Linking Invasive and Noninvasive Brain Stimulation in Parkinson's Disease: A Randomized Trial.

BACKGROUND: Recent imaging studies identified a brain network associated with clinical improvement following deep brain stimulation (DBS) in Parkinson's disease (PD), the PD response network. OBJECTIVES: This study aimed to assess the impact of neuromodulation on PD motor symptoms by targeting this network noninvasively using multifocal transcranial direct current stimulation (tDCS). METHODS: In a prospective, randomized, double-blinded, crossover trial, 21 PD patients (mean age 59.7 years, mean Hoehn & Yahr [H&Y] 2.4) received multifocal tDCS targeting the a-priori network. Twenty-minute sessions of tDCS and sham were administered on 2 days in randomized order. Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) scores were assessed. RESULTS: Before intervention, MDS-UPDRS-III scores were comparable in both conditions (stimulation days: 37.38 (standard deviation [SD] = 12.50, confidence interval [CI] = 32.04, 42.73) vs. sham days: 36.95 (SD = 13.94, CI = 30.99, 42.91), P = 0.63). Active stimulation resulted in a reduction by 3.6 points (9.7%) to 33.76 (SD = 11.19, CI = 28.98, 38.55) points, whereas no relevant change was observed after sham stimulation (36.43 [SD = 14.15, CI = 30.38, 42.48], average improvement: 0.5 [1.4%]). Repeated-measures analysis of variance (ANOVA) confirmed significance (main effect of time: F(1,20)=4.35, P < 0.05). Tukey's post hoc tests indicated MDS-UPDRS-III improvement after active stimulation (t [20] = 2.9, P = 0.03) but not after sham (t [20] = 0.42, P > 0.05). In a subset of patients that underwent DBS surgery later, their DBS response correlated with tDCS effects (R = 0.55, P(1) = 0.04). CONCLUSION: Noninvasive, multifocal tDCS targeting a DBS-derived network significantly improved PD motor symptoms. Despite a small effect size, this study provides proof of principle for the successful noninvasive neuromodulation of an invasively identified network. Future studies should investigate repeated tDCS sessions and their utility for screening before DBS surgery. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Engaging dystonia networks with subthalamic stimulation.

Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its complex surroundings have not been studied in depth. Indeed, multiple historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the exact same target. Therefore, a thorough investigation of the neural substrates underlying effects on dystonia symptoms is warranted. Here, we analyze a multi-center cohort of isolated dystonia patients with subthalamic implantations (N = 58) and relate their stimulation sites to improvement of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions was associated with improvement in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvement in limb dystonia and blepharospasm. This dissociation was also evident for structural connectivity, where the cerebellothalamic, corticospinal and pallidosubthalamic tracts were associated with improvement of cervical dystonia, while hyperdirect and subthalamopallidal pathways were associated with alleviation of limb dystonia and blepharospasm. Importantly, a single well-placed electrode may reach the three optimal target sites. On the level of functional networks, improvement of limb dystonia was correlated with connectivity to the corresponding somatotopic regions in primary motor cortex, while alleviation of cervical dystonia was correlated with connectivity to the recently described 'action-mode' network that involves supplementary motor and premotor cortex. Our findings suggest that different types of dystonia symptoms are modulated via distinct networks. Namely, appendicular dystonia and blepharospasm are improved with modulation of the basal ganglia, and, in particular, the subthalamic circuitry, including projections from the primary motor cortex. In contrast, cervical dystonia was more responsive when engaging the cerebello-thalamo-cortical circuit, including direct stimulation of ventral thalamic nuclei. These findings may inform DBS targeting and image-based programming strategies for patient-specific treatment of dystonia.

Establishing connectivity through microdissections of midbrain stimulation-related neural circuits.

Comprehensive understanding of the neural circuits involving the ventral tegmental area is essential for elucidating the anatomo-functional mechanisms governing human behaviour as well as the therapeutic and adverse effects of deep brain stimulation for neuropsychiatric diseases. While the ventral tegmental area has been successfully targeted with deep brain stimulation for different neuropsychiatric diseases, the axonal connectivity of the region has not been fully understood. Here using fiber micro-dissections in human cadaveric hemispheres, population-based high-definition fiber tractography, and previously reported deep brain stimulation hotspots, we find that the ventral tegmental area participates in an intricate network involving the serotonergic pontine nuclei, basal ganglia, limbic system, basal forebrain, and prefrontal cortex, which is implicated in the treatment of obsessive-compulsive disorder, major depressive disorder, Alzheimer's disease, cluster headaches, and aggressive behaviors.

