Low frequency oscillations in mid-rostral dorsolateral prefrontal cortex support response inhibition.

Executive control of movement enables inhibiting impulsive responses critical for successful navigation of the environment. Circuits mediating stop commands involve prefrontal and basal ganglia structures with fMRI evidence demonstrating increased activity during response inhibition in dorsolateral prefrontal cortex (dlPFC) - often ascribed to maintaining task attentional demands. Using direct intraoperative cortical recordings in male and female human subjects, we investigated oscillatory dynamics along the rostral-caudal axis of dlPFC during a modified Go/No-go task, probing components of both proactive and reactive motor control. We assessed whether cognitive control is topographically organized along this axis and observed that low frequency power increased prominently in mid-rostral dlPFC when inhibiting and delaying responses. These findings provide evidence for a key role for mid-rostral dlPFC low frequency oscillations in sculpting motor control.Significance Statement This work offers insights into the neural mechanisms underlying executive control of movement. By employing intraoperative cortical recordings, our study uncovers the specific role of low frequency oscillations in the mid-rostral dlPFC during response inhibition. We demonstrate a topographical organization of low frequency power along the rostral-caudal axis of the dlPFC. This finding supports existing work suggesting the PFC hierarchy may be rooted in cognitive demand and extends it by showing this hierarchy can be represented by low frequency oscillations. Finally, understanding the spatial and temporal dynamics of inhibitory control may enable more effective neuromodulation therapies in the future, such as those aimed at Parkinson Disease patients to address impulsivity.

Differential Cognitive Effects of Unilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

OBJECTIVE: The aim of this study was to investigate the cognitive effects of unilateral directional versus ring subthalamic nucleus deep brain stimulation (STN DBS) in patients with advanced Parkinson's disease. METHODS: We examined 31 participants who underwent unilateral STN DBS (left n = 17; right n = 14) as part of an National Institutes of Health (NIH)-sponsored randomized, double-blind, crossover study contrasting directional versus ring stimulation. All participants received unilateral DBS implants in the hemisphere more severely affected by motor parkinsonism. Measures of cognition included verbal fluency, auditory-verbal memory, and response inhibition. We used mixed linear models to contrast the effects of directional versus ring stimulation and implant hemisphere on longitudinal cognitive function. RESULTS: Crossover analyses showed no evidence for group-level changes in cognitive performance related to directional versus ring stimulation. Implant hemisphere, however, impacted cognition in several ways. Left STN participants had lower baseline verbal fluency than patients with right implants (t [20.66 = -2.50, p = 0.02]). Verbal fluency declined after left (p = 0.013) but increased after right STN DBS (p < 0.001), and response inhibition was faster following right STN DBS (p = 0.031). Regardless of hemisphere, delayed recall declined modestly over time versus baseline (p = 0.001), and immediate recall was unchanged. INTERPRETATION: Directional versus ring STN DBS did not differentially affect cognition. Similar to prior bilateral DBS studies, unilateral left stimulation worsened verbal fluency performance. In contrast, unilateral right STN surgery increased performance on verbal fluency and response inhibition tasks. Our findings raise the hypothesis that unilateral right STN DBS in selected patients with predominant right brain motor parkinsonism could mitigate declines in verbal fluency associated with the bilateral intervention. ANN NEUROL 2024;95:1205-1219.

Risk factors for wound-related complications after microvascular decompression.

