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Medial forebrain bundle structure is linked to human impulsivity.

ABSTRACT: Comparative research indicates that projections from midbrain dopamine nuclei [including the ventral tegmental area (VTA)] to the ventral striatum [including the nucleus accumbens (NAcc)] critically support motivated behavior. Using diffusion-weighted imaging and probabilistic tractography in humans, we characterized the trajectory and structure of two tracts connecting the VTA and NAcc, as well as others connecting the substantia nigra and dorsal striatum. Decreased structural coherence of an inferior VTA-NAcc tract was primarily and replicably associated with increased trait impulsivity and also distinguished individuals with a stimulant use disorder from healthy controls. These findings suggest that decreased coherence of the inferior VTA-NAcc tract is associated with increased impulsivity in humans and identify a previously uncharacterized structural target for diagnosing disorders marked by impulsivity.

SUBMITTER: MacNiven KH

PROVIDER: S-EPMC7494337 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Medial forebrain bundle structure is linked to human impulsivity.

MacNiven Kelly H KH Leong Josiah K JK Knutson Brian B

Science advances 20200916 38

Comparative research indicates that projections from midbrain dopamine nuclei [including the ventral tegmental area (VTA)] to the ventral striatum [including the nucleus accumbens (NAcc)] critically support motivated behavior. Using diffusion-weighted imaging and probabilistic tractography in humans, we characterized the trajectory and structure of two tracts connecting the VTA and NAcc, as well as others connecting the substantia nigra and dorsal striatum. Decreased structural coherence of an i ...[more]

PMID: 32938676

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Project description:Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/- 4) at baseline to 12.9 (SD +/- 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.

Project description:Deep brain stimulation (DBS) of the medial forebrain bundle (mfb) demonstrated anti-depressant effects both clinically and experimentally. Modulation of mesocorticolimbic dopaminergic (DA) activity could contribute-in part-to the therapeutic effects. By comparing selective and pathway specific midbrain DA optogenetic stimulation with the global, non-pathway specific mfb-DBS, the study explored changes in gene-expression of key biomarkers associated with neurocircuitry of depression. Rats received either optogenetic DAergic or mfb-DBS, delivered as acute/single or chronic/repeated stimulation. Micro-dissected regions were prepared for in situ hybridization targeting biomarkers of GABAergic, glutamatergic, and dopaminergic systems. Mfb-DBS mediated DA independent pathway increased GABAergic biomarkers (GABAA, GAD1) in frontal and accumbal regions, not in midbrain. The combinations of low frequency/high pulse width and high frequency/low pulse width stimulation generally increased biomarker expression similarly, but chronic/repetitive stimulation had no accumulative effect. Interestingly, unilateral stimulation had bilateral effects, but stimulation modalities had little impact on DAT and Vglut2 expression. In conclusion, both low and high frequency, acute/single and chronic/repetitive mfb-DBS-but not selective optogenetic stimulation -activated gene expression of biomarkers associated with GABAergic transmission. The increased expression was transitory and less chronic than predicted. Importantly, the study provides evidence that the anti-depressant therapeutic effects of clinical medial forebrain bundle DBS occurs-in part-be via modulation of GABAergic signalling which in turn could regulate the release of dopamine in frontal and accumbal regions. In addition, clinical implication of the data is that unilateral stimulation had bilateral consequences on the gene expression, although the physiological and functional sequelae of this are yet unknown.

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Medial forebrain bundle structure is linked to human impulsivity.

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Medial forebrain bundle structure is linked to human impulsivity.

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