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Background: The prognosis for patients with recurrent glioblastoma (GBM) is dismal, and the question of repeat surgery at time of recurrence is common. Re-operation in the management of these patients remains controversial, as there is no randomized evidence of benefit. An all-inclusive pragmatic care trial is needed to evaluate the role of repeat resection. Methods: 3rGBM is a multicenter, pragmatic, prospective, parallel-group randomized care trial, with 1:1 allocation to repeat resection or standard care with no repeat resection. To test the hypothesis that repeat resection can improve overall survival by at least 3 months (from 6 to 9 months), 250 adult patients with prior resection of pathology-proven glioblastoma for whom the attending surgeon believes repeat resection may improve quality survival will be enrolled. A surrogate measure of quality of life, the number of days outside of hospital/nursing/palliative care facility, will also be compared. Centers are invited to participate without financial compensation and without contracts. Clinicians may apply to local authorities to approve an investigator-led in-house trial, using a common protocol, web-based randomization platform, and simple standardized case report forms. Discussion: The 3rGBM trial is a modern transparent care research framework with no additional risks, tests, or visits other than what patients would encounter in normal care. The burden of proof remains on repeat surgical management of recurrent GBM, because this management has yet to be shown beneficial. The trial is designed to help patients and surgeons manage the uncertainty regarding optimal care. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT04838782.

Postactivation depression of the Hoffmann reflex is reduced in Parkinson's disease (PD), but how the recovery is influenced by the state of the muscle is unknown. The present pilot study examined postactivation depression in PD at rest and during a voluntary contraction while patients were off treatment and while receiving medications and/or deep brain stimulation.The authors recruited nine patients with PD treated with implanted deep brain stimulation and examined postactivation depression under four treatment conditions. Paired pulses were delivered 25 to 300 ms apart, and soleus Hoffmann reflex recovery was tested at rest and during voluntary plantar flexion. Trials were matched for background muscle activity and compared with 10 age-matched controls.Patients with Parkinson disease who were OFF medications (OFF meds) and OFF stimulation (OFF stim) at rest showed less postactivation depression at the 300 ms interpulse interval (86.1% ± 21.0%) relative to control subjects (36.4% ± 6.1%; P0.05). Postactivation depression was restored when dopaminergic medication and/or deep brain stimulation was applied. Comparisons between resting and active motor states revealed that the recovery curves were similar OFF meds/OFF stim owing to faster recovery in PD seen at rest. In contrast, the effect of the motor state was different ON meds/OFF stim and ON meds/ON stim (both P0.05), with a nonsignificant trend OFF meds/ON stim ( P0.08). During a contraction, recovery curves were similar between all treatment conditions in PD and control.Disrupted Hoffmann reflex recovery is restored to control levels in PD patients at rest when receiving medications and/or deep brain stimulation or when engaged in voluntary contraction.

Background Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) and globus pallidus interna (GPi) is an effective treatment for cardinal motor symptoms and motor complications in Parkinson’s Disease (PD). However, malpositioned DBS electrodes can result in suboptimal therapeutic response. Objective We explored whether recovery of the H-reflex—an easily measured electrophysiological analogue of the stretch reflex, known to be altered in PD—could serve as an adjunct biomarker of suboptimal versus optimal electrode position during STN- or GPi-DBS implantation. Methods Changes in soleus H-reflex recovery were investigated intraoperatively throughout awake DBS target refinement across 26 nuclei (14 STN). H-reflex recovery was evaluated during microelectrode recording (MER) and macrostimulation at multiple locations within and outside target nuclei, at varying stimulus intensities. Results Following MER, H-reflex recovery normalized (i.e., became less Parkinsonian) in 21/26 nuclei, and correlated with on-table motor improvement consistent with an insertional effect. During macrostimulation, H-reflex recovery was maximally normalized in 23/26 nuclei when current was applied at the location within the nucleus producing optimal motor benefit. At these optimal sites, H-reflex normalization was greatest at stimulation intensities generating maximum motor benefit free of stimulation-induced side effects, with subthreshold or suprathreshold intensities generating less dramatic normalization. Conclusion H-reflex recovery is modulated by stimulation of the STN or GPi in patients with PD and varies depending on the location and intensity of stimulation within the target nucleus. H-reflex recovery shows potential as an easily-measured, objective, patient-specific, adjunct biomarker of suboptimal versus optimal electrode position during DBS surgery for PD.

