Directional deep brain stimulation electrodes in Parkinson's disease: meta-analysis and systematic review of the literature.

BACKGROUND: Since their introduction in 2015, directional leads have practically replaced conventional leads for deep brain stimulation (DBS) in Parkinson's disease (PD). Yet, the benefits of directional DBS (dDBS) over omnidirectional DBS (oDBS) remain unclear. This meta-analysis and systematic review compares the literature on dDBS and oDBS for PD. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Database searches included Pubmed, Cochrane (CENTRAL) and EmBase, using relevant keywords such as 'directional', 'segmented', 'brain stimulation' and 'neuromodulation'. The screening was based on the title and abstract. RESULTS: 23 papers reporting on 1273 participants (1542 leads) were included. The therapeutic window was 0.70 mA wider when using dDBS (95% CI 0.13 to 1.26 mA, p=0.02), with a lower therapeutic current (0.41 mA, 95% CI 0.27 to 0.54 mA, p=0.01) and a higher side-effect threshold (0.56 mA, 95% CI 0.38 to 0.73 mA, p<0.01). However, there was no relevant difference in mean Unified Parkinson's Disease Rating Scale III change after dDBS (45.8%, 95% CI 30.7% to 60.9%) compared with oDBS (39.0%, 95% CI 36.9% to 41.2%, p=0.39), in the medication-OFF state. Median follow-up time for dDBS and oDBS studies was 6 months and 3 months, respectively (range 3-12 for both). The use of directionality often improves dyskinesia, dysarthria, dysesthesia and pyramidal side effects. Directionality was used in 55% of directional leads at 3-6 months, remaining stable over time (56% at a mean of 14.1 months). CONCLUSIONS: These findings suggest that stimulation parameters favour dDBS. However, these do not appear to have a significant impact on motor scores, and the availability of long-term data is limited. dDBS is widely accepted, but clinical data justifying its increased complexity and cost are currently sparse. PROSPERO REGISTRATION NUMBER: CRD42023438056.

Conflict Detection in a Sequential Decision Task Is Associated with Increased Cortico-Subthalamic Coherence and Prolonged Subthalamic Oscillatory Response in the ß Band.

Making accurate decisions often involves the integration of current and past evidence. Here, we examine the neural correlates of conflict and evidence integration during sequential decision-making. Female and male human patients implanted with deep-brain stimulation (DBS) electrodes and age-matched and gender-matched healthy controls performed an expanded judgment task, in which they were free to choose how many cues to sample. Behaviorally, we found that while patients sampled numerically more cues, they were less able to integrate evidence and showed suboptimal performance. Using recordings of magnetoencephalography (MEG) and local field potentials (LFPs; in patients) in the subthalamic nucleus (STN), we found that ß oscillations signaled conflict between cues within a sequence. Following cues that differed from previous cues, ß power in the STN and cortex first decreased and then increased. Importantly, the conflict signal in the STN outlasted the cortical one, carrying over to the next cue in the sequence. Furthermore, after a conflict, there was an increase in coherence between the dorsal premotor cortex and STN in the ß band. These results extend our understanding of cortico-subcortical dynamics of conflict processing, and do so in a context where evidence must be accumulated in discrete steps, much like in real life. Thus, the present work leads to a more nuanced picture of conflict monitoring systems in the brain and potential changes because of disease.SIGNIFICANCE STATEMENT Decision-making often involves the integration of multiple pieces of information over time to make accurate predictions. We simultaneously recorded whole-head magnetoencephalography (MEG) and local field potentials (LFPs) from the human subthalamic nucleus (STN) in a novel task which required integrating sequentially presented pieces of evidence. Our key finding is prolonged ß oscillations in the STN, with a concurrent increase in communication with frontal cortex, when presented with conflicting information. These neural effects reflect the behavioral profile of reduced tendency to respond after conflict, as well as relate to suboptimal cue integration in patients, which may be directly linked to clinically reported side-effects of deep-brain stimulation (DBS) such as impaired decision-making and impulsivity.

Trigeminal microvascular decompression for short-lasting unilateral neuralgiform headache attacks.