Retrosigmoid craniotomy for microvascular decompression (MVD) has been traditionally performed via craniectomy. Various closure techniques have been described, yet factors associated with wound-related complications remain undetermined. Accordingly, herein, we sought to identify risk factors associated with wound-related complications after such procedures. An institutional retrospective case-control study was performed; outcomes of interest were cerebrospinal fluid (CSF) leak, wound dehiscence, wound infection, and pseudomeningocele. Univariate analysis was performed using Wilcoxon rank sum test for non-parametric continuous outcomes and chi-square test for categorical outcomes. Multivariate logistic regression was performed on binomial outcome variables. The study population included 197 patients who underwent MVD for trigeminal neuralgia (83.2%), hemifacial spasm (12.2%), vestibular nerve section (3.0%), and glossopharyngeal neuralgia (1.5%). The overall wound-related complication rate was 14.2% (n = 28), including twelve patients (6.1%) with CSF leak, ten patients (5.1%) with wound infection, ten patients (5.1%) with pseudomeningocele, and nine (4.6%) patients with wound dehiscence. Using multivariate logistic regression, preoperative anemia and current tobacco use were associated with significantly higher rates of complications (OR 6.01 and 4.58, respectively; p < 0.05), including CSF leak (OR 12.83 and 12.40, respectively, p < 0.05). Of note, use of synthetic bone substitute for cranioplasty was associated with a significantly lower rate of complications (OR 0.13, p < 0.01). Preoperative anemia and current tobacco use significantly increased, while synthetic bone substitute cranioplasty significantly decreased, odds of wound-related complications, the need for treatment, and CSF leaks. Additionally, higher BMI, longer operative duration, and prior radiosurgery may increase risk for wound-related complications.

Stereotactic radiosurgery with MLC-defined arcs: Verification of dosimetry, spatial accuracy, and end-to-end tests.

PURPOSE: To measure dosimetric and spatial accuracy of stereotactic radiosurgery (SRS) delivered to targets as small as the trigeminal nerve (TN) using a standard external beam treatment planning system (TPS) and multileaf collimator-(MLC) equipped linear accelerator without cones or other special attachments or modifications. METHODS: Dosimetric performance was assessed by comparing computed dose distributions to film measurements. Comparisons included the γ-index, beam profiles, isodose lines, maximum dose, and spatial accuracy. Initially, single static 360° arcs of MLC-shaped fields ranging from 1.6 × 5 to 30 × 30 mm2 were planned and delivered to an in-house built block phantom having approximate dimensions of a human head. The phantom was equipped with markings that allowed accurate setup using planar kV images. Couch walkout during multiple-arc treatments was investigated by tracking a ball pointer, initially positioned at cone beam computed tomography (CBCT) isocenter, as the couch was rotated. Tracks were mapped with no load and a 90 kg stack of plastic plates simulating patient treatment. The dosimetric effect of walkout was assessed computationally by comparing test plans that corrected for walkout to plans that neglected walkout. The plans involved nine 160° arcs of 2.4 × 5 mm2 fields applied at six different couch angles. For end-to-end tests that included CT simulation, target contouring, planning, and delivery, a cylindrical phantom mimicking a 3 mm lesion was constructed and irradiated with the nine-arc regimen. The phantom, lacking markings as setup aids was positioned under CBCT guidance by registering its surface and internal structures with CTs from simulation. Radiochromic film passing through the target center was inserted parallel to the coronal and the sagittal plane for assessment of spatial and dosimetric accuracy. RESULTS: In the single-arc block phantom tests computed maximum doses of all field sizes agreed with measurements within 2.4 ± 2.0%. Profile widths at 50% maximum agreed within 0.2 mm. The largest targeting error was 0.33 mm. The γ-index (3%, 1 mm) averaged over 10 experiments was >1 in only 1% of pixels for field sizes up to 10 × 10 mm2 and rose to 4.4% as field size increased to 20 × 20 mm2 . Table walkout was not affected by load. Walkout shifted the target up to 0.6 mm from CBCT isocenter but, according to computations shifted the dose cloud of the nine-arc plan by only 0.16 mm. Film measurements verified the small dosimetric effect of walkout, allowing walkout to be neglected during planning and treatment. In the end-to-end tests average and maximum targeting errors were 0.30 ± 0.10 and 0.43 mm, respectively. Gamma analysis of coronal and sagittal dose distributions based on a 3%/0.3 mm agreement remained <1 at all pixels. To date, more than 50 functional SRS treatments using MLC-shaped static field arcs have been delivered. CONCLUSION: Stereotactic radiosurgery (SRS) can be planned and delivered on a standard linac without cones or other modifications with better than 0.5 mm spatial and 5% dosimetric accuracy.