Object:Many neurosurgeons pursue graduate degrees as part of their training. In some jurisdictions, graduate degrees are considered a necessary condition of employment in academic neurosurgery. However, the relationship between possession of a graduate degree and eventual research productivity is not well established. We used bibliometric methods to analyze publications from academic Canadian neurosurgeons, with an emphasis on level of graduate training.Methods:All neurosurgeons holding academic appointments at Canadian institutions from 2012–2016 were included. Over that time frame, Scopus was used to quantify the number of papers, number of citations, 5-year h-index and 5-year r-index, CiteScore, authorship position, and paper type (clinical or basic science). Publication output was compared between neurosurgeons grouped as MD-only, MD-Masters, or MD-PhD.Results:In total, 2557 abstracts from 131 Canadian neurosurgeons were analyzed. We found that MD-Masters neurosurgeons published significantly more total papers, clinical papers, and first/last author papers than MD-only neurosurgeons. MD-PhD neurosurgeons had the same findings, in addition to more basic science papers, in journals with a higher CiteScore, 5-year h-index, and 5-year r-index than both other groups. These results were preserved even with significant outliers removed. There was no difference if graduate degrees were obtained before or after starting residency. There was no correlation with career length and number of recent papers published.Conclusion:The attainment of a graduate degree has an important association with future publication productivity for academic neurosurgeons. These data should be useful for hiring committees considering the value of graduate degrees from applicants for positions in academic neurosurgery.

BACKGROUND Microvascular decompression (MVD) is an effective treatment for trigeminal neuralgia, but pain recurs in a substantial minority of patients. Two recently published scoring systems by Hardaway et al. and Panczykowski et al. use simple preoperative clinical and imaging features to predict durable pain relief following MVD, but their predictive performance has not been independently validated. This study aimed to compare predictive performance of the Hardaway et al. score (HS) and Panczykowski et al. score (PS) for 1-year, 3-year, and long-term pain-free outcomes after MVD for trigeminal neuralgia. METHODS HS and PS were computed for a retrospective, single-institution cohort of 68 patients with trigeminal neuralgia who underwent MVD. Primary outcome was pain recurrence after MVD. Predictive performance of HSs and PSs was evaluated with area under the curve sensitivity analysis and regression models for survival analyses at 1 year, 3 years, and last follow-up. RESULTS Area under the curve for predicting pain-free outcome was higher for PS versus HS at 1 year (0.873 vs. 0.775) and 3 years (0.793 vs. 0.704). Cox proportional hazard models showed that PS better predicted long-term pain-free outcomes compared with HS (P < 0.05). One-year pain-free outcome was best predicted by pain type; longer-term outcomes were better predicted by presence and degree of neurovascular compression on preoperative imaging. CONCLUSIONS PS is superior to HS in predicting pain-free outcomes after MVD, which may aid in patient selection and counseling. Overall, more significant neurovascular compression of the trigeminal nerve root, and to a lesser extent classical paroxysmal pain, are good predictors of durable pain relief after MVD.

This chapter explores the complex neuroethical aspects of neurosurgery and neuromodulation in the context of Canadian healthcare and innovation, as seen through the lens of the Pan Canadian Neurotechnology Ethics Consortium (PCNEC). Highlighted are key areas of ethical focus, each with its own unique challenges: technical advances, readiness and risk, vulnerable populations, medico-legal issues, training, and research. Through an exploration of Canadian neurotechnological practice from these various clusters, we provide a critical review of progress, describe opportunities to address areas of debate, and seek to foster ethical innovation. Underpinning this comprehensive review are the fundamental principles of solution-oriented, practical neuroethics, with beneficence and justice at the core. In our view, it is a moral imperative that neurotechnological advancements include a delineation of ethical priorities for future guidelines, oversight, and interactions.

Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a > 50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures. Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

Purpose To develop a method of using two-dimensional (2D) magnetic resonance thermometry, and three-dimensional (3D) Gaussian modeling to predict the volume, shape, and location of 1 day postoperative T1w high-intensity focused ultrasound lesions in medication refractory tremor patients; thereby facilitating a better comprehension of thermal damage thresholds, which can be utilized to reduce adverse events, and improve patient outcome. Methods Fifteen patients underwent magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy, which was performed at our center using an InSightec ExAblate 4000 system (Haifa, Israel), and guided by magnetic resonance imaging using a 3 T Discovery 750 (General Electric Healthcare, Waukesha, WI, USA). For treatment monitoring, 2D MR thermometry (temperature sensitivity: -0.00909 ppm/°C, bandwidth: 279 Hz/pixel) was performed in multiple orthogonal planes (sagittal, coronal, and axial) intraoperatively. These images were temporally filtered using a general linear model approach to reduce noise. Temporal volumes of filtered temperature maps with a peak temperature ≥ 47°C were aligned and fitted with a 3D Gaussian to create a canonical heating model. We then fitted the filtered 2D temperature maps with a 3D Gaussian, and used the relationships derived from the 3D heating model to estimate the 3D temperature distribution. These temperature distributions were converted into thermal dose distributions and accumulated across time to create an accumulated thermal dose (ATD) profile. Thresholded ATD profiles were then correlated with manually traced T1-weighted 1 day postoperative lesion volumes across patients, and linear regression slopes were plotted against varying ATD thresholds. Additionally, the Dice-Sorensen coefficient (DSC) was calculated to quantify the volumetric overlap between predicted, and actual lesions. Results On average, 18.1 (standard deviation (SD): ±4.6, range: 10-29) sonications were performed with an average peak temperature achieved of 62.4°C (SD: ±2.4, range: 58.2-67.7). An ATD threshold of 35.8 CEM43 was found to give a unity linear regression slope; this corresponded to an average DSC of 0.689 (SD: ±0.090, range: 0.476-0.815). Conclusions Using multiplanar 2D MR thermometry and 3D Gaussian modeling, we were able to achieve very good (DSC = 0.689) predictions of T1w 1 day postoperative lesion volume, shape and location at an ATD threshold of approximately 36 CEM43. Furthermore, this method has the potential to be used in clinical evaluations to further elucidate the relationship between thermal damage and clinical outcome. Accurate 3D lesion prediction will facilitate improved clinical decision making in future MRgFUS thalamotomies.

