BOLD frequency-dependent alterations in resting-state functional connectivity by pallidal deep brain stimulation in patients with Parkinson's disease.

OBJECTIVE: Functional MRI (fMRI) has been used to investigate the therapeutic mechanisms underlying deep brain stimulation (DBS) for Parkinson's disease (PD). However, the alterations in stimulation site-seeded functional connectivity induced by DBS at the internal globus pallidus (GPi) remain unclear. Furthermore, whether DBS-modulated functional connectivity is differentially affected within particular frequency bands remains unknown. The present study aimed to reveal the alterations in stimulation site-seeded functional connectivity induced by GPi-DBS and to examine whether there exists a frequency band effect in blood oxygen level-dependent (BOLD) signals related to DBS. METHODS: Patients with PD receiving GPi-DBS (n = 28) were recruited for resting-state fMRI with DBS on and DBS off under a 1.5-T MR scanner. Age- and sex-matched healthy controls (n = 16) and DBS-naïve PD patients (n = 24) also received fMRI scanning. The alterations in stimulation site-seeded functional connectivity in the stimulation-on state versus stimulation-off state, as well as the relationship between alterations in connectivity and improvement in motor function induced by GPi-DBS, were examined. Furthermore, the modulatory effect of GPi-DBS on the BOLD signals within the 4 frequency subbands (slow-2 to slow-5) was investigated. Finally, the functional connectivity of the motor-related network, consisting of multiple cortical and subcortical regions, was also examined among the groups. In this study, p < 0.05 with Gaussian random field correction indicates statistical significance. RESULTS: Functional connectivity seeding from the stimulation site (i.e., the volume of tissue activated [VTA]) increased in the cortical sensorimotor areas and decreased in the prefrontal regions with GPi-DBS. Alterations in connectivity between the VTA and the cortical motor areas were correlated with motor improvement by pallidal stimulation. The alterations in connectivity were dissociable between the frequency subbands in the occipital and cerebellar areas. The motor network analysis indicated decreased connectivity among most cortical and subcortical regions but increased connectivity between the motor thalamus and the cortical motor area in patients with GPi-DBS compared with those in DBS-naïve patients. The DBS-induced decrease in several cortical-subcortical connectivities within the slow-5 band correlated with motor improvement with GPi-DBS. CONCLUSIONS: These findings indicate that the alterations in functional connectivity from the stimulation site to the cortical motor areas, as well as multiple connectivities among the motor-related network, were associated with the efficacy of GPi-DBS for PD. Furthermore, the changing pattern of functional connectivity within the 4 BOLD frequency subbands is partially dissociable.

Mechanisms underlying capsulotomy for refractory obsessive-compulsive disorder: neural correlates of negative affect processing overlap with deep brain stimulation targets.

Ablative procedures such as anterior capsulotomy are potentially effective in refractory obsessive-compulsive disorder (OCD). Converging evidence suggests the ventral internal capsule white matter tracts traversing the rostral cingulate and ventrolateral prefrontal cortex and thalamus is the optimal target for clinical efficacy across multiple deep brain stimulation targets for OCD. Here we ask which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy by using both task fMRI and neuropsychological tests assessing OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted in capsulotomy. We tested OCD patients at least 6 months post-capsulotomy (n = 27), OCD controls (n = 33) and healthy controls (n = 34). We used a modified aversive monetary incentive delay paradigm with negative imagery and a within session extinction trial. Post-capsulotomy OCD subjects showed improved OCD symptoms, disability and quality of life with no differences in mood or anxiety or cognitive task performance on executive, inhibition, memory and learning tasks. Task fMRI revealed post-capsulotomy decreases in the nucleus accumbens during negative anticipation, and in the left rostral cingulate and left inferior frontal cortex during negative feedback. Post-capsulotomy patients showed attenuated accumbens-rostral cingulate functional connectivity. Rostral cingulate activity mediated capsulotomy improvement on obsessions. These regions overlap with optimal white matter tracts observed across multiple stimulation targets for OCD and might provide insights into further optimizing neuromodulation approaches. Our findings also suggest that aversive processing theoretical mechanisms may link ablative, stimulation and psychological interventions.

Subthalamic and Pallidal Stimulations in Patients with Parkinson's Disease: Common and Dissociable Connections.

OBJECTIVE: The subthalamic nucleus (STN) and internal globus pallidus (GPi) are the most effective targets in deep brain stimulation (DBS) for Parkinson's disease (PD). However, the common and specific effects on brain connectivity of stimulating the 2 nuclei remain unclear. METHODS: Patients with PD receiving STN-DBS (n = 27, 6 women, mean age 64.8 years) or GPi-DBS (n = 28, 13 women, mean age 64.6 years) were recruited for resting-state functional magnetic resonance imaging to assess the effects of STN-DBS and GPi-DBS on brain functional dynamics. RESULTS: The functional connectivity both between the somatosensory-motor cortices and thalamus, and between the somatosensory-motor cortices and cerebellum decreased in the DBS-on state compared with the off state (p < 0.05). The changes in thalamocortical connectivity correlated with DBS-induced motor improvement (p < 0.05) and were negatively correlated with the normalized intersection volume of tissues activated at both DBS targets (p < 0.05). STN-DBS modulated functional connectivity among a wider range of brain areas than GPi-DBS (p = 0.009). Notably, only STN-DBS affected connectivity between the postcentral gyrus and cerebellar vermis (p < 0.001) and between the somatomotor and visual networks (p < 0.001). INTERPRETATION: Our findings highlight common alterations in the motor pathway and its relationship with the motor improvement induced by both STN- and GPi-DBS. The effects on cortico-cerebellar and somatomotor-visual functional connectivity differed between groups, suggesting differentiated neural modulation of the 2 target sites. Our results provide mechanistic insight and yield the potential to refine target selection strategies for focal brain stimulation in PD. ANN NEUROL 2021;90:670-682.