Deep brain stimulation of symptom-specific networks in Parkinson's disease.

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.

Lesion network of oculogyric crises maps to brain dopaminergic transcriptomic signature.

Oculogyric crises are acute episodes of sustained, typically upward, conjugate deviation of the eyes. Oculogyric crises usually occur as the result of acute D2-dopamine receptor blockade, but the brain areas causally involved in generating this symptom remain elusive. Here, we used data from 14 previously reported cases of lesion-induced oculogyric crises and employed lesion network mapping to identify their shared connections throughout the brain. This analysis yielded a common network that included basal ganglia, thalamic and brainstem nuclei, as well as the cerebellum. Comparison of this network with gene expression profiles associated with the dopamine system revealed spatial overlap specifically with the gene coding for dopamine receptor type 2 (DRD2), as defined by a large-scale transcriptomic database of the human brain. Furthermore, spatial overlap with DRD2 and DRD3 gene expression was specific to brain lesions associated with oculogyric crises when contrasted to lesions that led to other movement disorders. Our findings identify a common neural network causally involved in the occurrence of oculogyric crises and provide a pathophysiological link between lesion locations causing this syndrome and its most common pharmacological cause, namely DRD2 blockade.

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

The role of the motor thalamus in deep brain stimulation for essential tremor.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.

Spatiotemporally-specific cortical-subthalamic coupling differentiates aspects of speech performance.

Speech provides a rich context for exploring human cortical-basal ganglia circuit function, but direct intracranial recordings are rare. We recorded electrocorticographic signals in the cortex synchronously with single units in the subthalamic nucleus (STN), a basal ganglia node that receives direct input from widespread cortical regions, while participants performed a syllable repetition task during deep brain stimulation (DBS) surgery. We discovered that STN neurons exhibited spike-phase coupling (SPC) events with distinct combinations of frequency, location, and timing that indexed specific aspects of speech. The strength of SPC to posterior perisylvian cortex predicted phoneme production accuracy, while that of SPC to perirolandic cortex predicted time taken for articulation Thus, STN-cortical interactions are coordinated via transient bursts of behavior-specific synchronization that involves multiple neuronal populations and timescales. These results both suggest mechanisms that support auditory-sensorimotor integration during speech and explain why firing-rate based models are insufficient for explaining basal ganglia circuit behavior.

WarpDrive: Improving spatial normalization using manual refinements.

Spatial normalization-the process of mapping subject brain images to an average template brain-has evolved over the last 20+ years into a reliable method that facilitates the comparison of brain imaging results across patients, centers & modalities. While overall successful, sometimes, this automatic process yields suboptimal results, especially when dealing with brains with extensive neurodegeneration and atrophy patterns, or when high accuracy in specific regions is needed. Here we introduce WarpDrive, a novel tool for manual refinements of image alignment after automated registration. We show that the tool applied in a cohort of patients with Alzheimer's disease who underwent deep brain stimulation surgery helps create more accurate representations of the data as well as meaningful models to explain patient outcomes. The tool is built to handle any type of 3D imaging data, also allowing refinements in high-resolution imaging, including histology and multiple modalities to precisely aggregate multiple data sources together.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

Connectivity Profile for Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson Disease.