Background Medically-refractory trigeminal neuralgia (TN) can be treated successfully with operative intervention, but a significant proportion of patients are non-responders despite undergoing technically successful surgery. The thalamus is a key component of the trigeminal sensory pathway involved in transmitting facial pain, but the role of the thalamus in TN, and its influence on durability of pain relief after TN surgery, are relatively understudied. We aimed to test the hypothesis that variations in thalamic structure and metabolism are related to surgical non-response in TN. Methods We performed a longitudinal, peri-operative neuroimaging study of the thalamus in medically-refractory TN patients undergoing microvascular decompression or percutaneous balloon compression rhizotomy. Patients underwent structural MRI and MR spectroscopy scans pre-operatively and at 1-week following surgery, and were classified as responders or non-responders based on 1-year post-operative pain outcome. Thalamus volume, shape, and metabolite concentration (choline/creatine [Cho/Cr] and N-acetylaspartate/creatine [NAA/Cr]) were evaluated at baseline and 1-week, and compared between responders, non-responders, and healthy controls. Results Twenty healthy controls and 23 patients with medically-refractory TN treated surgically (17 responders, 6 non-responders) were included. Pre-operatively, TN patients as a group showed significantly larger thalamus volume contralateral to the side of facial pain. However, vertex-wise shape analysis showed significant contralateral thalamus volume reduction in non-responders compared to responders in an axially-oriented band spanning the outer thalamic circumference (peak p = 0.019). Further, while pre-operative thalamic metabolite concentrations did not differ between responders and non-responders, as early as 1-week after surgery, long-term non-responders showed a distinct decrease in contralateral thalamic Cho/Cr and NAA/Cr, irrespective of surgery type, which was not observed in responders. Conclusions Atrophy of the contralateral thalamus is a consistent feature across patients with medically-refractory TN. Regional alterations in preoperative thalamic structure, and very early post-operative metabolic changes in the thalamus, both appear to influence the durability of pain relief after TN surgery.

We describe diffusion tensor imaging metrics of brain microstructure changes following magnetic resonance guided focused ultrasound (MRgFUS) ablation of the ventral intermediate nucleus of the thalamus for the treatment of tremor in order to explore the mechanisms of tremor reduction post-MRgFUS. Tractography was performed on pre-treatment images to identify the portion of the dentato-rubro-thalamo-cortical tract (DRTT) intersecting the MRgFUS thalamotomy lesions in 17 essential tremor patients. The resulting tract was divided into regions of interest (ROI), which were then analyzed on pre-, one day post-, and three months post-treatment scans. Fractional anisotropy (FA), and mean, axial, and radial diffusivity (MD, AD, and RD) were computed in each ROI at each time point. At both one day and three months post-treatment, we observed decreased FA and increased MD and RD in the section of the treated tract between the lesion and cortex. At three months post-treatment, we additionally observed increased AD in the section between the lesion and cortex, and decreased FA in the section between the dentate nucleus and the decussation of the superior cerebellar peduncles. Diffusion changes at one day post-treatment may reflect local, acute effects such as inflammation and edema, as opposed to chronic degenerative processes such as axonal degeneration and myelin loss that would be expected at later time points. No significant correlations were detected between diffusion measures and clinical effects, suggesting that microstructural changes in the treated portion of the DRTT alone do not fully explain tremor reduction and motivating additional research using higher spatial resolution diffusion imaging and multimodal approaches such as integrating diffusion and functional magnetic resonance imaging data. Our individualized approach, in which patient-specific lesions are incorporated into the tractography analysis, provided novel insight into both immediate and longer term MRgFUS-related microstructural brain changes.

This chapter explores the complex neuroethical aspects of neurosurgery and neuromodulation in the context of Canadian healthcare and innovation, as seen through the lens of the Pan Canadian Neurotechnology Ethics Consortium (PCNEC). Highlighted are key areas of ethical focus, each with its own unique challenges: technical advances, readiness and risk, vulnerable populations, medico-legal issues, training, and research. Through an exploration of Canadian neurotechnological practice from these various clusters, we provide a critical review of progress, describe opportunities to address areas of debate, and seek to foster ethical innovation. Underpinning this comprehensive review are the fundamental principles of solution-oriented, practical neuroethics, with beneficence and justice at the core. In our view, it is a moral imperative that neurotechnological advancements include a delineation of ethical priorities for future guidelines, oversight, and interactions.

