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Introduction: Deep Brain Stimulation (DBS) of the (sub)thalamic nucleus has been shown to be an effective treatment in medication-refractory Essential Tremor (ET). However, studies have reported a DBS-induced ataxia in some patients which can onset years after the start of DBS-therapy. In the ongoing debate on the cause a functional disruption of the cerebello-thalamo-cortical network is considered. In a previous study regions linked to stimulation induced side effects in the SCN, primary motor cortex, putamen, red nucleus and the posterior parietal cortex were identified. In this study we aim to test if the proposed connectivity to these nodes is associated with side-effects and could enable patient individual risk-predictions. Materials & Methods: In this study 50 patients (27 males; age 66±10 years; disease duration: 33±19 years) with Essential Tremor and bilateral thalamic DBS were clinically examined based on videos before surgery and at a follow up at least 3 years later using the Fahn-Tolosa-Martin scale (FTM) and the first three items of the scale for the assessment and rating of ataxia (SARA). Structural connectivity was estimated using a normative connectome and seeding the individual volumes of tissue activated (VTAs). Connectivity to the cortical regions previously linked to side effects was compared to the long-term tremor improvement as well to symptoms of ataxia. Based on an ordinal logistic regression analysis the best prediction model using patients' connectivity to these regions was identified. Using data of 40 randomly selected patients of the cohort to train the algorithm it was then tested against the remaining 10 patients. Results: On average tremor improved by 11±10 points on the FTM-scale and the SARA-score worsened by -2±2 points. Mild ataxia occurred in 21 patients and 5 patients showed severe ataxia. The normative structural connectivity to the entirety of the nodes correlated significantly to a worsening of ataxia (p < 0.01) but not to overall tremor control (p = 0.34). The best network-model prediction was based on connectivity to nodes in the primary motor cortex and the posterior parietal cortex and was able to correctly predict and categorize side effects in 7 out of 10 patients of the test cohort. Conclusion: This study supports the association of the predescribed cortical nodes to a network tied to stimulation induced ataxia side-effects in ET-patients. The results indicate that models based on the connectivity to this network could aid in the risk assessment of patients and improve individual outcome in the future. [ABSTRACT FROM AUTHOR]

Background: The thalamic ventral intermediate (Vim) nucleus is part of a network that appears to be disrupted in essential tremor (ET) and is the most relevant target of functional neurosurgery to alleviate ET symptoms. As the most important afferent of the VIM, the cerebellothalamic tract (CTT) transmits information from cerebellar nuclei. Disruption of this tract - in the past via subthalatomies and in the present via deep brain stimulation is considered the best option of tremor treatment, partly because of the high anatomical density of CTT fibers before entering the VIM, and partly because of the greater distance to sensory thalamic nuclei. Recently, initial pilot studies have also documented transcranial MRI-guided high-intensity focused ultrasound (MRIgFUS) as an effective treatment modality. Unilateral MRIgFUS lesioning was highly efficacious in reducing contralateral hand tremor in ET with mild and transient adverse effects. However, targeting of MRIgFUS has so far been based on MRI imaging without dedicated evidence of the underlying connectome. Here, we test a method for quantitative analysis of the involved fiber tracts and test whether the measured clinical effect correlates with overlap of the set lesion with individual fiber tracts, such as CTT. Materials and Methods: We revisited pre- and post-procedural MRIs of 6 ET patients (Øage 70,7 (± 8,5) years , Ø Tremor rating (TR) (pre): 43,8 (± 9,8)) who underwent unilateral ablation of the CTT by MRIgFUS. The images, obtained 48 hours (48H) and 3-6 months (3M+) after the procedure, were used to create 3D-models of the lesions which were localized within MNI-space with the pre-procedural MRI and atlas