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Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is a circuit-based treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear. In five participants receiving DBS for severe, refractory OCD (3 responders, 2 non-responders), we conducted a DBS On/Off cycling paradigm during the acquisition of functional MRI (23 fMRI runs) to determine the network effects of stimulation across a variety of bipolar configurations. We also performed tractography using diffusion-weighted imaging (DWI) to relate the functional impact of DBS to the underlying structural connectivity between active stimulation contacts and functional brain networks. We found that therapeutic DBS had a distributed effect, suppressing BOLD activity within regions such as the orbitofrontal cortex, dorsomedial prefrontal cortex, and subthalamic nuclei compared to non-therapeutic configurations. Many of the regions suppressed by therapeutic DBS were components of the default mode network (DMN). Moreover, the estimated stimulation field from the therapeutic configurations exhibited significant structural connectivity to core nodes of the DMN. Based upon these findings, we hypothesize that the suppression of the DMN by ALIC DBS is mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts.

BackgroundDespite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited.ObjectivesTo compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date.MethodsParticipants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons.ResultsThe primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (P

Neuromodulation treatment effect size for bothersome tinnitus may be larger and more predictable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Several corticostriatal mechanisms are likely to play a role in tinnitus, including the dorsal/ventral striatum and the putamen. We examined whether significant tinnitus treatment response by deep brain stimulation (DBS) of the caudate nucleus may be related to striatal network increased functional connectivity with tinnitus networks that involve the auditory cortex or ventral cerebellum. The first study was a cross-sectional 2-by-2 factorial design (tinnitus, no tinnitus; hearing loss, normal hearing, n = 68) to define cohort level abnormal functional connectivity maps using high-field 7.0 T resting-state fMRI. The second study was a pilot case-control series (n = 2) to examine whether tinnitus modulation response to caudate tail subdivision stimulation would be contingent on individual level striatal connectivity map relationships with tinnitus networks. Resting-state fMRI identified five caudate subdivisions with abnormal cohort level functional connectivity maps. Of those, two connectivity maps exhibited increased connectivity with tinnitus networks-dorsal caudate head with Heschl's gyrus and caudate tail with the ventral cerebellum. DBS of the caudate tail in the case-series responder resulted in dramatic reductions in tinnitus severity and loudness, in contrast to the nonresponder who showed no tinnitus modulation. The individual level connectivity map of the responder was in alignment with the cohort expectation connectivity map, where the caudate tail exhibited increased connectivity with tinnitus networks, whereas the nonresponder individual level connectivity map did not.

Background and objectivesTo report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations.MethodsPD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg.ResultsNo serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.DiscussionsVY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years.Trial registration informationNCT01973543.Classification of evidenceThis study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Neural recordings using invasive devices in humans can elucidate the circuits underlying brain disorders, but have so far been limited to short recordings from externalized brain leads in a hospital setting or from implanted sensing devices that provide only intermittent, brief streaming of time series data. Here, we report the use of an implantable two-way neural interface for wireless, multichannel streaming of field potentials in five individuals with Parkinson's disease (PD) for up to 15 months after implantation. Bilateral four-channel motor cortex and basal ganglia field potentials streamed at home for over 2,600 h were paired with behavioral data from wearable monitors for the neural decoding of states of inadequate or excessive movement. We validated individual-specific neurophysiological biomarkers during normal daily activities and used those patterns for adaptive deep brain stimulation (DBS). This technological approach may be widely applicable to brain disorders treatable by invasive neuromodulation.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

ObjectiveSurgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery.MethodsIn November 2013, a preoperative CHG shower protocol was implemented at the authors' institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates.ResultsThe overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67-13.1; p = 0.15).ConclusionsThis is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

