Radiosurgical thalamotomy for essential tremor: state of the art, current challenges and future directions.

INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder, affecting up to 5% of adults > 65 years old. In 30-50% of cases, optimal medical management provides insufficient tremor relief and surgical options are considered. Thalamotomy is a time-honored intervention, which can be performed using radiofrequency (RF), stereotactic radiosurgery (SRS), or magnetic resonance-guided focused ultrasounds (MRgFUS). While the latter has received considerable attention in the last decade, SRS has consistently been demonstrated as an effective and well-tolerated option. AREAS COVERED: This review discusses the evidence on SRS thalamotomy for ET. Modern workflows and emerging techniques are detailed. Current outcomes are analyzed, with a specific focus on tremor reduction, complications and radiological evolution of the lesions. Challenges for the field are highlighted. EXPERT OPINION: SRS thalamotomy improves tremor in > 80% patients. The efficacy appears comparable to other modalities, including DBS, RF and MRgFUS. Side effects result mostly from idiosyncratic hyper-responses to radiation, which occur in up to 10% of treatments, are usually self-resolving, and are symptomatic in < 4% of patients. Future research should focus on accumulating more data on bilateral treatments, collecting long-term outcomes, refining targeting, and improving lesion consistency.

Neural signatures of indirect pathway activity during subthalamic stimulation in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) produces an electrophysiological signature called evoked resonant neural activity (ERNA); a high-frequency oscillation that has been linked to treatment efficacy. However, the single-neuron and synaptic bases of ERNA are unsubstantiated. This study proposes that ERNA is a subcortical neuronal circuit signature of DBS-mediated engagement of the basal ganglia indirect pathway network. In people with Parkinson's disease, we: (i) showed that each peak of the ERNA waveform is associated with temporally-locked neuronal inhibition in the STN; (ii) characterized the temporal dynamics of ERNA; (iii) identified a putative mesocircuit architecture, embedded with empirically-derived synaptic dynamics, that is necessary for the emergence of ERNA in silico; (iv) localized ERNA to the dorsal STN in electrophysiological and normative anatomical space; (v) used patient-wise hotspot locations to assess spatial relevance of ERNA with respect to DBS outcome; and (vi) characterized the local fiber activation profile associated with the derived group-level ERNA hotspot.

Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata.

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

Diffusion and functional MRI in surgical neuromodulation.

Surgical neuromodulation has witnessed significant progress in recent decades. Notably, deep brain stimulation (DBS), delivered precisely within therapeutic targets, has revolutionized the treatment of medication-refractory movement disorders and is now expanding for refractory psychiatric disorders, refractory epilepsy, and post-stroke motor recovery. In parallel, the advent of incisionless treatment with focused ultrasound ablation (FUSA) can offer patients life-changing symptomatic relief. Recent research has underscored the potential to further optimize DBS and FUSA outcomes by conceptualizing the therapeutic targets as critical nodes embedded within specific brain networks instead of strictly anatomical structures. This paradigm shift was facilitated by integrating two imaging modalities used regularly in brain connectomics research: diffusion MRI (dMRI) and functional MRI (fMRI). These advanced imaging techniques have helped optimize the targeting and programming techniques of surgical neuromodulation, all while holding immense promise for investigations into treating other neurological and psychiatric conditions. This review aims to provide a fundamental background of advanced imaging for clinicians and scientists, exploring the synergy between current and future approaches to neuromodulation as they relate to dMRI and fMRI capabilities. Focused research in this area is required to optimize existing, functional neurosurgical treatments while serving to build an investigative infrastructure to unlock novel targets to alleviate the burden of other neurological and psychiatric disorders.

Hippocampus diffusivity abnormalities in classical trigeminal neuralgia.