OBJECTIVE: This study was undertaken to describe relationships between electrode localization and motor outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson disease (PD) pilot clinical trial. METHODS: To determine anatomical and network correlates associated with motor outcomes for subjects randomized to early DBS (n = 14), voxelwise sweet spot mapping and structural connectivity analyses were carried out using outcomes of motor progression (Unified Parkinson Disease Rating Scale Part III [UPDRS-III] 7-day OFF scores [∆baseline➔24 months, MedOFF/StimOFF]) and symptomatic motor improvement (UPDRS-III ON scores [%∆baseline➔24 months, MedON/StimON]). RESULTS: Sweet spot mapping revealed a location associated with slower motor progression in the dorsolateral STN (anterior/posterior commissure coordinates: 11.07 ± 0.82mm lateral, 1.83 ± 0.61mm posterior, 3.53 ± 0.38mm inferior to the midcommissural point; Montreal Neurological Institute coordinates: +11.25, -13.56, -7.44mm). Modulating fiber tracts from supplementary motor area (SMA) and primary motor cortex (M1) to the STN correlated with slower motor progression across STN DBS subjects, whereas fiber tracts originating from pre-SMA and cerebellum were negatively associated with motor progression. Robustness of the fiber tract model was demonstrated in leave-one-patient-out (R = 0.56, p = 0.02), 5-fold (R = 0.50, p = 0.03), and 10-fold (R = 0.53, p = 0.03) cross-validation paradigms. The sweet spot and fiber tracts associated with motor progression revealed strong similarities to symptomatic motor improvement sweet spot and connectivity in this early stage PD cohort. INTERPRETATION: These results suggest that stimulating the dorsolateral region of the STN receiving input from M1 and SMA (but not pre-SMA) is associated with slower motor progression across subjects receiving STN DBS in early stage PD. This finding is hypothesis-generating and must be prospectively tested in a larger study. ANN NEUROL 2023;94:271-284.

Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation.

Frontal circuits play a critical role in motor, cognitive, and affective processing - and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)function remains largely elusive. Here, we study 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregate the frontal cortex into circuits that became dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to rostral, ranging from interconnections with sensorimotor cortices in dystonia, with the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairment in the human brain.

Lead-DBS v3.0: Mapping deep brain stimulation effects to local anatomy and global networks.

Following its introduction in 2014 and with support of a broad international community, the open-source toolbox Lead-DBS has evolved into a comprehensive neuroimaging platform dedicated to localizing, reconstructing, and visualizing electrodes implanted in the human brain, in the context of deep brain stimulation (DBS) and epilepsy monitoring. Expanding clinical indications for DBS, increasing availability of related research tools, and a growing community of clinician-scientist researchers, however, have led to an ongoing need to maintain, update, and standardize the codebase of Lead-DBS. Major development efforts of the platform in recent years have now yielded an end-to-end solution for DBS-based neuroimaging analysis allowing comprehensive image preprocessing, lead localization, stimulation volume modeling, and statistical analysis within a single tool. The aim of the present manuscript is to introduce fundamental additions to the Lead-DBS pipeline including a deformation warpfield editor and novel algorithms for electrode localization. Furthermore, we introduce a total of three comprehensive tools to map DBS effects to local, tract- and brain network-levels. These updates are demonstrated using a single patient example (for subject-level analysis), as well as a retrospective cohort of 51 Parkinson's disease patients who underwent DBS of the subthalamic nucleus (for group-level analysis). Their applicability is further demonstrated by comparing the various methodological choices and the amount of explained variance in clinical outcomes across analysis streams. Finally, based on an increasing need to standardize folder and file naming specifications across research groups in neuroscience, we introduce the brain imaging data structure (BIDS) derivative standard for Lead-DBS. Thus, this multi-institutional collaborative effort represents an important stage in the evolution of a comprehensive, open-source pipeline for DBS imaging and connectomics.

Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Linking profiles of pathway activation with clinical motor improvements - A retrospective computational study.

BACKGROUND: Deep brain stimulation (DBS) is an established therapy for patients with Parkinson's disease. In silico computer models for DBS hold the potential to inform a selection of stimulation parameters. In recent years, the focus has shifted towards DBS-induced firing in myelinated axons, deemed particularly relevant for the external modulation of neural activity. OBJECTIVE: The aim of this project was to investigate correlations between patient-specific pathway activation profiles and clinical motor improvement. METHODS: We used the concept of pathway activation modeling, which incorporates advanced volume conductor models and anatomically authentic fiber trajectories to estimate DBS-induced action potential initiation in anatomically plausible pathways that traverse in close proximity to targeted nuclei. We applied the method on two retrospective datasets of DBS patients, whose clinical improvement had been evaluated according to the motor part of the Unified Parkinson's Disease Rating Scale. Based on differences in outcome and activation levels for intrapatient DBS protocols in a training cohort, we derived a pathway activation profile that theoretically induces a complete alleviation of symptoms described by UPDRS-III. The profile was further enhanced by analyzing the importance of matching activation levels for individual pathways. RESULTS: The obtained profile emphasized the importance of activation in pathways descending from the motor-relevant cortical regions as well as the pallidothalamic pathways. The degree of similarity of patient-specific profiles to the optimal profile significantly correlated with clinical motor improvement in a test cohort. CONCLUSION: Pathway activation modeling has a translational utility in the context of motor symptom alleviation in Parkinson's patients treated with DBS.