The efficacy of deep brain stimulation (DBS) depends on electrode placement accuracy, which can be jeopardized by brain shift due to burr hole and dura opening during surgery. Brain shift violates assumed rigid alignment between preoperative image and intraoperative anatomy, negatively impacting therapy.ObjectiveThis study presents a deformation-atlas biomechanical model-based approach to address shift.MethodsSix patients, who underwent interventional magnetic resonance (iMR) image-guided DBS burr hole surgery, were studied. A patient-specific model was employed under varying surgical conditions, generating a collection of possible intraoperative shift estimations or a 'deformation atlas.' An inverse problem was driven by sparse measurements derived from iMR to determine an optimal fit of solutions of the atlas. This fit was then used to obtain a volumetric deformation field, which was utilized to update preoperative MR and estimate shift at surgical target region localized on iMR. Model performance was examined by quantitatively comparing intraoperative subsurface measurements to their model-predicted counterparts, and qualitatively comparing iMR, preoperative MR, and model updated MR. A nonrigid image registration was introduced as a comparator.ResultsModel-based approach reduced general parenchyma shift from 8.2 ± 2.2 to 2.7 ± 1.1 mm (∼66.8% correction), and produced updated MR with better agreement to iMR than that of preoperative MR. The average model estimated shift at target region was 1.2 mm.ConclusionsThis study demonstrates the feasibility of a model-based shift correction strategy in DBS surgery with only sparse data.SignificanceThe developed strategy has the potential to complement and/or enhance current clinical approaches in addressing shift.

BackgroundAs Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements.ObjectivesThis substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration.MethodsParticipants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion.ResultsOf 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration.ConclusionsVY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition.

Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.

ObjectiveThe objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.MethodsSix participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.ResultsThe treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.ConclusionsBilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

ObjectiveTo understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.MethodsFifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.ResultsMRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.InterpretationNovel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714.

ObjectiveThe object of this study was to define caudate nucleus locations responsive to intraoperative direct electrical stimulation for tinnitus loudness modulation and relate those locations to functional connectivity maps between caudate nucleus subdivisions and auditory cortex.MethodsSix awake study participants who underwent bilateral deep brain stimulation (DBS) electrode placement in the caudate nucleus as part of a phase I clinical trial were analyzed for tinnitus modulation in response to acute stimulation at 20 locations. Resting-state 3-T functional MRI (fMRI) was used to compare connectivity strength between centroids of tinnitus loudness-reducing or loudness-nonreducing caudate locations and the auditory cortex in the 6 DBS phase I trial participants and 14 other neuroimaging participants with a Tinnitus Functional Index > 50.ResultsAcute tinnitus loudness reduction was observed at 5 caudate locations, 4 positioned at the body and 1 at the head of the caudate nucleus in normalized Montreal Neurological Institute space. The remaining 15 electrical stimulation interrogations of the caudate head failed to reduce tinnitus loudness. Compared to the caudate head, the body subdivision had stronger functional connectivity to the auditory cortex on fMRI (p < 0.05).ConclusionsAcute tinnitus loudness reduction was more readily achieved by electrical stimulation of the caudate nucleus body. Compared to the caudate head, the caudate body has stronger functional connectivity to the auditory cortex. These first-in-human findings provide insight into the functional anatomy of caudate nucleus subdivisions and may inform future target selection in a basal ganglia-centric neuromodulation approach to treat medically refractory tinnitus.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

Background/aimsNonrechargeable deep brain stimulation implantable pulse generators (IPGs) for movement disorders require surgical replacement every few years due to battery depletion. Rechargeable IPGs reduce frequency of replacement surgeries and inherent risks of complications but require frequent recharging. Here, we evaluate patient experience with rechargeable IPGs and define predictive characteristics for higher satisfaction.MethodsWe contacted all patients implanted with rechargeable IPGs at a single center in a survey-based study. We analyzed patient satisfaction with respect to age, diagnosis, target, charging duration, and body mass index. We tabulated hardware-related adverse events.ResultsDystonia patients had significantly higher satisfaction than Parkinson's disease patients in recharging, display, programmer, and training domains. Common positive responses were "fewer surgeries" and "small size." Common negative responses were "difficulty finding the right position to recharge" and "need to recharge every day." Hardware-related adverse events occurred in 21 of 59 participants.ConclusionPatient experience with rechargeable IPGs was largely positive; however, frustrations with recharging and adverse events were common. Dystonia diagnosis was most predictive of high satisfaction across multiple categories, potentially related to expected long disease duration with need for numerous IPG replacements.

