A multi-institutional group of researchers describes (“Characterization of the brain functional architecture of psychostimulant withdrawal using single-cell whole brain imaging“) in eNeuro how withdrawal from nicotine, methamphetamine, and cocaine altered the functional architecture and patterns in the brains of mice, compared to control animals. They found that each drug produced a unique pattern of activity in the brain, but that mouse brains in withdrawal shared similar features. Perhaps more notably, the researchers said all psychostimulants shared a common link: reduced modularity.

“Numerous brain regions have been identified as contributing to withdrawal behaviors, but unclear is the way in which these brain regions as a whole lead to withdrawal. The search for a final common brain pathway that is involved in withdrawal remains elusive. To address this question, we implanted osmotic minipumps containing either saline, nicotine (24 mg/kg/day), cocaine (60 mg/kg/day), or methamphetamine (4 mg/kg/day) for 1 week in male C57BL/6J mice,” write the investigators.

“After 1 week the minipumps were removed and brains collected 8 hours (saline, nicotine and cocaine) or 12 hours (methamphetamine) after removal. We then performed single-cell whole-brain imaging of neural activity during the withdrawal period when brains were collected. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modularity, with a shift from a cortical- to subcortical-driven network, including a decrease in total hub brain regions.

“These results demonstrate that psychostimulant withdrawal produces the drug-dependent remodeling of functional architecture of the brain and suggest that the decreased modularity of brain functional networks and not a specific set of brain regions may represent the final common pathway associated with withdrawal.”

“All brains are organized into semiautonomous groups of neurons with specific functions, such as the cortex, amygdala and thalamus. Each region, however, is connected and interacts with other regions performing similar functions, creating a functional unit called a module,” said senior author Olivier George, PhD, professor in Department of Psychiatry at University of California San Diego School of Medicine. “Think of it as many different workstations, one station is in control of your mood, another takes care of your needs, and many other stations takes care of your goals, memories, motivations, sensation, et cetera. The brain needs many modules to take care of all of these processes at the same time.

“We found that in withdrawal, there was a dramatic decrease in the number of modules compared to control mice. It’s like the whole brain was dedicated to the effect of the lack of drugs, all of the workstations doing the same thing.”

Complete restructuring of brain networks

That decreased modularity, the authors said, resulted in a complete restructuring of the brain networks. Reduced modularity has been shown in several brain disorders in humans, including traumatic brain injury and dementia. It may also be the common link between drugs of abuse.

To conduct their studies, the scientists implanted osmotic mini-pumps in mice that contained either nicotine, cocaine, methamphetamine or saline. The pumps remained in place for one week, with sufficient dosing and time to create a state of dependence. After the pumps were removed, the brains of mice were examined using single-cell whole-brain imaging at the peak of withdrawal symptoms, about eight to 12 hours post-pump removal.

“We found that cocaine, methamphetamine and nicotine withdrawal all produced a major shuffling of brain regions with major increases in functional connectivity throughout the brain compared to control (saline) mice,” said George, “with a decrease in modular structuring of the brain most strongly with methamphetamine and cocaine, then nicotine.”

The brains of methamphetamine and cocaine dependent mice were also very similar, consistent with their shared pharmacology, targeting the dopaminergic system.

This reduced modularity was associated with a shift of networks being controlled by the higher-level cortex to sub-cortical networks. The effect, said researchers, has been documented in humans after abstaining from alcohol dependence and in persons suffering from dementia and traumatic brain injury. Reduced modularity is associated with cognitive deficits and inflexible behavior which may explain the obsession and compulsion for the drug in people with substance use disorder.

George said the commonality of this kind of restructuring during withdrawal from psychostimulants helps explain why these drugs are so addictive. His team is currently using this approach to test experimental medications that may reverse and normalize brain network modularity.

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