Publications by authors named "Andres M Lozano"

486 Publications

Implantable Pulse Generators for Deep Brain Stimulation: Challenges, Complications, and Strategies for Practicality and Longevity.

Front Hum Neurosci 2021 26;15:708481. Epub 2021 Aug 26.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Deep brain stimulation (DBS) represents an important treatment modality for movement disorders and other circuitopathies. Despite their miniaturization and increasing sophistication, DBS systems share a common set of components of which the implantable pulse generator (IPG) is the core power supply and programmable element. Here we provide an overview of key hardware and software specifications of commercially available IPG systems such as rechargeability, MRI compatibility, electrode configuration, pulse delivery, IPG case architecture, and local field potential sensing. We present evidence-based approaches to mitigate hardware complications, of which infection represents the most important factor. Strategies correlating positively with decreased complications include antibiotic impregnation and co-administration and other surgical considerations during IPG implantation such as the use of tack-up sutures and smaller profile devices.Strategies aimed at maximizing battery longevity include patient-related elements such as reliability of IPG recharging or consistency of nightly device shutoff, and device-specific such as parameter delivery, choice of lead configuration, implantation location, and careful selection of electrode materials to minimize impedance mismatch. Finally, experimental DBS systems such as ultrasound, magnetoelectric nanoparticles, and near-infrared that use extracorporeal powered neuromodulation strategies are described as potential future directions for minimally invasive treatment.
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http://dx.doi.org/10.3389/fnhum.2021.708481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427803PMC
August 2021

Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.

Neuroimage 2021 Sep 4;243:118557. Epub 2021 Sep 4.

Krembil Research Institute, University Health Network, Toronto, ON, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique that can modulate the excitability of cortical and deep brain structures with a high degree of focality. Previous human studies showed that TUS decreases motor cortex (M1) excitability measured by transcranial magnetic stimulation (TMS), but whether the effects appear beyond sonication and whether TUS affects the excitability of other interconnected cortical areas is not known. The time course of M1 TUS on ipsilateral and contralateral M1 excitability was investigated in 22 healthy human subjects via TMS-induced motor-evoked potentials. With sonication duration of 500 ms, we found suppression of M1 excitability from 10 ms before to 20 ms after the end of sonication, and the effects were stronger with blocked design compared to interleaved design. There was no significant effect on contralateral M1 excitability. Using ex-vivo measurements, we showed that the ultrasound transducer did not affect the magnitude or time course of the TMS-induced electromagnetic field. We conclude that the online-suppressive effects of TUS on ipsilateral M1 cortical excitability slightly outlast the sonication but did not produce long-lasting effects. The absence of contralateral effects may suggest that there are little tonic interhemispheric interactions in the resting state, or the intensity of TUS was too low to induce transcallosal inhibition.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118557DOI Listing
September 2021

Focused Ultrasound Thalamotomy Sensory Side Effects Follow the Thalamic Structural Homunculus.

Neurol Clin Pract 2021 Aug;11(4):e497-e503

University Health Network (MP, AB, JG, GJBE, CTC, AL, WK, AML), Toronto; Joint Department of Medical Imaging (AB, WK), University of Toronto; Edmond J. Safra Program in Parkinson's Disease (AF), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, and Division of Neurology (AF), University of Toronto; Krembil Brain Institute (AF); Division of Neurosurgery (MLS), Sunnybrook Health Sciences Center, University of Toronto; and Division of Neurosurgery (AML), Department of Surgery, Toronto Western Hospital and University of Toronto, Ontario, Canada.

Objective: Focused ultrasound thalamotomy is an effective treatment for tremor; however, side effects may occur. The purpose of the present study was to investigate the spatial relationship between thalamotomies and specific sensory side effects and their functional connectivity with somatosensory cortex and relationship to the medial lemniscus (ML).

Methods: Sensory adverse effects were categorized into 4 groups based on the location of the disturbance: face/mouth/tongue numbness/paresthesia, hand-only paresthesia, hemibody/limb paresthesia, and dysgeusia. Then, areas of significant risk (ASRs) for each category were defined using voxel-wise mass univariate analysis and overlaid on corresponding odds ratio maps. The ASR associated with the maximum risk was used as a region of interest in a normative functional connectome to determine side effect-specific functional connectivity. Finally, each ASR was overlaid on the ML derived from normative template.

Results: Of 103 patients, 17 developed sensory side effects after thalamotomy persisting 3 months after the procedures. Lesions producing sensory side effects extended posteriorly into the principle sensory nucleus of the thalamus or below the thalamus in the ML. The topography of sensory adverse effects followed the known somatotopy of the ML and the sensory nucleus. Functional connectivity patterns between each sensory-specific thalamic seed and the primary somatosensory areas supported the role of the middle insula in processing of gustatory information and in multisensory integration.

Conclusions: Distinct regions in the sensory thalamus and its afferent connections rise to specific sensory disturbances. These findings demonstrate the relationship between the sensory thalamus, ML, and bilateral sensory cortical areas.
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http://dx.doi.org/10.1212/CPJ.0000000000001013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382439PMC
August 2021

Deep Brain Stimulation of the Habenula: Systematic Review of the Literature and Clinical Trial Registries.

Front Psychiatry 2021 17;12:730931. Epub 2021 Aug 17.

Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, Canada.

