Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor

Brinda, AnneMarie; Slopsema, Julia P.; Butler, Rebecca D.; Ikramuddin, Salman; Beall, Thomas; Guo, Wenqiang; Chu, Cong Qiu; Patriat, Rémi; Braun, Henry; Goftari, Mojgan; Palnitkar, Tara; Aman, Joshua E.; Schrock, Lauren E.; Cooper, Scott E.; Matsumoto, Joseph Y.; Vitek, Jerrold L.; Harel, Noam; Johnson, Matthew D.

doi:10.1016/j.brs.2023.02.002

Cited by 6 publications

(4 citation statements)

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“…Pathological tremor is linked to the cerebello–thalamo–cortical network 28 . The most plausible mechanism for the control of tremor with DBS is direct activation of the CBT pathway, 29 which can disrupt pathological co‐oscillatory activity of the deep cerebellar nuclei and the VIM nucleus of thalamus 4 . Numerous clinical studies have also demonstrated the efficacy of ZI DBS for the reduction of tremor 5,30,31 .…”

Section: Discussionmentioning

confidence: 99%

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation

Bingham,

McIntyre

2024

Movement Disorders

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BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) or ventral intermediate nucleus (VIM) are established targets for the treatment of Parkinson's disease (PD) or essential tremor (ET), respectively. However, DBS of the zona incerta (ZI) can be effective for both disorders. VIM DBS is assumed to achieve its therapeutic effect via activation of the cerebellothalamic (CBT) pathway, whereas the activation of the hyperdirect (HD) pathway likely plays a role in the mechanisms of STN DBS. Interestingly, HD pathway axons also emit collaterals to the ZI and red nucleus (RN) and the CBT pathway courses nearby to the ZI.ObjectiveThe aim was to examine the ability of ZI DBS to mutually activate the HD and CBT pathways in a detailed computational model of human DBS.MethodsWe extended a previous model of the human HD pathway to incorporate axon collaterals to the ZI and RN. The anatomical framework of the model system also included representations of the CBT pathway and internal capsule (IC) fibers of passage. We then performed detailed biophysical simulations to quantify DBS activation of the HD, CBT, and IC pathways with electrodes located in either the STN or ZI.ResultsSTN DBS and ZI DBS both robustly activated the HD pathway. However, STN DBS was limited by IC activation at higher stimulus amplitudes. Alternatively, ZI DBS avoided IC activation while simultaneously activating the HD and CBT pathways.ConclusionsFrom both neuroanatomical and biophysical perspectives, ZI DBS represents an advantageous target for coupled activation of the HD and CBT pathways. © 2024 International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 99%

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation

Bingham,

McIntyre

2024

Movement Disorders

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“…14 Results from DBS for both movement disorders and psychiatric conditions have demonstrated that activation of specific white matter tracts with stimulation may be crucial to improving specific clinical symptoms. [17][18][19] Prospective studies on clinical efficacy with tractography data incorporated may help further refine the optimal surgical target of cerebellar stimulation for spasticity.…”

Section: Tractography-based Dentate Nucleus Targetingmentioning

confidence: 99%

Neurosurgical treatment of spasticity: a potential return to the cerebellum

Cummins,

Park,

Panov

2024

Neurosurgical Focus

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OBJECTIVE Neurosurgical targeting of the cerebellar dentate nucleus via ablative dentatotomy and stimulation of the dentate nucleus was historically used for effective treatment of spasticity. Yet for decades, neurosurgical treatment of spasticity targeting the cerebellum was bypassed in favor of alternative treatments such as intrathecal baclofen pumps and selective dorsal rhizotomies. Cerebellar neuromodulation has recently reemerged as a promising and effective therapy for spasticity and related movement disorders. METHODS In this narrative review, the authors contextualize the historical literature of cerebellar neuromodulation, comparing it with modern approaches and exploring future directions with regard to cerebellar neuromodulation for spasticity. RESULTS Neurosurgical intervention on the cerebellum dates to the use of dentatotomy in the 1960s, which had progressed to electrical stimulation of the cerebellar cortex and dentate nucleus by the 1980s. By 2024, modern neurosurgical approaches such as tractography-based targeting of the dentate nucleus and transcranial magnetic stimulation of cerebellar cortex have demonstrated promise for treating spasticity. CONCLUSIONS Cerebellar neuromodulation of the dentate nucleus and cerebellar cortex are promising therapies for severe cases of spasticity. Open areas for exploration in the field include the following: tractography-based targeting, adaptive cerebellar stimulation, and investigations into the network dynamics between the cerebellar cortex, deep cerebellar nuclei, and the subcortical and cortical structures of the cerebrum.

