Neuroimaging of preclinical models of substance use disorders

National Institute On Drug Abuse

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Abstract

1. Whole brain dynamics during optogenetic self-stimulation of the medial prefrontal cortex in mice Intracranial self-stimulation, in which an animal performs an operant response to receive regional brain electrical stimulation, is a widely used procedure to study motivated behavior. While local neuronal activity has long been measured immediately before or after the operant, imaging the whole brain in real-time remains a challenge. Herein we report a method that permits functional MRI (fMRI) of brain dynamics while mice are cued to perform an operant task: licking a spout to receive optogenetic stimulation to the medial prefrontal cortex (MPFC) during a cue ON, but not cue OFF. Licking during cue ON results in activation of a widely distributed network consistent with underlying MPFC projections, while licking during cue OFF (without optogenetic stimulation) leads to negative fMRI signal in brain regions involved in acute extinction. Noninvasive whole brain readout combined with circuit-specific neuromodulation opens an avenue for investigating adaptive behavior in both healthy and disease models. (Cover et al., Communication Biology, 2021) 2. Development of focal, multisite transcranial magnetic stimulation (TMS) coil for neuromodulation of brain networks Coordinated whole-brain neural dynamics are essential for proper control of the functionality of different brain subsystems. Multisite simultaneous or sequential stimulations of these subsystems can provide tools for mechanistic studies of brain functions and potentially more effective treatment of neuropsychiatric disorders. Transcranial Magnetic Stimulation (TMS) provides unique prospects to explore the connectivity and plasticity between brain regions. However, conventional TMS coils are large in size, limiting commercial multisite stimulation to only two-site (dual coil) systems. The size cannot be meaningfully reduced, or the field spread will be high and causes other undesired issues. This work shows a novel emission field optimization idea that can significantly reduce the TMS coils effective size without degrading the spread performance. Three distinct features emerge from the proposed geometry: (i) a small planar surface area, permitting multiple coils to be placed in each hemisphere; (ii) achieving flexible electric field depth-spread by adjusting the coil parameters; (iii) reducing the field spread through breaking the symmetry of ring coils and producing a more elliptical near field distribution. The emitted electric field distributions were theoretically simulated and experimentally validated with field probes and in-vivo animal tests. The proposed angle-tuning concept can indeed significantly improve the depth-spread performance of individual coils. For composite structures, using the proposed coils as basic building blocks simplifies the design and manufacturing process and helps to accomplish a leading depth-spread performance. In addition, the footprint of the proposed system is intrinsically small, making them suitable for multisite stimulations. (Under review) 3. Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence Using a recently introduced rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking, we conducted a resting-state fMRI study to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving. We trained rats to self-administer for 14 days either intravenous oxycodone or palatable food. Three days later, we introduced an electric barrier for 12 days that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier-induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier-induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated opioid seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier-induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving. (Under review) 4. Long-term cocaine self-administration produces structural brain changes that correlate with altered cognition An enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed. We addressed this fundamental question of causality using longitudinal anatomical magnetic resonance imaging and neurocognitive assessments in rhesus macaques. Cognitive tasks employed were stimulus reversal learning as a measure of cognitive flexibility/inhibitory control and delayed match to sample as a measure of visual working memory. Time points examined were before and following 12 months of chronic cocaine (n = 8) or water (n = 6) self-administration. A magnetic resonance imaging-only time point was also obtained following 2 years of forced abstinence. We identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence. Cocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments. (Jedema, et al., Biological Psychiatry, 2020)