A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single-centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic short-lasting unilateral neuralgiform headache attacks with MRI evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an 'excellent response', defined as 90-100% weekly reduction in attack frequency, or 'good response', defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients, of whom 31 had short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and 16 had short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. MRI of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Postoperatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing = 7 and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms = 3) reported no postoperative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing and short-lasting unilateral neuralgiform headache attacks in the response to surgery (P = 0.463). Responders at the last follow-up were, however, more likely to not have interictal pain (77.42% versus 22.58%, P = 0.021) and to show morphological changes on the MRI (78.38% versus 21.62%, P = 0.001). The latter outcome was confirmed in the Kaplan-Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (P = 0.0001). All but one patient, who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for patients suffering short-lasting unilateral neuralgiform headache attacks with MRI evidence of neurovascular conflict with morphological changes.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson's disease.

Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson's disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson's disease, and that together these different states predict motor impairment with high fidelity. Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients' hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

Deep brain stimulation for refractory obsessive-compulsive disorder (OCD): emerging or established therapy?

A consensus has yet to emerge whether deep brain stimulation (DBS) for treatment-refractory obsessive-compulsive disorder (OCD) can be considered an established therapy. In 2014, the World Society for Stereotactic and Functional Neurosurgery (WSSFN) published consensus guidelines stating that a therapy becomes established when "at least two blinded randomized controlled clinical trials from two different groups of researchers are published, both reporting an acceptable risk-benefit ratio, at least comparable with other existing therapies. The clinical trials should be on the same brain area for the same psychiatric indication." The authors have now compiled the available evidence to make a clear statement on whether DBS for OCD is established therapy. Two blinded randomized controlled trials have been published, one with level I evidence (Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score improved 37% during stimulation on), the other with level II evidence (25% improvement). A clinical cohort study (N = 70) showed 40% Y-BOCS score improvement during DBS, and a prospective international multi-center study 42% improvement (N = 30). The WSSFN states that electrical stimulation for otherwise treatment refractory OCD using a multipolar electrode implanted in the ventral anterior capsule region (including bed nucleus of stria terminalis and nucleus accumbens) remains investigational. It represents an emerging, but not yet established therapy. A multidisciplinary team involving psychiatrists and neurosurgeons is a prerequisite for such therapy, and the future of surgical treatment of psychiatric patients remains in the realm of the psychiatrist.

Cortical connectivity of the nucleus basalis of Meynert in Parkinson's disease and Lewy body dementias.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are related conditions that are associated with cholinergic system dysfunction. Dysfunction of the nucleus basalis of Meynert (NBM), a basal forebrain structure that provides the dominant source of cortical cholinergic innervation, has been implicated in the pathogenesis of both PDD and DLB. Here we leverage the temporal resolution of magnetoencephalography with the spatial resolution of MRI tractography to explore the intersection of functional and structural connectivity of the NBM in a unique cohort of PDD and DLB patients undergoing deep brain stimulation of this structure. We observe that NBM-cortical structural and functional connectivity correlate within spatially and spectrally segregated networks including: (i) a beta band network to supplementary motor area, where activity in this region was found to drive activity in the NBM; (ii) a delta/theta band network to medial temporal lobe structures encompassing the parahippocampal gyrus; and (iii) a delta/theta band network to visual areas including lingual gyrus. These findings reveal functional networks of the NBM that are likely to subserve important roles in motor control, memory and visual function, respectively. Furthermore, they motivate future studies aimed at disentangling network contribution to disease phenotype.

Volitional Control of Brain Motor Activity and Its Therapeutic Potential.

BACKGROUND: Neurofeedback training is a closed-loop neuromodulatory technique in which real-time feedback of brain activity and connectivity is provided to the participant for the purpose of volitional neural control. Through practice and reinforcement, such learning has been shown to facilitate measurable changes in brain function and behavior. OBJECTIVES: In this review, we examine how neurofeedback, coupled with motor imagery training, has the potential to improve or normalize motor function in neurological diseases such as Parkinson disease and chronic stroke. We will also explore neurofeedback in the context of brain-machine interfaces (BMIs), discussing both noninvasive and invasive methods which have been used to power external devices (eg, robot hand orthosis or exoskeleton) in the context of motor neurorehabilitation. CONCLUSIONS: The published literature provides mounting high-quality evidence that neurofeedback and BMI control may lead to clinically relevant changes in brain function and behavior.

Long term evaluation of a multidisciplinary trigeminal neuralgia service.

