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Increased structural connectivity of thalamic stimulation sites to motor cortex relates to tremor suppression.

ABSTRACT: Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM-DBS) is a highly successful treatment for medication-refractory essential tremor (ET). Clinical outcomes are dependent on accurate targeting. Here, we aim to develop a framework for connectivity-guided DBS targeting by evaluating probabilistic tractography and clinical response at both initial programming (IP) and clinical follow-up (CF). Magnetic resonance imaging and clinical outcomes were evaluated in 23 ET patients who were treated by VIM-DBS at the University of California Los Angeles (20 at IP, 18 at CF, 14 at both). Lead-DBS was used to model the volume of tissue activated tissue (VTA) based on programming configurations at both IP and CF. Probabilistic tractography, calculated in FSL, was used to evaluate 1) clinically weighted whole brain connectivity of VTA; 2) connectivity between VTA and freesurfer-derived target regions of interest (ROI) including primary motor, premotor, and prefrontal cortices, and cerebellum; and 3) volume of intersection between VTA and probabilistic tractography-based segmentation of the thalamus. At IP, individual contacts were scored as high or low efficacy based on acute tremor improvement. At CF, clinical response was measured by percent of change of the Clinical Rating Scale for Tremor (CRST) compared to preoperative scores. Contributions from each target ROI to clinical response was measured using logistic regression for IP and linear regression for CF. The clinically weighted map of whole brain connectivity of VTA shows preferential connectivity to precentral gyrus and brainstem/cerebellum. The volume of intersection between VTA and thalamic segmentation map based on probabilistic connectivity to primary motor cortex was a significant predictor of contact efficacy at IP (OR = 2.26 per 100 mm³ of overlap, p = .04) and percent change in CRST at CF (β = 14.67 per 100 mm³ of overlap, p = .003). Targeting DBS to the area of thalamus most connected to primary motor cortex based on probabilistic tractography is associated with superior outcomes, providing a potential guide not only for lead targeting but also therapeutic programming.

SUBMITTER: Riskin-Jones HH

PROVIDER: S-EPMC8024765 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing.

Project description:IntroductionEvidence has indicated a strong association between hyperactivity in the cerebello-thalamo-motor cortical loop and resting tremor in Parkinson's disease (PD). Within this loop, the thalamus serves as a central hub based on its structural centrality in the generation of resting tremor. To study whether this thalamic abnormality leads to an alteration at the whole-brain level, our study investigated the role of the thalamus in patients with parkinsonian resting tremor in a large-scale brain network context.MethodsForty-one patients with PD (22 with resting tremor, TP and 19 without resting tremor, NTP) and 45 healthy controls (HC) were included in this resting-state functional MRI study. Graph theory-based network analysis was performed to examine the centrality measures of bilateral thalami across the three groups. To further provide evidence to the central role of the thalamus in parkinsonian resting tremor, the seed-based functional connectivity analysis was then used to quantify the functional interactions between the basal ganglia and the thalamus.ResultsCompared with the HC group, patients with the TP group exhibited increased degree centrality (p < .04), betweenness centrality (p < .01), and participation coefficient (p < .01) in the bilateral thalami. Two of these alterations (degree centrality and participation coefficient) were significantly correlated with tremor severity, especially in the left hemisphere (p < .02). The modular analysis showed that the TP group had more intermodular connections between the thalamus and the regions within the cerebello-thalamo-motor cortical loop. Furthermore, the data revealed significantly enhanced functional connectivity between the putamen and the thalamus in the TP group (p = .027 corrected for family-wise error).ConclusionsThese findings suggest increased thalamic centrality as a potential tremor-specific imaging measure for PD, and provide evidence for the altered putamen-thalamic interaction in patients with resting tremor.

