Comparative neural correlates of DBS and MRgFUS lesioning for tremor control in essential tremor.

BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.

Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Brain Structures and Networks Underlying Treatment Response to Deep Brain Stimulation Targeting the Inferior Thalamic Peduncle in Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating disease with a lifetime prevalence of 2-3%. Neuromodulatory treatments have been successfully used in severe cases. Deep brain stimulation (DBS) targeting the inferior thalamic peduncle (ITP) has been shown to successfully alleviate symptoms in OCD patients; however, the brain circuits implicated remain unclear. Here, we investigate the efficacious neural substrates following ITP-DBS for OCD. METHODS: High-quality normative structural and functional connectomics and voxel-wise probabilistic mapping techniques were applied to assess the neural substrates of OCD symptom alleviation in a cohort of 5 ITP-DBS patients. RESULTS: The region of most efficacious stimulation was located in the regions of the ITP and bed nucleus of the stria terminalis. Both functional and structural connectomics analyses demonstrated that successful symptom alleviation involved a brain network encompassing the bilateral amygdala and prefrontal regions. LIMITATIONS: The main limitation is the small size of the ITP-DBS cohort. While the findings are highly consistent and significant, these should be validated in larger studies. CONCLUSIONS: These results identify a tripartite brain network - composed of the bilateral amygdala and prefrontal regions 24 and 46 - whose engagement is associated with greater symptom improvement. They also provide information for optimizing targeting and identifying network components critically involved in ITP-DBS treatment response. Amygdala engagement in particular seems to be a key component for clinical benefits and could constitute a biomarker for treatment optimization.

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

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

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

Because of its involvement in a wide variety of cardiovascular, metabolic and behavioural 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 sequelae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied-at multiple international centres-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 grey and white matter structures. K-nearest neighbour classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves between 0.67 and 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.

A high-resolution in vivo magnetic resonance imaging atlas of the human hypothalamic region.

The study of the hypothalamus and its topological changes provides valuable insights into underlying physiological and pathological processes. Owing to technological limitations, however, in vivo atlases detailing hypothalamic anatomy are currently lacking in the literature. In this work we aim to overcome this shortcoming by generating a high-resolution in vivo anatomical atlas of the human hypothalamic region. A minimum deformation averaging (MDA) pipeline was employed to produce a normalized, high-resolution template from multimodal magnetic resonance imaging (MRI) datasets. This template was used to delineate hypothalamic (n = 13) and extrahypothalamic (n = 12) gray and white matter structures. The reliability of the atlas was evaluated as a measure for voxel-wise volume overlap among raters. Clinical application was demonstrated by superimposing the atlas into datasets of patients diagnosed with a hypothalamic lesion (n = 1) or undergoing hypothalamic (n = 1) and forniceal (n = 1) deep brain stimulation (DBS). The present template serves as a substrate for segmentation of brain structures, specifically those featuring low contrast. Conversely, the segmented hypothalamic atlas may inform DBS programming procedures and may be employed in volumetric studies.

Multimodal MRI for MRgFUS in essential tremor: post-treatment radiological markers of clinical outcome.