Introduction: Patients with chronic pain frequently report cognitive symptoms that affect memory and attention, which are functions attributed to the hippocampus. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysmal attacks of unilateral orofacial pain. Given the stereotypical nature of TN pain and lack of negative symptoms including sensory loss, TN provides a unique model to investigate the hippocampal implications of chronic pain. Recent evidence demonstrated that TN is associated with macrostructural hippocampal abnormalities indicated by reduced subfield volumes; however, there is a paucity in our understanding of hippocampal microstructural abnormalities associated with TN. Objectives: To explore diffusivity metrics within the hippocampus, along with its functional and structural subfields, in patients with TN. Methods: To examine hippocampal microstructure, we utilized diffusion tensor imaging in 31 patients with TN and 21 controls. T1-weighted magnetic resonance images were segmented into hippocampal subfields and registered into diffusion-weighted imaging space. Fractional anisotropy (FA) and mean diffusivity were extracted for hippocampal subfields and longitudinal axis segmentations. Results: Patients with TN demonstrated reduced FA in bilateral whole hippocampi and hippocampal body and contralateral subregions CA2/3 and CA4, indicating microstructural hippocampal abnormalities. Notably, patients with TN showed significant correlation between age and hippocampal FA, while controls did not exhibit this correlation. These effects were driven chiefly by female patients with TN. Conclusion: This study demonstrates that TN is associated with microstructural hippocampal abnormalities, which may precede and potentially be temporally linked to volumetric hippocampal alterations demonstrated previously. These findings provide further evidence for the role of the hippocampus in chronic pain and suggest the potential for targeted interventions to mitigate cognitive symptoms in patients with chronic pain.

Comprehensive characterization of intracranial hemorrhage in deep brain stimulation: a systematic review of literature from 1987 to 2023.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for medically refractory movement disorders and other neurological conditions. To comprehensively characterize the prevalence, locations, timing of detection, clinical effects, and risk factors of DBS-related intracranial hemorrhage (ICH), the authors performed a systematic review of the published literature. METHODS: PubMed, EMBASE, and Web of Science were searched using 2 concepts: cerebral hemorrhage and brain stimulation, with filters for English, human studies, and publication dates 1980-2023. The inclusion criteria were the use of DBS intervention for any human neurological condition, with documentation of hemorrhagic complications by location and clinical effect. Studies with non-DBS interventions, no documentation of hemorrhage outcome, patient cohorts of ≤ 10, and pediatric patients were excluded. The risk of bias was assessed using Centre for Evidence-Based Medicine Levels of Evidence. The authors performed proportional meta-analysis for ICH prevalence. RESULTS: A total of 63 studies, with 13,056 patients, met the inclusion criteria. The prevalence of ICH was 2.9% (fixed-effects model, 95% CI 2.62%-3.2%) per patient and 1.6% (random-effects model, 95% CI 1.34%-1.87%) per DBS lead, with 49.6% being symptomatic. The ICH rates did not change with time. ICH most commonly occurred around the DBS lead, with 16% at the entry point, 31% along the track, and 7% at the target. Microelectrode recording (MER) during DBS was associated with increased ICH rate compared to DBS without MER (3.5 ± 2.2 vs 2.1 ± 1.4; p[T ≤ t] 1-tail = 0.038). Other reported ICH risk factors include intraoperative systolic blood pressure > 140 mm Hg, sulcal DBS trajectories, and multiple microelectrode insertions. Sixty percent of ICH was detected at 24 hours postoperatively and 27% intraoperatively. The all-cause mortality rate of DBS was 0.4%, with ICH accounting for 22% of deaths. Single-surgeon DBS experience showed a weak inverse correlation (r = -0.27, p = 0.2189) between the rate of ICH per lead and the number of leads implanted per year. CONCLUSIONS: This study provides level III evidence that MER during DBS is a risk factor for ICH. Other risk factors include intraoperative systolic blood pressure > 140 mm Hg, sulcal trajectories, and multiple microelectrode insertions. Avoidance of these risk factors may decrease the rate of ICH.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei-including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)-across different DBS frequencies. MATERIALS AND METHODS: Both synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim-across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. RESULTS: Our model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. CONCLUSIONS: The result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

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.

Subthalamic and pallidal neurons are modulated during externally cued movements in Parkinson's disease.

External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13-30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD.

Microvascular Decompression and Trigeminal Neuralgia: Patient Sentiment Analysis Using Natural Language Processing.

