Impact of brain shift on subcallosal cingulate deep brain stimulation

Background

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment-resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from preoperatively collected diffusion-weighted imaging (DWI) data. However, brain shift induced by opening burr holes in the skull may alter the position of the target pathways.

StimVision v2: Examples and Applications in Subthalamic Deep Brain Stimulation for Parkinson’s Disease

ObjectiveSubthalamic deep brain stimulation (DBS) is an established therapy for Parkinson’s disease. Connectomic DBS modeling is a burgeoning subfield of research aimed at characterizing the axonal connections activated by DBS. This article describes our approach and methods for evolving the StimVision software platform to meet the technical demands of connectomic DBS modeling in the subthalamic region.Materials and MethodsStimVision v2 was developed with Visualization Toolkit (VTK) libraries and integrates four major components: 1) medical image visualization, 2) axonal pathway visualization, 3) electrode positioning, and 4) stimulation calculation.ResultsStimVision v2 implemented two key technological advances for connectomic DBS analyses in the subthalamic region. First was the application of anatomical axonal pathway models to patient-specific DBS models. Second was the application of a novel driving-force method to estimate the response of those axonal pathways to DBS. Example simulations with directional DBS electrodes and clinically defined therapeutic DBS settings are presented to demonstrate the general outputs of StimVision v2 models.ConclusionsStimVision v2 provides the opportunity to evaluate patient-specific axonal pathway activation from subthalamic DBS using anatomically detailed pathway models and electrically detailed electric field distributions with interactive adjustment of the DBS electrode position and stimulation parameter settings.     

Axonal pathways linked to therapeutic and nontherapeutic outcomes during psychiatric deep brain stimulation

Objective:

The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS.

Experimental design:

Our approach combined clinical data, diffusion tensor tractography, and computer models of patient‐specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment‐resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS).

Principal observations:

Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders.

Conclusions:

Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

     

Variability of white matter anatomy in the subcallosal cingulate area

The subcallosal cingulate (SCC) area is a putative hub in the brain network underlying depression. Deep brain stimulation (DBS) targeting a particular subregion of SCC, identified as the intersection of forceps minor (FM), uncinate fasciculus (UCF), cingulum and fronto‐striatal fiber bundles, may be critical to a therapeutic response in patients with severe, treatment‐resistant forms of major depressive disorder (MDD). The pattern and variability of the white matter anatomy and organization within SCC has not been extensively characterized across individuals. The goal of this study is to investigate the variability of white matter bundles within the SCC that structurally connect this region with critical nodes in the depression network. Structural and diffusion data from 100 healthy subjects from the Human Connectome Project database were analyzed. Anatomically defined SCC regions were used as seeds to perform probabilistic tractography and to estimate the connectivity from the SCC to subject‐specific target areas believed to be involved in the pathology of MDD including ventral striatum (VS), UCF, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC). Four distinct areas of connectivity were identified within SCC across subjects: (a) postero‐lateral SCC connectivity to medial temporal regions via UCF, (b) postero‐medial connectivity to VS, (c) superior‐medial connectivity to ACC via cingulum bundle, and (d) antero‐lateral connectivity to mPFC regions via forceps minor. Assuming white matter connectivity is critical to therapeutic response, the improved anatomic understanding of SCC as well as an appreciation of the intersubject variability are critical to developing optimized therapeutic targeting for SCC DBS.     

Subthalamic nucleus deep brain stimulation evokes resonant neural activity

Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target‐specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large‐amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes. Ann Neurol 2018;83:1027–1031     

DBSproc: An open source process for DBS electrode localization and tractographic analysis

Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Although stimulation sites for movement disorders such as Parkinson's disease are established, the therapeutic mechanisms of DBS remain controversial. Recent research suggests that specific white‐matter tract and circuit activation mediates symptom relief. To investigate these questions, we have developed a patient‐specific open‐source software pipeline called ‘DBSproc’ for (1) localizing DBS electrodes and contacts from postoperative CT images, (2) processing structural and diffusion MRI data, (3) registering all images to a common space, (4) estimating DBS activation volume from patient‐specific voltage and impedance, and (5) understanding the DBS contact‐brain connectivity through probabilistic tractography. In this paper, we explain our methodology and provide validation with anatomical and tractographic data. This method can be used to help investigate mechanisms of action of DBS, inform surgical and clinical assessments, and define new therapeutic targets. Hum Brain Mapp 37:422–433, 2016. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

Postmortem diffusion MRI of the human brainstem and thalamus for deep brain stimulator electrode localization

Deep brain stimulation (DBS) is an established surgical therapy for medically refractory tremor disorders including essential tremor (ET) and is currently under investigation for use in a variety of other neurologic and psychiatric disorders. There is growing evidence that the anti‐tremor effects of DBS for ET are directly related to modulation of the dentatorubrothalamic tract (DRT), a white matter pathway that connects the cerebellum, red nucleus, and ventral intermediate nucleus of the thalamus. Emerging white matter targets for DBS, like the DRT, will require improved three‐dimensional (3D) reference maps of deep brain anatomy and structural connectivity for accurate electrode targeting. High‐resolution diffusion MRI of postmortem brain specimens can provide detailed volumetric images of important deep brain nuclei and 3D reconstructions of white matter pathways with probabilistic tractography techniques. We present a high spatial and angular resolution diffusion MRI template of the postmortem human brainstem and thalamus with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We demonstrate registration of these data to in vivo, clinical images from patients receiving DBS therapy, and correlate electrode proximity to tractography of the DRT with improvement of ET symptoms. Hum Brain Mapp 36:3167–3178, 2015. © 2015 Wiley Periodicals, Inc.     

Biophysical reconstruction of the signal conduction underlying short-latency cortical evoked potentials generated by subthalamic deep brain stimulation

ObjectiveDirect activation of the hyperdirect (HD) pathway has been linked to therapeutic benefit from subthalamic deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD). We sought to quantify the axonal conduction biophysics of corticofugal axons directly stimulated by subthalamic DBS and reconcile those findings with short-latency cortical evoked potential (EP) results.MethodsWe used a detailed computational model of human subthalamic DBS to quantify axonal activation and conduction. Signal propagation to cortex was evaluated for medium (5.7 µm), large (10.0 µm), and exceptionally large (15.0 µm) diameter corticofugal axons associated with either internal capsule (IC) fibers of passage or the HD pathway. We then compared the modeling results to human cortical EP measurements that have described an exceptionally fast component (EP0) occurring ~1 ms after the stimulus pulse, a fast component (EP1) at ~3 ms, and a slower component (EP2) at ~5 ms.ResultsSubthalamic stimulation of the HD pathway with large and medium diameter axons propagated action potentials to cortex with timings that coincide with the EP1 and EP2 signals, respectively. Only direct activation of exceptionally large diameter fibers in the IC generated signals that could approach the EP0 timing. However, the action potential biophysics do not generally support the existence of a cortical EP less than 1.5 ms after DBS onset.ConclusionsThe EP1 and EP2 signals can be biophysically linked to antidromic activation of the HD pathway.SignificanceTheoretical reconstruction of cortical EPs from subthalamic DBS demonstrate a convergence of anatomical, biophysical, and electrophysiological results.     

Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor

BackgroundWhile deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear.MethodsUsing ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects.ResultsThe lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05).ConclusionsThis study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.     

