Modeling circuit-specific psychiatric deep brain stimulation and its cognitive effects in macaques

模拟回路特异性精神深部脑刺激及其对猕猴的认知影响

• 批准号: 10668349
• 负责人: BENJAMIN Y HAYDEN
• 金额: $ 68.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668349
• 关键词: Anatomy; Animal Model; Animals; Axon; Behavioral; Biological Models; Brain; Cell Nucleus; Clinical; Clinical Trials; Cognition; Cognitive; Collaborations; Complex; Corpus striatum structure; Deep Brain Stimulation; Disease; Distal; Electrodes; Electrophysiology (science); Elements; Engineering; Fiber; Functional disorder; Goals; Homologous Gene; Human; Impairment; Implant; Individual; Institution; Internal Capsule; Lateral; Macaca; Macaca mulatta; Maps; Mental Depression; Mental disorders; Methods; Modeling; Movement Disorders; Mus; Obsessive-Compulsive Disorder; Pathway interactions; Patients; Pattern; Performance; Post-Traumatic Stress Disorders; Prefrontal Cortex; Primates; Process; Psychiatry; Rattus; Research; Research Domain Criteria; Research Personnel; Resolution; Rodent; Role; Running; Site; Structure; Techniques; Testing; Thalamic structure; Ventral Striatum; Viral; Work; addiction; clinical efficacy; clinical practice; cognitive ability; cognitive control; cognitive neuroscience; genetic manipulation; gray matter; improved; insight; neural; neural correlate; nonhuman primate; response; success; tool; white matter

Abstract Neurostimulation, including invasive methods like deep brain stimulation (DBS), is an increasingly important approach to treating mental illness. It offers the possibility of directly targeting specific circuits to reverse circuit dysfunctions that underpin mental disorders. Unfortunately, the clinical efficacy of brain stimulation is still unreliable. DBS, for instance, has extraordinary results in the hands of expert academics, but has not passed a well-controlled US-based clinical trial. The critical barrier is that it is very difficult to study or optimize DBS’ mechanisms of action in psychiatric illness. Animal studies would be ideal for refining stimulation strategies, but the primary species for modeling mental illness are rats and mice. The most promising DBS treatments act on circuits that lack true rodent homologues. We and other investigators have shown that, at multiple brain targets, effective DBS alters neural activity distally, especially in lateral prefrontal cortex (LPFC), which is only found in primates. Non-human primates (NHPs), especially macaques, which have strong LFPC homology to humans, would thus be an excellent model for understanding how DBS works. Macaque studies have yielded major insight in other DBS applications such as movement disorders. In this project, we demonstrate an approach to modeling DBS in non-human primates by focusing on cognitive control. Cognitive control is the ability to regulate one’s own cognition, such as withholding a habitual response in favor of a more goal-aligned option. It is disrupted in depression, obsessive compulsive disorder (OCD), and emerging DBS indications like addiction. Co-PI Widge recently showed that DBS at a well-studied target, the ventral internal capsule/ ventral striatum (VCVS), acts in part by improving cognitive control. That improvement appears to involve PFC activity changes. The challenge is that it is not clear why or through what pathways VCVS DBS improves cognitive control, and thus we lack the ability to optimize the effect. We propose to answer that question by stimulating individual tracts and gray matter nuclei that comprise the VCVS DBS target, in rhesus macaques performing a standard cognitive control task (the Flanker task). During stimulation, we will record single units and local field potentials from multiple PFC structures, identifying mechanisms by which VCVS DBS exerts pro-cognitive effects. Aim 1 maps these mechanisms relative to cortico-thalamic tracts in the internal capsule, while Aim 2 extends that mapping to cortico-striatal tracts and striatal nuclei. These studies are possible through a unique clinical, engineering, and neuroscientific collaboration. Co-I Johnson has developed methods for “steering” electrical neurostimulation to preferentially target structures surrounding a DBS electrode, allowing circuit-targeted neurostimulation without the use of viral/genetic manipulations. His expertise supports our team’s capabilities in macaque cognitive neuroscience (contact PI Hayden), clinical DBS (Widge), and striatal anatomy (co-I Heilbronner).

摘要