The habenula is a small bilateral epithalamic structure that plays a key role in the regulation of the main monoaminergic systems. It is implicated in many aspects of behavior such as reward processing, motivational behavior, behavioral adaptation, and sensory integration. A role of the habenula has been indicated in the pathophysiology of a number of neuropsychiatric disorders such as depression, addiction, obsessive-compulsive disorder, and bipolar disorder. Neuromodulation of the habenula using deep brain stimulation (DBS) as potential treatment has been proposed and a first successful case of habenula DBS was reported a decade ago. To provide an overview of the current state of habenula DBS in human subjects for the treatment of neuropsychiatric disorders we conducted a systematic review of both the published literature using PUBMED and current and past registered clinical trials using ClinicalTrials.gov as well as the International Clinical Trials Registry Platform. Using PRISMA guidelines five articles and five registered clinical trials were identified. The published articles detailed the results of habenula DBS for the treatment of schizophrenia, depression, obsessive-compulsive disorder, and bipolar disorder. Four are single case studies; one reports findings in two patients and positive clinical outcome is described in five of the six patients. Of the five registered clinical trials identified, four investigate habenula DBS for the treatment of depression and one for obsessive-compulsive disorder. One trial is listed as terminated, one is recruiting, two are not yet recruiting and the status of the fifth is unknown. The planned enrollment varies between 2 to 13 subjects and four of the five are open label trials. While the published studies suggest a potential role of habenula DBS for a number of indications, future trials and studies are necessary. The outcomes of the ongoing clinical trials will provide further valuable insights. Establishing habenula DBS, however, will depend on successful randomized clinical trials to confirm application and clinical benefit of this promising intervention.
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http://dx.doi.org/10.3389/fpsyt.2021.730931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415908PMC
August 2021

Neuromodulatory treatments for psychiatric disease: A comprehensive survey of the clinical trial landscape.

Brain Stimul 2021 Aug 27;14(5):1393-1403. Epub 2021 Aug 27.

Krembil Research Institute, University of Toronto, Toronto, Canada; Department of Psychiatry, University Health Network & University of Toronto, Toronto, Canada; Centre for Depression & Suicide Studies, St. Michael's Hospital & University of Toronto, Toronto, Canada. Electronic address:

Background: Numerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions.

Objective/hypothesis: We sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field.

Methods: ClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source.

Results: From 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased.

Conclusion(s): These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field.
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http://dx.doi.org/10.1016/j.brs.2021.08.021DOI Listing
August 2021

Neurophysiological responses of globus pallidus internus during the auditory oddball task in Parkinson's disease.

Neurobiol Dis 2021 Aug 27;159:105490. Epub 2021 Aug 27.

Department of Physiology, University of Toronto, Canada; Department of Surgery, University of Toronto, Canada; Division of Neurosurgery, Toronto Western Hospital - University Health Network, Canada; Krembil Research Institute, Toronto, Canada. Electronic address:

Parkinson's disease can be associated with significant cognitive impairment that may lead to dementia. Deep brain stimulation (DBS) of the subthalamic nucleus is an effective therapy for motor symptoms but is associated with cognitive decline. DBS of globus pallidus internus (GPi) poses less risk of cognitive decline so may be the preferred target. A research priority is to identify biomarkers of cognitive decline in this population, but efforts are hampered by a lack of understanding of the role of the different basal ganglia nuclei, such as the globus pallidus, in cognitive processing. During deep brain stimulation (DBS) surgery, we monitored single units, beta oscillatory LFP activity as well as event related potentials (ERPs) from the globus pallidus internus (GPi) of 16 Parkinson's disease patients, while they performed an auditory attention task. We used an auditory oddball task, during which one standard tone is presented at regular intervals and a second deviant tone is presented with a low probability that the subject is requested to count and report at the end of the task. All forms of neuronal activity studied were selective modulated by the attended tones. Of 62 neurons studied, the majority (51 or 82%) responded selectively to the deviant tone. Beta oscillatory activity showed an overall desynchronization during both types of attended tones interspersed by bursts of beta activity giving rise to peaks at a latency of around 200 ms after tone onset. cognitive ERPs recorded in GPi were selective to the attended tone and the right-side cERP was larger than the left side. The averages of trials showing a difference in beta oscillatory activity between deviant and standard also had a significant difference in cERP amplitude. In one block of trials, the random occurrence of 3 deviant tones in short succession silenced the activity of the GPi neuron being recorded. Trial blocks where a clear difference in LFP beta was seen were twice as likely to yield a correct tone count (25 vs 11). The data demonstrate strong modulation of GPi neuronal activity during the auditory oddball task. Overall, this study demonstrates an involvement of GPi in processing of non-motor cognitive tasks such as working memory and attention, and suggests that direct effects of DBS in non-motor GPi may contribute to cognitive changes observed post-operatively.
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http://dx.doi.org/10.1016/j.nbd.2021.105490DOI Listing
August 2021

Local Field Potential-Based Programming: A Proof-of-Concept Pilot Study.

Neuromodulation 2021 Aug 18. Epub 2021 Aug 18.

Krembil Brain Institute, University Health Network, Toronto, ON, Canada.

Objectives: Programming deep brain stimulation (DBS) is still based on a trial-and-error approach, often becoming a time-consuming process for both treating physicians and patients. Several strategies have been proposed to streamline DBS programming, most of which are preliminary and mainly address Parkinson's disease, a condition readily responsive to DBS adjustments. In the present proof-of-principle pilot study, we successfully demonstrate that local field potentials (LFP)-based programming can be an effective approach when used for DBS indications that have a delayed temporal onset of benefit.

Materials And Methods: A recently commercialized implantable pulse generator (IPG) with the capability to non-invasively and chronically stream live and/or record LFPs from DBS electrode after implantation was used to program one pediatric patient with generalized dystonia and an adult with seizures refractory to multiple medications and vagal nerve stimulation.