Cortical Activation Elicited by Subthalamic Deep Brain Stimulation Predicts Postoperative Motor Side Effects.

OBJECTIVE: Although deep brain stimulation (DBS) is an effective treatment for movement disorders, improvement varies substantially in individuals, across clinical trials, and over time. Noninvasive biomarkers that predict the individual response to DBS could be used to optimize outcomes and drive technological innovation in neuromodulation. We sought to evaluate whether noninvasive event related potentials elicited by subthalamic DBS during surgical targeting predict the tolerability of a given stimulation site in patients with advanced Parkinson's disease. METHODS: Using electroencephalography, we measured event related potentials elicited by 20 Hz DBS over a range of stimulus intensities across the spatial extent of the implanted electrode array in 11 patients. We correlated event related potential timing and morphology with the stimulus amplitude thresholds for motor side effects during postoperative programming at ≥130 Hz. RESULTS: During surgical targeting, DBS at 20 Hz elicits large amplitude, high frequency activity (evoked HFA) with mean onset latency of 9.0 ± 0.3 msec and a mean frequency of 175.8 ± 7.8 Hz. The lowest DBS amplitude that elicits the HFA predicts thresholds for motor side effects during postoperative stimulation at ≥130 Hz (p < 0.001, ANOVA). CONCLUSION: Event related potentials elicited by DBS can predict clinically relevant corticospinal activation by stimulation after surgery. Noninvasive scalp physiology requires no patient interaction and could serve as a biomarker to guide targeting, postoperative programming, and emerging technologies such as directional and closed-loop stimulation.

A method for pre-operative single-subject thalamic segmentation based on probabilistic tractography for essential tremor deep brain stimulation.

PURPOSE: Deep brain stimulation is a common treatment for medication-refractory essential tremor. Current coordinate-based targeting methods result in variable outcomes due to variation in thalamic structure and the optimal patient-specific functional location. The purpose of this study was to compare the coordinate-based pre-operative targets to patient-specific thalamic segmentation utilizing a probabilistic tractography methodology. METHODS: Using available diffusion MRI of 32 subjects from the Human Connectome Project database, probabilistic tractography was performed. Each thalamic voxel was coded based on one of six predefined cortical targets. The segmentation results were analyzed and compared to a 2-mm spherical target centered at the coordinate-based location of the ventral intermediate thalamic nucleus. RESULTS: The traditional coordinate-based target had maximal overlap with the junction of the region most connected to primary motor cortex (M1) (36.6 ± 25.7% of voxels on left; 58.1 ± 28.5% on right) and the area connected to the supplementary motor area/premotor cortex (SMA/PMC) (44.9 ± 21.7% of voxels on left; 28.9 ± 22.2% on right). There was a within-subject coefficient of variation from right-to-left of 69.4 and 63.1% in the volume of overlap with the SMA/PMC and M1 regions, respectively. CONCLUSION: Thalamic segmentation based on structural connectivity measures is a promising technique that may enhance traditional targeting methods by generating reproducible, patient-specific pre-operative functional targets. Our results highlight the problematic intra- and inter-subject variability of indirect, coordinate-based targets. Future prospective clinical studies will be needed to validate this targeting methodology in essential tremor patients.

The Relationship of Electrophysiologic Subthalamic Nucleus Length as a Predictor of Outcomes in Deep Brain Stimulation for Parkinson Disease.

