Four Deep Brain Stimulation Targets for Obsessive-Compulsive Disorder: Are They Different?

Abstract

Deep brain stimulation is a promising therapeutic approach for patients with treatment-resistant obsessive-compulsive disorder, a condition linked to abnormalities in corticobasal ganglia networks. Effective targets are placed in one of four subcortical areas with the goal of capturing prefrontal, anterior cingulate, and basal ganglia connections linked to the limbic system. These include the anterior limb of the internal capsule, the ventral striatum, the subthalamic nucleus, and a midbrain target. The goal of this review is to examine these 4 targets with respect to the similarities and differences of their connections. Following a review of the connections for each target based on anatomic studies in nonhuman primates, we examine the accuracy of diffusion magnetic resonance imaging tractography to replicate those connections in nonhuman primates, before evaluating the connections in the human brain based on diffusion magnetic resonance imaging tractography. Results demonstrate that the four targets generally involve similar connections, all of which are part of the internal capsule. Nonetheless, some connections are unique to each site. Delineating the similarities and differences across targets is a critical step for evaluating and comparing the effectiveness of each and how circuits contribute to the therapeutic outcome. It also underscores the importance that the terminology used for each target accurately reflects its position and its anatomic connections, so as to enable comparisons across clinical studies and for basic scientists to probe mechanisms underlying deep brain stimulation.

Keywords: Anatomic tracing; Anterior limb of the internal capsule; Diffusion magnetic resonance imaging; Medial forebrain bundle; Subthalamic nucleus; Ventral striatum; White matter pathways.

Figure 1.

Connections through the ALIC(A/B) and VS (C/D) sites. A. Organization of PFC/ACC fibers in the ALIC-coronal view. B. electrode position to capture OFC fibers-sagittal view. C. Schematic showing convergence of frontal terminals fields in the striatum. D. Electrode placement positioned to capture OFC fibers. It also illustrates the additional connections of the VS in the area of the electrode. Inset demonstrates the electrode placement with respect to the small fascicles traveling through the VS. Abbreviations: Amy=amygdala, BNST=bed nucleus of the stria terminalis, Cd=caudate nucleus, Pu=putamen, Hipp=hippocampus, hypo=hypothalamus, MD=mediodorsal nucleus of the thalamus, NB=nucleus basalis, PPT=pedunculopontine nucleus, VP/GP=ventral pallidum/globus pallidus, VS=ventral striatum, VTA/SN= ventral tegmental area/substantia nigra. Color code: Fuchsia=vACC/mOFC, red=OFC, dark orange=dACC, light orange=vlPFC, yellow=dPFC, green=premotor cortex, blue=motor cortex.

Figure 2.

Connections through the STN(A/B) and midbrain (C/D) sites. A. Fiber bundles and connections through the STN. Red arrows=targeted connections, blue arrows=other pathways through the area. B. Organization of cortical terminals in the STN. Color code: Fuchsia=vACC/mOFC, red=OFC, orange=dACC, yellow=dPFC/vlPFC, blue= premotor/motor cortex. C. Dark field illumination demonstrating TH-positive fiber-positive staining (appears gold) as they travel from the VTA laterally, cross the IC to terminate in the globus pallidus and striatum. D. Sagittal section demonstrating the trajectory of TH-positive fibers to frontal cortex. Note, the TH-positive fibers are only found in the striatum, but not in the IC. E. Fibers bundles and connections through the midbrain site. Red arrows=targeted connections, blue arrows=other pathways through the area. Abbreviations: AC=anterior commissure, ALIC=anterior limb of the internal capsule, Cd=caudate, GP=globus pallidus, H=H fields of Forel, HD=hyperdirect pathway, Hypo=hypothalamus, IC= internal capsule, MT=mammillothalamic tract. PPT=pedunculopontine nucleus, OT=optic tract, R=red nucleus, SN=substantia nigra, STN=subthalamic nucleus, TH=tyrosine hydroxylase, Thal=thalamus, VTA=ventral tegmental area, ZI=ZI, 3n=third nerve. Scale bar=5mm.