Functional neurosurgery techniques remain integral to the neurosurgical treatment armamentarium but data on global implementation remains scarce. In comparison to high-income countries (HIC), low- and middle-income countries (LMIC) suffer from an increased prevalence of diseases like epilepsy, which may be amenable to functional techniques, and therefore, LMIC may benefit from an increased utilization of these treatment modalities. However, functional techniques tend to be expensive and thus difficult to implement in the LMIC setting. A review was performed to assess the current status of functional neurosurgical techniques in LMIC as a starting point for future initiatives. For methodology, a review of the current body of literature on functional neurosurgery in LMIC was conducted through the United States National Library of Medicine Pubmed search engine. Search terms included "functional neurosurgery," "developing countries," "low and middle income," and other related terms. It was found that though five billion people lack access to safe surgical care, the burden of disease amenable to treatment with functional neurosurgical procedures remains unknown. Increasingly, reports of successful, long-term, international neurosurgical collaborations are being reported, but reports in the sub-field of functional neurosurgery are lacking. In conclusion, awareness of global surgical disparities has increased dramatically while global guidelines for functional techniques are currently lacking. A concerted effort can harness these techniques for wider practice. Partnerships between centers in LMIC and HIC are making progress to better understand the burden of disease in LMIC and to create context-specific solutions for practice in the LMIC setting, but more collaborations are warranted.

BACKGROUND/AIMS:Interventional MRI (iMRI) allows real-time confirmation of electrode and microcatheter location in anesthetized patients; however, MRI-compatible pneumatic compression devices (PCD) to reduce the periprocedural venous thromboembolism (VTE) risk are not commercially available. Given the paucity of literature on VTE following iMRI surgery, better characterizing patients suffering this complication and the incidence of this event following iMRI procedures is pivotal for defining best surgical practices. We aim to investigate the incidence of postoperative VTE in iMRI procedures without the use of PCD. METHODS:Medical records and operative times of patients were retrospectively reviewed. Patient demographics and mean surgical durations were reported with statistical comparisons via ANOVA and the 2-tailed Student t test, an α of 0.05, and the Bonferroni correction. Patients experiencing postoperative VTE underwent an in-depth chart review. RESULTS:Two out of two hundred ten (0.95%) iMRI procedures resulted in postoperative VTE events. There were statistically significant differences in procedure times between unilateral electrode (157.5 ± 5.7 min), bilateral electrode (193.6 ± 2.9 min), and bilateral gene therapy procedures (467.3 ± 26.5 min). Both patients had longer-than-average operative times for their respective procedures. CONCLUSIONS:The incidence of postoperative VTE is low following iMRI procedures, even without the use of PCD during surgery.

By forcing with Pmax over strong models of determinacy, we obtain models where different square principles at ω2 and ω3 fail. In particular, we obtain a model of 2ℵ0=2ℵ1=ℵ2+¬◻(ω2)+¬◻(ω3).

Background and objectivesMany US medical schools and family medicine departments have responded to a growing interest in global health by developing global health fellowships. However, there are no guidelines or consensus statements outlining competencies for global health fellows. Our objective was to develop a mission and core competencies for Family Medicine Global Health Fellowships.MethodsA modified Delphi technique was used to develop consensus on fellowship competencies. A panel, comprised of 13 members with dual expertise in global health and medical education, undertook an iterative consensus process, followed by peer review, from April to December 2014.ResultsThe panel developed a mission statement and identified six domains for family medicine global health fellowships: patient care, medical knowledge, professionalism, communication and leadership, teaching, and scholarship. Each domain includes a set of core and program-specific competencies.ConclusionThe family medicine global health competencies are intended to serve as an educational framework for the design, implementation, and evaluation of individual family medicine global health fellowship programs.