BACKGROUND: Trigeminal neuralgia is an episodic severe neuralgic pain and can be managed both medically and surgically. If possible, this should be directed by a Multidisciplinary Team (MDT) of specialised surgeons, physicians, dentists, psychologists and specialist nurses with access to all treatment modalities, which enables patients to make an informed decision about their future management. OBJECTIVE: The aim of this study was to review the outcomes of patients managed by an MDT clinic, in a single institute over an eleven-year period. METHODS: A prospective database was used to identify patients with trigeminal neuralgia or its variants who had attended a joint MDT clinic. The electronic notes were examined for demographics, onset and duration of trigeminal neuralgia, medications history, pain scores and details of surgical procedures if any by two independent assessors. RESULTS: Three hundred thirty-four patients attended the MDT between 2008-2019. Forty-nine of them had surgery before being referred to the service and were included but analysed as a subgroup. Of the remaining patients, 54% opted to have surgery following the MDT either immediately or at a later date. At the last reported visit 55% of patients who opted to have surgery were pain free and off medications, compared to 15.5% of medically managed patients. Surgical complications were mostly attributable to numbness and in the majority of cases this was temporary. All patients who were not pain free, had complications after surgery or opted to remain on medical therapy were followed up in a facial pain clinic which has access to pain physicians, clinical nurse specialists and a tailored pain management program. Regular patient related outcome measures are collected to evaluate outcomes. CONCLUSION: An MDT clinic offers an opportunity for shared decision making with patients deciding on their personal care pathway which is valued by patients. Not all patients opt for surgery, and some continue to attend a multidisciplinary follow up program. Providing a full range of services including psychological support, improves outcomes.

Entraining Stepping Movements of Parkinson's Patients to Alternating Subthalamic Nucleus Deep Brain Stimulation.

Patients with advanced Parkinson's can be treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson's patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients' stepping movements as evidence of the STN's involvement in stepping control. Group analyses of 10 Parkinson's patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study suggests that the STN is causally involved in dynamic control of step timing and motivates further exploration of this biomimetic stimulation pattern as a potential basis for the development of DBS strategies to ameliorate gait impairments.SIGNIFICANCE STATEMENT We tested whether the subthalamic nucleus (STN) in humans is causally involved in controlling stepping movements. To this end, we studied patients with Parkinson's disease who have undergone therapeutic deep brain stimulation (DBS), as in these individuals we can stimulate the STNs in a controlled manner. We developed an alternating pattern of stimulation that mimics the pattern of activity modulation recorded in this nucleus during stepping. The alternating DBS (altDBS) could entrain patients' stepping rhythm, suggesting a causal role of the STN in dynamic gait control. This type of stimulation may potentially form the basis for improved DBS strategies for gait.

Ventralis intermedius nucleus anatomical variability assessment by MRI structural connectivity.

The ventralis intermedius nucleus (Vim) is centrally placed in the dentato-thalamo-cortical pathway (DTCp) and is a key surgical target in the treatment of severe medically refractory tremor. It is not visible on conventional MRI sequences; consequently, stereotactic targeting currently relies on atlas-based coordinates. This fails to capture individual anatomical variability, which may lead to poor long-term clinical efficacy. Probabilistic tractography, combined with known anatomical connectivity, enables localisation of thalamic nuclei at an individual subject level. There are, however, a number of confounds associated with this technique that may influence results. Here we focused on an established method, using probabilistic tractography to reconstruct the DTCp, to identify the connectivity-defined Vim (cd-Vim) in vivo. Using 100 healthy individuals from the Human Connectome Project, our aim was to quantify cd-Vim variability across this population, measure the discrepancy with atlas-defined Vim (ad-Vim), and assess the influence of potential methodological confounds. We found no significant effect of any of the confounds. The mean cd-Vim coordinate was located within 1.88 mm (left) and 2.12 mm (right) of the average midpoint and 3.98 mm (left) and 5.41 mm (right) from the ad-Vim coordinates. cd-Vim location was more variable on the right, which reflects hemispheric asymmetries in the probabilistic DTC reconstructed. The method was reproducible, with no significant cd-Vim location differences in a separate test-retest cohort. The superior cerebellar peduncle was identified as a potential source of artificial variance. This work demonstrates significant individual anatomical variability of the cd-Vim that atlas-based coordinate targeting fails to capture. This variability was not related to any methodological confound tested. Lateralisation of cerebellar functions, such as speech, may contribute to the observed asymmetry. Tractography-based methods seem sensitive to individual anatomical variability that is missed by conventional neurosurgical targeting; these findings may form the basis for translational tools to improve efficacy and reduce side-effects of thalamic surgery for tremor.