Figure 3.

Anatomic tracing and dMRI through the ALIC. (A). Histology showing fiber pathways following an injection site in the dACC. Scale bar=5mm. (B). NHP dMRI streamlines generated from a seed at the injection site location from (A). Scale bar=4.9. The coronal levels match those shown in (A). Correct streamlines are indicated with yellow arrows, incorrect streamlines with blue arrows. (C-D). Human dMRI data illustrating streamlines following placement of a seed in a similar area of dACC. Based on the NHP data, yellow arrows show the likely correct streamlines, and blue arrows show the likely incorrect ones. Scale bar=10mm. Abbreviations: AC=anterior commissure, Cd=caudate, CC=corpus callosum, GP=globus pallidus, IC= internal capsule, Pu=putamen. Republished from Safadi et al.

4.

Projections from the VTA. Top panels= NHP histology following a tracer injection into the VTA, bottom panels, left=NHP dMRI tractography in NHP, right= human dMRI tractography. Top panel. A. asterisk=tracer injection site, Red=seed placement at the same site as the injection in monkey and human dMRI. Similar to the anatomic tracing, streamlines cross the IC, to the striatum. However, unlike the anatomic tracing experiment, streamlines also enter the IC and continue to travel rostrally, through the ALIC. B-C. Histology demonstrates fibers in the MFB, ventral and medial to the anterior commissure. There are no fibers in the ALIC. In contrast, the dMRI tractography in both the monkey and human show streamlines in the ALIC. Abbreviations: AC=anterior commissure, ALIC= anterior limb of the internal capsule, GP=globus pallidus, IC=internal capsule, MFB=medial forebrain bundle, OT=optic tract, PO=preoptic area, SN=substantia nigra, VS=ventral striatum. Scale bars: top panel-5mm; bottom panel, NHP-4.9mm; human-10mm.

5.

Summary of connections through the four DBS target: A. summary of the PFC-subcortical circuits. Color coding represents the topography of cortico-striatal connections. Arrows indication the projections through each structures. Color code: Fuchsia=vACC/mOFC, red=OC, dark orange=dACC, light orange=vlPFC, yellow=dPFC, green=premotor cortex, blue=motor cortex. Abbreviations: dACC= dorsal anterior cingulate cortex, dPFC=dorsal prefrontal cortex, GPe=globus pallidus, external segment, GPi=globus pallidus, internal segment, mOFC=medial orbitofrontal cortex, OFC=orbitofrontal cortex, STN=subthalamic nucleus, Thal=thalamus, vACC=ventral anterior cingulate cortex, vlPFC=ventrolateral prefrontal cortex, SN=substantia nigra. B. Electrode placement demonstrates cortical pathways likely modulated through the ALIC site. C. Electrode placement demonstrates cortical and subcortical pathways likely modulated through the VS site. D. Black asterisk indicates cortical and basal ganglia pathways likely modulated through the STN site. E. Electrode placement demonstrates cortical pathways likely modulated through the midbrain site. Asterisks=electrode contacts. Color code: Fuchsia=vACC/mOFC, red=OC, dark orange=dACC, light orange=vlPFC, yellow=dPFC, green=premotor cortex, blue=motor cortex. Abbreviations: Amy=amygdala, BNST=bed nucleus of the stria terminalis, Cd=caudate nucleus, dACC= dorsal anterior cingulate cortex, dPFC=dorsal prefrontal cortex, GPe=globus pallidus, external segment, GPi=globus pallidus, internal segment, Hipp=hippocampus, hypo=hypothalamus, MD=mediodorsal nucleus of the thalamus, mOFC=medial orbitofrontal cortex, PPT=pedunculopontine nucleus, Pu=putamen, OFC=orbitofrontal cortex, NB=nucleus basalis, STN=subthalamic nucleus, Thal=thalamus, vACC=ventral anterior cingulate cortex, vlPFC=ventrolateral prefrontal cortex, SN=substantia nigra, VP/GP=ventral pallidum/globus pallidus, VS=ventral striatum, VTA/SN= ventral tegmental area/substantia nigra.