Abstract
BackgroundDeep 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) modelMethodsAnimals (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 scanResultsWe 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 stimulationConclusionsOur 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
Highlights
The discovery of chlopromazine in 1952 by the French Surgeon and anesthesiologist Henri Laborit [1] sparked the new era of psychopharmacology and set the stage for biological treatment of various psychiatric illnesses
Validation of Experimental Paradigm In order to confirm that the experimental setup did not produce artifacts in Blood Oxygenation Level-Dependent (BOLD) signal responses, we assessed a series of control conditions
We conducted experiments in which we performed Deep Brain Stimulation (DBS) electrode implantation into the nucleus accumbens (NAc) followed by a sham stimulation functional Magnetic Resonance Imaging (fMRI) sequence conducted with a nearly identical setup to the experimental conditions, with wires extended from the scan room but not connected to the stimulator outside the scan room during the scanning sequence
Summary
The discovery of chlopromazine in 1952 by the French Surgeon and anesthesiologist Henri Laborit [1] sparked the new era of psychopharmacology and set the stage for biological treatment of various psychiatric illnesses. Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is emerging as an effective treatment for reducing symptom severity in obsessive compulsive disorder (OCD) [2,3,4,5], Tourette’s syndrome [6,7,8,9], major depressive disorder [10,11,12], and alcoholism [13] This practice is supported by preclinical models, in which NAc stimulation reduces compulsive checking in quinpirole rat models of OCD [14], decreases alcohol consumption in alcohol preferring [15,16] and attenuates re-instatement in cocaine-seeking [17], and morphine-preference in rats [18]. 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
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