Clinical applications of magnetic resonance imaging based functional and structural connectivity.

Advances in computational neuroimaging techniques have expanded the armamentarium of imaging tools available for clinical applications in clinical neuroscience. Non-invasive, in vivo brain MRI structural and functional network mapping has been used to identify therapeutic targets, define eloquent brain regions to preserve, and gain insight into pathological processes and treatments as well as prognostic biomarkers. These tools have the real potential to inform patient-specific treatment strategies. Nevertheless, a realistic appraisal of clinical utility is needed that balances the growing excitement and interest in the field with important limitations associated with these techniques. Quality of the raw data, minutiae of the processing methodology, and the statistical models applied can all impact on the results and their interpretation. A lack of standardization in data acquisition and processing has also resulted in issues with reproducibility. This limitation has had a direct impact on the reliability of these tools and ultimately, confidence in their clinical use. Advances in MRI technology and computational power as well as automation and standardization of processing methods, including machine learning approaches, may help address some of these issues and make these tools more reliable in clinical use. In this review, we will highlight the current clinical uses of MRI connectomics in the diagnosis and treatment of neurological disorders; balancing emerging applications and technologies with limitations of connectivity analytic approaches to present an encompassing and appropriate perspective.

Normative vs. patient-specific brain connectivity in deep brain stimulation.

Brain connectivity profiles seeding from deep brain stimulation (DBS) electrodes have emerged as informative tools to estimate outcome variability across DBS patients. Given the limitations of acquiring and processing patient-specific diffusion-weighted imaging data, a number of studies have employed normative atlases of the human connectome. To date, it remains unclear whether patient-specific connectivity information would strengthen the accuracy of such analyses. Here, we compared similarities and differences between patient-specific, disease-matched and normative structural connectivity data and their ability to predict clinical improvement. Data from 33 patients suffering from Parkinson's Disease who underwent surgery at three different centers were retrospectively collected. Stimulation-dependent connectivity profiles seeding from active contacts were estimated using three modalities, namely patient-specific diffusion-MRI data, age- and disease-matched or normative group connectome data (acquired in healthy young subjects). Based on these profiles, models of optimal connectivity were calculated and used to estimate clinical improvement in out of sample data. All three modalities resulted in highly similar optimal connectivity profiles that could largely reproduce findings from prior research based on this present novel multi-center cohort. In a data-driven approach that estimated optimal whole-brain connectivity profiles, out-of-sample predictions of clinical improvements were calculated. Using either patient-specific connectivity (R = 0.43 at p = 0.001), an age- and disease-matched group connectome (R = 0.25, p = 0.048) and a normative connectome based on healthy/young subjects (R = 0.31 at p = 0.028), significant predictions could be made. Our results of patient-specific connectivity and normative connectomes lead to similar main conclusions about which brain areas are associated with clinical improvement. Still, although results were not significantly different, they hint at the fact that patient-specific connectivity may bear the potential of explaining slightly more variance than group connectomes. Furthermore, use of normative connectomes involves datasets with high signal-to-noise acquired on specialized MRI hardware, while clinical datasets as the ones used here may not exactly match their quality. Our findings support the role of DBS electrode connectivity profiles as a promising method to investigate DBS effects and to potentially guide DBS programming.

Trigeminal neurovascular contact in SUNCT and SUNA: a cross-sectional magnetic resonance study.

