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. Author manuscript; available in PMC: 2015 Jul 1.
Published in final edited form as: Brain Stimul. 2014 May 2;7(4):603–607. doi: 10.1016/j.brs.2014.04.007

Subthalamic nucleus deep brain stimulation induces motor network BOLD activation: Use of a high precision MRI guided stereotactic system for nonhuman primates

Hoon-Ki Min 1,2,3,#, Erika K Ross 1,#, Kendall H Lee 1,2,**, Kendall Dennis 3, Seong Rok Han 1,4, Ju Ho Jeong 1,5, Michael P Marsh 1, Bryan Striemer 6, Joel P Felmlee 6, J Luis Lujan 1,2,3, Steve Goerss 1, Penelope S Duffy 1, Charles Blaha 7, Su-Youne Chang 1,2, Kevin E Bennet 1,3
PMCID: PMC4108508  NIHMSID: NIHMS603271  PMID: 24933029

Abstract

Background

Functional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS).

Objective

Identify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP).

Method

An in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling.

Results

STN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001).

Conclusion

Our results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.

Keywords: deep brain stimulation, subthalamic nucleus, functional magnetic resonance imaging, nonhuman primate, motor cortex, pedunculopontine nucleus

Introduction

Deep brain stimulation (DBS) has been shown to be an effective treatment option for movement disorders including Parkinson’s disease (PD) (1). Although the mechanisms of stimulation-induced neuromodulation are not completely understood, it is known that modification of given brain functions by DBS depends on targeting specific sites in the complex neuronal circuitry underlying disease state dysfunction (2-4).

There has been increasing interest in using functional imaging to investigate the global brain effects of subthalamic nucleus (STN) DBS in PD patients (5-9). To characterize the functional neural network of DBS, our group previously developed a method for functional magnetic resonance imaging (fMRI) in a swine model of DBS (10-12).

Given that STN is a key relay area in the basal ganglia (BG)–thalamocortical circuitry (13), the sensorimotor subregion of STN has become the clinical DBS target for PD (14). Thus, the importance of precise targeting within the STN and the induced functional network effects on the BG and cortical circuitry by high frequency stimulation warrants examination.

Here, we describe a novel stereotactic system that facilitates miniature DBS electrode implantation in the nonhuman primate (NHP). To increase targeting precision in the small and irregularly shaped STN, this system was designed with an orthogonal coordinate system (X, Y, Z, arc, and collar) using an arc system similar to that of clinical stereotactic systems (15). Using this system, we were able to identify specific global functional neural network and circuitry effects induced by STN DBS in normal NHP.

Materials and Methods

Animals and Surgical Procedure

Study procedures were performed in accordance with the National Institutes of Health Guidelines for Animal Research (Guide for the Care and Use of Laboratory Animals) and approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC). The subject group consisted of two male rhesus macaques (Macaca mulatta) weighing 7±1 kg. Sedation was maintained with 1.75-2.5% isoflurane during surgery and 1.5%-1.75% during the fMRI experiment. Vital signs were continuously monitored throughout the procedures.

An MR image-guided stereotactic targeting system specifically developed by our group for NHP, was used for stimulating electrode targeting and implantation (Supplementary Figure S1A). A miniature Platinum-Iridium DBS electrode consisting of six cylindrical contacts (625 μm in diameter and 500 μm in length) separated by 500 μm (NuMed, Inc.) was introduced to the right hemisphere STN. Imaging was conducted by a 3-Tesla MR scanner (Signa HDx, General Electric) with a custom, in-house designed four-channel phased array radiofrequency coil (Mayo Clinic). A T1-weighted 3D magnetization prepared rapid gradient echo (MP-RAGE) and T2-weighted 2D fast spin echo (FSE) (Supplementary Table S1) were used to identify the STN, based on the Rhesus Macaque brain atlas (16) and anatomical landmarks (e.g., red nucleus in the axial view) in the MR image (see Supplementary Figure S1 and S3 for coordinate details). Electrode location was confirmed by x-ray fluoroscopy (SIREMOBIL Compact, Siemens AG) during surgery and by 3D computer tomography (CT) (Dual source Somatom Definition, Siemens AG) post-operatively (Supplementary Figure S1D).