OBJECTIVE: Microvascular decompression (MVD) as a treatment for trigeminal neuralgia (TGN) has high success rate but is associated with risks of complication. This study analyzes Twitter to provide insights into discussions surrounding MVD for patients with TGN. METHODS: A Twitter search performed in April 2022 yielded 491 tweets from 426 accounts. Tweets and accounts were classified thematically, and descriptive statistics were used for various social media metrics. Using a natural language processing machine learning algorithm, sentiment analysis (SA) was performed to evaluate patient perspectives before and after surgery, and a multivariate regression model was used to identify predictors of higher engagement metrics (likes, retweets, quote tweets, replies). RESULTS: Most accounts were patients, caregivers, and other members of the public (70%). The most encountered themes were research (47%) and personal experiences (33.4%). SA of tweets about patient experiences showed that 40.2% of tweets were positive, 31.1% were neutral and 28.7% were negative. Negative tweets decreased significantly in postoperative tweets and mostly discussed complications or failure of surgery (63%). On multivariate analysis, only inclusion of media (photo or video) in a Tweet was associated with higher engagement metrics. CONCLUSIONS: This study provides a comprehensive review of Twitter use discussing MVD in TGN and is the first to assess patient satisfaction after treatment using SA. The data presented on patient perspectives on social media could help physicians establish direct lines of communication with patients, fostering a more patient-focused care.

Trends and disparities in deep brain stimulation utilization in the United States: a Nationwide Inpatient Sample analysis from 1993 to 2017.

Background: Deep brain stimulation (DBS) is an approved treatment option for Parkinson's Disease (PD), essential tremor (ET), dystonia, obsessive-compulsive disorder and epilepsy in the United States. There are disparities in access to DBS, and clear understanding of the contextual factors driving them is important. Previous studies aimed at understanding these factors have been limited by single indications or small cohort sizes. The aim of this study is to provide an updated and comprehensive analysis of DBS utilization for multiple indications to better understand the factors driving disparities in access. Methods: The United States based National Inpatient Sample (NIS) database was utilized to analyze the surgical volume and trends of procedures based on indication, using relevant ICD codes. Predictors of DBS use were analyzed using a logistic regression model. DBS-implanted patients in each indication were compared based on the patient-, hospital-, and outcome-related variables. Findings: Our analysis of 104,356 DBS discharges from 1993 to 2017 revealed that the most frequent indications for DBS were PD (67%), ET (24%), and dystonia (4%). Although the number of DBS procedures has consistently increased over the years, radiofrequency ablation utilization has significantly decreased to only a few patients per year since 2003. Negative predictors for DBS utilization in PD and ET cohorts included age increase and female sex, while African American status was a negative predictor across all cohorts. Significant differences in patient-, hospital-, and outcome-related variables between DBS indications were also determined. Interpretation: Demographic and socioeconomic-based disparities in DBS use are evident. Although racial disparities are present across all indications, other disparities such as age, sex, wealth, and insurance status are only relevant in certain indications. Funding: This work was supported by Alan & Susan Hudson Cornerstone Chair in Neurosurgery at University Health Network.

Brain imaging signatures of neuropathic facial pain derived by artificial intelligence.

Advances in neuroimaging have permitted the non-invasive examination of the human brain in pain. However, a persisting challenge is in the objective differentiation of neuropathic facial pain subtypes, as diagnosis is based on patients' symptom descriptions. We use artificial intelligence (AI) models with neuroimaging data to distinguish subtypes of neuropathic facial pain and differentiate them from healthy controls. We conducted a retrospective analysis of diffusion tensor and T1-weighted imaging data using random forest and logistic regression AI models on 371 adults with trigeminal pain (265 classical trigeminal neuralgia (CTN), 106 trigeminal neuropathic pain (TNP)) and 108 healthy controls (HC). These models distinguished CTN from HC with up to 95% accuracy, and TNP from HC with up to 91% accuracy. Both classifiers identified gray and white matter-based predictive metrics (gray matter thickness, surface area, and volume; white matter diffusivity metrics) that significantly differed across groups. Classification of TNP and CTN did not show significant accuracy (51%) but highlighted two structures that differed between pain groups-the insula and orbitofrontal cortex. Our work demonstrates that AI models with brain imaging data alone can differentiate neuropathic facial pain subtypes from healthy data and identify regional structural indicates of pain.