Project description:Ventral intermediate thalamic deep brain stimulation is a standard therapy for the treatment of medically refractory essential tremor and tremor-dominant Parkinson's disease. Despite the therapeutic benefits, the mechanisms of action are varied and complex, and the pathophysiology and genesis of tremor remain unsubstantiated. This intraoperative study investigated the effects of high frequency microstimulation on both neuronal firing and tremor suppression simultaneously. In each of nine essential tremor and two Parkinson's disease patients who underwent stereotactic neurosurgery, two closely spaced (600 µm) microelectrodes were advanced into the ventral intermediate nucleus. One microelectrode recorded action potential firing while the adjacent electrode delivered stimulation trains at 100 Hz and 200 Hz (2-5 s, 100 µA, 150 µs). A triaxial accelerometer was used to measure postural tremor of the contralateral hand. At 200 Hz, stimulation led to 68 ± 8% (P < 0.001) inhibition of neuronal firing and a 53 ± 5% (P < 0.001) reduction in tremor, while 100 Hz reduced firing by 26 ± 12% (not significant) with a 17 ± 6% (P < 0.05) tremor reduction. The degree of cell inhibition and tremor suppression were significantly correlated (P < 0.001). We also found that the most ventroposterior stimulation sites, closest to the border of the ventral caudal nucleus, had the best effect on tremor. Finally, prior to the inhibition of neuronal firing, microstimulation caused a transient driving of neuronal activity at stimulus onset (61% of sites), which gave rise to a tremor phase reset (73% of these sites). This was likely due to activation of the excitatory glutamatergic cortical and cerebellar afferents to the ventral intermediate nucleus. Temporal characteristics of the driving responses (duration, number of spikes, and onset latency) significantly differed between 100 Hz and 200 Hz stimulation trains. The subsequent inhibition of neuronal activity was likely due to synaptic fatigue. Thalamic neuronal inhibition seems necessary for tremor reduction and may function in effect as a thalamic filter to uncouple thalamo-cortical from cortico-spinal reflex loops. Additionally, our findings shed light on the gating properties of the ventral intermediate nucleus within the cerebello-thalamo-cortical tremor network, provide insight for the optimization of deep brain stimulation technologies, and may inform controlled clinical studies for assessing optimal target locations for the treatment of tremor.

Project description:Chronic refractory central post-stroke pain (CPSP), one of the most disabling consequences of cerebral stroke, occurs in up to 10% of patients with CPSP. Because a considerable proportion of these patients with chronic pain remain resistant to pharmacological and behavioral therapies, adjunctive invasive and non-invasive brain stimulation therapies are needed. We performed a review of human studies applying burst and conventional motor cortex stimulation (burstMCS and cMCS, respectively) for chronic pain states, on the basis of data sources identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, as well as manual searches of the bibliographies of known primary and review articles. Our aim was to review and discuss clinical data on the indications of burstMCS for various chronic pain states originating from central stroke (excluding trigeminal facial pain). In addition, we assessed the efficacy and safety of burst versus cMCS for central post-stroke pain with an extended follow-up of 5 years in a 60-year-old man. According to our review, uncontrolled observational human cohort studies and one RCT using cMCS waveforms have revealed a meaningful clinical response; however, these studies lacked placebo groups and extended observation periods. In our case report, we found that 3 months of adjunctive cMCS reduced pain levels [visual analog scale (VAS) pre: 9/10 versus VAS post 7/10], whereas the pain decreased further under burstMCS (VAS pre: 7/10 versus VAS post: 2/10); the study involved a follow-up of 5 years and the following parameters: burst rate 40 Hz (500 Hz), 1-1.75 mA, 1 ms, bipolar configuration. To date, only limited evidence exists for the efficacy and safety of burst motor cortex stimulation for the treatment of refractory chronic pain. BurstMCS resulted in significantly decreased post-stroke pain observed after 5 years of cMCS. The available literature suggests similar efficacy as that of conventional (tonic) motor cortex stimulation, although the results are preliminary. Mechanistically, the precise mechanism of action is not fully understood. However, burstMCS may interact with the nociceptive thalamic-cingulate and descending spinal pain networks. To determine the potential utility of this treatment, large-scale sham-controlled trials comparing cMCS and burstMCS are highly recommended.

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Increased structural connectivity of thalamic stimulation sites to motor cortex relates to tremor suppression.

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