Role of the Cortico-Subthalamic Hyperdirect Pathway in Deep Brain Stimulation for the Treatment of Parkinson Disease: A Diffusion Tensor Imaging Study

doi:10.1016/j.wneu.2018.03.149

World Neurosurgery

Volume 114, June 2018, Pages e1079-e1085

https://doi.org/10.1016/j.wneu.2018.03.149 Get rights and content

Highlights

•
STN-DBS can influence the pathological activity of the cortex through antidromic activation of the HDP.
•
Stimulation of the HDP was correlated with the improvement of motor symptoms in patients with PD.
•
An improvement of the direct visualization method based on fiber tractography achieves more precise target location and helps guide individualized treatment.

Objective

To evaluate the clinical effect of the position of stimulation contacts relative to the hyperdirect pathway (HDP) on the alleviation of motor symptoms in patients with Parkinson disease (PD).

Methods

A group of 11 patients diagnosed with idiopathic PD were included in this study, and all selected targets were in the subthalamic nucleus (STN). In 1 patient, a single side electrode was implanted because of unilateral symptoms; in all other patients, bilateral electrodes each containing 4 discrete contacts were implanted. Nine contacts were excluded due to adverse reactions caused by stimulation, and thus a total of 75 active contacts were evaluated using the same stimulus parameters. Fiber tractography results were individually processed using StealthViz software before all data were subjected to statistical analysis.

Results

Under the same stimulus parameters, the shortest distance of each contact to the HDP was smaller in group I (n = 45; >50% improvement rate) compared with group II (n = 30; ≤50% improvement rate) (mean, 1.18 ± 0.86 mm vs. 2.14 ± 1.20 mm; t = 3.78; P < 0.05), and the shortest distance had a negative correlation with the improvement of motor symptoms (r = −0.48; P < 0.05).

Conclusions

Stimulation of the HDP coincided with the improvement of motor symptoms in patients with PD. We propose an improvement of the direct visualization method based on diffusion tensor imaging fiber tractography of the HDP to select the motor part of the STN. Further rigorous clinical trials are needed to verify the value of this method for achieving precise target location and individualized treatment.

Introduction

For more than a decade, deep brain stimulation (DBS) has been widely used in to relieve symptoms associated with advanced Parkinson disease (PD) because of its reversibility, adjustability, and less invasive nature.¹ The dorsolateral part of the subthalamic nucleus (STN) serves as the target for planning the trajectory of the electrodes to improve symptoms.² Studies have shown that the corticosubthalamic network, more precisely the hyperdirect pathway (HDP), may play an important role in the clinical effectiveness of stimulation.3, 4 The HDP can be visualized using fiber tractography based on diffusion tensor imaging (DTI).⁵ The aim of this study was to evaluate the association between improvement of motor symptoms and the stimulation contacts relative to HDP to achieve precise target location and individualized treatment.

Section snippets

Patients

For this study, we retrospectively reviewed 11 patients (7 males and 4 females) with primary PD who underwent DBS at our institution between March 1 and December 1, 2017. The mean patient age was 59.9 ± 8.3 years, and the mean duration of disease was 9.5 ± 2.8 years. The inclusion criteria for study were primary uncontrolled PD, age <75 years, and good residual response to the levodopa intake test (>30%). The exclusion criteria were psychiatric disorders and contraindication to magnetic

Results

A group of 11 patients diagnosed with idiopathic PD treated with DBS were included in the study. One patient was implanted with a single-side electrode due to monoliteral symptoms, and the others had bilateral symptoms and were implanted with bilateral stimulation. Nine contacts were excluded due to adverse reactions to stimulation. Thus, a total of 75 active contacts were evaluated using the same stimulus parameters (2.5 V; frequency, 130 Hz; pulse width, 60 μs) to assess improvement in the

Discussion

Our findings demonstrate that the HDP directly connecting the STN with motor-related cortical areas can be reconstructed using by DTI technology (StealthViz; Medtronic). We found that stimulation of the HDP coincided with the improvement of motor symptoms in patients with PD. Antidromic cortical activation via STN-DBS might provide the underlying mechanism responsible for this effect. The significance of this study based on DTI fiber tractography of the HDP is an improvement in the direct

Conclusions

High-frequency electrical stimulation that targets the STN has proven beneficial in alleviating the motor symptoms of many patients with PD. The therapeutic efficacy of DBS in reducing motor function-related symptoms is closely related to accurate stereotactic placement of the electrode into the motor subregion of the STN. Our present findings show that stimulation of the HDP coincides with the improvement of motor symptoms in patients with PD. The HDP rebuilt by DTI technology directly

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Cited by (24)