ObjectiveAfter deep brain stimulation (DBS) for Parkinson disease (PD), patients often do not report the level of satisfaction anticipated. This misalignment can relate to patients' expectations for an invasive treatment and insufficient knowledge of DBS's effectiveness in relieving motor and nonmotor symptoms (NMS). Patient satisfaction depends on expectations and goals for treatment. We hypothesized that improving patient education with a patient-centered shared decision-making tool emphasizing autonomy would improve patient satisfaction and clinical outcome.MethodsWe developed a computer application (DBS-Edmonton app), allowing patients with PD to input their symptoms and to learn how effective DBS addresses their prioritized symptoms. Sixty-two volunteers referred for DBS used the DBS-Edmonton app. DBS-related knowledge and patient perceptions of the DBS-Edmonton app were assessed with pre- and post-use questionnaires. Fourteen of 24 patients who proceeded to DBS achieved optimization at 6 months. Perceived functional improvement was assessed and compared with 12 control patients with DBS who did not use the DBS-Edmonton app.ResultsAll 62 volunteers considered the DBS-Edmonton app helpful and would recommend it to others. There was improved knowledge about how NMS and axial symptoms respond to DBS. Postoperatively, there was no significant difference in symptoms improvement assessed by standard scales between the groups. Volunteers who used the DBS-Edmonton app had greater satisfaction (p = 0.014).ConclusionThis interventional study showed that the DBS-Edmonton app improved DBS-related knowledge and patient satisfaction, independent of the objective motor outcome. It may assist patients in deciding to proceed to DBS and can be easily incorporated into practice to improve patient satisfaction post-DBS.

Diffusion tensor imaging (DTI) can provide markers of axonal micro-structure of the trigeminal nerve (cranial nerve five [CNV]), which may be affected in trigeminal neuralgia (TN) and other disorders. Previous attempts to image CNV have used low spatial resolution DTI protocols designed for whole-brain acquisition that are susceptible to errors from partial volume effects, particularly with adjacent cerebrospinal fluid (CSF). The purpose of this study was to develop a nerve-specific DTI protocol in healthy subjects that provides more accurate CNV tractography and diffusion quantification than whole-brain protocols. Four DTI protocols were compared in five healthy individuals (age 22-45 years, three males) on a 3 T Siemens Prisma MRI scanner: two newly developed nerve-specific high resolution (1.2 x 1.2 x 1.2 = 1.7 mm3 ) DTI protocols without (3.5 minutes) and with CSF suppression (fluid-attenuated inversion recovery [FLAIR]; 7.5 minutes) with limited slice-coverage, and two typical whole-brain protocols with either isotropic (2 x 2 x 2 = 8 mm3 ) or thicker slice anisotropic (1.9 x 1.9 x 3 = 10.8 mm3 ) voxels. Deterministic tractography was used to identify the CNV and quantify bilateral fractional anisotropy (FA), and mean (MD), axial (AD) and radial diffusivity (RD). CNV volume was determined by manual tracing on T1-weighted images. High spatial resolution nerve-specific protocols yielded better delineation of CNV, with less distortions and blurring, and markedly different diffusion parameters (42% higher FA, 35% lower MD, 27% lower RD and 43% lower AD) compared with the two lower resolution whole-brain protocols. The anisotropic whole-brain protocol showed a positive correlation between CNV FA and volume. The high resolution nerve-specific protocol with FLAIR yielded additional reductions in CNV AD and MD with a value of 1.0 x 10-3 mm2 /s, approaching that expected for healthy young adult white matter. In conclusion, high resolution nerve-specific DTI with FLAIR enhances the identification of CNV and provides more accurate quantification of diffusion compared with lower resolution whole-brain approaches.

Modulation of a Hoffmann (H)-reflex following transcranial magnetic stimulation (TMS) has been used to assess the nature of signals transmitted from cortical centers to lower motor neurons. Further characterizing the recruitment and time-course of the TMS-induced effect onto the soleus H-reflex adds to the discussion of these pathways and may improve its utility in clinical studies. In 10 healthy controls, TMS was used to condition the soleus H-reflex using TMS intensities from 65 to 110% of the resting motor threshold (RMT). Early facilitation [− 5 to − 3 ms condition-test (C-T) interval] was evident when TMS was 110% of RMT (P

