Thalamic Deep Brain Stimulation Research Articles

Connectivity profile of thalamic deep brain stimulation to effectively treat essential tremor.

Essential tremor is the most prevalent movement disorder and is often refractory to medical treatment. Deep brain stimulation offers a therapeutic approach that can efficiently control tremor symptoms. Several deep brain stimulation targets (ventral intermediate nucleus, zona incerta, posterior subthalamic area) have been discussed for tremor treatment. Effective deep brain stimulation therapy for tremor critically involves optimal targeting to modulate the tremor network. This could potentially become more robust and precise by using state-of-the-art brain connectivity measurements. In the current study, we used two normative brain connectomes (structural and functional) to show the pattern of effective deep brain stimulation electrode connectivity in 36 patients with essential tremor. Our structural and functional connectivity models were significantly predictive of postoperative tremor improvement in out-of-sample data (P < 0.001 for both structural and functional leave-one-out cross-validation). Additionally, we segregated the somatotopic brain network based on head and hand tremor scores. These resulted in segregations that mapped onto the well-known somatotopic maps of both motor cortex and cerebellum. Crucially, this shows that slightly distinct networks need to be modulated to ameliorate head versus hand tremor and that those networks could be identified based on somatotopic zones in motor cortex and cerebellum. Finally, we propose a multi-modal connectomic deep brain stimulation sweet spot that may serve as a reference to enhance clinical care, in the future. This spot resided in the posterior subthalamic area, encroaching on the inferior borders of ventral intermediate nucleus and sensory thalamus. Our results underscore the importance of integrating brain connectivity in optimizing deep brain stimulation targeting for essential tremor.

Is Deep Brain Stimulation still an option for tremor recurrence after Focused Ultrasound thalamotomy? A case report

With the development of MRI-guided focused ultrasound (FUS), there is an ongoing renewal of interest for ablative procedures as a surgical option for tremor disorders. One of the main criticisms regarding FUS thalamotomy is the potential recurrence of tremor symptoms during follow-up. In case of tremor reappearance, repeating the ultrasound ablation may represent a reasonable option. However, tremor is often perceived as a highly disabling condition and patients may be reluctant to undergo the same unsuccessful treatment again. In this context, few data are available about the feasibility of Deep Brain Stimulation (DBS) in case of tremor recurrence after FUS. Moreover, concerns exist that FUS lesioning could preclude or limit the effectiveness of future DBS. Here we present the case of a 73-year-old right-handed man with a disabling, right-hand, mixed tremor recurring after initial successful FUS thalamotomy and that was properly managed in the end with thalamic Deep Brain Stimulation. Our case suggests that DBS and FUS thalamotomy are not mutually exclusive, but rather they represent complementary tools in the surgical approach to tremor.

MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat

BackgroundSocial deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. ObjectiveWe first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model. MethodsBrain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. ResultsThe DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. ConclusionsApplying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.

Longitudinal follow-up of dual-lead thalamic deep brain stimulation for patients with treatment refractory multiple sclerosis tremor (P4.8-044)

Longitudinal follow-up of dual-lead thalamic deep brain stimulation for patients with treatment refractory multiple sclerosis tremor (P4.8-044)

Energy Cost of Action Potential Generation and Propagation in Thalamocortical Relay Neurons During Deep Brain Stimulation.

Thalamocortical (TC) relay neurons generate antidromic and orthodromic action potentials (APs) during thalamic deep brain stimulation (DBS). To maintain signaling, each AP requires Na+/K+ pump to expend adenosine triphosphate (ATP) to restore Na+ and K+ gradients. Our aim was to estimate the energy demand associated with AP generation and propagation within TC relay cells during DBS. We used a morphology-based computational model to simulate the APs at different locations. We determined AP energy cost by calculating the amount of ATP required to reverse Na+ influx during the spike and measured metabolic efficiency by using Na+/K+ charge overlap. The ATP cost for AP generation exhibited location dependence, which was determined by spike shape, spatial morphology, and heterogeneously distributed currents. The APs in the axonal initial segment (AIS) were energetically efficient, but backpropagation to the soma and forward propagation to the axon were inefficient. Due to large surface area, the soma and AIS dominated the overall ATP usage. The AP cost also depended on membrane potential, which controlled T-type Ca2+ conductance and degree of availability of Na+ and K+ channels. The excitatory/inhibitory synaptic inputs affected spike cost by increasing/reducing the excitability of local cells. There was a tradeoff between AP cost and firing rate at high firing frequencies. We explained a fundamental link between biophysics of ionic currents, spatial morphology of neural segments, and ATP cost per AP. The predictions should be considered when understanding the functional magnetic resonance imaging data of thalamic DBS.