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease
2023, Neuromodulation
Deep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.
We measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.
A short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).
Our results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.
The ClinicalTrials.gov registration number for the study is NCT04658641.
Electrophysiological characterization of the hyperdirect pathway and its functional relevance for subthalamic deep brain stimulation
2022, Experimental Neurology
Citation Excerpt :
All of these connections are part of the cortico-subthalamic HDP. In humans, the HDP has been identified anatomically using MRI tractography (Akram et al., 2017; Chen et al., 2018; Petersen et al., 2017; Plantinga et al., 2016). In line with those anatomical studies, electrophysiological studies also indicate the existence of cortico-STN projections and STN subsections (Giuffrida et al., 1985; Kitai and Deniau, 1981; Maurice et al., 1998; Rouzaire-Dubois and Scarnati, 1985).
The subthalamic nucleus (STN) receives input from various cortical areas via hyperdirect pathway (HDP) which bypasses the basal-ganglia loop. Recently, the HDP has gained increasing interest, because of its relevance for STN deep brain stimulation (DBS). To understand the HDP's role cortical responses evoked by STN-DBS have been investigated. These responses have short (<2 ms), medium (2–15 ms), and long (20–70 ms) latencies. Medium-latency responses are supposed to represent antidromic cortical activations via HDP. Together with long-latency responses the medium responses can potentially be used as biomarker of DBS efficacy as well as side effects. We here propose that the activation sequence of the cortical evoked responses can be conceptualized as high frequency oscillations (HFO) for signal analysis. HFO might therefore serve as marker for antidromic activation. Using existing knowledge on HFO recordings, this approach allows data analyses and physiological modeling to advance the pathophysiological understanding of cortical DBS-evoked high-frequency activity.
Linking profiles of pathway activation with clinical motor improvements – A retrospective computational study
2022, NeuroImage: Clinical
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.
Conveyance of cortical pacing for parkinsonian tremor-like hyperkinetic behavior by subthalamic dysrhythmia
2021, Cell Reports
Citation Excerpt :
The causal link between the oscillation and the behavioral output remains obscure. Although there have been scattered anatomical reports proposing reduced cortical innervation in STN neurons in parkinsonian animals recently (Mathai et al., 2015; Chu et al., 2017; Wang et al., 2018), there are actually more findings (including those in human) arguing for the increase of functional cortico-STN connections in PD (Baudrexel et al., 2011; Kurani et al., 2015; Sanders, 2017; Shen et al., 2017; Chen et al., 2018; Jia et al., 2018). In any case, it is not clear whether the anatomically decreased cortico-subthalamic connection is responsible for the parkinsonian symptoms.
Parkinson’s disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K⁺ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.
Atlas-independent, N-of-1 tissue activation modeling to map optimal regions of subthalamic deep brain stimulation for Parkinson disease
2021, NeuroImage: Clinical
Citation Excerpt :
The DT imaging data used to estimate the anisotropic tissue conductivity for each patient can also be used to perform tractography. Doing so would allow direct comparison of gray and white matter stimulation, such as the hyperdirect pathway and internal capsule, and their effects on DBS outcomes (Akram et al., 2017; Chen et al., 2018; Gunalan et al., 2017). However, the accuracy of the tractography results would be limited by the voxel resolution of the DT imaging (Rodrigues et al., 2018).
Motor outcomes after subthalamic deep brain stimulation (STN DBS) for Parkinson disease (PD) vary considerably among patients and strongly depend on stimulation location. The objective of this retrospective study was to map the regions of optimal STN DBS for PD using an atlas-independent, fully individualized (N-of-1) tissue activation modeling approach and to assess the relationship between patient-level therapeutic volumes of tissue activation (VTAs) and motor improvement.
The stimulation-induced electric field for 40 PD patients treated with bilateral STN DBS was modeled using finite element analysis. Neurostimulation models were generated for each patient, incorporating their individual STN anatomy, DBS lead position and orientation, anisotropic tissue conductivity, and clinical stimulation settings. A voxel-based analysis of the VTAs was then used to map the optimal location of stimulation. The amount of stimulation in specific regions relative to the STN was measured and compared between STNs with more and less optimal stimulation, as determined by their motor improvement scores and VTA. The relationship between VTA location and motor outcome was then assessed using correlation analysis. Patient variability in terms of STN anatomy, active contact position, and VTA location were also evaluated. Results from the N-of-1 model were compared to those from a simplified VTA model.
Tissue activation modeling mapped the optimal location of stimulation to regions medial, posterior, and dorsal to the STN centroid. These regions extended beyond the STN boundary towards the caudal zona incerta (cZI). The location of the VTA and active contact position differed significantly between STNs with more and less optimal stimulation in the dorsal-ventral and anterior-posterior directions. Therapeutic stimulation spread noticeably more in the dorsal and posterior directions, providing additional evidence for cZI as an important DBS target. There were significant linear relationships between the amount of dorsal and posterior stimulation, as measured by the VTA, and motor improvement. These relationships were more robust than those between active contact position and motor improvement. There was high variability in STN anatomy, active contact position, and VTA location among patients. Spherical VTA modeling was unable to reproduce these results and tended to overestimate the size of the VTA.
Accurate characterization of the spread of stimulation is needed to optimize STN DBS for PD. High variability in neuroanatomy, stimulation location, and motor improvement among patients highlights the need for individualized modeling techniques. The atlas-independent, N-of-1 tissue activation modeling approach presented in this study can be used to develop and evaluate stimulation strategies to improve clinical outcomes on an individual basis.
Subthalamic deep brain stimulation identifies frontal networks supporting initiation, inhibition and strategy use in Parkinson's disease
2020, NeuroImage
Citation Excerpt :
Careful measurement of longitudinal changes in behavioural or symptom profiles arising after DBS can be related to the site and distribution of stimulation in order to characterise brain circuit dysfunction. Parkinson's disease is a neurodegenerative disorder in which DBS is established as an advanced treatment for motor symptoms and in which network effects associated with clinical effectiveness have previously been delineated (Accolla et al., 2016; Vanegas-Arroyave et al., 2016; Akram et al., 2017; Horn et al., 2017; Chen et al., 2018). Notably, Parkinson's disease is also a model neuropsychiatric disorder (Weintraub and Burn, 2011), although the anatomical determinants of non-motor symptoms have received much less attention.
Initiation and inhibition are executive functions whose disruption in Parkinson's disease impacts substantially on everyday activities. Management of Parkinson's disease with subthalamic deep brain stimulation (DBS) modifies initiation and inhibition, with prior work suggesting that these effects may be mediated via the connectivity of the subthalamic nucleus (STN) with the frontal cortex. Here, we employed high-resolution structural neuroimaging to investigate the variability in initiation, inhibition and strategy use in a cohort of twenty-five (ten females, mean age 62.5, mean Hoehn and Yahr stage 2.5) participants undertaking subthalamic DBS for Parkinson's disease. Neuropsychological assessment of initiation and inhibition was performed preoperatively and at six months postoperatively. We first reconstructed the preoperative connectivity of the STN with a frontal network of anterior and superior medial cortical regions. We then modelled the postoperative site of subthalamic stimulation and reconstructed the connectivity of the stimulation field within this same network. We found that, at both pre- and postoperative intervals, inter-individual variability in inhibition and initiation were strongly associated with structural network connectivity. Measures of subcortical atrophy and local stimulation effects did not play a significant role. Preoperatively, we replicated prior work, including a role for the right inferior frontal gyrus in inhibition and strategy use, as well as the left inferior frontal gyrus in tasks requiring selection under conditions of maintained inhibition. Postoperatively, greater connectivity of the stimulation field with right anterior cortical regions was associated with greater rule violations and suppression errors, supporting prior work implicating right-hemispheric STN stimulation in disinhibition. Our findings suggest that, in Parkinson's disease, connectivity of the frontal cortex with the STN is an important mediator of individual variability in initiation and inhibition,. Personalised information on brain network architecture could guide individualised brain circuit manipulation to minimise neuropsychological disruption after STN-DBS.