Lead-OR: A multimodal platform for deep brain stimulation surgery.

Background: Deep brain stimulation (DBS) electrode implant trajectories are stereotactically defined using preoperative neuroimaging. To validate the correct trajectory, microelectrode recordings (MERs) or local field potential recordings can be used to extend neuroanatomical information (defined by MRI) with neurophysiological activity patterns recorded from micro- and macroelectrodes probing the surgical target site. Currently, these two sources of information (imaging vs. electrophysiology) are analyzed separately, while means to fuse both data streams have not been introduced. Methods: Here, we present a tool that integrates resources from stereotactic planning, neuroimaging, MER, and high-resolution atlas data to create a real-time visualization of the implant trajectory. We validate the tool based on a retrospective cohort of DBS patients (N = 52) offline and present single-use cases of the real-time platform. Results: We establish an open-source software tool for multimodal data visualization and analysis during DBS surgery. We show a general correspondence between features derived from neuroimaging and electrophysiological recordings and present examples that demonstrate the functionality of the tool. Conclusions: This novel software platform for multimodal data visualization and analysis bears translational potential to improve accuracy of DBS surgery. The toolbox is made openly available and is extendable to integrate with additional software packages. Funding: Deutsche Forschungsgesellschaft (410169619, 424778381), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti), National Institutes of Health (2R01 MH113929), and Foundation for OCD Research (FFOR).

Deep brain stimulation is an established therapy for patients with Parkinson's disease and an emerging option for other neurological conditions. Electrodes are implanted deep in the brain to stimulate precise brain regions and control abnormal brain activity in those areas. The most common target for Parkinson's disease, for instance, is a structure called the subthalamic nucleus, which sits at the base of the brain, just above the brain stem. To ensure electrodes are placed correctly, surgeons use various sources of information to characterize the patient's brain anatomy and decide on an implant site. These data include brain scans taken before surgery and recordings of brain activity taken during surgery to confirm the intended implant site. Sometimes, the brain activity signals from this last confirmation step may slightly alter surgical plans. It represents one of many challenges for clinical teams: to analyse, assimilate, and communicate data as it is collected during the procedure. Oxenford et al. developed a software pipeline to aggregate the data surgeons use to implant electrodes. The open-source platform, dubbed Lead-OR, visualises imaging data and brain activity recordings (termed electrophysiology data) in real time. The current set-up integrates with commercial tools and existing software for surgical planning. Oxenford et al. tested Lead-OR on data gathered retrospectively from 32 patients with Parkinson's who had electrodes implanted in their subthalamic nucleus. The platform showed good agreement between imaging and electrophysiology data, although there were some unavoidable discrepancies, arising from limitations in the imaging pipeline and from the surgical procedure. Lead-OR was also able to correct for brain shift, which is where the brain moves ever so slightly in the skull. With further validation, this proof-of-concept software could serve as a useful decision-making tool for surgical teams implanting electrodes for deep brain stimulation. In time, if implemented, its use could improve the accuracy of electrode placement, translating into better surgical outcomes for patients. It also has the potential to integrate forthcoming ultra-high-resolution data from current brain mapping projects, and other commercial surgical planning tools.

Personalizing Deep Brain Stimulation Using Advanced Imaging Sequences.

OBJECTIVE: With a growing appreciation for interindividual anatomical variability and patient-specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice. METHODS: Using fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity, we retrospectively analyzed 65 patients (26 female, mean age = 69.1 ± 12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity's ability to predict clinical outcome using stimulation volume modeling and voxelwise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient-specific level. RESULTS: Anatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentatorubrothalamic tract. Overlap between DBS stimulation volumes and the hypointensity in standard space significantly correlated with tremor improvement (R2  = 0.16, p = 0.017) and distance to hotspots previously reported in the literature (R2  = 0.49, p = 7.9e-4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further (R2  = 0.37, p = 0.002). INTERPRETATION: Our findings introduce and validate a novel imaging-based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor. ANN NEUROL 2022;91:613-628.