Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals

Abstract

Background Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome (TS). Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS. Methods The combination of DBS and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. Using a with-in subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n=5). Results Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS. Conclusions Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of TS as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.

Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens

“…Given the ability of fornix stimulation to modulate dopaminergic transmission in the NAc, global BOLD changes were determined following pharmacological blockade of dopamine and glutamate receptors in the NAc to determine the functional connectivity between the medial limbic and corticolimbic circuits (Kim et al, 2013; Min et al, 2012). Rather than investigating differential dopamine D1-like and D2-like receptor actions in the NAc the D1/D2 dopamine receptor antagonist α-flupenthixol was employed.…”

“…All experiments began with stimulating lead implantation in the fornix, followed by fMRI and intracranial drug microinfusions or carbon fiber microelectrode implantation and FSCV (Figure 1A). In order to accurately and consistently implant the DBS electrode lead while minimizing inter-subject variability, high-resolution image-based targeting was performed as previously described (Min et al, 2012; Kim et al, 2013). The DBS electrode was implanted anterior and parallel to the medial portion of the fornix, in order to avoid penetrating the tract, as damage to these fibers is known to cause memory deficits (Laxton et al, 2010; Tsivilis et al, 2008; Vann et al, 2009; Wilson et al, 2008).…”

“…DBS electrode targeting and implantation was performed with an MR image-guided Leksell stereotactic targeting system (Elekta Inc., Stockholm, Sweden) modified for large animals (Min et al, 2012; Kim et al, 2013). A 3 Tesla MR scanner (General Electric Healthcare, Wakasha, WI; Signa HDx, 16× software) with a custom four-channel transmit-receive radiofrequency coil was used for preoperative anatomical imaging.…”

“…Double-gamma hemodynamic response function (onset = 6 sec, time to response peak = 11 sec, time to undershoot peak = 21 sec, response undershoot ratio = 3) correlated voxel-wise BOLD signal changes with the given stimulus protocol were calculated by linear regression. For group analysis, the fMRI data were co-registered to the anatomical 3D MPRAGE images using acquired 2D GRE-EPI images and 3D swine brain atlas, as previously described (Min et al, 2012; Kim et al, 2013). …”

Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia deep brain stimulation

“…In this regard, a recent study investigating centromedial/parafascicular DBS in a large animal model supports that thalamic DBS has an inhibitory effect in regions that contribute to impaired sensory-motor and emotional processing (Kim et al, 2013). Only more recently the GPi has also been considered as a DBS target to treat Tourette syndrome.…”