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Multiple surgical targets for treating obsessive-compulsive disorder with deep brain stimulation (DBS) have been proposed. However, different targets may modulate the same neural network responsible for clinical improvement. We analyzed data from four cohorts of patients ( N  = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens or the subthalamic nucleus (STN). The same fiber bundle was associated with optimal clinical response in cohorts targeting either structure. This bundle connected frontal regions to the STN. When informing the tract target based on the first cohort, clinical improvements in the second could be significantly predicted, and vice versa. To further confirm results, clinical improvements in eight patients from a third center and six patients from a fourth center were significantly predicted based on their stimulation overlap with this tract. Our results show that connectivity-derived models may inform clinical improvements across DBS targets, surgeons and centers. The identified tract target is openly available in atlas form. Li et al. analyzed structural connectivity of deep brain stimulation electrodes in 50 patients suffering from obsessive-compulsive disorder operated at four centers. Connectivity to a specific tract within the anterior limb of the internal capsule was associated with optimal treatment response across cohorts, surgeons and centers.

Parkinson’s disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21–30 Hz) but not low (13-21 Hz) beta frequency range correlated with ‘hyperdirect pathway’ fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD. In Parkinson’s disease (PD), beta frequency oscillations are synchronised across the cortico-basal-ganglia circuit. The authors show in human participants that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway, indicating a pathophysiological role for this pathway in PD.

Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. High angular resolution diffusion imaging in twenty patients with advanced Parkinson's disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p < 0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X = −10(−9.5), Y = −13(-1) and Z = −7(−3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia. •Optimal DBS tissue activation areas are identified in the subthalamic nucleus.•Stimulation in the supero-lateral subthalamic nucleus is most effective.•Connectivity pattern predicts improvement in cardinal symptoms in Parkinson's.

Introduction & objectivesAdaptive deep brain stimulation (aDBS) uses feedback from brain signals to guide stimulation. A recent acute trial of unilateral aDBS showed that aDBS can lead to substantial improvements in contralateral hemibody Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and may be superior to conventional continuous DBS in Parkinson’s disease (PD). We test whether potential benefits are retained with bilateral aDBS and in the face of concurrent medication.MethodsWe applied bilateral aDBS in 4 patients with PD undergoing DBS of the subthalamic nucleus. aDBS was delivered bilaterally with independent triggering of stimulation according to the amplitude of β activity at the corresponding electrode. Mean stimulation voltage was 3.0±0.1 volts. Motor assessments consisted of double-blinded video-taped motor UPDRS scores that included both limb and axial features.ResultsUPDRS scores were 43% (p=0.04; Cohen’s d=1.62) better with aDBS than without stimulation. Motor improvement with aDBS occurred despite an average time on stimulation (ToS) of only 45%. Levodopa was well tolerated during aDBS and led to further reductions in ToS.ConclusionBilateral aDBS can improve both axial and limb symptoms and can track the need for stimulation across drug states.

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.

The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinson's disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery. ► Three distinct sub-regions within the human STN are demonstrated in vivo using DWI. ► Limbic, associative and motor zones are labelled based on the regional connectivity. ► The findings agree with previous results from the animal literature. ► A somatotopic arrangement of STN projections to subcortical structures is shown. ► An overlap between motor STN projections and extra-STN hemiballismus is demonstrated.

•Connectivity-based Vim position varied markedly between subjects and from atlas-defined coordinates.•This positional variability was not related to any methodological confound tested.•Hemispheric asymmetry was observed in connectivity-based Vim position.•We hypothesise lateralization of cerebellar functions, such as language, may contribute to asymmetry.•Knowledge of Vim position variability could help inform neurosurgical planning in the management of tremor. 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.

•Connectomics can help treatment planning in epilepsy and neuro-oncology.•Tractography can help motor thalamus targeting and has potential with other targets.•Combined with other modalities, connectomics can help elucidate pathophysiology.•Lack of standards in image acquisition and processing limit widespread utilization.•Improved acquisition and process automation can increase reliability of these tools. 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.

Background Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinson's disease (PD) insufficiently controlled with medical therapies. This study presents the long-term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI-verified approach without microelectrode recording. Methods A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8–11 years. Motor status was evaluated using part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes. Results STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow-up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively. Conclusions Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor ‘off’ symptoms of PD in the long term with low morbidity.

Background Pharmaco-psychiatric techniques remain the mainstay, first line treatments in substance use disorders (SUD), assisting in detoxification but largely ineffective at reducing dependence. The path to rehabilitation and freedom from addiction often proves uncertain and laborious for both patients and their significant others. Relapse rates for multiple substances of abuse are considerable and the number of SUD patients is on the increase worldwide. Objective To assess efficacy of deep brain stimulation (DBS) as a therapeutic solution for SUDs. Methods A systematic electronic database search of PubMed and EMBASE retrieved DBS addiction-focused studies on humans, of which a total of 26 ( n  = 71) from 2007 to 2023 were deemed eligible, including the first randomized controlled trial (RCT) in this field. This review was prospectively registered with PROSPERO: CRD42023411631. Results In addressing SUDs, DBS targeting primarily the nucleus accumbens (NAcc), with or without the anterior limb of the internal capsule, presented encouraging levels of efficacy in reducing cravings and consumption, followed by remission in some subjects, but still reporting relapses in 73.2% of patients. Conclusions For treatment-refractory addictions DBS use seems limited to reducing cravings with a satisfactory degree of success, yet not clinically consistent in inducing abstinence, suggesting involvement of factors unaffected by DBS intervention. Furthermore, costs and the scale of the problem are such that DBS is unlikely to have a significant societal impact. Nevertheless, DBS may provide insight into the biology of addiction and is worthy of further research using increased methodological rigor, standardized outcome measures, and pre-established surgical protocols.