Gait worsening and the microlesion effect following deep brain stimulation for essential tremor

ObjectiveTo investigate the effects of unilateral thalamic deep brain stimulation (DBS) on walking in persons with medication-refractory essential tremor (ET).MethodsWe performed laboratory-based gait analyses on 24 persons with medication-refractory ET...

Differential impact on speech production from chronic thalamic DBS in Essential Tremor and that from STN DBS in Parkinson's disease

Essential Tremor (ET) is the most common tremor syndrome seen in adults. The characteristic tremor in ET is postural and action tremors, with a frequency of 4–7 Hz; while in patients with Parkinson’s disease (PD), the dominant tremor is resting tremor with a typical frequency of 5 Hz. Deep brain stimulation (DBS) in the ventral intermediate nuclei (Vim) has been shown effective in treating action or intention tremors in medically resistant ET, while DBS in the subthalamic nucleus (STN) has been shown effective in treating rigidity, rest tremor and Dopa-induced dyskinesias in PD. However, chronic bilateral DBS, whether in Vim or STN, may have negative impact on speech production. We report two cases where both patients received DBS greater than one year and developed speech impairment. When the stimulation in Vim was turned off for 30 min in ET, the patient's speech returned to the baseline while turning the STN stimulation off for 30 min in PD, minimal changes were observed and 12 h with stimulation-off were required for speech to return to the non-stimulated state.Essential Tremor (ET) is the most common tremor syndrome seen in adults. The characteristic tremor in ET is postural and action tremors, with a frequency of 4–7 Hz; while in patients with Parkinson’s disease (PD), the dominant tremor is resting tremor with a typical frequency of 5 Hz. Deep brain stimulation (DBS) in the ventral intermediate nuclei (Vim) has been shown effective in treating action or intention tremors in medically resistant ET, while DBS in the subthalamic nucleus (STN) has been shown effective in treating rigidity, rest tremor and Dopa-induced dyskinesias in PD. However, chronic bilateral DBS, whether in Vim or STN, may have negative impact on speech production. We report two cases where both patients received DBS greater than one year and developed speech impairment. When the stimulation in Vim was turned off for 30 min in ET, the patient's speech returned to the baseline while turning the STN stimulation off for 30 min in PD, minimal changes were observed and 12 h with stimulation-off w...

Unilateral Thalamic Deep Brain Stimulation Versus Focused Ultrasound Thalamotomy for Essential Tremor

The predominant neurosurgical approach to medication-refractory essential tremor is thalamic deep brain stimulation (DBS). The emergence of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has reawakened the debate surrounding the use of DBS versus thalamotomy for this indication. Herein, we aimed to provide a contemporary comparison between DBS and MRgFUS. Two controlled trials that evaluated DBS and MRgFUS for the unilateral treatment of refractory essential tremor were compared. Clinical outcomes extracted included postural tremor score in the treated upper extremity, quality of life (QoL), and incidence of adverse events (AE). Baseline patient characteristics were comparable in the 2 studies, except that DBS patients were younger and had more severe baseline tremor. Both DBS- and MRgFUS-treated patients had significant tremor improvement that was sustained for 1-year posttreatment, and significant improvement in QoL. The MRgFUS cohort had higher rates of persistent neurologic AE, whereas the DBS group had higher rates of surgery- and hardware-related AEs, including intracranial hemorrhage. In context of prior literature, both DBS and MRgFUS significantly improve tremor control and QoL. The 2 approaches are predominantly differentiated by their AE-profile. Additional head-to-head comparison on matched clinical populations are required to more accurately compare clinical efficacy and long-term outcomes.

Daytime Central Thalamic Deep Brain Stimulation Modulates Sleep Dynamics in the Severely Injured Brain: Mechanistic Insights and a Novel Framework for Alpha-Delta Sleep Generation.