Emerging data-points towards a possible aetiological and therapeutic relevance of trigeminal neurovascular contact in short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and perhaps in short lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We aimed to assess the prevalence and significance of trigeminal neurovascular contact in a large cohort of consecutive SUNCT and SUNA patients and evaluate the radiological differences between them. The standard imaging protocol included high spatial and nerve-cistern contrast resolution imaging acquisitions of the cisternal segments of the trigeminal nerves and vessels. MRI studies were evaluated blindly by two expert evaluators and graded according to the presence, location and degree of neurovascular contact. The degree of contact was graded as with or without morphological changes. Neurovascular contact with morphological changes was defined as contact with distortion and/or atrophy. A total of 159 patients (SUNCT = 80; SUNA = 79) were included. A total of 165 symptomatic and 153 asymptomatic trigeminal nerves were analysed. The proportion of neurovascular contact on the symptomatic trigeminal nerves was higher (80.0%) compared to the asymptomatic trigeminal nerves (56.9%). The odds on having neurovascular contact over the symptomatic nerves was significantly higher than on the asymptomatic nerves [odds ratio (OR): 3.03, 95% confidence interval (CI) 1.84-4.99; P < 0.0001]. Neurovascular contact with morphological changes were considerably more prevalent on the symptomatic side (61.4%), compared to the asymptomatic side (31.0%) (OR 4.16, 95% CI 2.46-7.05; P < 0.0001). On symptomatic nerves, neurovascular contact with morphological changes was caused by an artery in 95.0% (n = 77/81). Moreover, the site of contact and the point of contact around the trigeminal root were respectively proximal in 82.7% (67/81) and superior in 59.3% (48/81). No significant radiological differences emerged between SUNCT and SUNA. The multivariate analysis of radiological predictors associated with the symptomatic side, indicated that the presence of neurovascular contact with morphological changes was strongly associated with the side of the pain (OR: 2.80, 95% CI 1.44-5.44; P = 0.002) even when adjusted for diagnoses. Our findings suggest that neurovascular contact with morphological changes is involved in the aetiology of SUNCT and SUNA. Along with a similar clinical phenotype, SUNCT and SUNA also display a similar structural neuroimaging profile, providing further support for the concept that the separation between them should be abandoned. Furthermore, these findings suggest that vascular compression of the trigeminal sensory root, may be a common aetiological factor between SUNCT, SUNA and trigeminal neuralgia thereby further expanding the overlap between these disorders.

Structural connectivity predicts clinical outcomes of deep brain stimulation for Tourette syndrome.

Deep brain stimulation may be an effective therapy for select cases of severe, treatment-refractory Tourette syndrome; however, patient responses are variable, and there are no reliable methods to predict clinical outcomes. The objectives of this retrospective study were to identify the stimulation-dependent structural networks associated with improvements in tics and comorbid obsessive-compulsive behaviour, compare the networks across surgical targets, and determine if connectivity could be used to predict clinical outcomes. Volumes of tissue activated for a large multisite cohort of patients (n = 66) implanted bilaterally in globus pallidus internus (n = 34) or centromedial thalamus (n = 32) were used to generate probabilistic tractography to form a normative structural connectome. The tractography maps were used to identify networks that were correlated with improvement in tics or comorbid obsessive-compulsive behaviour and to predict clinical outcomes across the cohort. The correlated networks were then used to generate 'reverse' tractography to parcellate the total volume of stimulation across all patients to identify local regions to target or avoid. The results showed that for globus pallidus internus, connectivity to limbic networks, associative networks, caudate, thalamus, and cerebellum was positively correlated with improvement in tics; the model predicted clinical improvement scores (P = 0.003) and was robust to cross-validation. Regions near the anteromedial pallidum exhibited higher connectivity to the positively correlated networks than posteroventral pallidum, and volume of tissue activated overlap with this map was significantly correlated with tic improvement (P < 0.017). For centromedial thalamus, connectivity to sensorimotor networks, parietal-temporal-occipital networks, putamen, and cerebellum was positively correlated with tic improvement; the model predicted clinical improvement scores (P = 0.012) and was robust to cross-validation. Regions in the anterior/lateral centromedial thalamus exhibited higher connectivity to the positively correlated networks, but volume of tissue activated overlap with this map did not predict improvement (P > 0.23). For obsessive-compulsive behaviour, both targets showed that connectivity to the prefrontal cortex, orbitofrontal cortex, and cingulate cortex was positively correlated with improvement; however, only the centromedial thalamus maps predicted clinical outcomes across the cohort (P = 0.034), but the model was not robust to cross-validation. Collectively, the results demonstrate that the structural connectivity of the site of stimulation are likely important for mediating symptom improvement, and the networks involved in tic improvement may differ across surgical targets. These networks provide important insight on potential mechanisms and could be used to guide lead placement and stimulation parameter selection, as well as refine targets for neuromodulation therapies for Tourette syndrome.

Stimulation Sweet Spot in Subthalamic Deep Brain Stimulation - Myth or Reality? A Critical Review of Literature.