Functional MRI during DBS

Following two to four weeks of post-surgical recovery, fMRI experiments were conducted using a gradient echo (GRE) echo-planar imaging (EPI) pulse sequence (integrated spatial spectral pulse for fat suppression) with an anatomical 2D T2-weighted GRE image (Supplementary Table 1). Based on the MRI-CT fusion image, the selected stimulation contacts included the medial to dorsolateral portion of the STN and zona incerta area (Supplementary Figure S3). The electrical stimulation parameters were biphasic 5 V pulses at 130 Hz and pulse widths of 150 μsec (A-M system, Model 12100 isolated pulse stimulator). An event-related-like block design was used to detect putative BOLD signal responses evoked by electrical stimulation, performing five stimulus/rest blocks (6 s ON/60 s OFF). Two fMRI experiments were performed on each subject, resulting in total four fMRI data sets that was conducted in four separate days (n=2, data set=4). The stimulating electrode was not active between imaging sessions.

Data Processing and Analysis

A standard pre-processing sequence, including slice scan time correction, 3D motion correction, temporal filtering, and spatial smoothing (Gaussian filter with FWHM: 1.3 pixel size) was applied to each data set (Brain Innovation, BrainVoyager QX). Double-gamma hemodynamic response function (onset 0 s, time to response peak 5 s, time to undershoot peak 15 s) correlated voxel-wise BOLD signal changes with the given stimulus protocol. To visualize the group BOLD pattern, the fMRI dataset was normalized to one subject’s brain using a nonlinear co-registration based on the anterior and posterior commissure points and six boundaries of the brain (anterior, posterior, superior, inferior, right and left borders) using each subject’s 3D MP-RAGE image (Brain Innovation, BrainVoyager QX). These datasets were further analyzed using linear regression analysis with the general linear model and multi-subject analysis. To correct for multiple comparisons and exclude false positive voxels, we considered only voxels with a False Discovery Rate (FDR) significance level of < 0.001 as representing sites of activation (Table 1). In addition to and separate from the FDR, we applied the more stringent Bonferroni correction (<0.001) to the original data. The brain areas that survived Bonferri correction are listed in Table 1. To measure event-related BOLD response (BOLD signal/5 volume average of baseline), regions of interest (ROI) were selected from the normalized group data based on the brain atlas (16). Factor analysis based on principal component analysis (PCA) with varimax rotation of the correlation matrix was performed on the ROI followed by k-means clustering of the three-dimensional Eigen plot (IBM Co., Statistical Package for the Social Sciences, version 20, IBM) (10).

Table. 1.