Results: The IPG survey function detected a peak in the delta range (1.95 Hz) in the left globus pallidus of first patient. This LFP was detected when recording in the brain area adjacent to contacts 9 and 10 and absent when recording from other areas. The chronic recording of the 1.95 Hz LFP with two sets of stimulation showed a greater power increase with the settings associated with a worsening of dystonia. Broadband LFP home recording of "absence seizure" and "focal/partial seizure" was used in the second patient and reviewer with the IPG "timeline" and "event" functions. The chronic recording of the 2.93 Hz and 8.79 Hz (spit sensing) showed a reduced power with the stimulation setting associated with seizure control.

Conclusions: The approach presented in this pilot proof-of-concept study may inform and streamline the DBS programming for conditions requiring clinicians and patients to wait weeks before appreciating any clinical benefit. Prospective studies on larger samples of patients are warranted.
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http://dx.doi.org/10.1111/ner.13520DOI Listing
August 2021

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

Stereotact Funct Neurosurg 2021 Aug 11:1-12. Epub 2021 Aug 11.

Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, Ontario, Canada.

Background: Chronic pain is a debilitating condition that imposes a tremendous burden on health-care systems around the world. While frontline treatments for chronic pain involve pharmacological and psychological approaches, neuromodulation can be considered for treatment-resistant cases. Neuromodulatory approaches for pain are diverse in both modality and target and their mechanism of action is incompletely understood.

Objectives: The objectives of this study were to (i) understand the current landscape of pain neuromodulation research through a comprehensive survey of past and current registered clinical trials (ii) investigate the network underpinnings of these neuromodulatory treatments by performing a connectomic mapping analysis of cortical and subcortical brain targets that have been stimulated for pain relief.

Methods: A search for clinical trials involving pain neuromodulation was conducted using 2 major trial databases (ClinicalTrials.gov and the International Clinical Trials Registry Platform). Trials were categorized by variables and analyzed to gain an overview of the contemporary research landscape. Additionally, a connectomic mapping analysis was performed to investigate the network connectivity patterns of analgesic brain stimulation targets using a normative connectome based on a functional magnetic resonance imaging dataset.

Results: In total, 487 relevant clinical trials were identified. Noninvasive cortical stimulation and spinal cord stimulation trials represented 49.3 and 43.7% of this count, respectively, while deep brain stimulation trials accounted for <3%. The mapping analysis revealed that superficial target connectomics overlapped with deep target connectomics, suggesting a common pain network across the targets.

Conclusions: Research for pain neuromodulation is a rapidly growing field. Our connectomic network analysis reinforced existing knowledge of the pain matrix, identifying both well-described hubs and more obscure structures. Further studies are needed to decode the circuits underlying pain relief and determine the most effective targets for neuromodulatory treatment.
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http://dx.doi.org/10.1159/000517873DOI Listing
August 2021

Clinical perspectives of adaptive deep brain stimulation.

Brain Stimul 2021 Aug 8;14(5):1238-1247. Epub 2021 Aug 8.

Aldo Ravelli Research Center for Neurotechnology and Experimental Neurotherapeutics, Department of Health Sciences, University of Milan, Via Antonio di Rudinì, 8, 20142, Milan, Italy; ASST Santi Paolo e Carlo, Milan, Italy. Electronic address:

Background: The application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients' changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models.

Objective: To review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors.

Findings: while aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging.

Conclusions: While aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising.
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http://dx.doi.org/10.1016/j.brs.2021.07.063DOI Listing
August 2021

Programming Directional Deep Brain Stimulation in Parkinson's Disease: A Randomized Prospective Trial Comparing Early versus Delayed Stimulation Steering.

Stereotact Funct Neurosurg 2021 Jun 29:1-7. Epub 2021 Jun 29.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, UHN, Toronto, Ontario, Canada.

Introduction: Programming directional leads poses new challenges as the optimal strategy is yet to be established. We designed a randomized control study to establish an evidence-based programming algorithm for patients with Parkinson's disease undergoing subthalamic nucleus deep brain stimulation with directional leads.

Methods: Fourteen consecutive patients were randomized to programming with either early or delayed (i.e., starting with a "ring mode") steered stimulation. Motor scores, number of programming visits, calls to the clinic, battery consumption, and stimulation adjustments required were recorded and compared between groups, using the Wilcoxon signed-ranks test, after 3 months of open-label programming.

Results: Thirteen patients (25 electrodes) were included, of which 23 were steerable. Nine out of 14 electrodes allocated to delayed steered stimulation were changed to steered mode due to side effects during the course of the study. No patients (11 electrodes) initially allocated to early steered stimulation were converted to ring mode. The 2 study arms did not differ in any of the considered measures at 3 months.

Conclusion: Programming with early or delayed steered stimulation is equally effective in the short term. However, delayed steering is less time consuming and is not always needed.
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http://dx.doi.org/10.1159/000517054DOI Listing
June 2021

Structuro-functional surrogates of response to subcallosal cingulate deep brain stimulation for depression.

Brain 2021 Jul 29. Epub 2021 Jul 29.

Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, M5T 2S8, Canada.