Beta band oscillations in the motor thalamus are modulated by visuomotor coordination in essential tremor patients.

Introduction: Beta oscillations in sensorimotor structures contribute to the planning, sequencing, and stopping of movements, functions that are typically associated with the role of the basal ganglia. The presence of beta oscillations (13-30 Hz) in the cerebellar zone of the thalamus (the ventral intermediate nucleus - Vim) indicates that this rhythm may also be involved in cerebellar functions such as motor learning and visuomotor adaptation. Methods: To investigate the possible role of Vim beta oscillations in visuomotor coordination, we recorded local field potential (LFP) and multiunit activity from the Vim of essential tremor (ET) patients during neurosurgery for the implantation of deep brain stimulation (DBS) electrodes. Using a computer, patients performed a visuomotor adaptation task that required coordinating center-out movements with incongruent visual feedback imposed by inversion of the computer display. Results: The results show that, in ET, Vim beta oscillations of the LFP were lower during the incongruent center-out task than during the congruent orientation. Vim firing rates increased significantly during periods of low beta power, particularly on approach to the peripheral target. In contrast, beta power in the subthalamic nucleus of Parkinson's disease (PD) patients did not differ significantly between the incongruent and the congruent orientation of the center-out task. Discussion: The findings support the hypothesis that beta oscillations of the Vim are modulated by novel visuomotor tasks. The inverse relationship between the power of Vim-LFP beta oscillations and Vim firing rates suggest that the suppression of beta oscillations may facilitate information throughput to the thalamocortical circuit by modulation of Vim firing rates.

Top-down control of human motor thalamic neuronal activity during the auditory oddball task.

The neurophysiology of selective attention in visual and auditory systems has been studied in animal models but not with single unit recordings in human. Here, we recorded neuronal activity in the ventral intermediate nucleus as well as the ventral oral anterior, and posterior nuclei of the motor thalamus in 25 patients with parkinsonian (n = 6) and non-parkinsonian tremors (n = 19) prior to insertion of deep brain stimulation electrodes while they performed an auditory oddball task. In this task, patients were requested to attend and count the randomly occurring odd or "deviant" tones, ignore the frequent standard tones and report the number of deviant tones at trial completion. The neuronal firing rate decreased compared to baseline during the oddball task. Inhibition was specific to auditory attention as incorrect counting or wrist flicking to the deviant tones did not produce such inhibition. Local field potential analysis showed beta (13-35 Hz) desynchronization in response to deviant tones. Parkinson's disease patients off medications had more beta power than the essential tremor group but less neuronal modulation of beta power to the attended tones, suggesting that dopamine modulates thalamic beta oscillations for selective attention. The current study demonstrated that ascending information to the motor thalamus can be suppressed during auditory attending tasks, providing indirect evidence for the searchlight hypothesis in humans. These results taken together implicate the ventral intermediate nucleus in non-motor cognitive functions, which has implications for the brain circuitry for attention and the pathophysiology of Parkinson's disease.

Should trigeminal neuralgia be considered a clinically isolated syndrome?

The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. Many MS patients with TN have magnetic resonance imaging (MRI) evidence of a symptomatic demyelinating lesion. Although infratentorial presentations are included in the diagnostic criteria for MS, there remains confusion in clinical practice as to whether TN should be considered a clinically isolated syndrome for the application of McDonald criteria. In this case series, we discuss this diagnostic quandary in patients presenting with TN and additional MRI findings suggestive of MS and highlight the unmet need for data in such patients to optimally guide their care.

Long-Term Recording of Subthalamic Aperiodic Activities and Beta Bursts in Parkinson's Disease.

BACKGROUND: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown. OBJECTIVES: The study aimed to characterize the long-term effects of STN-deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts. METHODS: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN-LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular-resampling auto-spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN-LFP signals in beta band. RESULTS: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications. CONCLUSIONS: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma-aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long-term STN-DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society.