registration using Suretune®. The models were subsequently used to calculate interferences with fiber tracts. A linear model was employed to assess the correlation between the quantitative interference and improvement of the clinical score at two timepoints after the procedure (48H, n=6: TR: 16,7 (±5,5) ; 3M+, n= 5: TR: 19,2 (±7,2)). Results: The lesions volume differed between the 48H (Ø 281.78mm3(±77.77), n=6) and 3M+(Ø 53.82mm3(±22), n=5) conditions (p<0.01). After 48H primarily the CTT (Ø72,4 % (±34)) but also the M1 (Ø36,05 % (±43)) interfered, while after 3M+ the overlap reduced tremendously for the CTT (Ø1% (±1,6), p=0.017) and slightly for the M1(Ø26,7% (±28,4), p=0.67). Preliminary results could not show a correlation between the observed clinical improvement with the interference of the lesions with a specific tract. Discussion: Interestingly, there is no clear correlation between clinical outcome and the overlap between the lesion placed by MRIgFUS and the fibers of the CTT. This might indicate that the observed clinical effect would have to be explained only partially by the targeted CTT but also by other fiber tracts. The data set was too small for a meaningful multivariate regression analysis, but pooling data sets from different centers may mean a solution to this problem in the future. [ABSTRACT FROM AUTHOR]

Introduction: Nucleus Basalis of Meynert (NBM) is a cholinergic relay in the basal forebrain that has a role in cognition. Postmortem studies reveal projections to cortical and subcortical cognitive-related areas. In cases of Alzheimer's and Parkinson's disease dementia (PDD) patients, it suffers cellular degeneration[1]. Deep Brain Stimulation (DBS) of NBM is an experimental treatment for cognitive impairment symptoms of dementia, with however variable effects across different centers[2]. Objective: Through structural and functional connectomic analytics, we aim to explore the widespread connectivity achieved through NBM-DBS and potentially identify stimulation locations within the nucleus responsible for optimal clinical effect. Patients and Methods: 10 PDD patients that underwent a Phase Ib clinical trial at Würzburg University Hospital receiving bilateral NBM-DBS were retrospectively analyzed. Image co-registration and local neurostimulation effects were computed using Brainlab GuideXT software. Normative functional and structural connectome templates were applied for connectivity analysis. Data-driven (voxel-wise t-test, Threshold-Free Cluster Enhancement) and hypothesis-driven analyses were employed. Corresponding patientś clinical impression scores were correlated on each of their Volume of Tissue Activated (VTA) and a beneficial implantation spot in the nucleus was calculated. Results: NBM-DBS enhances fiber projections to the network of Papez and other cognitive-related regions. Amygdala, fornix, subiculum, and parietal, cingulate, occipital and temporal cortices received significantly high structural connectivity through NBM-DBS (p<0.05). In areas like the ventromedial pre-frontal cortex and insula that displayed no significance in structural connectivity, high functional correlation (p<0.05) could be detected. VTAs of subjects with beneficial outcomes demonstrate an inferolateral clustering within the intermediate sector of NMB (p=0.04 on x axis). Better modulation of the memory circuit described by Ferguson et al.[3] was correlated with this beneficial VTA location. Conclusion: NBM-DBS is associated with widespread structural and functional connectivity in cortical and subcortical areas involved in cognition. The precise location within the NBM could be crucial for clinical efficacy. An inferolateral targeting approach within the intermediate sector of the nucleus might result in a better clinical effect. References [1] Gratwicke et al., "The nucleus basalis of Meynert: A new target for deep brain stimulation in dementia?," Neurosci. Biobehav. Rev., vol. 37, no. 10, pp. 2676–2688, 2013. [2] Nazmuddin, I. H. C. H. M. Philippens, and T. van Laar, "Electrical stimulation of the nucleus basalis of meynert: a systematic review of preclinical and clinical data," Sci. Rep., vol. 11, no. 1, pp. 1–14, 2021. [3] Ferguson et al., "A human memory circuit derived from brain lesions causing amnesia," Nat. Commun., vol. 10, no. 1, pp. 1–9, 2019. [ABSTRACT FROM AUTHOR]