Project Details
Description
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).
Status | Active |
---|---|
Effective start/end date | 9/1/20 → 7/31/24 |
Funding
- National Institute of Mental Health: $682,439.00
- National Institute of Mental Health: $727,629.00
- National Institute of Mental Health: $682,439.00
- National Institute of Mental Health: $726,687.00
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