1) Characterize the evolution of microstructural changes in the contralateral, non-operated hippocampus-using longitudinal diffusion tensor imaging (DTI)-following surgery for temporal lobe epilepsy (TLE). 2) Characterize the downstream extra-hippocampal volumetric changes of the fornix and mammillary bodies after TLE surgery. 3) Examine the relationship between these measures and seizure/cognitive outcome.Serial structural and DTI brain MRI scans were collected in 25 TLE patients pre- and post-surgery (anterior temporal lobectomy, ATL - 13; selective amygdalohippocampectomy, SelAH - 12) and in 12 healthy controls. Contralateral hippocampal fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were computed with manual hippocampal tracings as volumes of interest following co-registration to anatomical images. Fornix and mammillary body volumetry was performed by manual segmentation.After surgery, the non-resected hippocampus showed significant postoperative decline in FA (p = 0.0001), with increase of MD (p = 0.01) and RD (p = 0.0001). In contrast to the timing of our previously reported volume changes where atrophy is observed in the first week, diffusion changes occurred late, taking 1-3 years to develop and are not significant at one week after surgery. Diffusion changes are accompanied by delayed limbic circuit volume loss in the mammillary bodies (35%; p 0.0001) and fornix (24%; p 0.0001) compared to baseline. There was no correlation between postoperative diffusion or structural changes and memory score nor did the degree of postoperative change in hippocampal DTI parameters, mammillary body volume or fornix volume vary significantly based on seizure outcome.Differences observed in the timing of postoperative volume (first week) and FA/MD (one year) changes would suggest that early contralateral hippocampal atrophy is not secondary to fluid shifts (dehydration) while the late DTI changes suggest ongoing microstructural changes extending beyond the early postoperative period. Postoperative hippocampal diffusion changes are accompanied by delayed mammillary body and fornix volume loss which did not differ when stratified by seizure outcome nor was correlated with degree of hippocampal diffusion change. Finally, we did not identify any significant correlation between postoperative diffusion parameter change and memory performance.

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

OBJECTIVEThe aim of this study was to evaluate the safety of 3-T MRI in patients with implanted deep brain stimulation (DBS) systems.METHODSThis study was performed in 2 phases. In an initial phantom study, a Lucite phantom filled with tissue-mimicking gel was assembled. The system was equipped with a single DBS electrode connected to an internal pulse generator. The tip of the electrode was coupled to a fiber optic thermometer with a temperature resolution of 0.1°C. Both anatomical (T1- and T2-weighted) and functional MRI sequences were tested. A temperature change within 2°C from baseline was considered safe. After findings from the phantom study suggested safety, 10 patients with implanted DBS systems targeting various brain areas provided informed consent and underwent 3-T MRI using the same imaging sequences. Detailed neurological evaluations and internal pulse generator interrogations were performed before and after imaging.RESULTSDuring phantom testing, the maximum temperature increase was registered using the T2-weighted sequence. The maximal temperature changes at the tip of the DBS electrode were < 1°C for all sequences tested. In all patients, adequate images were obtained with structural imaging, although a significant artifact from lead connectors interfered with functional imaging quality. No heating, warmth, or adverse neurological effects were observed.CONCLUSIONSTo the authors' knowledge, this was the first study to assess the clinical safety of 3-T MRI in patients with a fully implanted DBS system (electrodes, extensions, and pulse generator). It provided preliminary data that will allow further examination and assessment of the safety of 3-T imaging studies in patients with implanted DBS systems. The authors cannot advocate widespread use of this type of imaging in patients with DBS implants until more safety data are obtained.

Hippocampal atrophy rate-measured using automated techniques applied to structural MRI scans-is considered a sensitive marker of disease progression in Alzheimer's disease, frequently used as an outcome measure in clinical trials. Using publicly accessible data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined 1-year hippocampal atrophy rates generated by each of five automated or semiautomated hippocampal segmentation algorithms in patients with Alzheimer's disease, subjects with mild cognitive impairment, or elderly controls. We analyzed MRI data from 398 and 62 subjects available at baseline and at 1 year at MRI field strengths of 1.5 T and 3 T, respectively. We observed a high rate of hippocampal segmentation failures across all algorithms and diagnostic categories, with only 50.8% of subjects at 1.5 T and 58.1% of subjects at 3 T passing stringent segmentation quality control. We also found that all algorithms identified several subjects (between 2.94% and 48.68%) across all diagnostic categories showing increases in hippocampal volume over 1 year. For any given algorithm, hippocampal "growth" could not entirely be explained by excluding patients with flawed hippocampal segmentations, scan-rescan variability, or MRI field strength. Furthermore, different algorithms did not uniformly identify the same subjects as hippocampal "growers," and showed very poor concordance in estimates of magnitude of hippocampal volume change over time (intraclass correlation coefficient 0.319 at 1.5 T and 0.149 at 3 T). This precluded a meaningful analysis of whether hippocampal "growth" represents a true biological phenomenon. Taken together, our findings suggest that longitudinal hippocampal volume change should be interpreted with considerable caution as a biomarker. Hum Brain Mapp 38:2875-2896, 2017. © 2017 Wiley Periodicals, Inc.