Mechanisms of action underlying the efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: central role of disease severity

Despite consensus on some neurophysiological hallmarks of the Parkinsonian state (such as beta) band increase) a single mechanism is unlikely to explain the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Most experimental evidence to date correlates with an extreme degree of nigral neurodegeneration and not with different stages of PD progression. It seems inappropriate to combine substantially different patients – newly diagnosed, early fluctuators or advanced dyskinetic individuals – within the same group. An efficacious STN‐DBS imposes a new activity pattern within brain circuits, favouring alpha‐ and gamma‐like neuronal discharge, and restores the thalamo‐cortical transmission pathway through axonal activation. In addition, stimulation via the dorsal contacts of the macro‐electrode may affect cortical activation antidromically. However, basal ganglia (BG) modulation remains cardinal for ‘OFF’‐’ON’ transition (as revealed by cGMP increase occurring during STN‐DBS in the substantia nigra pars reticulata and internal globus pallidus). New research promises to clarify to what extent STN‐DBS restores striato‐centric bidirectional plasticity, and whether non‐neuronal cellular actions (microglia, neurovascular) play a part. Future studies will assess whether extremely anticipated DBS or lesioning in selected patients are capable of providing neuroprotection to the synuclein‐mediated alterations of synaptic efficiency. This review addresses these open issues through the specific mechanisms prevailing in a given disease stage. In patients undergoing early protocol, alteration in endogenous transmitters and recovery of plasticity are concurrent players. In advanced stages, re‐modulation of endogenous band frequencies, disruption of pathological pattern and/or antidromic cortical activation are, likely, the prominent modes.     

Tractography-Activation Models Applied to Subcallosal Cingulate Deep Brain Stimulation

Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCWM) is an experimental therapy for major depressive disorder (MDD). The specific axonal pathways that mediate the anti-depressant effects of DBS remain unknown. Patient-specific tractography-activation models (TAMs) are a new tool to help identify pathways modulated by DBS. TAMs consist of four basic components: 1) anatomical and diffusion-weighted imaging data acquired on the patient; 2) probabilistic tractography from the brain region surrounding the implanted DBS electrode; 3) finite element models of the electric field generated by the patient-specific DBS parameter settings; and 4) application of the DBS electric field to multi-compartment cable models of axons, with trajectories defined by the tractography, to predict action potential generation in specific pathways. This study presents TAM predictions from DBS of the SCCWM in one MDD patient. Our findings suggest that small differences in electrode location can generate substantial differences in the directly activated pathways.     

Tract-based analysis of target engagement by subcallosal cingulate deep brain stimulation for treatment resistant depression

BackgroundDeep brain stimulation (DBS) of subcallosal cingulate cortex (SCC) is a promising investigational therapy for treatment-resistant depression (TRD). However, outcomes vary, likely due to suboptimal DBS placement. Ideal placement is proposed to stimulate 4 SCC white matter bundles; however, no quantitative data have linked activation of these target tracts to response.ObjectiveHere we used the volume of tissue activated (VTA) and probabilistic diffusion tensor imaging (DTI) to quantify tract activation relating to response.MethodsDTI was performed in 19 TRD patients who received SCC-DBS. We defined clinical response as >48% reduction from baseline in the Hamilton Depression Rating Scale. Bilateral VTAs were generated based on subject-specific stimulation parameters. Patient-specific tract maps emanating from the VTAs were calculated using whole-brain probabilistic DTI. The four target tracts were isolated using tract-specific quantification and examined for overlap with DBS activated tissue.ResultsMedial frontal and temporal projections were stimulated in all responders at 6 and 12 months. Individual tract-based generalized linear mixed model analysis revealed a significant tract-by-response interaction at both 6 (F(1,135) = 3.828, p = 0.001) and 12 (F(1,135) = 5.688, p < 0.001) months, with post hoc tests revealing a response-related increase in cingulum activation at 6 months (t(135) = 2.418, p = 0.017) and decrease in forceps minor activation at 12 months (t(135) = -2.802, p = 0.006).ConclusionsA wider profile of white matter tracts, particularly to the medial frontal, was associated with DBS response. Cingulum bundle stimulation may promote early response and excess stimulation of the forceps minor might be detrimental. Our work supports prospective patient-specific targeting to inform personalized DBS.     