Loss of organized sleep electrophysiology is a characteristic finding following severe brain injury. The return of structured elements of sleep architecture has been associated with positive prognosis across injury etiologies, suggesting a role for sleep dynamics as biomarkers of wakeful neuronal circuit function. In a continuing study of one minimally conscious state patient studied over the course of ~8½ years, we sought to investigate whether changes in daytime brain activation induced by central thalamic deep brain stimulation (CT-DBS) influenced sleep electrophysiology. In this patient subject, we previously reported significant improvements in sleep electrophysiology during 5½ years of CT-DBS treatment, including increased sleep spindle frequency and SWS delta power. We now present novel findings that many of these improvements in sleep electrophysiology regress following CT-DBS discontinuation; these regressions in sleep features correlate with a significant decrease in behavioral responsiveness. We also observe the re-emergence of alpha-delta sleep, which had been previously suppressed by daytime CT-DBS in this patient subject. Importantly, CT-DBS was only active during the daytime and has been proposed to mediate recovery of consciousness by driving synaptic activity across frontostriatal systems through the enhancement of thalamocortical output. Accordingly, the improvement of sleep dynamics during daytime CT-DBS and their subsequent regression following CT-DBS discontinuation implicates wakeful synaptic activity as a robust modulator of sleep electrophysiology. We interpret these findings in the context of the “synaptic homeostasis hypothesis,” whereby we propose that daytime upregulation of thalamocortical output in the severely injured brain may facilitate organized frontocortical circuit activation and yield net synaptic potentiation during wakefulness, providing a homeostatic drive that reconstitutes sleep dynamics over time. Furthermore, we consider common large-scale network dynamics across several neuropsychiatric disorders in which alpha-delta sleep has been documented, allowing us to formulate a novel mechanistic framework for alpha-delta sleep generation. We conclude that the bi-directional modulation of sleep electrophysiology by daytime thalamocortical activity in the severely injured brain: (1) emphasizes the cyclical carry-over effects of state-dependent circuit activation on large-scale brain dynamics, and (2) further implicates sleep electrophysiology as a sensitive indicator of wakeful brain activation and covert functional recovery in the severely injured brain.

CM-Pf deep brain stimulation and the long term management of motor and psychiatric symptoms in a case of Tourette syndrome

Tourette syndrome is a rare neuropsychiatric disorder affecting the cortico-striato-thalamo-cortical system. The disease manifests in childhood with tics and various psychiatric comorbidities. Cases of refractory Tourette syndrome are valuable candidates for functional neurosurgery. The thalamic centromedian-parafascicular complex is an experimental target that shows a promising role in Tourette syndrome deep brain stimulation, due to pathophysiologic evidences. We have shown on a long term follow-up, that thalamic deep brain stimulation, targeted on the centromedian-parafascicular complex, could modulate motor (i.e. tics) symptoms and owns a putative effect on various psychiatric aspects. Non-responding psychiatric symptoms could be due to the aberrant developmental environment of young Tourette patients more than disease itself. Centromedian-parafascicular complex is intriguingly embedded in motor, associative and limbic pathways and should be further investigated in his role for neuromodulation of human movement and behavior.

Anterior thalamic deep brain stimulation in epilepsy and persistent psychiatric side effects following discontinuation.

We report a case of a patient with drug-resistant epilepsy treated with deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS). The patient developed psychiatric side effects (PSEs), namely irritability, hostility, aggressiveness, and paranoia, after implantation and stimulation initiation. The stimulation was discontinued and the PSEs were mitigated, but the patient did not return to her pre-implantation state, as documented by repeated psychiatric reports and hospitalizations. To our knowledge, this is the first report of a patient who developed long-term PSEs that did not disappear after stimulation discontinuation. We suppose that ANT-DBS caused a persistent perturbation of the thalamic neuronal networks that are responsible for long-term PSEs.

Anterior thalamic deep brain stimulation in refractory epilepsy: A randomized, double-blinded study.