INTRODUCTION: While deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been extensively used for more than 20 years in Parkinson's disease (PD), the optimal area of stimulation to relieve motor symptoms remains elusive. OBJECTIVE: We aimed at localizing the sweet spot within the subthalamic region by performing a systematic review of the literature. METHOD: PubMed database was searched for published studies exploring optimal stimulation location for STN DBS in PD, published between 2000 and 2019. A standardized assessment procedure based on methodological features was applied to select high-quality publications. Studies conducted more than 3 months after the DBS procedure, employing lateralized scores and/or stimulation condition, and reporting the volume of tissue activated or the position of the stimulating contact within the subthalamic region were considered in the final analysis. RESULTS: Out of 439 references, 24 were finally retained, including 21 studies based on contact location and 3 studies based on volume of tissue activated (VTA). Most studies (all VTA-based studies and 13 of the 21 contact-based studies) suggest the superior-lateral STN and the adjacent white matter as the optimal sites for stimulation. Remaining contact-based studies were either inconclusive (5/21), favoured the caudal zona incerta (1/21), or suggested a better outcome of STN stimulation than adjacent white matter stimulation (2/21). CONCLUSION: Using a standardized methodological approach, our review supports the presence of a sweet spot located within the supero-lateral STN and extending to the adjacent white matter.

Endurance of Short Pulse Width Thalamic Stimulation Efficacy in Intention Tremor.

The benefit of short pulse width stimulation in patients suffering from essential tremor (ET) refractory to thalamic deep brain stimulation remains controversial. Here, we add to the minimal body of evidence available by reporting the effect of this type of stimulation in 3 patients with a persistent and severe intention tremor component despite iterative DBS setting adjustments. While a reduction in pulse width to 30 µs initially showed promise in these patients by improving tremor control and mitigating cerebellar side effects arguably by widening the therapeutic window, these benefits seemed to dissipate during early follow-up. Our experience supports the need for measuring longer-term outcomes when reporting the usefulness of this mode of stimulation in ET.

Pedunculopontine Nucleus Deep Brain Stimulation for Parkinsonian Disorders: A Case Series.

BACKGROUND: Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been investigated for the treatment of levodopa-refractory gait dysfunction in parkinsonian disorders, with equivocal results so far. OBJECTIVES: To summarize the clinical outcomes of PPN-DBS-treated patients at our centre and elicit any patterns that may guide future research. MATERIALS AND METHODS: Pre- and post-operative objective overall motor and gait subsection scores as well as patient-reported outcomes were recorded for 6 PPN-DBS-treated patients, 3 with Parkinson's disease (PD), and 3 with progressive supranuclear palsy (PSP). Electrodes were implanted unilaterally in the first 3 patients and bilaterally in the latter 3, using an MRI-guided MRI-verified technique. Stimulation was initiated at 20-30 Hz and optimized in an iterative manner. RESULTS: Unilaterally treated patients did not demonstrate significant improvements in gait questionnaires, UPDRS-III or PSPRS scores or their respective gait subsections. This contrasted with at least an initial response in bilaterally treated patients. Diurnal cycling of stimulation in a PD patient with habituation to the initial benefit reproduced substantial improvements in freezing of gait (FOG) 3 years post-operatively. Among the PSP patients, 1 with a parkinsonian subtype had a sustained improvement in FOG while another with Richardson syndrome (PSP-RS) did not benefit. CONCLUSIONS: PPN-DBS remains an investigational treatment for levodopa-refractory FOG. This series corroborates some previously reported findings: bilateral stimulation may be more effective than unilateral stimulation; the response in PSP patients may depend on the disease subtype; and diurnal cycling of stimulation to overcome habituation merits further investigation.

The sensitivity to change of the cluster headache quality of life scale assessed before and after deep brain stimulation of the ventral tegmental area.