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“…The contralateral deep cerebellar nuclei, the decussation of the superior cerebellar peduncle, and the ipsilateral red nucleus were segmented using the T1-and T2-MR images. Segmentation of the VIM of the thalamus was completed by resampling the T1-MR image to anterior commissure-posterior commissure (AC-PC) space and warping the Mai Atlas of the Human Brain to the T1-MRI images using fiducials placed within and on the thalamic border based on nucleispecific contrast within the thalamus (10,11,23,24).…”

Section: T Mr Imaging Acquisition and Active Contract Extractionmentioning

confidence: 99%

“…Activation of cerebellothalamic pathways with DBS has been associated with tremor reduction (8), and robust tremor suppression can be achieved via MR-guided focused ultrasound of the CTT in patients with chronic therapy-resistant ET (9). Similarly, in a computational study utilizing directional DBS leads and multicompartment neuron models of the thalamocortical, cerebellothalamic, and medial lemniscal pathways, tremor suppression was most closely associated with activation of the CTT (10,11). Further study is needed to build upon these studies to better understand the role of the CTT pathway over time.…”

Section: Introductionmentioning

confidence: 96%

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI

Ikramuddin,

Brinda,

Butler

et al. 2023

Front. Neurol.

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ObjectiveTo characterize how the proximity of deep brain stimulation (DBS) active contact locations relative to the cerebellothalamic tract (CTT) affect clinical outcomes in patients with essential tremor (ET).BackgroundDBS is an effective treatment for refractory ET. However, the role of the CTT in mediating the effect of DBS for ET is not well characterized. 7-Tesla (T) MRI-derived tractography provides a means to measure the distance between the active contact and the CTT more precisely.MethodsA retrospective review was conducted of 12 brain hemispheres in 7 patients at a single center who underwent 7T MRI prior to ventral intermediate nucleus (VIM) DBS lead placement for ET following failed medical management. 7T-derived diffusion tractography imaging was used to identify the CTT and was merged with the post-operative CT to calculate the Euclidean distance from the active contact to the CTT. We collected optimized stimulation parameters at initial programing, 1- and 2-year follow up, as well as a baseline and postoperative Fahn-Tolosa-Marin (FTM) scores.ResultsThe therapeutic DBS current mean (SD) across implants was 1.8 mA (1.8) at initial programming, 2.5 mA (0.6) at 1 year, and 2.9 mA (1.1) at 2-year follow up. Proximity of the clinically-optimized active contact to the CTT was 3.1 mm (1.2), which correlated with lower current requirements at the time of initial programming (R2 = 0.458, p = 0.009), but not at the 1- and 2-year follow up visits. Subjects achieved mean (SD) improvement in tremor control of 77.9% (14.5) at mean follow-up time of 22.2 (18.9) months. Active contact distance to the CTT did not predict post-operative tremor control at the time of the longer term clinical follow up (R2 = -0.073, p = 0.58).ConclusionActive DBS contact proximity to the CTT was associated with lower therapeutic current requirement following DBS surgery for ET, but therapeutic current was increased over time. Distance to CTT did not predict the need for increased current over time, or longer term post-operative tremor control in this cohort. Further study is needed to characterize the role of the CTT in long-term DBS outcomes.

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Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor

Cited by 6 publications

References 84 publications

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation

Neurosurgical treatment of spasticity: a potential return to the cerebellum

Active contact proximity to the cerebellothalamic tract predicts initial therapeutic current requirement with DBS for ET: an application of 7T MRI

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