OBJECTIVE The objective of this study was to assess the incidence of postoperative hardware infection following interventional (i)MRI-guided implantation of deep brain stimulation (DBS) electrodes in a diagnostic MRI scanner. METHODS A diagnostic 1.5-T MRI scanner was used over a 10-year period to implant DBS electrodes for movement disorders. The MRI suite did not meet operating room standards with respect to airflow and air filtration but was prepared and used with conventional sterile procedures by an experienced surgical team. Deep brain stimulation leads were implanted while the patient was in the magnet, and patients returned 1-3 weeks later to undergo placement of the implantable pulse generator (IPG) and extender wire in a conventional operating room. Surgical site infections requiring the removal of part or all of the DBS system within 6 months of implantation were scored as postoperative hardware infections in a prospective database. RESULTS During the 10-year study period, the authors performed 164 iMRI-guided surgical procedures in which 272 electrodes were implanted. Patients ranged in age from 7 to 78 years, and an overall infection rate of 3.6% was found. Bacterial cultures indicated Staphylococcus epidermis (3 cases), methicillin-susceptible Staphylococcus aureus (2 cases), or Propionibacterium sp. (1 case). A change in sterile practice occurred after the first 10 patients, leading to a reduction in the infection rate to 2.6% (4 cases in 154 procedures) over the remainder of the procedures. Of the 4 infections in this patient subset, all occurred at the IPG site. CONCLUSIONS Interventional MRI-guided DBS implantation can be performed in a diagnostic MRI suite with an infection risk comparable to that reported for traditional surgical placement techniques provided that sterile procedures, similar to those used in a regular operating room, are practiced.

IntroductionDeep brain stimulation (DBS) is an established therapy for movement disorders, and is under active investigation for other neurologic and psychiatric indications. While many studies describe outcomes and complications related to stimulation therapies, the majority of these are from large academic centers, and results may differ from those in general neurosurgical practice.MethodsUsing data from both the Centers for Medicare and Medicaid Services (CMS) and the National Surgical Quality Improvement Program (NSQIP), we identified all DBS procedures related to primary placement, revision, or removal of intracranial electrodes. Cases of cortical stimulation and stimulation for epilepsy were excluded.ResultsOver 28,000 cases of DBS electrode placement, revision, and removal were identified during the years 2004-2013. In the Medicare dataset, 15.2% and of these procedures were for intracranial electrode revision or removal, compared to 34.0% in the NSQIP dataset. In NSQIP, significant predictors of revision and removal were decreased age (odds ratio (OR) of 0.96; 95% CI: 0.94, 0.98) and higher ASA classification (OR 2.41; 95% CI: 1.22, 4.75). Up to 48.5% of revisions may have been due to improper targeting or lack of therapeutic effect.ConclusionData from multiple North American databases suggest that intracranial neurostimulation therapies have a rate of revision and removal higher than previously reported, between 15.2 and 34.0%. While there are many limitations to registry-based studies, there is a clear need to better track and understand the true prevalence and nature of such failures as they occur in the wider surgical community.

BACKGROUND Spinal subdural abscesses, also known as empyemas, are rare infectious lesions, the exact incidence of which is unknown. Presentation is typically dramatic, with back pain, fever, motor, and sensory deficits. Rapid identification and surgical in