BACKGROUND: MRI-guided focused ultrasound (MRgFUS) thalamotomy is a promising non-invasive treatment option for medication-resistant essential tremor. However, it has been associated with variable efficacy and a relatively high incidence of adverse effects. OBJECTIVES: To assess the evolution of radiological findings after MRgFUS thalamotomy and to evaluate their significance for clinical outcomes. METHODS: Ninety-four patients who underwent MRgFUS between 2012 and 2017 were retrospectively evaluated. Lesion characteristics were assessed on routine MRI sequences, as well as with tractography. Relationships between imaging appearance, extent of white matter tract lesioning (59/94, on a 4-point scale) and clinical outcome were investigated. Recurrence was defined as >33% loss of tremor suppression at 3 months relative to day 7. RESULTS: Acute lesions demonstrated blood products, surrounding oedema and peripheral diffusion restriction. The extent of dentatorubrothalamic tract (DRTT) lesioning was significantly associated with clinical improvement at 1 year (t=4.32, p=0.001). Lesion size decreased over time (180.8±91.5 mm3 at day 1 vs 19.5±19.3 mm3 at 1-year post-treatment). Higher post-treatment oedema (t=3.59, p<0.001) was associated with larger lesions at 3 months. Patients with larger lesions at day 1 demonstrated reduced rates of tremor recurrence (t=2.67, p=0.019); however, lesions over 170 mm3 trended towards greater incidence of adverse effects (sensitivity=0.60, specificity=0.63). Lesion encroachment on the medial lemniscus (Sn=1.00, Sp=0.32) and pyramidal tract (Sn=1.00, Sp=0.12) were also associated with increased adverse effects incidence. CONCLUSION: Lesion size at day 1 predicts symptom recurrence, with fewer recurrences seen with larger lesions. Greater DRTT lesioning is associated with treatment efficacy. These findings may have implications for lesion targeting and extent. TRIAL REGISTRATION NUMBER: NCT02252380.

Mapping the network underpinnings of central poststroke pain and analgesic neuromodulation.

Central poststroke pain (CPSP) is a debilitating and often treatment-refractory condition that affects numerous stroke patients. The location of lesions most likely to cause pain and the identity of the functional brain networks that they impinge upon remain incompletely understood. We aimed to (1) elucidate which lesion locations are most frequently accompanied by pain; (2) explore CPSP-associated functional networks; and (3) examine how neuromodulation interacts with these networks. This multisite study investigated 17 CPSP patients who received deep brain stimulation (DBS; n = 12) or motor cortex stimulation (MCS; n = 5). Pain-causing lesions were manually segmented and normalized to standard space. To identify areas linked to high risk of pain, the locations of CPSP lesions and 220 control lesions were compared using voxelwise odds ratio mapping. The functional connectivity of pain-causing lesions was obtained using a large (n = 1000) normative resting-state functional MRI connectome and compared to that of control lesions and therapeutic DBS activation volumes. Brain regions most associated with CPSP risk (highest value = 63 times) were located along the ascending somatosensory pathways. These areas and the majority of individual CPSP lesions were functionally connected to anterior/middle cingulate cortex, insula, thalamus, and inferior parietal lobule (PBonferroni < 0.05). The extent of connectivity to the thalamus, inferior parietal lobule, and precuneus also differed between CPSP and control lesions (PBonferroni < 0.05). Posterior insula and thalamus shared connectivity with both CPSP lesions and pain-alleviating DBS activation volumes (PBonferroni < 0.05). These findings further clarify the topography and functional connectivity of pain-causing brain lesions, and provide new insights into the network-level mechanism of CPSP neuromodulation.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy to Treat Essential Tremor in Nonagenarians.

Essential tremor (ET) is a disabling movement disorder that is most prevalent among the elderly. While deep brain stimulation surgery targeting the ventral intermediate nucleus of the thalamus is commonly used to treat ET, the most elderly patients or those with multiple medical comorbidities may not qualify as surgical candidates. Magnetic resonance-guided focused ultrasound (MRgFUS) constitutes a less invasive modality that may be used to perform thalamotomy without the need for a burr hole craniotomy. Here, we report on 2 patients over the age of 90 years who benefited significantly from MRgFUS thalamotomy to relieve their symptoms and improve their quality of life. The procedure was well tolerated and performed safely in both patients. We conclude that age should not be a limiting factor in the treatment of patients with MRgFUS.

Probing the circuitry of panic with deep brain stimulation: Connectomic analysis and review of the literature.