OBJECTIVEDiffusion tensor imaging (DTI) tractography is commonly used in neurosurgical practice but is largely limited to the preoperative setting. This is due primarily to image degradation caused by susceptibility artifact when conventional single-shot (SS) echo-planar imaging (EPI) DTI (SS-DTI) is acquired for open cranial, surgical position intraoperative DTI (iDTI). Readout-segmented (RS) EPI DTI (RS-DTI) has been reported to reduce such artifact but has not yet been evaluated in the intraoperative MRI (iMRI) environment. The authors evaluated the performance of RS versus SS EPI for DTI of the human brain in the iMRI setting.METHODSPre- and intraoperative 3-T 3D T1-weighted and 2D multislice RS-iDTI (called RESOLVE [readout segmentation of long variable echo-trains] on the Siemens platform) and SS-iDTI images were acquired in 22 adult patients undergoing intraaxial iMRI resections for suspected low-grade glioma (14; 64%), high-grade glioma (7; 32%), or focal cortical dysplasia. Regional susceptibility artifact, anatomical deviation relative to T1-weighted imaging, and tractographic output for surgically relevant tracts were compared between iDTI sequences as well as the intraoperative tract shifts from preoperative DTI.RESULTSRS-iDTI resulted in qualitatively less regional susceptibility artifact (resection cavity, orbitofrontal and anterior temporal cortices) and mean anatomical deviation in regions most prone to susceptibility artifact (RS-iDTI 2.7 ± 0.2 vs SS-iDTI 7.5 ± 0.4 mm) compared to SS-iDTI. Although tract reconstruction success did not significantly differ by DTI method, susceptibility artifact–related tractography failure (of at least 1 surgically relevant tract) occurred for SS-iDTI in 8/22 (36%) patients, and in 5 of these 8 patients RS-iDTI permitted successful reconstruction. Among cases with successful tractography for both sequences, maximal intersequence differences were substantial (mean 9.5 ± 5.7 mm, range −27.1 to 18.7 mm).CONCLUSIONSRS EPI enables higher quality and more accurate DTI for surgically relevant tractography of major white matter tracts in intraoperative, open cranium neurosurgical applications at 3 T.

Background: The skull diploic venous space (DVS) represents a potential route for cerebrospinal fluid (CSF) diversion and absorption in the treatment of hydrocephalus. The goal of this study was to carry out a detailed characterization of the drainage pattern of the DVS of the skull using high-resolution MRI, especially the diploic veins draining to the lacunae laterales (LLs) since the LLs constitute an important channel for the CSF to access the superior sagittal sinus and subsequently the systemic circulation. The objective was to identify those skull regions optimally suited for an intraosseous CSF diversion system. Methods: High-resolution, T1-weighted MRI scans from 20 adult and 16 pediatric subjects were selected for analysis. Skulls were divided into four regions, that is, frontal, parietal, temporal, and occipital. On each scan, a trained observer counted all diploic veins in every skull region. Each diploic vein was also followed to determine its final drainage pathway (i.e., dural venous sinus, dural vein, LL, or indeterminate). Results: In the adult age group, the frontal and occipital skull regions showed the highest number of diploic veins. However, the highest number of draining diploic veins connecting to the lacunae lateralis was found in the frontal and parietal skull region, just anterior and just posterior to the coronal suture. In the pediatric age group, the parietal skull region, just posterior to the coronal suture, showed the highest overall number of diploic veins and also the highest number of draining diploic veins connecting to the LL. Conclusion: This study suggested that diploic venous density across the skull varies with age, with more parietal diploic veins in the pediatric age range, and more occipital and frontal diploic veins in adults. If the DVS is ultimately used for CSF diversion, our anatomical data point to optimal sites for the insertion of specially designed intraosseous infusion devices for the treatment of hydrocephalus. Likely the optimal sites for CSF diversion would be the parietal region just posterior to the coronal suture in children, and in adults, frontal and/or parietal just anterior or just posterior to the coronal suture.

Traumatic brain injury (TBI) is a major cause of infant morbidity and mortality. In these patients, magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) is the test of choice to describe the extent of microstructural injury. In this case series, we describe novel acute and chronic MRI findings in four infants (6–19 months) with small, unilateral subdural hematomas in whom the etiology of head injury was suspicious for non-accidental trauma (NAT). Acute (