The safety and effect on seizure frequency of anterior thalamic nucleus deep brain stimulation were studied in this prospective, randomized, double-blinded study. Patients were followed for 12months. The first 6months were blinded with regard to active stimulation or not. After 6months, all patients received active stimulation. Bilateral ANT electrodes were implanted into 18 patients suffering from focal, pharmacoresistant epilepsy. Antiepileptic treatment was kept unchanged from three months prior to operation. The Liverpool seizure severity scale (LSSS) was used to measure the burden of epilepsy. There was no significant difference between the 2 groups at the end of the blinded period at 6months. However, when considering all patients and comparing 6months of stimulation with baseline, there was a significant, 22% reduction in the frequency of all seizures (P=0.009). Four patients had ≥50% reduction in total seizure frequency and 5 patients ≥50% reduction in focal seizures after 6months of stimulation. No increased effect over time was shown. LSSS at 6 months compared to baseline showed no significant difference between the 2 groups, but a small, significant reduction in LSSS was found when all patients had received stimulation for 6 months. Our study supports results from earlier studies concerning DBS as a safe treatment option, with effects even in patients with severe, refractory epilepsy. However, our results are not as encouraging as those reported from many other, mainly unblinded, and open studies.

Editorial introductions

Editorial introductions

Inferior thalamic peduncle deep brain stimulation for treatment-refractory obsessive-compulsive disorder: A phase 1 pilot trial

BackgroundSeveral different surgical procedures targeting the limbic circuit have been utilized for severe, treatment resistant obsessive-compulsive disorder; however, there has only been limited exploration of the inferior thalamic peduncle (ITP). The aim of this study was to determine the safety and initial efficacy of ITP deep brain stimulation (DBS) in patients with severe obsessive-compulsive disorder. MethodsPatients with severe, treatment-refractory obsessive-compulsive disorder were enrolled into this open-label phase 1 DBS pilot study. Bilateral ITP DBS devices were implanted between November 2010 and December 2015. The primary outcome was safety. The initial efficacy was determined by Yale-Brown Obsessive-Compulsive scale (YBOCs) scores. Component Y-BOCs scores, Hamilton Depression Severity Scale, Quality of Life Assessment (SF-36), Oxford Happiness Questionnaire, Warwick-Edinburgh Mental Well-Being Scale, and Sheehan Disability Scale were also analyzed for a minimum of 2 years after surgery. Additionally, preoperative and three-month postoperative FDG-PET studies were performed on two patients. ResultsFive patients (2 males, 3 females; age range 25–48 years) received ITP DBS. All five patients were considered responders at one year (52% improvement in YBOCs scores compared to baseline (range 39–73%, p < 0.01) and last follow-up (54% improvement; range 38–85%; p < 0.01). At two years follow-up, there were three adverse events that occurred in two patients. One patient had his DBS system removed after one year due to the device becoming the object of his obsession. The other two adverse events were not related to the device. Post-operative FDG-PET imaging in two patients demonstrated decreased glucose uptake within the right caudate, right putamen, right supplementary motor area, and right cingulum and increased glucose uptake in bilateral motor areas, left temporal pole, and left orbitfrontal cortex. ConclusionsITP DBS has a favorable safety profile and is potentially an efficacious treatment for severe obsessive-compulsive disorder. Larger clinical trials are necessary to determine efficacy.

Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor

Background: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13–40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit “confined stimulation.” We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. Methods: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. Results: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). Conclusions: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

Alternating Thalamic Deep Brain Stimulation for Essential Tremor: A Trial to Reduce Habituation.

DBS in the ventral intermediate nucleus (VIM) of the thalamus has been a revolutionary treatment for patients with essential tremor (ET) by reducing tremor. Unfortunately, some patients develop habituation to DBS and thus experience reduced efficacy and loss of tremor control. There are no standardized methods of addressing habituation to DBS. We propose alternating stimulation patterns as a way to reduce habituation. This was a randomized, placebo-controlled trial for patients with VIM DBS for ET. Patients were randomized to either experimental treatment arm of alternating stimulation patterns on a weekly basis or standard care arm of continuous stimulation settings for 12 weeks. Primary outcome was change in the performance subscale of The Essential Tremor Rating Assessment Scale (TETRAS), which was performed at initial visit and 12-week follow-up. Secondary outcome included change in the activities of daily living subscale of TETRAS. Twenty-two patients were enrolled in the trial, and 16 were analyzed at follow-up. Experimental treatment subjects displayed sustained tremor control compared to standard care, as measured by the change in TETRAS performance subscale (-0.6 vs. 6.7 point change, respectively) with a 7.3 difference between the arms (P = 0.006). Alternating stimulation patterns on a weekly basis for ET patients with VIM DBS reduced habituation in this pilot study. This study suggests that exposure to different stimulation groups may maintain better tremor control compared to constant stimulation parameters.