Areas of Significant Brain Activation

Location Cluster Size (mm Coordinates (x, y, z) Max t-Score Possible circuits involved
130Hz 5V 0.15ms Cerebellum (C) 2019 −5, −7, 15 16.47 ** Motor cortex-cerebellum connection, DS of cerebello-thalamic fibers
Primary motor cortex (I) 487 4, 9, 38 9.22 ** BGTC loop (Indirect pathway), Antidromic STN-Cortex, DS of CST in IC
Primary somatosensory cortex (I) 607 26, 19, 16 8.66 ** BGTC loop (Indirect pathway), Antidromic STN-Cortex, DS of CST in IC
Cingulate cortex (I,C) 59 −3, 7, 32 7.36 ** Limbic territory of STN
Auditory cortex/Parietal operculum (C) 199 22, 3, 30 6.50 ** Sensory imput
Caudate nucleus (I) 79 6, 27, 16 5.97 STN-SNc, DS of SN, DS of NSF, PPN-SNc
Periaqueductal gray (I) 45 2, 2, 12 5.75 N/A
Putamen (I) 18 8, 22, 16 5.58 STN-SNc, DS of SN, DS of NSF, PPN-SNc
Supplementary motor area (C) 28 −2, 18, 31 5.46 BGTC loop (Indirect pathway), Antidromic STN-Cortex, DS of CST in IC
Parahippocampal gyrus (I) 20 14, 2, 7 5.37 Limbic territory of STN
Pedunculopontine nucleus (I) 29 3, 3, 7 5.37 STN-PPN
Primary motor cortex (C) 33 −16, 15, 29 5.00 BGTC loop (Indirect pathway), Antidromic STN-Cortex, DS of CST in IC
Medial lemniscus (I) 6 5, 2, 6 4.91 Sensory imput
Cerebellum (I) 13 17, −5, 7 4.78 Motor cortex-cerebellum connection, DS of cerebello-thalamic fibers
Insular cortex (I) 8 19, 15, 18 4.50 Limbic territory of STN
Caudate nucleus (C) 30 −8, 22, 19 −4.76 STN-SNc, DS of SN, DS of NSF, PPN-SNc
Ventral lateral thalamic nucleus (C) 34 −6, 15, 20 −5.15 BGTC loop (Indirect pathway), Antidromic STN-CmPf, DS of thalamus
Putamen (C) 35 −16, 23, 14 −5.27 STN-SNc, DS of SN, DS of NSF, PPN-SNc
Amygdala (C) 84 −11, 22, 5 −5.83 Limbic territory of STN
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**

Areas showing with Bonferroni correction P<0.001

Coordinates (mm): x=mediolateral, y=rostrocaudal, and z=dorsoventral. Abbreviations: BGTC, Basal ganglia-thalamocortical; C, Contralateral; CST, Corticospinal tract; DS, Direct stimulation through electric spread; I, Ipsilateral; IC, Internal capsule; NSF, Nigrostriatal fiber; PPN, Pedunculopontine nucleus; SNc, Substantia Nigra pars compacta; STN, Subthalamic nucleus

Results

We designed and fabricated a stereotactic head frame to investigate DBS-induced functional activation in the NHP. Sub-millimeter accuracy (dx=0.30±0.08, dy=0.49±0.16, dz=0.76±0.06 mm) was achieved in the final stereotactic targeting phantom test (see Supplementary Information and Figure S2. The combined, concurrent fMRI - STN DBS (5V, 130Hz, and 150 μs) experiment revealed significant BOLD activation in the sensorimotor network, including primary motor cortex (MC), primary somatosensory cortex, supplementary motor area (SMA), the pedunculopontine nucleus (PPN) and the cerebellum (FDR < 0.001) with the contralateral cerebellum showing the highest t-score (See Figure 1A and Table 1). The sensorimotor network results remained significant even after Bonferroni correction (p < 0.001 (Table 1)).

Figure 1. STN DBS (5V, 130Hz, and 150 μs).

Figure 1

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(A) Areas of activation with STN stimulation (n=2, data set=4); (B) Event-related BOLD percent change during and after STN DBS. Error bars represent standard error; (C) Principal component analysis between functionally defined regions of interest for STN DBS.

Abbreviations: AC, auditory cortex; AM, amygdala; BOLD, blood oxygen level dependent; C, contralateral; CB, cerebellum; CC, cingulate cortex; CD, caudate nucleus; CP, caudate nucleus and putamen; CS, central sulcus; DBS, deep brain stimulation; FDR, false discovery rate; I, ipsilateral; IC, insular cortex; MC, primary motor cortex; ML, medial lemniscus; PAG, pariaqueductal gray; PC, principal component; PCA, principal component analysis; PPH, parahippocampal gyrus; PPN, pedunculopontine nucleus; PU, putamen; SS, primary somatosensory cortex; Stim, stimulation; STN, subthalamic nucleus; TH, thalamus; VL, ventral lateral thalamic nucleus.