Subcallosal cingulate deep brain stimulation (SCC-DBS) produces long-term clinical improvement in approximately half of patients with severe treatment-resistant depression (TRD). We hypothesized that both structural and functional brain attributes may be important in determining responsiveness to this therapy. In a TRD SCC-DBS cohort, we retrospectively examined baseline and longitudinal differences in MRI-derived brain volume (n = 65) and 18F-fluorodeoxyglucose-PET glucose metabolism (n = 21) between responders and non-responders. Support-vector machines (SVMs) were subsequently trained to classify patients' response status based on extracted baseline imaging features. A machine learning model incorporating pre-operative frontopolar, precentral/frontal opercular, and orbitofrontal local volume values classified binary response status (12 months) with 83% accuracy (leave-one-out cross-validation (LOOCV): 80% accuracy) and explained 32% of the variance in continuous clinical improvement. It was also predictive in an out-of-sample SCC-DBS cohort (n = 21) with differing primary indications (bipolar disorder/anorexia nervosa) (76% accuracy). Adding pre-operative glucose metabolism information from rostral anterior cingulate cortex and temporal pole improved model performance, enabling it to predict response status in the TRD cohort with 86% accuracy (LOOCV: 81% accuracy) and explain 67% of clinical variance. Response-related patterns of metabolic and structural post-DBS change were also observed, especially in anterior cingulate cortex and neighbouring white matter. Areas where responders differed from non-responders - both at baseline and longitudinally - largely overlapped with depression-implicated white matter tracts, namely uncinate fasciculus, cingulum bundle, and forceps minor/rostrum of corpus callosum. The extent of patient-specific engagement of these same tracts (according to electrode location and stimulation parameters) also served as a predictor of TRD response status (72% accuracy; LOOCV: 70% accuracy) and augmented performance of the volume-based (88% accuracy; LOOCV: 82% accuracy) and combined volume/metabolism-based SVMs (100% accuracy; LOOCV: 94% accuracy). Taken together, these results indicate that responders and non-responders to SCC-DBS exhibit differences in brain volume and metabolism, both pre- and post-surgery. Baseline imaging features moreover predict response to treatment (particularly when combined with information about local tract engagement) and could inform future patient selection and other clinical decisions.
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http://dx.doi.org/10.1093/brain/awab284DOI Listing
July 2021

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

Mov Disord 2021 Jul 20. Epub 2021 Jul 20.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Background: In patients with medically refractory essential tremor, unilateral magnetic resonance-guided focused ultrasound thalamotomy can improve contralateral tremor. However, this procedure does not address ipsilateral symptoms.

Objective: The objective of the current study was to determine whether bilateral thalamotomies can be performed with an acceptable safety profile where benefits outweigh adverse effects.

Methods: We conducted a prospective, single-arm, single-blinded phase 2 trial of second-side magnetic resonance-guided focused ultrasound thalamotomy in patients with essential tremor. Patients were followed for 3 months. The primary outcome was the change in quality of life relative to baseline, as well as the answer to the question "Given what you know now, would you treat the second side again?". Secondary outcomes included tremor, gait, speech, and adverse effects.

Results: Ten patients were analyzed. The study met both primary outcomes, with the intervention resulting in clinically significant improvement in quality of life at 3 months (mean Quality of Life in Essential Tremor score difference, 19.7; 95%CI, 8.0-31.4; P = 0.004) and all patients reporting that they would elect to receive the second-side treatment again. Tremor significantly improved in all patients. Seven experienced mild adverse effects, including 2 with transient gait impairment and a fall, 1 with dysarthria and dysphagia, and 1 with mild dysphagia persisting at 3 months.

Conclusions: Staged bilateral magnetic resonance-guided focused ultrasound thalamotomy can be performed with a reasonable safety profile similar to that seen with unilateral thalamotomy and improves the tremor and quality of life of patients with essential tremor. Longer-term follow-up and continued accrual in the phase 3 trial will be required to validate these findings. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28716DOI Listing
July 2021

Flexible vs. standard subthalamic stimulation in Parkinson disease: A double-blind proof-of-concept cross-over trial.

Parkinsonism Relat Disord 2021 Aug 8;89:93-97. Epub 2021 Jul 8.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, UHN, Toronto, Canada; Krembil Brain Institute, Toronto, Canada; The Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada. Electronic address:

Background: Deep brain stimulation (DBS) of the subthalamus (STN) is effective for the treatment of cardinal motor signs of Parkinson disease (PD). Structures around the STN can suppress dyskinesia and tremor (zona incerta) and improve gait and balance (substantia nigra pars reticulata).

Objective: Is the newer 8-contact linear lead connected to a 'flexible' DBS system superior to standard 4-contact stimulation in PD patients receiving STN DBS?

Methods: After 3 months of open label programming, 10 patients were randomized to standard or flexible stimulation before crossing over to the other arm (3 months each period). Patients and assessors were blinded.

Results: A trend to improvement in Patient Global Impression of Change scores was seen with standard to flexible stimulation and worsening from flexible to standard stimulation (mean ± SD: 0.7 ± 1.2 and -0.4 ± 1.5 respectively, p = 0.152). There was a significant reduction in the number of troublesome symptoms reported prior to DBS (2.6 ± 3.3 per patient), more so with flexible stimulation (0.4 ± 0.6 vs. 1.5 ± 1.6 with standard stimulation, p = 0.001 and p = 0.034). There was no significant difference between the flexible and standard stimulation groups.

Conclusion: Further studies confirming that flexible stimulation is superior to standard DBS are warranted.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.003DOI Listing
August 2021

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

Epilepsy Behav 2021 09 18;122:108153. Epub 2021 Jun 18.