Determine the extent and time course of volumetric changes in the contralateral hippocampus following surgery for medically refractory temporal lobe epilepsy (TLE).Serial T1-weighted MRI brain scans were obtained in 26 TLE patients pre- and post-temporal lobe epilepsy surgery as well as in 12 control subjects of similar age. Patients underwent either anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH). Blinded, manual hippocampal volumetry (head, body, and tail) was performed in two groups: 1) two scan group [ATL (n=6); SAH (n=10)], imaged pre-surgery and on average at 5.4 years post-surgery; and 2) longitudinal group [ATL (n=8); SAH (n=2)] imaged pre-surgery and on post-operative day 1, 2, 3, 6, 60, 120 and a delayed time point (average 2.4 years).In the two scan group, there was atrophy by 12% of the unresected contralateral hippocampus (p0.001), with atrophy being most pronounced (27%) in the hippocampal body (p0.001) with no significant differences seen for the hippocampal head or tail. In the longitudinal group, significant atrophy was also observed for the whole hippocampus and the body with atrophy seen as early as post-operative day #1 which progressed significantly over the first post-operative week (1.3%/day and 3.0%./day, respectively) before stabilizing over the long-term to a 13% reduction in total volume. There was no significant difference in atrophy compared by surgical approach (ATL vs. SAH; p=0.94) or side (p=0.31); however, atrophy was significantly more pronounced in patients with ongoing post-operative seizures (hippocampal body, p=0.019; whole hippocampus, p=0.048). There were no detectable post-operative neuropsychological deficits attributable to contralateral hippocampal atrophy.Significant contralateral hippocampal atrophy occurs following TLE surgery, which begins immediately and progresses over the first post-operative week. The observation that seizure free patients had significantly less atrophy of the contralateral hippocampus after surgery suggests the possibility of an early post-operative imaging marker to predict surgical outcome.

During the “DBS Canada Day” symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson’s disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.

Supplemental material, CEP877659 Supplemetal Material for Hippocampal and trigeminal nerve volume predict outcome of surgical treatment for trigeminal neuralgia by Hayden Danyluk, Esther Kyungsu Lee, Scott Wong, Samiha Sajida, Robert Broad, Matt Wheatley, Cameron Elliott and Tejas Sankar in Cephalalgia

Background Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS. Methods Here we applied 6 h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5 days. We investigated the “micro-lesion” effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry. Results The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size. Conclusions Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy.

Background Deep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological disorders by modulating activity within dysfunctional brain circuits. To date, there is no evidence that DBS counteracts progressive neurodegeneration in any particular disorder. Objective/Hypothesis We hypothesized that DBS applied to the fornix in patients with Alzheimer's Disease (AD) could have an effect on brain structure. Methods In six AD patients receiving fornix DBS, we used structural MRI to assess one-year change in hippocampal, fornix, and mammillary body volume. We also used deformation-based morphometry to identify whole-brain structural changes. We correlated volumetric changes to hippocampal glucose metabolism. We also compared volumetric changes to those in an age-, sex-, and severity-matched group of AD patients ( n = 25) not receiving DBS. Results We observed bilateral hippocampal volume increases in the two patients with the best clinical response to fornix DBS. In one patient, hippocampal volume was preserved three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower in the DBS group compared to the matched AD group, and no matched AD patients demonstrated bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based morphometry in DBS patients revealed local volume expansions in several regions typically atrophied in AD. Conclusion We present the first in-human evidence that, in addition to modulating neural circuit activity, DBS may influence the natural course of brain atrophy in a neurodegenerative disease.

Background Currently, the literature lacks reliable data regarding operative case volumes at Canadian neurosurgery residency programs. Our objective was to provide a snapshot of the operative landscape in Canadian neurosurgical training using the trainee-led Canadian Neurosurgery Research Collaborative. Methods: Anonymized administrative operative data were gathered from each neurosurgery residency program from January 1, 2014, to December 31, 2014. Procedures were broadly classified into cranial, spine, peripheral nerve, and miscellaneous procedures. A number of prespecified subspecialty procedures were recorded. We defined the resident case index as the ratio of the total number of operations to the total number of neurosurgery residents in that program. Resident number included both Canadian medical and international medical graduates, and included residents on the neurosurgery service, off-service, or on leave for research or other personal reasons. Results: Overall, there was an average of 1845 operative cases per neurosurgery residency program. The mean numbers of cranial, spine, peripheral nerve, and miscellaneous procedures were 725, 466, 48, and 193, respectively. The nationwide mean resident case indices for cranial, spine, peripheral nerve, and total procedures were 90, 58, 5, and 196, respectively. There was some variation in the resident case indices for specific subspecialty procedures, with some training programs not performing carotid endarterectomy or endoscopic transsphenoidal procedures. Conclusions: This study presents the breadth of neurosurgical training within Canadian neurosurgery residency programs. These results may help inform the implementation of neurosurgery training as the Royal College of Physicians and Surgeons residency training transitions to a competence-by-design curriculum.