Neuroanatomical Substrates and Predictors of Response to Capsulotomy in Intractable Obsessive-Compulsive Disorder.

BACKGROUND: Anterior capsulotomy that surgically targets fiber tracts connecting prefrontal cortex and subcortical nuclei is a therapeutic option for a subgroup of patients with treatment-refractory obsessive-compulsive disorder. The goal of this study was to investigate neural correlates to anterior capsulotomy and find predictors of clinical improvement following this procedure. METHODS: Structural and diffusion imaging data and clinical evaluation were acquired from 31 patients with refractory obsessive-compulsive disorder who underwent anterior capsulotomy. Of the 31 patients, 16 were clinical responders defined by a ≥35% reduction in the Yale-Brown Obsessive Compulsive Scale scores. Analysis of variance was applied on 2 levels (surgery and response) to examine alterations of gray matter volume and fiber tract integrity (measured by generalized fractional anisotropy). The correlation between preoperative data and clinical response was further investigated. RESULTS: After surgery, generalized fractional anisotropy was significantly decreased in the bilateral anterior limb of the internal capsule and anterior thalamic radiation, accompanied by a decrease in gray matter volume in the prefrontal cortex, anterior cingulate cortex, striatum, thalamus, and cerebellum. Moreover, atrophy of the right caudate was greater in responders than in nonresponders, which correlated with alteration in Yale-Brown Obsessive Compulsive Scale score. In addition, preoperative gray matter volume in the right inferior frontal gyrus and generalized fractional anisotropy in the left superior longitudinal fasciculus and right cingulum predicted improved response. More anterior location of the lesion area predicted better clinical response. CONCLUSIONS: These results demonstrate that reduced volume of the right caudate might be associated with therapeutic response of capsulotomy and might offer a potential predictor of treatment outcome and a guide for lesion site.

Deep Brain Stimulation and Thalamotomy for the Treatment of Dystonia Acquired by Moyamoya Disease with Stroke.

Background: Moyamoya disease (MMD) is a type of chronic cerebrovascular disease. Currently, revascularization surgery including direct/indirect procedure is recommended for symptomatic patients. However, some patients still respond poorly to the treatment or develop secondary symptoms. Case report: We report the first case of an MMD patient treated with deep brain stimulation (DBS) and thalamotomy. Symptoms of dystonia due to hemorrhage in the thalamus responded poorly to revascularization surgery, but were considerably alleviated by stereotactic neurosurgery. Discussion: Our case report provides a potential strategy for management of refractory symptomatic MMD patients with dystonia and also supports the combined efficacy of DBS with thalamotomies. Highlights: Approximately 30% of patients with Moyamoya disease (MMD) presenting movement symptoms do not respond well to revascularization surgery. We reported an MMD patient treated with deep brain stimulation (DBS) and thalamotomy with significant dystonia and dystonic tremor symptom amelioration. It indicates that DBS or stereotactic lesioning might be a potential treatment for the refractory movement symptoms of MMD.

Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study.

BACKGROUND: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

Divergent Structural Responses to Pharmacological Interventions in Orbitofronto-Striato-Thalamic and Premotor Circuits in Obsessive-Compulsive Disorder.

Prior efforts to dissect etiological and pharmacological modulations in brain morphology in obsessive-compulsive disorder (OCD) are often undermined by methodological and sampling constraints, yielding conflicting conclusions and no reliable neuromarkers. Here we evaluated alteration of regional gray matter volume including effect size (Cohen's d value) in 95 drug-naïve patients (age range: 18-55) compared to 95 healthy subjects (age: 18-63), then examined pharmacological effects in 65 medicated (age: 18-57) and 73 medication-free patients (age: 18-61). Robustness of statistical outcomes and effect sizes was rigorously tested with Monte Carlo cross-validation. Relative to controls, both drug-naïve and medication-free patients exhibited comparable volumetric increases mainly in the left thalamus (d=0.90, 0.82, respectively), left ventral striatum (d=0.88, 0.67), bilateral medial orbitofrontal cortex (d=0.86, 0.71; 0.90, 0.73), and left inferior temporal gyrus (d=0.83, 0.66), and decreased volumes in left premotor/presupplementary motor areas (d=-0.83, -0.71). Interestingly, abnormalities in the thalamus and medial orbitofrontal cortex were present in medicated patients whereas entirely absent in premotor and ventral striatum. It suggests that pharmacotherapy elicited divergent responses in orbitofronto-striato-thalamic and premotor circuits, which warrants the design of longitudinal studies investigating the potential of these neuromarkers in stratified treatments of OCD.