Division of Neurosurgery, University Health Network Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada; KrembilResearch Institute, Toronto, Ontario, Canada. Electronic address:

Objective: Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) has shown promise as a treatment for medically refractory epilepsy. To better understand the mechanism of this intervention, we used functional magnetic resonance imaging (fMRI) to map the acute blood oxygen level-dependent (BOLD) response pattern to thalamic DBS in fully implanted patients with epilepsy.

Methods: Two patients with epilepsy implanted with bilateral ANT-DBS devices underwent four fMRI acquisitions each, during which active left-sided monopolar stimulation was delivered in a 30-s DBS-ON/OFF cycling paradigm. Each fMRI acquisition featured left-sided stimulation of a different electrode contact to vary the locus of stimulation within the thalamus and to map the brain regions modulated as a function of different contact selection. To determine the extent of peri-electrode stimulation and the engagement of local structures during each fMRI acquisition, volume of tissue activated (VTA) modeling was also performed.

Results: Marked changes in the pattern of BOLD response were produced with thalamic stimulation, which varied with the locus of the active contact in each patient. BOLD response patterns to stimulation that directly engaged at least 5% of the anterior nuclear group by volume were characterized by changes in the bilateral putamen, thalamus, and posterior cingulate cortex, ipsilateral middle cingulate cortex and precuneus, and contralateral medial prefrontal and anterior cingulate.

Significance: The differential BOLD response patterns associated with varying thalamic DBS parameters provide mechanistic insights and highlight the possibilities of fMRI biomarkers of optimizing stimulation in patients with epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2021.108153DOI Listing
September 2021

Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease.

J Alzheimers Dis 2021 ;82(3):1243-1257

Memory and Alzheimer's Treatment Center & Alzheimer's Disease Research Center, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Age may affect treatment outcome in trials of mild probable Alzheimer's disease (AD).

Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD.

Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation ("on") or sham DBS-f ("off") for 12 months.

Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the "on" and "off" groups in the intent to treat (ITT) population. There was a significant age by time interaction with the Alzheimer's Disease Assessment Scale; ADAS-cog-13 (p = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p = 0.005). While not significant, post-hoc analyses favored DBS-f "off" versus "on" over 12 months in the < 65 age group but favored DBS-f "on" versus "off" in the≥65 age group on all clinical metrics. On the integrated Alzheimer's Disease rating scale (iADRS), the effect size contrasting DBS-f "on" versus "off" changed from +0.2 (favoring "off") in the < 65 group to -0.52 (favoring "on") in the≥65 age group.

Conclusion: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials.
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http://dx.doi.org/10.3233/JAD-210530DOI Listing
September 2021

Potential optimization of focused ultrasound capsulotomy for obsessive compulsive disorder.

Brain 2021 Jun 18. Epub 2021 Jun 18.

Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, Canada.

Obsessive-compulsive disorder is a debilitating and often refractory psychiatric disorder. Magnetic resonance-guided focused ultrasound is a novel, minimally invasive neuromodulatory technique that has shown promise in treating this condition. We investigated the relationship between lesion location and long-term outcome in obsessive-compulsive disorder patients treated with focused ultrasound to discern the optimal lesion location and elucidate the efficacious network underlying symptom alleviation. Postoperative images of eleven patients who underwent focused ultrasound capsulotomy were used to correlate lesion characteristics with symptom improvement at one year follow-up. Normative resting-state functional MRI and normative diffusion MRI-based tractography analyses were used to determine the networks associated with successful lesions. Obsessive-compulsive disorder patients treated with inferior thalamic peduncle deep brain stimulation (n = 5) and lesions from the literature implicated in obsessive-compulsive disorder (n = 18) were used for external validation. Successful long-term relief of obsessive-compulsive disorder was associated with lesions that included a specific area in the dorsal anterior limb of the internal capsule. Normative resting-state functional MRI analysis showed that lesion engagement of areas 24 and 46 was significantly associated with clinical outcomes (R = 0.79, p = 0.004). The key role of areas 24 and 46 was confirmed by (1) normative diffusion MRI-based tractography analysis showing that streamlines associated with better outcome projected to these areas, (2) association of these areas with inferior thalamic peduncle deep brain stimulation patients' outcome (R = 0.83, p = 0.003); (3) the connectedness of these areas to obsessive-compulsive disorder-causing lesions, as identified using literature-based lesion network mapping. These results provide considerations for target improvement, outlining the specific area of the internal capsule critical for successful magnetic resonance-guided focused ultrasound outcome and demonstrating that discrete frontal areas are involved in symptom relief. This could help refine focused ultrasound treatment for obsessive-compulsive disorder and provide a network-based rationale for potential alternative targets.
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http://dx.doi.org/10.1093/brain/awab232DOI Listing
June 2021

Dysgeusia induced and resolved by focused ultrasound thalamotomy: case report.

J Neurosurg 2021 Jun 18:1-6. Epub 2021 Jun 18.

1Division of Neurosurgery, Department of Surgery, Toronto Western Hospital-University Health Network.

Dysgeusia, or distorted taste, has recently been acknowledged as a complication of thalamic ablation or thalamic deep brain stimulation as a treatment of tremor. In a unique patient, left-sided MR-guided focused ultrasound thalamotomy improved right-sided essential tremor but also induced severe dysgeusia. Although dysgeusia persisted and caused substantial weight loss, tremor slowly relapsed. Therefore, 19 months after the first procedure, the patient underwent a second focused ultrasound thalamotomy procedure, which again improved tremor but also completely resolved the dysgeusia. On the basis of normative and patient-specific whole-brain tractography, the authors determined the relationship between the thalamotomy lesions and the medial border of the medial lemniscus-a surrogate for the solitariothalamic gustatory fibers-after the first and second focused ultrasound thalamotomy procedures. Both tractography methods suggested partial and complete disruption of the solitariothalamic gustatory fibers after the first and second thalamotomy procedures, respectively. The tractography findings in this unique patient demonstrate that incomplete and complete disruption of a neural pathway can induce and resolve symptoms, respectively, and serve as the rationale for ablative procedures for neurological and psychiatric disorders.
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http://dx.doi.org/10.3171/2020.11.JNS202882DOI Listing
June 2021

Impact of Mesial Temporal Lobe Resection on Brain Structure in Medically Refractory Epilepsy.

