciting and expanding field, showing that the combination of DBS and fMRI represents a uniquely powerful tool for simultaneously manipulating and observing neural circuitry. Future work should focus on relatively understudied disease cohorts and stimulated regions, while focusing on the prospective validation of putative fMRI-based biomarkers.

Clinical outcomes and complications of peripheral nerve field stimulation in the management of refractory trigeminal pain: a systematic review and meta-analysis.

OBJECTIVE: Peripheral nerve field stimulation (PNFS) is a tool in the armamentarium of treatment options for trigeminal pain. The efficacy of this modality in mitigating trigeminal pain remains unclear. The aim of this study was to examine the existing literature on PNFS and elucidate pain score outcomes associated with its use in patients with trigeminal pain. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA framework. The PubMed, Web of Science, and Scopus databases were queried on June 10, 2020. Studies reporting pain outcomes in more than 5 adult patients treated with PNFS for facial pain were included. The primary outcome of the study was the mean difference in the visual analog scale (VAS) score from the last follow-up to baseline, and it was analyzed by an inverse-variance, random-effect model. The risk of bias was assessed using the Newcastle-Ottawa Scale and a funnel plot. RESULTS: Of the 4597 studies screened for inclusion, 46 relevant full-text articles were assessed for eligibility. Eleven observational cohort studies from the 46 articles were found to be eligible, and reported on a total of 109 patients. In 86% (94/109) of cases, trial stimulation was successful and followed by a permanent system implantation. VAS scores improved by 75% (mean difference 6.32/10 points, 95% CI 5.38-7.27 points) compared to baseline. Seventy-six percent (42/55) of patients became medication free or required lower doses of medications. The complication rate necessitating surgical revision was estimated at 32% per procedure. CONCLUSIONS: These findings support the belief that PNFS provides effective, long-term pain control for trigeminal pain. Statistical heterogeneity was considerable across all studies. Future work should be aimed at conducting double-blind randomized controlled trials to determine the utility of PNFS for treating various forms of trigeminal pain for which limited therapeutic options exist.

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.

Laser interstitial thermal therapy for the treatment of insular lesions: A systematic review.

Background: The surgical treatment of insular lesions has been historically associated with high morbidity. Laser interstitial thermal therapy (LITT) has been increasingly used in the treatment of insular lesions, commonly neoplastic or epileptogenic. Stereotaxis is used to guide laser probes to the insula where real-time magnetic resonance thermometry defines lesion creation. There is an absence of previously published reviews on insular LITT, despite a rapid uptake in use, making further study imperative. Methods: Here we present a systematic review of the PubMed and Scopus databases, examining the reported clinical indications, outcomes, and adverse effects of insular LITT. Results: A review of the literature revealed 10 retrospective studies reporting on 53 patients (43 pediatric and 10 adults) that were treated with insular LITT. 87% of cases were for the treatment of epilepsy, with 89% of patients achieving seizure outcomes of Engle I-III following treatment. The other 13% of cases reported on insular tumors and radiological improvement was seen in all cases following treatment. All but one study reported adverse events following LITT with a rate of 37%. The most common adverse events were transient hemiparesis (29%) and transient aphasia (6%). One patient experienced an intracerebral hemorrhage, which required a decompressive hemicraniectomy, with subsequent full recovery. Conclusion: This systematic review highlights the suitability of LITT for the treatment of both insular seizure foci and insular tumors. Despite the growing use of this technique, prospective studies remain absent in the literature. Future work should directly evaluate the efficacy of LITT with randomized and controlled trials.