Outcomes from stereotactic surgery for essential tremor

There are several different surgical procedures that are used to treat essential tremor (ET), including deep brain stimulation (DBS) and thalamotomy procedures with radiofrequency (RF), radiosurgery (RS) and most recently,...

Pallidal and thalamic neural oscillatory patterns in tourette's syndrome.

Aberrant oscillatory activity has been hypothesized to play a role in the pathophysiology of Tourette's syndrome (TS). Deep brain stimulation (DBS) has recently been established as an effective treatment for severe TS. Modulation of symptom-specific oscillations may underlie the mechanism of action of DBS and could be used for adaptive neuromodulation to improve therapeutic efficacy. The objective of this study was to demonstrate a pathophysiological association of pallidal and thalamic local field potentials (LFPs) with TS. Nine medication-refractory TS patients were included in the study. Intracerebral LFPs were recorded simultaneously from bilateral pallidal and thalamic DBS electrodes. Spectral and temporal dynamics of pallidal and thalamic oscillations were characterized and correlated with preoperative Yale Global Tic Severity Scale (YGTSS) scores. Peaks of activity in the theta (3-12Hz) and beta (13-35Hz) were present in pallidal and thalamic recordings from all patients (3 women/6 men; mean age, 29.8 years) and coupled through coherence across targets. Presence of prolonged theta bursts in both targets was associated with preoperative motor tic severity. Total preoperative YGTSS scores (mean, 38.1) were correlated with pallidal and thalamic LFP activity using multivariable linear regression (R² = 0.96; p = 0.02). Our findings suggest that pallidothalamic oscillations may be implicated in the pathophysiology of TS. Furthermore, our results highlight the utility of multisite and -spectral oscillatory features in severely affected patients for future identification and clinical use of oscillatory physiomarkers for adaptive stimulation in TS. Ann Neurol 2018;84:505-514.

Effects of short pulse-width stimulation on gait ataxia of Essential Tremor patients implanted with thalamic Deep Brain Stimulation

Effects of short pulse-width stimulation on gait ataxia of Essential Tremor patients implanted with thalamic Deep Brain Stimulation

Differences in functional connectivity profiles as a predictor of response to anterior thalamic nucleus deep brain stimulation for epilepsy: a hypothesis for the mechanism of action and a potential biomarker for outcomes.

OBJECTIVE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising therapy for refractory epilepsy. Unfortunately, the variability in outcomes from ANT DBS is not fully understood. In this pilot study, the authors assess potential differences in functional connectivity related to the volume of tissue activated (VTA) in ANT DBS responders and nonresponders as a means for better understanding the mechanism of action and potentially improving DBS targeting. METHODS This retrospective analysis consisted of 6 patients who underwent ANT DBS for refractory epilepsy. Patients were classified as responders (n = 3) if their seizure frequency decreased by at least 50%. The DBS electrodes were localized postoperatively and VTAs were computationally generated based on DBS programming settings. VTAs were used as seed points for resting-state functional MRI connectivity analysis performed using a control dataset. Differences in cortical connectivity to the VTA were assessed between the responder and nonresponder groups. RESULTS The ANT DBS responders showed greater positive connectivity with the default mode network compared to nonresponders, including the posterior cingulate cortex, medial prefrontal cortex, inferior parietal lobule, and precuneus. Interestingly, there was also a consistent anticorrelation with the hippocampus seen in responders that was not present in nonresponders. CONCLUSIONS Based on their pilot study, the authors observed that successful ANT DBS in patients with epilepsy produces increased connectivity in the default mode network, which the authors hypothesize increases the threshold for seizure propagation. Additionally, an inhibitory effect on the hippocampus mediated through increased hippocampal γ-aminobutyric acid (GABA) concentration may contribute to seizure suppression. Future studies are planned to confirm these findings.