World Neurosurg 2021 Aug 16;152:e652-e665. Epub 2021 Jun 16.

Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective: Surgical resection can decrease seizure frequency in medically intractable temporal lobe epilepsy. However, the functional and structural consequences of this intervention on brain circuitry are poorly understood. We investigated structural changes that occur in brain circuits after mesial temporal lobe resection for refractory epilepsy. Specifically, we used neuroimaging techniques to evaluate changes in 1) contralesional hippocampal and bilateral mammillary body volume and 2) brain-wide cortical thickness.

Methods: Serial T1-weighted brain magnetic resonance images were acquired before and after surgery (1.6 ± 0.5 year interval) in 21 patients with temporal lobe epilepsy (9 women, 12 men; mean age, 39.4 ± 11.5 years) who had undergone unilateral temporal lobe resection (14 anterior temporal lobectomy; 7 selective amygdalohippocampectomy). Blinded manual segmentation of the unresected hippocampal formation and bilateral mammillary bodies was performed using the Pruessner and Copenhaver protocols, respectively. Brain-wide cortical thickness estimates were computed using the CIVET pipeline.

Results: Surgical resection was associated with a 5% reduction in contralesional hippocampal volume (P < 0.01) and a 9.5% reduction in mammillary body volume (P = 0.03). In addition, significant changes in cortical thickness were observed in contralesional anterior and middle cingulate gyrus and insula (P < 0.01) as well as in other temporal, frontal, and occipital regions (P < 0.05). Postoperative verbal memory function was significantly associated with cortical thickness change in contralesional inferior temporal gyrus (R = 0.39; P = 0.03).

Conclusions: These results indicate that mesial temporal lobe resection is associated with both volume loss in spared Papez circuitry and changes in cortical thickness across the brain.
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http://dx.doi.org/10.1016/j.wneu.2021.06.039DOI Listing
August 2021

Fronto-subthalamic phase synchronization and cross-frequency coupling during conflict processing.

Neuroimage 2021 09 30;238:118205. Epub 2021 May 30.

Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease, University Health Network, Toronto, Ontario, Canada. Electronic address:

Growing evidence suggests that both the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) play crucial roles in conflict processing, but how these two structures coordinate their activities remains poorly understood. We simultaneously recorded electroencephalogram from the mPFC and local field potentials from the STN using deep brain stimulation electrodes in 13 Parkinson's disease patients while they performed a Stroop task. Both mPFC and STN showed significant increases in theta activities (2-8 Hz) in incongruent trials compared to the congruent trials. The theta activity in incongruent trials also demonstrated significantly increased phase synchronization between mPFC and STN. Furthermore, the amplitude of gamma oscillation was modulated by the phase of theta activity at the STN in incongruent trials. Such theta-gamma phase-amplitude coupling (PAC) was much stronger for incongruent trials with faster reaction times than those with slower reaction times. Elevated theta-gamma PAC in the STN provides a novel mechanism by which the STN may operationalize its proposed "hold-your-horses" role. The co-occurrence of mPFC-STN theta phase synchronization and STN theta-gamma PAC reflects a neural substrate for fronto-subthalamic communication during conflict processing. More broadly, it may be a general mechanism for neuronal interactions in the cortico-basal ganglia circuits via a combination of long-range, within-frequency phase synchronization and local cross-frequency PAC.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118205DOI Listing
September 2021

Predicting optimal deep brain stimulation parameters for Parkinson's disease using functional MRI and machine learning.

Nat Commun 2021 05 24;12(1):3043. Epub 2021 May 24.

Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, Canada.

Commonly used for Parkinson's disease (PD), deep brain stimulation (DBS) produces marked clinical benefits when optimized. However, assessing the large number of possible stimulation settings (i.e., programming) requires numerous clinic visits. Here, we examine whether functional magnetic resonance imaging (fMRI) can be used to predict optimal stimulation settings for individual patients. We analyze 3 T fMRI data prospectively acquired as part of an observational trial in 67 PD patients using optimal and non-optimal stimulation settings. Clinically optimal stimulation produces a characteristic fMRI brain response pattern marked by preferential engagement of the motor circuit. Then, we build a machine learning model predicting optimal vs. non-optimal settings using the fMRI patterns of 39 PD patients with a priori clinically optimized DBS (88% accuracy). The model predicts optimal stimulation settings in unseen datasets: a priori clinically optimized and stimulation-naïve PD patients. We propose that fMRI brain responses to DBS stimulation in PD patients could represent an objective biomarker of clinical response. Upon further validation with additional studies, these findings may open the door to functional imaging-assisted DBS programming.
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http://dx.doi.org/10.1038/s41467-021-23311-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144408PMC
May 2021

A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation.

Brain Stimul 2021 Jul-Aug;14(4):807-821. Epub 2021 May 12.

Krembil Brain Institute, University Health Network, Toronto, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Canada; KITE, Toronto Rehabilitation Institute, University Health Network, Toronto, Canada.