Areas of activation were also found in the BG circuitry, including the caudate nucleus and putamen. STN DBS also affected the contralateral MC, SMA, cingulate, caudate nucleus, putamen, ventral lateral thalamic nucleus, amygdala, and auditory cortex/parietal operculum. Of note, several of these contralateral areas including the caudate nucleus, putamen, ventral lateral thalamic nucleus, and amygdala showed negative BOLD response (Table 1). Limbic circuitry BOLD response was evoked in bilateral cingulate cortex, ipsilateral parahippocampus, insular cortex, and contralateral amygdala. Additional areas of sensory activation included the auditory cortex, the parietal lobe, and the medial lemniscus. Figure 1B shows event-related time courses of BOLD percent changes with delayed hemodynamics peaking at 8 - 14 s in brain areas evoked by STN DBS. The ipsilateral primary motor cortex and bilateral cingulate cortex showed initial negative signal in the BOLD change.

Factor analysis was performed to identify jointly varying patterns of correlation among the eighteen ROIs (Figure 1C). The PCA and subsequent cluster analysis revealed the following three distinct clusters associated with STN DBS (p<0.001): a) Cluster 1: ipsilateral primary motor cortex, primary sensory cortex, pedunculopontine nucleus (PPN) and bilateral cerebellum; b) Cluster 2: contralateral primary motor cortex, primary sensory cortex, ventral lateral thalamic nucleus, caudate nucleus, putamen, amygdala, auditory cortex, and bilateral cingulate cortex; and c) Cluster 3 ipsilateral caudate nucleus, putamen, insular cortex, periaqueductal gray, parahippocampal gyrus, and medial lemniscus.

Discussion

There is increasing evidence that DBS modulation of the disease state is based on a circuitry effect related to the target stimulation area. This concept is supported by preclinical and clinical electrophysiological studies of DBS in movement disorders and psychiatric disease (2, 4, 17, 18). While region-specific DBS mechanisms have been investigated using electrophysiology and electrochemistry, the complex, dense wiring of the brain makes it extremely challenging to understand neuronal communication beyond a few synapses. Functional brain imaging has the advantage of providing global assessment of simultaneous neural activity.

We previously reported that STN DBS induced non-specific BOLD responses in both motor and non-motor networks in swine (10). In the current study, we used a miniature DBS electrode to stimulate the medial-dorsal portion of the STN in an NHP model of DBS to further explore global functional circuitry effects.

Our results support clinical studies of human PD patients using fMRI, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) during STN DBS. These studies report activation in ipsilateral primary sensorimotor cortex, premotor cortex, SMA, dorsolateral prefrontal cortex, BG, insular cortex, and contralateral cerebellum (7, 8, 19-21).

In addition, recent studies suggest that STN DBS might have a role in modulating cortical activity by normalizing the intracortical inhibitory mechanism (18, 22). A regional cerebral blood flow (rCBF) PET study showed that when effective STN stimulation was delivered during a movement task, motor areas were recruited, and there was also a widespread “normalization” of activity in primary motor cortex, SMA, and BG compared to the control group (23). A rCBF SPECT study reported a correlation between improved motor scores and an increase in rCBF in the pre-SMA and primary motor cortex (9).

Recent optogenetic and cortical evoked potential studies suggest that the therapeutic effects of STN DBS may be induced by the modulation of select afferent neuronal populations projecting to the STN (24, 25). The direct antidromic activation of the motor cortex through the motor cortex-to-STN hyperdirect pathway (26, 27) has been mentioned as contributing to the therapeutic effect of DBS in PD animal studies (27, 28). The contralateral STN DBS effect in our results may be indicative of the antidromic effects on the bilateral afferent cortical projections associated with this circuitry(29-31). However, further study is needed to understand the effects of negative BOLD in the contralateral hemisphere.

To investigate the pattern of relationships among the activated brain areas, factor analysis revealed three distinct patterns of correlation among functionally defined ROIs. Cluster 1 consisted of brain areas that are predominantly in the ipsilateral motor network. Cluster 2 consisted mainly of contralateral brains areas, and cluster 3 consisted mainly of the basal ganglia and limbic components.