Frontal theta cordance predicts 6-month antidepressant response to subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study

Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCC) may be an effective approach for treatment-resistant depression (TRD) that otherwise fails to respond to more conventional therapies, but DBS is invasive, costly, and has potential for adverse effects. Therefore, it is important to identify potential biomarkers for predicting antidepressant response before intervention. Resting-state EEG was recorded from 12 TRD patients at pre-treatment baseline, after 4 weeks SCC DBS, and after 24 weeks SCC DBS. Lower frontal theta cordance (FTC) at baseline (and higher FTC after 4 weeks) predicted lower depression severity scores after 24 weeks. Greater FTC increases (baseline-4 weeks) predicted greater decreases in depression severity scores subsequently (4-24 weeks) and over the course of the study (baseline-24 weeks). Predictive relationships were topographically specific to theta cordance for frontal electrodes. Thus, results from this pilot study suggest that baseline FTC and changes early in treatment each have utility as biomarkers for predicting 6-month clinical response to SCC DBS for TRD.     

On-demand deep brain stimulation for essential tremor: a report on four cases.

Deep brain stimulation (DBS) is an established therapy for essential tremor (ET), but loss of efficacy due to tolerance can occur. Our objective was to evaluate if it is feasible to use DBS only on-demand and if this would prevent tolerance. We report on the effects of left-side thalamic DBS in 4 ET patients who were instructed to switch on stimulation only when using their right hand for motor tasks and were followed-up to 30 months after surgery. The patients were capable of using DBS only on-demand (DBS use of 22.0+/-13.5%/day). DBS led to a stable suppression of right arm tremor throughout the follow-up. No problems associated with tolerance such as tremor rebound or late therapy failure occurred. In comparison to publications stating that ET patients had been using DBS continuously during the daytime, the use of on-demand DBS saves battery life, which delays surgical replacement of the stimulator. Thus, on-demand DBS saves money, may help to prevent tolerance, and should be adopted for the long-term treatment of ET patients.     

Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

Deep brain stimulation (DBS) provides therapeutic benefit for several neuropathologies, including Parkinson disease (PD), epilepsy, chronic pain, and depression. Despite well‐established clinical efficacy, the mechanism of DBS remains poorly understood. In this review, we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies (e.g., human electrometer and closed‐loop smart devices) for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.     

Imaging versus electrographic connectivity in human mood-related fronto-temporal networks

BackgroundThe efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography.ObjectiveLeverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses.MethodsEvoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression – the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) – in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography.ResultsEvoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials.ConclusionThe two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation.     

Deep brain stimulation of terminating axons

BackgroundDeep brain stimulation (DBS) of the subthalamic region is an established treatment for the motor symptoms of Parkinson's disease. Several types of neural elements reside in the subthalamic region, including subthalamic nucleus (STN) neurons, fibers of passage, and terminating afferents. Recent studies suggest that direct activation of a specific population of subthalamic afferents, known as the hyperdirect pathway, may be responsible for some of the therapeutic effects of subthalamic DBS.ObjectiveThe goal of this study was to quantify how axon termination affects neural excitability from DBS. We evaluated how adjusting different stimulation parameters influenced the relative excitability of terminating axons (TAs) compared to fibers of passage (FOPs).MethodsWe used finite element electric field models of DBS, coupled to multi-compartment cable models of axons, to calculate activation thresholds for populations of TAs and FOPs. These generalized models were used to evaluate the response to anodic vs. cathodic stimulation, with short vs. long stimulus pulses.Results: Terminating axons generally exhibited lower thresholds than fibers of passage across all tested parameters. Short pulse widths accentuated the relative excitability of TAs over FOPs.Conclusion(s): Our computational results demonstrate a hyperexcitability of terminating axons to DBS that is robust to variation in the stimulation parameters, as well as the axon model parameters.     