PurposeFluoroscopic systems in modern interventional suites have the ability to perform flat panel detector CT (FDCT) with navigational guidance. Fusion with MR allows navigational guidance towards FDCT occult targets. We aim to evaluate the accuracy of this system using single-pass needle placement in a deep brain stimulation (DBS) phantom.Materials and methodsMR was performed on a head phantom with DBS lead targets. The head phantom was placed into fixation and FDCT was performed. FDCT and MR datasets were automatically fused using the integrated guidance system (iGuide, Siemens). A DBS target was selected on the MR dataset. A 10 cm, 19 G needle was advanced by hand in a single pass using laser crosshair guidance. Radial error was visually assessed against measurement markers on the target and by a second FDCT. Ten needles were placed using CT-MR fusion and 10 needles were placed without MR fusion, with targeting based solely on FDCT and fusion steps repeated for every pass.ResultsMean radial error was 2.75±1.39 mm as defined by visual assessment to the centre of the DBS target and 2.80±1.43 mm as defined by FDCT to the centre of the selected target point. There were no statistically significant differences in error between MR fusion and non-MR guided series.ConclusionsSingle pass needle placement in a DBS phantom using FDCT guidance is associated with a radial error of approximately 2.5-3.0 mm at a depth of approximately 80 mm. This system could accurately target sub-centimetre intracranial lesions defined on MR.

Local delivery of therapeutic agents into the brain has many advantages; however, the inability to predict, visualize and confirm the infusion into the intended target has been a major hurdle in its clinical development. Here, we describe the current workflow and application of the interventional MRI (iMRI) system for catheter placement and real time visualization of infusion. We have applied real time convection-enhanced delivery (CED) of therapeutic agents with iMRI across a number of different clinical trials settings in neuro-oncology and movement disorders. Ongoing developments and accumulating experience with the technique and technology of drug formulations, CED platforms, and iMRI systems will continue to make local therapeutic delivery into the brain more accurate, efficient, effective and safer.

BackgroundInterventional magnetic resonance imaging (iMRI) allows deep brain stimulator lead placement under general anesthesia. While the accuracy of lead targeting has been described for iMRI systems utilizing 1.5-tesla magnets, a similar assessment of 3-tesla iMRI procedures has not been performed.ObjectiveTo compare targeting accuracy, the number of lead targeting attempts, and surgical duration between procedures performed on 1.5- and 3-tesla iMRI systems.MethodsRadial targeting error, the number of targeting attempts, and procedure duration were compared between surgeries performed on 1.5- and 3-tesla iMRI systems (SmartFrame and ClearPoint systems).ResultsDuring the first year of operation of each system, 26 consecutive leads were implanted using the 1.5-tesla system, and 23 consecutive leads were implanted using the 3-tesla system. There was no significant difference in radial error (Mann-Whitney test, p = 0.26), number of lead placements that required multiple targeting attempts (Fisher's exact test, p = 0.59), or bilateral procedure durations between surgeries performed with the two systems (p = 0.15).ConclusionsAccurate DBS lead targeting can be achieved with iMRI systems utilizing either 1.5- or 3-tesla magnets. The use of a 3-tesla magnet, however, offers improved visualization of the target structures and allows comparable accuracy and efficiency of placement at the selected targets.

Intracerebral cell transplantation is being pursued as a treatment for many neurological diseases, and effective cell delivery is critical for clinical success. To facilitate intracerebral cell transplantation at the scale and complexity of the human brain, we developed a platform technology that enables radially branched deployment (RBD) of cells to multiple target locations at variable radial distances and depths along the initial brain penetration tract with real-time interventional magnetic resonance image (iMRI) guidance. iMRI-guided RBD functioned as an "add-on" to standard neurosurgical and imaging workflows, and procedures were performed in a commonly available clinical MRI scanner. Multiple deposits of super paramagnetic iron oxide beads were safely delivered to the striatum of live swine, and distribution to the entire putamen was achieved via a single cannula insertion in human cadaveric heads. Human embryonic stem cell-derived dopaminergic neurons were biocompatible with the iMRI-guided RBD platform and successfully delivered with iMRI guidance into the swine striatum. Thus, iMRI-guided RBD overcomes some of the technical limitations inherent to the use of straight cannulas and standard stereotactic targeting. This platform technology could have a major impact on the clinical translation of a wide range of cell therapeutics for the treatment of many neurological diseases.