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: Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

: Yukun Chen, Shunnan Ge, and Yang Li contributed equally to this work and should be considered co–first authors.

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Original ArticleRole of the Cortico-Subthalamic Hyperdirect Pathway in Deep Brain Stimulation for the Treatment of Parkinson Disease: A Diffusion Tensor Imaging Study

Highlights

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Conclusions

Biophys J

Neuroimage

Brain Res Brain Res Rev

Neurotherapeutics

Neuroimage

Trends Neurosci

Neurosci Lett

Neuroimage

Curr Opin Neurobiol

Neuron

Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease

Appl Neurophysiol

Most effective stimulation site in subthalamic deep brain stimulation for Parkinson's disease

Mov Disord

Optical deconstruction of parkinsonian neural circuitry

Science

Cortical effects of deep brain stimulation: implications for pathogenesis and treatment of Parkinson disease

JAMA Neurol

Tractographical model of the cortico-basal ganglia and corticothalamic connections: improving our understanding of deep brain stimulation

Clin Anat

Bilateral subthalamic stimulation for Parkinson's disease by using three-dimensional stereotactic magnetic resonance imaging and electrophysiological guidance

J Neurosurg

Assessment of a method to determine deep brain stimulation targets using deterministic tractography in a navigation system

Neurosurg Rev

Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging

Ann Neurol

Fiber tracking: principles and strategies: a technical review

NMR Biomed

Three-dimensional visualization of the pyramidal tract in a neuronavigation system during brain tumor surgery: first experiences and technical note

Neurosurgery

Diffusion tractography in deep brain stimulation surgery: a review

Front Neuroanat

Postoperative neuroimaging analysis of DRT deep brain stimulation revision surgery for complicated essential tremor

Acta Neurochir (Wien)

Deep brain stimulation: anatomical, physiological, and computational mechanisms

Network

Original Article
Role of the Cortico-Subthalamic Hyperdirect Pathway in Deep Brain Stimulation for the Treatment of Parkinson Disease: A Diffusion Tensor Imaging Study