Background: Deep brain stimulation is an established therapy for several neurological disorders; however, its effects on neuronal activity vary across brain regions and depend on stimulation settings. Understanding these variable responses can aid in the development of physiologically-informed stimulation paradigms in existing or prospective indications.

Objective: Provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity.

Methods: In patients with movement disorders, single-neuron recordings were acquired from the subthalamic nucleus, substantia nigra pars reticulata, ventral intermediate nucleus, or reticular thalamus during microstimulation across various frequencies (1-100 Hz) to assess single-pulse and frequency-response functions. Moreover, a biophysically-realistic computational framework was developed which generated postsynaptic responses under the assumption that electrical stimuli simultaneously activated all convergent presynaptic inputs to stimulation target neurons. The framework took into consideration the relative distributions of excitatory/inhibitory afferent inputs to model site-specific responses, which were in turn embedded within a model of short-term synaptic plasticity to account for stimulation frequency-dependence.

Results: We demonstrated microstimulation-evoked excitatory neuronal responses in thalamic structures (which have predominantly excitatory inputs) and inhibitory responses in basal ganglia structures (predominantly inhibitory inputs); however, higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression. The model confirmed that site-specific responses could be simulated by accounting for local neuroanatomical/microcircuit properties, while suppression of neuronal activity during high-frequency stimulation was mediated by short-term synaptic depression.

Conclusions: Brain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties.
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http://dx.doi.org/10.1016/j.brs.2021.04.022DOI Listing
May 2021

Evolution of the Neurosurgeon's Role in Clinical Trials for Glioblastoma: A Systematic Overview of the Clinicaltrials.Gov Database.

Neurosurgery 2021 07;89(2):196-203

Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada.

Background: The therapeutic challenge of glioblastoma (GBM) has catalyzed the development of clinical trials to evaluate novel interventions. With increased understanding of GBM biology and technological advances, the neurosurgeon's role in neuro-oncology has evolved.

Objective: To evaluate the current landscape of procedure-based clinical trials for GBM to characterize this evolution, gain insight into past failures, and accordingly outline implications for future research and practice that may inform future studies.

Methods: The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM. Demographics, specific intervention, trial phase, and main outcome measures were abstracted.

Results: A total of 224 of 2311 GBM trials (9.7%) were identified as procedural, with the majority being based in the United States (155/224, 69.2%), single-center (155/224, 69.2%), and not randomized (176/224, 78.6%). Primary and recurrent GBMs were evenly addressed. The leading interventions were local delivery of therapeutics (50.0%), surgical techniques (33.9%), such as image-guided surgery, and novel device applications (14.3%). Phase I designs predominated (82/224, 36.6%). The top primary outcome was safety/tolerability/feasibility (88/224, 39.3%), followed by survival (46/224, 20.5%). Approximately 17% of studies were terminated, withdrawn, or suspended. Fifty-two linked publications were identified, among which 42 were classified as having a positive result.

Conclusion: Procedural interventions comprised ∼10% of all registered GBM trials. Local delivery of therapeutics, use of surgical imaging techniques and novel device applications, predominantly through phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved reporting of trial designs, outcomes, and results are needed to better inform the field and increase efficiency.
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http://dx.doi.org/10.1093/neuros/nyab169DOI Listing
July 2021

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease.

Brain Stimul 2021 Jul-Aug;14(4):754-760. Epub 2021 Apr 30.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON, M5T 2S8, Canada; Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5-12 Hz) are important in cognition.

Methods: We tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients' peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation.

Results: Acute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions.

Conclusion: Here, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.
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http://dx.doi.org/10.1016/j.brs.2021.04.016DOI Listing
April 2021

Mapping autonomic, mood, and cognitive effects of hypothalamic region deep brain stimulation.

Brain 2021 Apr 26. Epub 2021 Apr 26.

Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

Due to its involvement in a wide variety of cardiovascular, metabolic, and behavioral functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequalae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied at multiple international centers 58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer's disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation - including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear - were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic gray- and white-matter structures. K-nearest neighbor classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves (AUROC) between 0.67 - 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.
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http://dx.doi.org/10.1093/brain/awab170DOI Listing
April 2021

Implantable photonic neural probes for light-sheet fluorescence brain imaging.

Neurophotonics 2021 Apr 19;8(2):025003. Epub 2021 Apr 19.

California Institute of Technology, Division of Physics, Mathematics, and Astronomy, Pasadena, California, United States.

Light-sheet fluorescence microscopy (LSFM) is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. We demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200-mm-diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed, , and mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. The probes had 5 to 10 addressable sheets and average sheet thicknesses for propagation distances up to in free space. Imaging areas were as large as in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. The neural probes can lead to new variants of LSFM for deep brain imaging and experiments in freely moving animals.
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http://dx.doi.org/10.1117/1.NPh.8.2.025003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059764PMC
April 2021

Sign-specific stimulation 'hot' and 'cold' spots in Parkinson's disease validated with machine learning.

Brain Commun 2021 10;3(2):fcab027. Epub 2021 Mar 10.

University Health Network, Toronto, ON, Canada.