BACKGROUND: Intraoperative measurement of subthalamic nucleus (STN) width through microelectrode recording (MER) is a common proxy for optimal electrode location during deep brain stimulation (DBS) surgery for Parkinson disease. We assessed whether the MER-determined STN width is a predictor of postoperative Unified Parkinson Disease Rating Scale (UPDRS) improvement. METHODS: Records were reviewed for patients who underwent single-sided STN DBS placement for Parkinson disease between 2005 and 2010 at the UAB Medical Center. Reviews of preoperative and 3-month postoperative UPDRS part III, intraoperative MER records, and postoperative MRI scans were conducted. RESULTS: The final cohort consisted of 73 patients (mean age 59 ± 9.7 years, length of disease 13 ± 9.7 years). STN widths were defined as depths associated with increased background activity and motor-driven, spiking action potentials on MER. The mean contralateral UPDRS improvement was 58% (± 24). The mean STN width was 5.1 mm (± 1.6, min = 0.0, max = 8.7). No significant relationship between STN width and UPDRS improvement was found, with and without AC-PC normalization (R2 < 0.05). CONCLUSION: This analysis raises questions about seeking the maximal electrophysiological width of STN as a proxy for optimal outcome in DBS for PD. We suggest this strategy for DBS placement in Parkinson disease be subject to more robust prospective investigation.

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial.

OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. METHODS: We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.

Lessons Learned From Google Glass: Telemedical Spark or Unfulfilled Promise?

IMPORTANCE: Wearable devices such as Google Glass could potentially be used in the health care setting to expand access and improve quality of care. OBJECTIVE: This study aims to assess the demographics of Google Glass users in health care and determine the obstacles to using Google Glass by surveying those who are known to use the device. DESIGN: A 48-question survey was designed to assess demographics of users, technological limitations of Google Glass, and obstacles to implementation of the device. SETTING: The physicians surveyed worked in various fields of health care, with 50% of the respondents being surgeons. PARTICIPANTS: Potential participants were found using an Internet search for physicians using Google Glass in their practice. MAIN OUTCOME MEASURES: Outcome measures were divided into demographic information of users, technological limitations of the device, and administrative obstacles. RESULTS: A 43.6% response rate was observed. The majority of users were male, assistant professors, in academic hospitals, and in the United States. Numerous technological limitations were observed by the majority, including device ergonomics, display location, video quality, and audio quality. Patient confidentiality and data security were the major concerns among administrative obstacles. CONCLUSIONS AND RELEVANCE: Despite the potential of Google Glass, numerous obstacles exist that limit its use in health care. While Google Glass has been discontinued, the results of this study may be used to guide future designs of wearable devices.

Differential cognitive effects of unilateral left and right subthalamic nucleus deep brain stimulation for Parkinson disease.

Objective: To investigate hemispheric effects of directional versus ring subthalamic nucleus (STN) deep brain stimulation (DBS) surgery on cognitive function in patients with advanced Parkinson's disease (PD). Methods: We examined 31 PD patients (Left STN n = 17; Right STN n = 14) who underwent unilateral subthalamic nucleus (STN) DBS as part of a NIH-sponsored randomized, cross-over, double-blind (ring vs directional) clinical trial. Outcome measures were tests of verbal fluency, auditory-verbal memory, and response inhibition. First, all participants were pooled together to study the effects of directional versus ring stimulation. Then, we stratified the groups by surgery hemisphere and studied the longitudinal changes in cognition post-unilateral STN DBS. Results: Relative to pre-DBS cognitive baseline performances, there were no group changes in cognition following unilateral DBS for either directional or ring stimulation. However, assessment of unilateral DBS by hemisphere revealed a different pattern. The left STN DBS group had lower verbal fluency than the right STN group (t(20.66 = -2.50, p = 0.02). Over a period of eight months post-DBS, verbal fluency declined in the left STN DBS group (p = 0.013) and improved in the right STN DBS group over time (p < .001). Similarly, response inhibition improved following right STN DBS (p = 0.031). Immediate recall did not significantly differ over time, nor was it affected by implant hemisphere, but delayed recall equivalently declined over time for both left and right STN DBS groups (left STN DBS p = 0.001, right STN DBS differ from left STN DBS p = 0.794). Conclusions: Directional and ring DBS did not differentially or adversely affect cognition over time. Regarding hemisphere effects, verbal fluency decline was observed in those who received left STN DBS, along with the left and right STN DBS declines in delayed memory. The left STN DBS verbal fluency decrement is consistent with prior bilateral DBS research, likely reflecting disruption of the basal-ganglia-thalamocortical network connecting STN and inferior frontal gyrus. Interestingly, we found an improvement in verbal fluency and response inhibition following right STN DBS. It is possible that unilateral STN DBS, particularly in the right hemisphere, may mitigate cognitive decline.

Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease.

Multiple studies have shown bilateral improvement in motor symptoms in Parkinson disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal segment of the globus pallidus, yet the mechanism(s) underlying this phenomenon are poorly understood. We hypothesized that STN neuronal activity is altered by contralateral STN DBS. This hypothesis was tested intraoperatively in humans with advanced PD using microelectrode recordings of the STN during contralateral STN DBS. We demonstrate alterations in the discharge pattern of STN neurons in response to contralateral STN DBS including short latency, temporally precise, stimulation frequency-independent responses consistent with antidromic activation. Furthermore, the total discharge frequency during contralateral high frequency stimulation (160 Hz) was greater than during low frequency stimulation (30 Hz) and the resting state. These findings demonstrate complex responses to DBS and imply that output activation throughout the basal ganglia-thalamic-cortical network rather than local inhibition is a therapeutic mechanism of DBS.

High-frequency deep brain stimulation of the putamen improves bradykinesia in Parkinson's disease.

Deep brain stimulation is effective for a wide range of neurological disorders; however, its mechanisms of action remain unclear. With respect to Parkinson's disease, the existence of multiple effective targets suggests that putamen stimulation also may be effective and raises questions as to the mechanisms of action. Are there as many mechanisms of action as there are effective targets or some single or small set of mechanisms common to all effective targets? During the course of routine surgery of the globus pallidus interna in patients with Parkinson's disease, the deep brain stimulation lead was placed in the putamen en route to the globus pallidus interna. Recordings of hand opening and closing during high-frequency and no stimulation were made. Speed of the movements, based on the amplitude and frequency of the repetitive hand movements as well as the decay in amplitude, were studied. Hand speed in 6 subjects was statistically significantly faster during active deep brain stimulation than the no-stimulation condition. There were no statistically significant differences in decay in the amplitude of hand movements. High-frequency deep brain stimulation of the putamen improves bradykinesia in a hand-opening and -closing task in patients with Parkinson's disease. Consequently, high-frequency deep brain stimulation of virtually every structure in the basal ganglia-thalamic-cortical system improves bradykinesia. These observations, together with microelectrode recordings reported in the literature, argue that deep brain stimulation effects may be system specific and not structure specific.

Preoperative Decision-Making in Microvascular Decompression for Trigeminal Neuralgia: A Survey of Practicing Neurosurgeons.

OBJECTIVE: Microvascular decompression (MVD) for trigeminal neuralgia (TN) results in durable pain freedom in a large percentage of appropriately selected patients. The decision to perform MVD is based on a combination of clinical symptomatic presentation and imaging findings demonstrating neurovascular compression (NVC) with surgeons weighting these variables differently. This study sought to determine the relative importance of clinical symptomatic presentation and imaging findings of NVC in decision-making to pursue MVD for TN among North American board-certified neurosurgeons. METHODS: An online survey detailing the decision-making process involved in the workup and treatment of TN with MVD was distributed to all American Association of Neurological Surgeons registered board-certified neurosurgeons in North America. RESULTS: From 3010 functional email addresses, there were 309 responses to the survey (10% response rate). The majority of respondents (76%) reported only operating on patients with classic type 1 TN (T1TN) while only 32% chose to operate on patients with imaging findings of vascular compression in the absence of T1TN symptoms. In contrast to low-volume surgeons, high-volume surgeons weighed imaging evidence of vascular compression more heavily into the decision-making process to operate. CONCLUSIONS: The majority of responding neurosurgeons weigh symptomatic presentation more heavily than imaging evidence of NVC when deciding on whom to perform MVD. High-volume surgeons tend to be more attentive to NVC in their decision-making to perform MVD when compared with low-volume surgeons.

