Functional Connectivity of Chronic Cocaine Use Reveals Progressive Neuroadaptations in Neocortical, Striatal, and Limbic Networks

Abstract

Brain imaging studies indicate that chronic cocaine users display altered functional connectivity between prefrontal cortical, thalamic, striatal, and limbic regions; however, the use of cross-sectional designs in these studies precludes measuring baseline brain activity prior to cocaine use. Animal studies can circumvent this limitation by comparing functional connectivity between baseline and various time points after chronic cocaine use. In the present study, adult male Long–Evans rats were trained to self-administer cocaine intravenously for 6 h sessions daily over 14 consecutive days. Two additional groups serving as controls underwent sucrose self-administration or exposure to the test chambers alone. Functional magnetic resonance imaging was conducted before self-administration and after 1 and 14 d of abstinence (1d and 14d Abs). After 1d Abs from cocaine, there were increased clustering coefficients in brain areas involved in reward seeking, learning, memory, and autonomic and affective processing, including amygdala, hypothalamus, striatum, hippocampus, and thalamus. Similar changes in clustering coefficient after 1d Abs from sucrose were evident in predominantly thalamic brain regions. Notably, there were no changes in strength of functional connectivity at 1 or 14 d after either cocaine or sucrose self-administration. The results suggest that cocaine and sucrose can change the arrangement of functional connectivity of brain regions involved in cognition and emotion, but that these changes dissipate across the early stages of abstinence. The study also emphasizes the importance of including baseline measures in longitudinal functional neuroimaging designs seeking to assess functional connectivity in the context of substance use.

Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age

“…Network analysis. Brain connectivity networks were analyzed using the Brain Connectivity Toolbox for Matlab (Rubinov and Sporns, 2010) and as previously reported Orsini et al, 2018). Symmetrical connectivity graphs with a total 11,175 matrix entries were first organized in Matlab [graph size = n(n-1)/2, where n is the number of nodes represented in the graph or 150 ROI].…”

Characterization of the brain functional architecture of psychostimulant withdrawal using single-cell whole brain imaging

“…The 0.75R threshold was chosen because all of the brain regions in each network showed connections to other regions at this threshold. Previous animal model studies used various thresholds, ranging from 0.3R to 0.85R [21, 22], to examine connectivity. Negative network connectivity was not examined herein because the precise meaning of such connectivity is controversial and thus is not often examined in network-based approaches [23–26].…”

“…Substantial evidence corroborates the importance of the thalamus in psychostimulant addiction and withdrawal. In a rat model of cocaine self-administration, the thalamus was found to be heavily involved in network function during acute abstinence, but changes in the network disappeared after 2 weeks [22]. Interestingly, the thalamus in humans has been shown to be hypoactive in cocaine abusers [53], and thalamic connectivity is predictive of cocaine dependence [54] and altered in infants who are exposed to cocaine [55].…”

“…Interestingly, the thalamus in humans has been shown to be hypoactive in cocaine abusers [53], and thalamic connectivity is predictive of cocaine dependence [54] and altered in infants who are exposed to cocaine [55]. Although network changes that are induced by acute withdrawal are reversed over time [22], prolonged use may lead to more permanent restructuring of the brain, and major differences between the nicotine and methamphetamine/cocaine networks may account for differences in the severity of each drug after long-term use [35, 45, 56].…”

“…Previous rat and mouse studies that examined functional connectivity used 5-8 animals [21, 22]. The number of samples that are examined in functional connectivity studies is the number of potential connections (i.e., 178 total brain regions all connecting with each other for each treatment).…”