BACKGROUND: Panic attacks affect a sizeable proportion of the population. The neurocircuitry of panic remains incompletely understood. OBJECTIVE: To investigate the neuroanatomical underpinnings of panic attacks induced by deep brain stimulation (DBS) through (1) connectomic analysis of an obsessive-compulsive disorder patient who experienced panic attacks during inferior thalamic peduncle DBS; (2) appraisal of existing clinical reports on DBS-induced panic attacks. METHODS: Panicogenic, ventral contact stimulation was compared with benign stimulation at other contacts using volume of tissue activated (VTA) modelling. Networks associated with the panicogenic zone were investigated using state-of-the-art normative connectivity mapping. In addition, a literature search for prior reports of DBS-induced panic attacks was conducted. RESULTS: Panicogenic VTAs impinged primarily on the tuberal hypothalamus. Compared to non-panicogenic VTAs, panicogenic loci were significantly functionally coupled to limbic and brainstem structures, including periaqueductal grey and amygdala. Previous studies found stimulation of these areas can also provoke panic attacks. CONCLUSIONS: DBS in the region of the tuberal hypothalamus elicited panic attacks in a single obsessive-compulsive disorder patient and recruited a network of structures previously implicated in panic pathophysiology, reinforcing the importance of the hypothalamus as a hub of panicogenic circuitry.

Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor.

Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemniscus, pyramidal, and dentato-rubro-thalamic). The area of optimal tremor response at 3 months after the procedure was identified at the posterior portion of the ventral intermediate nucleus. Lesions extending beyond the posterior region of the ventral intermediate nucleus and lateral to the lateral thalamic border were associated with increased risk of acute adverse sensory and motor effects, respectively. Acute adverse effects on gait and dysmetria occurred with lesions inferolateral to the thalamus. Lesions inferolateral to the thalamus or medial to the ventral intermediate nucleus were also associated with acute adverse speech effects. Diffusion-weighted imaging revealed that lesions associated with adverse sensory and gait/dysmetria effects compromised the medial lemniscus and dentato-rubro-thalamic tracts, respectively. Lesions associated with adverse motor and speech effects encroached on the pyramidal tract. Lesions larger than 170 mm3 were associated with an increased risk of acute adverse effects. Tremor improvement and acute adverse effects of MRgFUS for essential tremor are highly dependent on the location and size of lesions. These novel findings could refine current MRgFUS treatment planning and targeting, thereby improving clinical outcomes in patients.

Comparison of piece-wise linear, linear, and nonlinear atlas-to-patient warping techniques: analysis of the labeling of subcortical nuclei for functional neurosurgical applications.

Digital atlases are commonly used in pre-operative planning in functional neurosurgical procedures performed to minimize the symptoms of Parkinson's disease. These atlases can be customized to fit an individual patient's anatomy through atlas-to-patient warping procedures. Once fitted to pre-operative magnetic resonance imaging (MRI) data, the customized atlas can be used to plan and navigate surgical procedures. Linear, piece-wise linear and nonlinear registration methods have been used to customize different digital atlases with varying accuracies. Our goal was to evaluate eight different registration methods for atlas-to-patient customization of a new digital atlas of the basal ganglia and thalamus to demonstrate the value of nonlinear registration for automated atlas-based subcortical target identification in functional neurosurgery. In this work, we evaluate the accuracy of two automated linear techniques, two piece-wise linear techniques (requiring the identification of manually placed anatomical landmarks), and four different automated nonlinear atlas-to-patient warping techniques (where two of the four nonlinear techniques are variants of the ANIMAL algorithm). Since a gold standard of the subcortical anatomy is not available, manual segmentations of the striatum, globus pallidus, and thalamus are used to derive a silver standard for evaluation. Four different metrics, including the kappa statistic, the mean distance between the surfaces, the maximum distance between surfaces, and the total structure volume are used to compare the warping techniques. The results show that nonlinear techniques perform statistically better than linear and piece-wise linear techniques. In addition, the results demonstrate statistically significant differences between the nonlinear techniques, with the ANIMAL algorithm yielding better results.