The Use of MRI in Preoperative Decision-Making for Trigeminal Neuralgia: A Single-Center Study.

OBJECTIVE: Few studies have examined associations between vascular compression and postoperative pain relief in patients undergoing microvascular decompression (MVD) for treatment of medically refractory type 1 trigeminal neuralgia (TN). The authors sought to examine for associations between vascular compression and postoperative pain relief to determine the utility of preoperative magnetic resonance imaging (MRI) in surgical decision-making for TN. METHODS: The charts of 59 patients who underwent 60 MVDs for TN between 2007 and 2017 at a single academic institution were reviewed. Patient demographics, the presence of compressing vessel on preoperative MRI and intraoperatively, complications, follow-up time, performance of a partial sensory rhizotomy, and pain resolution at most recent follow-up were recorded. Sensitivity and specificity of MRI for detecting vascular compression were calculated and associations between preoperative and intraoperative evidence of vascular compression with postoperative pain relief were examined. RESULTS: Sensitivity and specificity of preoperative MRI determined through blinded reads by the senior author were 65.3% (95% confidence interval, 13.5-32.0) and 90.9% (95% confidence interval, 86.1-100.0), respectively. Overall, 76.3% of patients were pain free at most recent follow-up. Preoperative MRI and intraoperative evidence of vascular compression were not associated with postoperative pain relief at most recent follow-up (P = 0.47 and 0.43, respectively). CONCLUSIONS: The findings of lower sensitivity and poor interrater reliability of MRI, as well as a lack of association between compressive vessel and postoperative pain relief reported in this study, suggest the decision to pursue MVD for TN should be based more heavily on classic symptomatic presentation over preoperative evidence of vascular compression.

Subcortical short-term plasticity elicited by deep brain stimulation.

OBJECTIVE: To investigate local short-term neuroplasticity elicited by subthalamic, thalamic, and pallidal deep brain stimulation (DBS) for movement disorders. METHODS: During DBS surgery, we delivered pairs of stimulus pulses with both circular and directional leads across 90 interstimulus intervals in 17 participants and recorded local field potentials from unused contacts on the implanted electrode array. We removed the stimulus artifact, validated the neural origin of the underlying signals, and examined short-term plasticity as a function of interstimulus interval and DBS target, using linear mixed effects models. RESULTS: DBS evokes short latency local field potentials that are readily detected with both circular and directional leads at all stimulation targets (0.31 ± 0.10 msec peak latency, mean ± SD). Peak amplitude, area, and latency are modified strongly by interstimulus interval (P < 0.001) and display absolute and relative refractory periods (0.56 ± 0.08 and 2.94 ± 1.05 msec, respectively). We also identified later oscillatory activity in the subthalamic-pallidal circuit (4.50 ± 1.11 msec peak latency) that displays paired pulse facilitation (present in 5/8 subthalamic, 4/5 pallidal, and 0/6 thalamic trajectories, P = 0.018, Fisher's exact test), and correlates with resting beta frequency power (P < 0.001), therapeutic DBS frequencies, and stimulation sites chosen later for therapy in the ambulatory setting (P = 0.031). INTERPRETATION: Paired DBS pulses synchronize local circuit electrophysiology and elicit short-term neuroplasticity in the subthalamic-pallidal circuit. Collectively, these responses likely represent the earliest detectable interaction between the DBS pulse and local neuronal tissue in humans. Evoked subcortical field potentials could serve as a predictive biomarker to guide the implementation of next-generation directional and adaptive stimulation devices.