ObjectiveRecently, an iMRI-guided technique for implanting DBS electrodes without MER was developed at our center. Here we report the clinical outcomes of PD patients undergoing STN DBS surgery using this surgical approach.MethodsConsecutive PD patients undergoing bilateral STN DBS using this method were prospectively studied. Severity of PD was determined using the UPDRS scores, Hoehn and Yahr staging score, stand-sit-walk testing, and the dyskinesia rating scale. The primary outcome measure was the change in UPDRS III off medication score at 6 months. DBS stimulation parameters, adverse events, levodopa equivalent daily dose (LEDD), and DBS lead locations were also recorded. Seventeen advanced PD patients (9M/8F) were enrolled from 2007 to 2009.ResultsThe mean UPDRS III off medication score improved from 44.5 to 22.5 (49.4%) at 6 months (p=0.001). Other secondary outcome measures (UPDRS II, III on medication, and IV) significantly improved as well (p

BackgroundIn preclinical studies, cell transplantation into the brain has shown great promise for the treatment of a wide range of neurological diseases. However, the use of a straight cannula and syringe for cell delivery to the human brain does not approximate cell distribution achieved in animal studies. This technical deficiency may limit the successful clinical translation of cell transplantation.ObjectiveTo develop a stereotactic device that effectively distributes viable cells to the human brain. Our primary aims were to (1) minimize the number of transcortical penetrations required for transplantation, (2) reduce variability in cell dosing and (3) increase cell survival.MethodsWe developed a modular cannula system capable of radially branched deployment (RBD) of a cell delivery catheter at variable angles from the longitudinal device axis. We also developed an integrated catheter-plunger system, eliminating the need for a separate syringe delivery mechanism. The RBD prototype was evaluated in vitro and in vivo with subcortical injections into the swine brain. Performance was compared to a 20G straight cannula with dual side ports, a device used in current clinical trials.ResultsRBD enabled therapeutic delivery in a precise 'tree-like' pattern branched from a single initial trajectory, thereby facilitating delivery to a volumetrically large target region. RBD could transplant materials in a radial pattern up to 2.0 cm from the initial penetration tract. The novel integrated catheter-plunger system facilitated manual delivery of small and precise volumes of injection (1.36 ± 0.13 µl per cm of plunger travel). Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. While reflux of infusate along the penetration tract was problematic with the use of the 20G cannula, RBD was resistant to this source of cell dose variability in agarose. RBD enabled radial injections to the swine brain when used with a modern clinical stereotactic system.ConclusionsBy increasing the total delivery volume through a single transcortical penetration in agarose models, RBD strategy may provide a new approach for cell transplantation to the human brain. Incorporation of RBD or selected aspects of its design into future clinical trials may increase the likelihood of successful translation of cell-based therapy to the human patient.

ObjectiveEssential tremor (ET) is characterized by an action tremor believed to be due to excessive theta-alpha activity in the cerebello-thalamo-cortical system. This study aimed to test the hypothesis that therapeutic thalamic stimulation in patients with ET decreases theta-alpha oscillatory activity in primary motor (M1) and sensory (S1) cortices.MethodsDuring surgical treatment of ET in 10 patients, an electrocorticography (ECoG) strip electrode was placed temporarily over the arm region of M1 and S1. Local field potentials (LFP) were recorded at rest, during a tremor-inducing posture, during acute therapeutic thalamic stimulation, and following therapeutic thalamotomy (three patients). Power spectral density (PSD) was calculated using the Fast Fourier Transform.ResultsAt rest, alpha activity (8-13Hz) in M1 was significantly decreased during high-frequency stimulation, while theta activity (4-8Hz) decreased in S1. Following thalamotomy, theta and beta (13-30Hz) was increased in M1. Induction of postural tremor reduced M1 theta, alpha and beta activity compared to the resting state.ConclusionsHigh-frequency thalamic deep brain stimulation (DBS) significantly reduces alpha oscillatory activity in the primary motor cortex of patients with ET, though this change is probably not critical for therapeutic efficacy.SignificanceWe demonstrate that ECoG can be effectively used to study the effect of subcortical stimulation on cortical oscillations.