Functional mapping of DBS is also important in that the sporadic cognitive/psychiatric complications of STN DBS have been attributed to current spread into adjacent neuronal structures (32-34). Recent clinical studies indicate that there is a distinct relationship between specific electrode location within the STN and the corresponding therapeutic outcome (35, 36). Our finding of predominant activation in motor networks with associated limbic activation might be attributed to current spread into ventral STN and nearby associated regions (37, 38).

Of note, the activation of PPN in both the NHP results reported here as well as in our previous swine models (10) suggest the importance of PPN in reduced gait freezing with STN DBS (39, 40).

Using broad stimulation contact coverage with large current spread effects, the present study allowed us to estimate the maximum circuitry effect induced by STN DBS and thus to establish a proof-of-principle setup for future more refined circuitry studies. Despite the limitations of the anesthetized and non-disease state of our subjects, our results reveal neural network grouping within the motor network and the BG by STN DBS and highlight the importance of their specific neural circuitry activation patterns and functional connectivity. This study demonstrates an effective technique for both surgical targeting and functional network mapping for DBS in nonhuman primates.

Supplementary Material

01

Supplementary Figure S1. DBS electrode implantation surgery. (A) MR safe nonhuman primate stereotactic head frame 3D CAD design (SolidWorks). Panel 2 shows head frame targeting accuracy test with a stereotactic MRI phantom; (B) aseptic surgery with the head frame and microdriver for electrode implantation; (C) T2-weighted GRE scan confirming STN; (D) Representative MRI and CT fusion image confirming actual electrode position in 2 rhesus macaques.

Supplementary Figure S2. Stereotactic Head Frame Phantom Total Accuracy Test. (A) Photo of the stereotactic targeting phantom; (B) Confirming the mechanical accuracy of the head frame arc; (C) Confirming stereotactic targeting accuracy through CT scan; (D) Targeting using MR image guided Compass navigational software; (E) Photo representation of stereotactic targeting of the phantom targets based on the coordinates.

Supplementary Figure S3. DBS contact position for each subject. AC-PC aligned axial view image was reconstructed from a coronal T2-weighted 2D FSE MR image for each subject and displayed with 1mm gap between images. The DBS contact position is mark in a red dote. For each subject biphasic stimulation was applied between contact 2-3 and 5-6. Two close contacts 2&3 and 5&6 was connected, respectively, and used as one contact.

Acknowledgements

This work was supported by the National Institutes of Health (R01 NS 70872 awarded to KHL) and by The Grainger Foundation. We also thank the Center for Advanced Imaging Research, Opus Building, Mayo Clinic for their support.

Footnotes

Financial Disclosure The authors declare no competing financial interests.

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Associated Data

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Supplementary Materials

01

Supplementary Figure S1. DBS electrode implantation surgery. (A) MR safe nonhuman primate stereotactic head frame 3D CAD design (SolidWorks). Panel 2 shows head frame targeting accuracy test with a stereotactic MRI phantom; (B) aseptic surgery with the head frame and microdriver for electrode implantation; (C) T2-weighted GRE scan confirming STN; (D) Representative MRI and CT fusion image confirming actual electrode position in 2 rhesus macaques.

Supplementary Figure S2. Stereotactic Head Frame Phantom Total Accuracy Test. (A) Photo of the stereotactic targeting phantom; (B) Confirming the mechanical accuracy of the head frame arc; (C) Confirming stereotactic targeting accuracy through CT scan; (D) Targeting using MR image guided Compass navigational software; (E) Photo representation of stereotactic targeting of the phantom targets based on the coordinates.

Supplementary Figure S3. DBS contact position for each subject. AC-PC aligned axial view image was reconstructed from a coronal T2-weighted 2D FSE MR image for each subject and displayed with 1mm gap between images. The DBS contact position is mark in a red dote. For each subject biphasic stimulation was applied between contact 2-3 and 5-6. Two close contacts 2&3 and 5&6 was connected, respectively, and used as one contact.

NIHMS603271-supplement-01.pdf (6.1MB, pdf)

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