Deep brain stimulation of the subthalamic nucleus has become a standard therapy for Parkinson's disease. Despite extensive experience, however, the precise target of optimal stimulation and the relationship between site of stimulation and alleviation of individual signs remains unclear. We examined whether machine learning could predict the benefits in specific Parkinsonian signs when informed by precise locations of stimulation. We studied 275 Parkinson's disease patients who underwent subthalamic nucleus deep brain stimulation between 2003 and 2018. We selected pre-deep brain stimulation and best available post-deep brain stimulation scores from motor items of the Unified Parkinson's Disease Rating Scale (UPDRS-III) to discern sign-specific changes attributable to deep brain stimulation. Volumes of tissue activated were computed and weighted by (i) tremor, (ii) rigidity, (iii) bradykinesia and (iv) axial signs changes. Then, sign-specific sites of optimal ('hot spots') and suboptimal efficacy ('cold spots') were defined. These areas were subsequently validated using machine learning prediction of sign-specific outcomes with in-sample and out-of-sample data ( = 51 subthalamic nucleus deep brain stimulation patients from another institution). Tremor and rigidity hot spots were largely located outside and dorsolateral to the subthalamic nucleus whereas hot spots for bradykinesia and axial signs had larger overlap with the subthalamic nucleus. Using volume of tissue activated overlap with sign-specific hot and cold spots, support vector machine classified patients into quartiles of efficacy with ≥92% accuracy. The accuracy remained high (68-98%) when only considering volume of tissue activated overlap with hot spots but was markedly lower (41-72%) when only using cold spots. The model also performed poorly (44-48%) when using only stimulation voltage, irrespective of stimulation location. Out-of-sample validation accuracy was ≥96% when using volume of tissue activated overlap with the sign-specific hot and cold spots. In two independent datasets, distinct brain areas could predict sign-specific clinical changes in Parkinson's disease patients with subthalamic nucleus deep brain stimulation. With future prospective validation, these findings could individualize stimulation delivery to optimize quality of life improvement.
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http://dx.doi.org/10.1093/braincomms/fcab027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042250PMC
March 2021

Self-adjustment of deep brain stimulation delays optimization in Parkinson's disease.

Brain Stimul 2021 May-Jun;14(3):676-681. Epub 2021 Apr 11.

Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, Ontario, Canada; Krembil Brain Institute, Toronto, Ontario, Canada; CenteR for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada. Electronic address:

Background: Parkinson's Disease patients undergo time-consuming programming to refine stimulation parameters after deep brain stimulation surgery.

Objective: To assess whether the use of the advanced functions of a patient's programmer would facilitate programming of deep brain stimulation.

Methods: Thirty patients were randomly allocated to the use of advanced versus simple mode of the patient programmer in this single-centre, prospective, randomized, controlled study. Primary outcome was the number of days required to optimize the stimulation settings.

Results: The number of days required to optimize stimulation was significantly lower in the simple mode (88.5 ± 33.1 vs. 142.1 ± 67.4, p = 0.01). In addition, the advanced mode group had a higher number of side effects (5.4 ± 3.1 vs. 2.6 ± 1.9, p = 0.0055).

Conclusions: The use of the advanced functions of patient programmer delays programming optimization and it is associated with a higher number of side effects. These findings highlight the need for other methods for faster and safer stimulation programming.
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http://dx.doi.org/10.1016/j.brs.2021.04.001DOI Listing
April 2021

Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.

EMBO Mol Med 2021 May 14;13(5):e13258. Epub 2021 Apr 14.

Section Cell Biology, Center for Molecular Medicine, Institute of Biomembranes, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41 and VPS41 ; VPS41 and VPS41 ) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41 enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41 /VPS41 abolished the neuroprotective function of VPS41 against α-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.
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http://dx.doi.org/10.15252/emmm.202013258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103106PMC
May 2021

Advanced Therapies for the Management of Dopamine Dysregulation Syndrome in Parkinson's Disease.

Mov Disord Clin Pract 2021 Apr 11;8(3):400-405. Epub 2021 Mar 11.

Division of Neurology University of Toronto Toronto Ontario Canada.

Background: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson's disease. The current literature on this syndrome is limited, and it remains underdiagnosed and challenging to manage.

Objective: To assess the role of advanced therapies in the management of DDS.

Methods: We performed a retrospective chart review and identified patients who fit the inclusion criteria for DDS. They were classified according to risk factors that have been identified in the literature, motor and complication scores, intervention (medical or surgical) and outcome. Multivariate analyses were performed to analyze these characteristics.

Results: Twenty-seven patients were identified (23 males, mean age of onset: 49 ± 8.8 years). Average levodopa equivalent daily dose was 1916.7 ± 804 mg and a history of impulse control disorders, psychiatric illness, and substance abuse was present in 89%, 70% and 3.7% of the patients, respectively. Overall 81.5% of patients had symptom resolution at follow up, on average 4.8 ± 3.5 years after management, with medication only (7/9), levodopa-carbidopa intestinal gel (1/3), deep brain stimulation of subthalamic nucleus (10/13), or globus pallidus pars interna (2/2). Reduction of medications occurred with deep brain stimulation of subthalamic nucleus ( = 0.01) but was associated with a relapse in two patients.

Conclusion: Although the small sample size of some subgroups limits our ability to draw meaningful conclusions, our results did not suggest superiority of a single treatment option. Advanced therapies including deep brain stimulation can be considered in patients with DDS refractory to conservative measures, but outcome is variable and relapse is possible.
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http://dx.doi.org/10.1002/mdc3.13154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015898PMC
April 2021

A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets.

J Neurosurg 2021 Mar 26:1-14. Epub 2021 Mar 26.

1University Health Network, Toronto.

Objective: Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature.

Methods: The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review.

Results: A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging.

Conclusions: Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning.
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http://dx.doi.org/10.3171/2020.8.JNS201125DOI Listing
March 2021
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