Construction of relational topographies from the quantitative measurements of functional deep brain stimulation using a 'roving window' interpolation algorithm.

The delivery of stimulus by a deep brain stimulation (DBS) contact electrode at a particular location may lead to a quantifiable physiologic effect, both intraoperatively and postoperatively. Consequently, measured data values can be attributed to discrete scattered points in neuroanatomic space, allowing for interpolative techniques to generate a topographic map of spatial patterns. Ultimately, by relating the topographies of various intraoperative measurements to the postoperative counterparts and neuroanatomic atlases, outcome-guided adjustments to electrode position can be pursued intraoperatively. In this study, 52 Parkinson's disease patients were tested with a postoperative trial of stimulation and thresholds were recorded for motor adverse effects. A 'roving window' interpolation algorithm was adapted to generate a topographic map of voltage threshold along selected axial, coronal and sagittal planes. By developing these relational topographies for a variety of intraoperative and postoperative effects, a multivariable approach towards DBS optimization emerges.

Burosumab in tumor-induced osteomalacia: A case report.

Tumor-induced osteomalacia is a rare cause of acquired hypophosphatemia due to the paraneoplastic overproduction of fibroblast growth factor-23. Unlike many causes of osteomalacia, tumor-induced osteomalacia is curable by resection of the offending tumor. If a patient has a tumor that is unidentifiable, unresectable, or makes the decision to forgo surgery, medical treatment is recommended. Burosumab (KRN23) is a fully human monoclonal antibody against fibroblast growth factor-23 that was recently approved for the treatment of X-linked hypophosphatemia. We present a case of tumor-induced osteomalacia due to two somatostatin receptor avid meningiomas. The patient initially was wheelchair bound due to symptoms of diffuse bone and muscle pain with recurrent traumatic and nontraumatic fractures. Serum phosphate was 1.8mg/dL (reference range: 2.4-5.0mg/dL) with no other laboratory or historical cause. Workup revealed two widely separated intracranial meningiomas with typical magnetic resonance imaging characteristics. The duplicity of tumors precluded safe surgery and the potential delay in, or lack of, efficacy using radiosurgery prompted the treatment team to opt for medical treatment. Burosumab was initiated resulting in improvement in pain symptoms and mobility. Serum phosphate normalized. Trials are ongoing to assess the utility of burosumab in the treatment of tumor-induced osteomalacia.

Walking Speed Reliably Measures Clinically Significant Changes in Gait by Directional Deep Brain Stimulation.

Introduction: Although deep brain stimulation (DBS) often improves levodopa-responsive gait symptoms, robust therapies for gait dysfunction from Parkinson's disease (PD) remain a major unmet need. Walking speed could represent a simple, integrated tool to assess DBS efficacy but is often not examined systematically or quantitatively during DBS programming. Here we investigate the reliability and functional significance of changes in gait by directional DBS in the subthalamic nucleus. Methods: Nineteen patients underwent unilateral subthalamic nucleus DBS surgery with an eight-contact directional lead (1-3-3-1 configuration) in the most severely affected hemisphere. They arrived off dopaminergic medications >12 h preoperatively and for device activation 1 month after surgery. We measured a comfortable walking speed using an instrumented walkway with DBS off and at each of 10 stimulation configurations (six directional contacts, two virtual rings, and two circular rings) at the midpoint of the therapeutic window. Repeated measures of ANOVA contrasted preoperative vs. maximum and minimum walking speeds across DBS configurations during device activation. Intraclass correlation coefficients examined walking speed reliability across the four trials within each DBS configuration. We also investigated whether changes in walking speed related to modification of step length vs. cadence with a one-sample t-test. Results: Mean comfortable walking speed improved significantly with DBS on vs. both DBS off and minimum speeds with DBS on (p < 0.001, respectively). Pairwise comparisons showed no significant difference between DBS off and minimum comfortable walking speed with DBS on (p = 1.000). Intraclass correlations were ≥0.949 within each condition. Changes in comfortable walk speed were conferred primarily by changes in step length (p < 0.004). Conclusion: Acute assessment of walking speed is a reliable, clinically meaningful measure of gait function during DBS activation. Directional and circular unilateral subthalamic DBS in appropriate configurations elicit acute and clinically significant improvements in gait dysfunction related to PD. Next-generation directional DBS technologies have significant potential to enhance gait by individually tailoring stimulation parameters to optimize efficacy.