BACKGROUND: Cluster headache (CH) is a trigeminal autonomic cephalalgia (TAC) characterized by a highly disabling headache that negatively impacts quality of life and causes limitations in daily functioning as well as social functioning and family life. Since specific measures to assess the quality of life (QoL) in TACs are lacking, we recently developed and validated the cluster headache quality of life scale (CH-QoL). The sensitivity of CH-QoL to change after a medical intervention has not been evaluated yet. METHODS: This study aimed to test the sensitivity to change of the CH-QoL in CH. Specifically we aimed to (i) assess the sensitivity of CH-QoL to change before and following deep brain stimulation of the ventral tegmental area (VTA-DBS), (ii) evaluate the relationship of changes on CH-QoL with changes in other generic measures of quality of life, as well as indices of mood and pain. Ten consecutive CH patients completed the CH-QoL and underwent neuropsychological assessment before and after VTA-DBS. The patients were evaluated on headache frequency, severity, and load (HAL) as well as on tests of generic quality of life (Short Form-36 (SF-36)), mood (Beck Depression Inventory, Hospital Anxiety and Depression Rating Scale), and pain (McGill Pain Questionnaire, Headache Impact Test, Pain Behaviour Checklist). RESULTS: The CH-QoL total score was significantly reduced after compared to before VTA-DBS. Changes in the CH-QoL total score correlated significantly and negatively with changes in HAL, the SF-36, and positively and significantly with depression and the evaluative domain on the McGill Pain Questionnaire. CONCLUSIONS: Our findings demonstrate that changes after VTA-DBS in CH-QoL total scores are associated with the reduction of frequency, duration, and severity of headache attacks after surgery. Moreover, post VTA-DBS improvement in CH-QoL scores is associated with an amelioration in quality of life assessed with generic measures, a reduction of depressive symptoms, and evaluative pain experience after VTA-DBS. These results support the sensitivity to change of the CH-QoL and further demonstrate the validity and applicability of CH-QoL as a disease specific measure of quality of life for CH.

Resting state activity and connectivity of the nucleus basalis of Meynert and globus pallidus in Lewy body dementia and Parkinson's disease dementia.

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are two related diseases which can be difficult to distinguish. There is no objective biomarker which can reliably differentiate between them. The synergistic combination of electrophysiological and neuroimaging approaches is a powerful method for interrogation of functional brain networks in vivo. We recorded bilateral local field potentials (LFPs) from the nucleus basalis of Meynert (NBM) and the internal globus pallidus (GPi) with simultaneous cortical magnetoencephalography (MEG) in six PDD and five DLB patients undergoing surgery for deep brain stimulation (DBS) to look for differences in underlying resting-state network pathophysiology. In both patient groups we observed spectral peaks in the theta (2-8 Hz) band in both the NBM and the GPi. Furthermore, both the NBM and the GPi exhibited similar spatial and spectral patterns of coupling with the cortex in the two disease states. Specifically, we report two distinct coherent networks between the NBM/GPi and cortical regions: (1) a theta band (2-8 Hz) network linking the NBM/GPi to temporal cortical regions, and (2) a beta band (13-22 Hz) network coupling the NBM/GPi to sensorimotor areas. We also found differences between the two disease groups: oscillatory power in the low beta (13-22Hz) band was significantly higher in the globus pallidus in PDD patients compared to DLB, and coherence in the high beta (22-35Hz) band between the globus pallidus and lateral sensorimotor cortex was significantly higher in DLB patients compared to PDD. Overall, our findings reveal coherent networks of the NBM/GPi region that are common to both DLB and PDD. Although the neurophysiological differences between the two conditions in this study are confounded by systematic differences in DBS lead trajectories and motor symptom severity, they lend support to the hypothesis that DLB and PDD, though closely related, are distinguishable from a neurophysiological perspective.

Identification of nonlinear features in cortical and subcortical signals of Parkinson's Disease patients via a novel efficient measure.

This study offers a novel and efficient measure based on a higher order version of autocorrelative signal memory that can identify nonlinearities in a single time series. The suggested method was applied to simultaneously recorded subthalamic nucleus (STN) local field potentials (LFP) and magnetoencephalography (MEG) from fourteen Parkinson's Disease (PD) patients who underwent surgery for deep brain stimulation. Recordings were obtained during rest for both OFF and ON dopaminergic medication states. We analyzed the bilateral LFP channels that had the maximum beta power in the OFF state and the cortical sources that had the maximum coherence with the selected LFP channels in the alpha band. Our findings revealed the inherent nonlinearity in the PD data as subcortical high beta (20-30 Hz) band and cortical alpha (8-12 Hz) band activities. While the former was discernible without medication (p=0.015), the latter was induced upon the dopaminergic medication (p<6.10-4). The degree of subthalamic nonlinearity was correlated with contralateral tremor severity (r=0.45, p=0.02). Conversely, for the cortical signals nonlinearity was present for the ON medication state with a peak in the alpha band and correlated with contralateral akinesia and rigidity (r=0.46, p=0.02). This correlation appeared to be independent from that of alpha power and the two measures combined explained 34 % of the variance in contralateral akinesia scores. Our findings suggest that particular frequency bands and brain regions display nonlinear features closely associated with distinct motor symptoms and functions.