Patient-specific models of deep brain stimulation: Influence of field model complexity on neural activation predictions

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the surgical therapy of choice for medically intractable Parkinson's disease. However, quantitative understanding of the interaction between the electric field generated by DBS and the underlying neural tissue is limited. Recently, computational models of varying levels of complexity have been used to study the neural response to DBS. The goal of this study was to evaluate the quantitative impact of incrementally incorporating increasing levels of complexity into computer models of STN DBS. Our analysis focused on the direct activation of experimentally measureable fiber pathways within the internal capsule (IC). Our model system was customized to an STN DBS patient and stimulation thresholds for activation of IC axons were calculated with electric field models that ranged from an electrostatic, homogenous, isotropic model to one that explicitly incorporated the voltage-drop and capacitance of the electrode-electrolyte interface, tissue encapsulation of the electrode, and diffusion-tensor based 3D tissue anisotropy and inhomogeneity. The model predictions were compared to experimental IC activation defined from electromyographic (EMG) recordings from eight different muscle groups in the contralateral arm and leg of the STN DBS patient. Coupled evaluation of the model and experimental data showed that the most realistic predictions of axonal thresholds were achieved with the most detailed model. Furthermore, the more simplistic neurostimulation models substantially overestimated the spatial extent of neural activation.     

Involvement of cathepsin B in the processing and secretion of interleukin‐1β in chromogranin A‐stimulated microglia

Cathepsin B (CB) is a cysteine lysosomal protease implicated in a number of inflammatory diseases. Although it is now evident that caspase‐1, an essential enzyme for maturation of interleukin‐1β (IL‐1β), can be activated through the inflammasome, there is still evidence suggesting the existence of lysosomal‐proinflammatory caspase pathways. In the present study, a marked induction of pro‐IL‐1β, its processing to the mature form and secretion were observed in the primary cultured microglia prepared from wild‐type mice after stimulation with chromogranin A (CGA). Although pro‐IL‐1β also markedly increased in microglia prepared from CB‐deficient mice, CB‐deficiency abrogated the pro‐IL‐1β processing. CA‐074Me, a specific inhibitor for CB, inhibited the pro‐IL‐1β maturation and its release from microglia. Furthermore, the caspase‐1 activation was also inhibited by CA‐074Me and E‐64d, a broad cysteine protease inhibitor. After treatment with CGA, CB was markedly induced at both protein and mRNA levels. The induced pro‐CB was rapidly processed to its mature form. The immunoreactivity for CB co‐localized with both that for caspase‐1 and the cleaved IL‐1β, in the acidic enlarged lysosomes. Inconsistent with these in vitro observations, the immunoreactivity for the cleaved IL‐1β was markedly observed in microglia of the hippocampus from aged wild‐type but not CB‐deficient mice. These observations strongly suggest that CB plays a key role in the pro‐IL‐1β maturationthrough the caspase‐1 activation in enlarged lysosomes ofCGA‐treated microglia. Therefore, either pharmacological or genetic inhibition of CB may provide therapeutic intervention in inflammation‐associated neurological diseases. © 2009 Wiley‐Liss, Inc.     

Subthalamic nucleus and globus pallidus interna influence firing of tonically active neurons in the primate striatum through different mechanisms

Both the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) are major targets for neuromodulation therapy for movement disorders. An example of such a therapy is deep brain stimulation (DBS). The striatum is the primary target for pharmacological treatment of these disorders. To further our understanding of both the functional relationships among motor nuclei and the mechanisms of therapies for movement disorders, it is important to clarify how changing the neuronal activity of one target, either by medication or by artificial electrical stimulation, affects the other connected nuclei. To investigate this point, we recorded single‐unit activity from tonically active neurons (TANs), which are putative cholinergic interneurons in the striatum, of healthy monkeys (Macaca fuscata) during electrical stimulation of the STN or GPi. Both STN stimulation and GPi stimulation reduced the TAN spike rate. Local infusion of a D2 receptor antagonist in the striatum blocked the reduction in spike rate induced by STN stimulation but not that induced by GPi stimulation. Further, STN stimulation induced phasic dopamine release in the striatum as revealed by in vivo fast‐scan cyclic voltammetry. These results suggest the presence of multiple, strong functional relationships among the STN, GPi, and striatum that have different pathways and imply distinct therapeutic mechanisms for STN‐ and GPi‐DBS.