Incidence and risk factors for seizures associated with deep brain stimulation surgery.

OBJECTIVE: The objective of this study was to determine the incidence of seizures following deep brain stimulation (DBS) electrode implantation and to evaluate factors associated with postoperative seizures. METHODS: The authors performed a single-center retrospective case-control study. The outcome of interest was seizure associated with DBS implantation. Univariate analyses were performed using the Student t-test for parametric continuous outcomes. The authors used the Kruskal-Wallis test or Wilcoxon rank-sum test for nonparametric continuous outcomes, chi-square statistics for categorical outcomes, and multivariate logistic regression for binomial variables. RESULTS: A total of 814 DBS electrode implantations were performed in 645 patients (478 [58.7%] in men and 520 [63.9%] in patients with Parkinson's disease). In total, 22 (3.4%) patients who had undergone 23 (2.8%) placements experienced seizure. Of the 23 DBS implantation-related seizures, 21 were new-onset seizures (3.3% of 645 patients) and 2 were recurrence or worsening of a prior seizure disorder. Among the 23 cases with postimplantation-related seizure, epilepsy developed in 4 (17.4%) postoperatively; the risk of DBS-associated epilepsy was 0.50% per DBS electrode placement and 0.63% per patient. Nine (39.1%) implantation-related seizures had associated postoperative radiographic abnormalities. Multivariate analyses suggested that age at surgery conferred a modest increased risk for postoperative seizures (OR 1.06, 95% CI 1.02-1.10). Sex, primary diagnosis, electrode location and sidedness, and the number of trajectories were not significantly associated with seizures after DBS surgery. CONCLUSIONS: Seizures associated with DBS electrode placement are uncommon, typically occur early within the postoperative period, and seldom lead to epilepsy. This study suggests that patient characteristics, such as age, may play a greater role than perioperative variables in determining seizure risk. Multiinstitutional studies may help better define and mitigate the risk of seizures after DBS surgery.

Latency of subthalamic nucleus deep brain stimulation-evoked cortical activity as a potential biomarker for postoperative motor side effects.

OBJECTIVE: Here, we investigate whether cortical activation predicts motor side effects of deep brain stimulation (DBS) and whether these potential biomarkers have utility under general anesthesia. METHODS: We recorded scalp potentials elicited by DBS during surgery (n = 11), both awake and under general anesthesia, and in an independent ambulatory cohort (n = 8). Across a range of stimulus configurations, we measured the amplitude and timing of short- and long-latency response components and linked them to motor side effects. RESULTS: Regardless of anesthesia state, in both cohorts, DBS settings with capsular side effects elicited early responses with peak latencies clustering at <1 ms. This early response was preserved under anesthesia in all participants (11/11). In contrast, the long-latency components were suppressed completely in 6/11 participants. Finally, the latency of the earliest response could predict the presence of postoperative motor side effects both awake and under general anesthesia (84.8% and 75.8% accuracy, awake and under anesthesia, respectively). CONCLUSION: DBS elicits short-latency cortical activation, both awake and under general anesthesia, which appears to reveal interactions between the stimulus and the corticospinal tract. SIGNIFICANCE: Short-latency evoked cortical activity can potentially be used to aid both DBS lead placement and post-operative programming.