Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study

Abstract

Background: Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model

Methods: Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan

Results: We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation

Conclusions: Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS.

Figure 1. DBS surgery and Lead Confirmation.

A) Custom designed MRI-compatible head frame. B) Screenshot of MR-image based targeting procedure using modified COMPASS software. C) Surgical introduction of the Medtronic 3389 DBS electrode using the Lexsell stereotactic arc. D) fMRI Experimental Setup. Extension wiring connected the externalized DBS lead with a pulse generator located outside the scan room. E) Representative pre-surgical anatomical MP-RAGE scan. F) Post-surgical CT scan demonstrating electrode location in the left NAc G) MR-CT fusion with atlas overlay demonstrating the location of the electrode tip in the left NAc. H) Diagram plotting the location of the 0 contact in each animal (red asterisks), as determined by the MR-CT fusion on a stereotaxic pig brain atlas, sagittal slice (lateral 2.00 mm from midline) .

Figure 2. NAc DBS elicits distal network BOLD changes.

A–C) Areas of activation with left unilateral NAc stimulation at 5 V 130 Hz 500 µs (n = 7), normalized to a 3D pig brain template Significant activation q(FDR)<0.001 was observed in the anterior and dorsolateral prefrontal (red), insula (brown), parahippocampal (green) and cingulate cortex (blue). Decrease in BOLD signal was observed in the dorsal region of the thalamus (tan). Slice locations are presented in distance (mm) from the posterior commissure. D) Event-related analysis of the average time course for each region of interest was plotted as average percent change in BOLD signal from baseline vs. time (one scan is equal to TR = 3 seconds) using ten frames (30 seconds) prior to stimulation onset as the baseline. Duration of stimulation is marked by the vertical purple lines. In all regions of interest, there is a clear peak in percent change associated with stimulation.

Figure 3. Voltage Dependency of fMRI BOLD signal.

A) Comparison of data from left unilateral NAc stimulation at 3 V 130 Hz 500 µs (i; n = 7) with stimulation at 5 V 130 Hz 500 µs (ii; n = 7). Both voltages showed regions of activation in the prefrontal cortex and insula as well as an area of deactivation in the dorsal region of the thalamus. B) i. Region of interest cluster sizes (mm³) comparing the percent size of areas of activation with 3 V 130 Hz 500 µs (yellow; n = 7) and 5 V 130 Hz 500 µs (red; n = 7), represented by the relative size of the two circles. ii. Event-related time course of percent change in BOLD signal from baseline with 1 V (blue; n = 5), 3 V (yellow; n = 7), and 5 V at 130 Hz (red; n = 7), 500 µs pulse width. C) Unilateral stimulation to the left (left) right (middle) and bilateral (right) NAc (n = 1). Stimulation of the right NAc activated areas corresponding to those of left NAc stimulation, including prefrontal cortex and insula, ipsilateral to the side of stimulation.

Figure 4. Pulse Width dependency of fMRI BOLD signal.

A) Comparison of data from left unilateral NAc stimulation at 5 V 130 Hz 500 µs (i; n = 3) with stimulation at 3 V 130 Hz 100 µs (ii; n = 3). Both pulse widths showed regions of activation in the prefrontal cortex, insula, dorsal anterior cingulate, caudate. There was an additional area of activation in parahippocampal cortex present only with stimulation at 5 V 130 Hz 500 µs. B) i. Region of interest cluster sizes (mm³) comparing the percent size of areas of activation with 5 V 130 Hz 100 µs (yellow; n = 3) and 5 V 130 Hz 500 µs (red; n = 3), represented by the relative size of the two circles. ii. Event-related time course of percent change in BOLD signal from baseline with 100 µs (yellow; n = 3) and 500 µs (red; n = 3) pulse widths at 5 V and 130 Hz.