Ventromedial prefrontal cortex (vmPFC) forms a core region of larger brain circuits that assign value to sensory inputs and interfaces motivational and cognitive dominated brain processes. This network function of the vmPFC could be realized by synchronizing local activity at time scales that are shared by connected brain areas, but it is unknown whether vmPFC circuitry engages in functionally specific synchronization. Here, we recorded in human subcallosal vmPFC while subjects engaged in an emotion tracking task that required the assignment of positive or negative affective value to ambiguous (happy-sad) facial expressions. We found that vmPFC engages in low beta-band (15-20 Hz) coherent activation just before subjects subjectively judged ambiguous facial expressions as conveying negative valence ('sad') information, but not before positive valence ('happy') judgments. The predictive beta coherence emerged particularly for conflicting rather than pure emotional facial cues and dissipated slowly after the choice was made. These results suggest that 15-20 Hz coherent activity within vmPFC marks a functional signature of a valuation process that informs categorical affective choices. We hypothesize that coherent beta band activation signifies functional interactions to anatomical vmPFC projection targets, raising the possibility that dysfunctional biases in affective valuation and an enhanced decision conflict in clinical depression could be indexed by alterations of beta coherent network activation.

Deep brain stimulation (DBS) is now widely used in the treatment of Parkinson's disease, tremor, and dystonia. This review examines recent developments in the application of DBS to the management of movement disorders.In Parkinson's disease, recent work has demonstrated that early DBS may have a significant benefit on quality of life and motor symptoms while permitting a decrease in levodopa equivalent dosage. Thalamic DBS continues to be a well established target for the treatment of tremor, although recent work suggests that alternative targets such as the posterior subthalamic area may be similarly efficacious. The treatment of primary dystonia with DBS has been established in multiple recent trials, demonstrating prolonged symptomatic benefit.DBS is now an established symptomatic treatment modality for Parkinson's disease and other movement disorders. Future work will undoubtedly involve establishing new indications and targets in the treatment of movement disorders with further refinements to existing technology. Ultimately, these methods combined with biologically based therapies may catalyze a shift from symptomatic treatment to actually modifying the natural history of neurodegenerative diseases such as Parkinson's disease.

Objective To evaluate the safety of repetitive transcranial magnetic stimulation (rTMS) in patients with implanted subdural cortical electrodes. Methods We performed ex-vivo experiments to test the temperature, displacement and current induced in the electrodes with single pulse transcranial magnetic stimulation (TMS) from 10 to 100% of stimulator output and tested a typical rTMS protocol used in a clinical setting. We then used rTMS to the motor cortex to treat a patient with refractory post-herpetic neuralgia who had previously been implanted with a subdural motor cortical electrode for pain management. The rTMS protocol consisted of ten sessions of 2000 stimuli at 20 Hz and 90% of resting motor threshold. Results The ex-vivo study showed an increase in the coil temperature of 2 °C, a maximum induced charge density of 30.4 μC/cm2/phase, and no electrode displacement with TMS. There was no serious adverse effect associated with rTMS treatment of the patient. Cortical tremor was observed in the intervals between trains of stimuli during one treatment session. Conclusions TMS was safe in a patient with implanted Medtronic Resume II electrode (model 3587A) subdural cortical electrode. Significance TMS may be used as a therapeutic, diagnostic or research tool in patients this type of with implanted cortical electrodes.

Classical neurosurgical teaching suggests that corticosteroid administration reduces the diagnostic yield of stereotactic brain biopsy for primary central nervous system lymphoma (PCNSL). In a single-center series spanning 6 years, we reviewed 155 consecutive biopsy patients, 135 treated with prebiopsy corticosteroids. PCNSL was correctly diagnosed on initial biopsy in 15 of 16 steroid-treated patients; in the single nondiagnostic specimen, polymerase chain reaction reanalysis by an outside institution showed evidence of lymphoproliferative disease consistent with PCNSL. Our data challenge the notion that it is necessary to withhold corticosteroid therapy for cerebral edema in patients awaiting stereotactic biopsy for suspected PCNSL.

UNLABELLED Deep brain stimulation (DBS) for psychiatric disorders needs to be investigated in proper research trials. However, there are rare circumstances in which DBS could be offered to psychiatric patients as a form of surgical innovation, therefore potentially blurring the lines between these research trials and health care. In this article, we discuss the conditions under which surgical innovation may be accepted as a practice falling at the frontiers of standard clinical care and research per se. However, recognizing this distinction does not settle all ethical issues. Our article offers ethical guideposts to allow clinicians, surgical teams, institutions, and institutional review boards to deliberate about some of the fundamental issues that should be considered before surgical innovation with psychiatric DBS is undertaken. We provide key guiding questions to sustain this deliberation. Then we review the normative and empirical literature that exists to guide reflection about the ethics of surgical innovation and psychiatric DBS with respect to general ethical questions pertinent to psychiatric DBS, multidisciplinary team perspectives in psychiatric DBS, mechanisms for oversight in psychiatric DBS, and capacity and consent in psychiatric DBS. The considerations presented here are to recognize the very specific nature of surgical innovation and to ensure that surgical innovation in the context of psychiatric DBS remains a limited, special category of activity that does not replace appropriate surgical research or become the standard of care based on limited evidence. ABBREVIATIONS DBS, deep brain stimulationIRB, institutional review boardOCD, obsessive-compulsive disorder.