Rules Ventral Prefrontal Cortical Axons Use to Reach Their Targets: Implications for Diffusion Tensor Imaging Tractography and Deep Brain Stimulation for Psychiatric Illness

Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, New York 14642, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2011; 31(28):10392-402. DOI: 10.1523/JNEUROSCI.0595-11.2011
Source: PubMed


The ventral prefrontal cortex (vPFC) is involved in reinforcement-based learning and is associated with depression, obsessive-compulsive disorder, and addiction. Neuroimaging is increasingly used to develop models of vPFC connections, to examine white matter (WM) integrity, and to target surgical interventions, including deep brain stimulation. We used primate (Macaca nemestrina/Macaca fascicularis) tracing studies and 3D reconstructions of WM tracts to delineate the rules vPFC projections follow to reach their targets. vPFC efferent axons travel through the uncinate fasciculus, connecting different vPFC regions and linking different functional regions. The uncinate fasciculus also is a conduit for vPFC fibers to reach other cortical bundles. Fibers in the internal capsule are organized according to destination. Thalamic fibers from each vPFC region travel dorsal to their brainstem fibers. The results show regional differences in the trajectories of fibers from different vPFC areas. Overall, the medial/lateral vPFC position dictates the route that fibers take to enter major WM tracts, as well as the position within specific tracts: axons from medial vPFC regions travel ventral to those from more lateral areas. This arrangement, coupled with dorsal/ventral organization of thalamic/brainstem fibers through the internal capsule, results in a complex mingling of thalamic and brainstem axons from different vPFC areas. Together, these data provide the foundation for dividing vPFC WM bundles into functional components and for predicting what is likely to be carried at different points through each bundle. These results also help determine the specific connections that are likely to be captured at different neurosurgical targets.

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    • "Fibers of passage in this region connect dorsal prefrontal cortex (DPFC), dorsal anterior cingulate cortex (dACC), orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (vmPFC) with the thalamus (principally mediodorsal, anterior medial, medial pulvinar, and midline-intralaminar nuclei), amygdala, hypothalamus and brainstem (substantia nigra, ventral tegmental area, raphe nuclei and peduncolopontine tegmental nucleus). The trajectories of these fibers of passage show a characteristic general pattern of topographic organization in VC/VS, but the individual projections and bundles overlap considerably (Jbabdi et al. 2013; Lehman et al. 2011; Yang et al. 2015). In DBS practice, anatomical inhomogeneity in VC/VS results in the stimulation of multiple different structures by implanted electrodes. "
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    ABSTRACT: Deep Brain Stimulation (DBS) is a neurosurgical procedure that can reduce symptoms in medically intractable obsessive-compulsive disorder (OCD). Conceptually, DBS of the ventral capsule/ventral striatum (VC/VS) region targets reciprocal excitatory connections between the orbitofrontal cortex (OFC) and thalamus, decreasing abnormal reverberant activity within the OFC-caudate-pallidal-thalamic circuit. In this study, we investigated these connections using diffusion magnetic resonance imaging (dMRI) on human connectome datasets of twenty-nine healthy young-adult volunteers with two-tensor unscented Kalman filter based tractography. We studied the morphology of the lateral and medial orbitofrontothalamic connections and estimated their topographic variability within the VC/VS region. Our results showed that the morphology of the individual orbitofrontothalamic fibers of passage in the VC/VS region is complex and inter-individual variability in their topography is high. We applied this method to an example OCD patient case who underwent DBS surgery, formulating an initial proof of concept for a tractography-guided patient-specific approach in DBS for medically intractable OCD. This may improve on current surgical practice, which involves implanting all patients at identical stereotactic coordinates within the VC/VS region.
    Full-text · Article · Oct 2015 · Brain Imaging and Behavior
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    • "prefrontal and insular cortices) and subcortical (e.g. ventral striatum) affective structures implicated in the effects of DBS for psychiatric illness [69] "
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    ABSTRACT: Anorexia nervosa is characterized by extreme low body weight and alterations in affective processing. The subcallosal cingulate regulates affect through wide-spread white matter connections and is implicated in the pathophysiology of anorexia nervosa. We examined whether those with treatment refractory anorexia nervosa undergoing deep brain stimulation (DBS) of the subcallosal white matter (SCC) show: 1) altered anatomical SCC connectivity compared to healthy controls, 2) white matter microstructural changes, and 3) microstructural changes associated with clinically-measured affect. Diffusion magnetic resonance imaging (dMRI) and deterministic multi-tensor tractography were used to compare anatomical connectivity and microstructure in SCC-associated white matter tracts. Eight women with treatment-refractory anorexia nervosa were compared to 8 age- and sex-matched healthy controls. Anorexia nervosa patients also completed affect-related clinical assessments presurgically and 12 months post-surgery. 1) Higher (e.g. left parieto-occipital cortices) and lower (e.g. thalamus) connectivity in those with anorexia nervosa compared to controls. 2) Decreases in fractional anisotropy, and alterations in axial and radial diffusivities, in the left fornix crus, anterior limb of the internal capsule (ALIC), right anterior cingulum and left inferior fronto-occipital fasciculus. 3) Correlations between dMRI metrics and clinical assessments, such as low pre-surgical left fornix and right ALIC fractional anisotropy being related to post-DBS improvements in quality-of-life and depressive symptoms, respectively. We identified widely-distributed differences in SCC connectivity in anorexia nervosa patients consistent with heterogenous clinical disruptions, although these results should be considered with caution given the low number of subjects. Future studies should further explore the use of affect-related connectivity and behavioral assessments to assist with DBS target selection and treatment outcome. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Brain Stimulation
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    • "Outflow structures of the basal ganglia innervate the mediodorsal and ventral anterior thalamic nuclei, which in turn project back to the prefrontal and orbitofrontal regions (Drevets et al., 2008; Ongur and Price, 2000; Price and Drevets, 2010; Price et al., 1996). In primates, the main fiber pathways interconnecting the above-mentioned structures are the white matter fibers of the frontal lobe, the anterior limb of the internal capsule and the inferior thalamic peduncle (Lehman et al., 2011; Velasco et al., 2005). "
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    ABSTRACT: Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioural, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regards to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induce distinct changes in regional brain activity and functional connectivity.
    Full-text · Article · Aug 2014 · Neurobiology of Disease
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