Seeking Answers to Addiction

The ability of neuroscience to shine light into the dark corners of substance use, and the promise of real-world applications were dominant themes of the Sixth Annual Aspen Brain Forum, “The Addicted Brain and New Treatment Frontiers,” presented at the New York Academy of Sciences.

Identifying people at risk and understanding the roots of that risk could lead to more effective interventions against substance use disorders, perhaps making it possible to go beyond treatment to prevention, said several speakers.

Looking into the adolescent brain

In her keynote address, Nora D. Volkow, director of the National Institute on Drug Abuse, focused on the single group most at risk of drug and alcohol problems: adolescents. “We know that those vulnerable to start using drugs are also those more vulnerable to transition from drug experimentation to compulsive drug taking, which is the loss of control we call addiction. Intervention as prevention should be targeted to this high-risk group,” she said. “Based on imaging studies, we have a pretty clear idea of why adolescents are at greatest risk of drug experimentation and addiction.”

The brain develops, through early adulthood, in a roughly back-to-front sequence in which the prefrontal cortex, central to executive functions of judgment and decision making, lags behind limbic and dopaminergic reward circuits. Neuroimaging studies have characterized more subtle aspects of this developmental process: Functional connectivity between the prefrontal cortex and striatal nuclei is weaker in children and adolescents than in adults, an apparent indicator of the relative lack of inhibitory control over responses that drives the motivation to take drugs and facilitates the conversion from voluntary to compulsive use.

On an individual level, biology and environment influence brain development, further shaping vulnerability to addiction. They work together, Volkow emphasized: “genes are important, but the brain is plastic, responding to social and cultural events, particularly during development. People often polarize these things; we need to integrate them.”

Imaging studies give some insight into these factors and their interaction. “It has been shown that connectivity to the prefrontal cortex is less in children with ADHD or other conditions that place them at greater risk for addiction,” she said. On the environmental level, investigators have clarified how social circumstances influence connectivity.

One diffusion tensor imaging [DTI] study of children raised in orphanages associated the length of time spent in the institutions with reductions in functional connectivity between the brain and limbic areas. In a recent follow-up to this research, “an intervention that placed children in supportive families was able to strengthen connections from frontal areas that are necessary for self-control,” Volkow said.

Such studies suggest that “we can create a supportive system that can counteract the negative effects of environment, even the negative effects that come from genetic vulnerability,” she said.

The promise of prevention

In a later talk, Diane L. Fishbein, director of the Prevention Research Center at Pennsylvania State University, elaborated on the implications of such studies for the possibility of preventing, rather than treating addiction. “We’re on the cusp of [research] that has the potential to inform the development of preventive interventions in a more targeted and precise way,” she said.

Fishbein proposed a cumulative model for substance abuse risk, where genetic variants confer vulnerability or resilience, which are “ramped up or down, depending on what the individual experiences and is exposed to. Adversity, discrimination, and poverty increase risk, while good education, quality health care, or a nurturing family increase resilience.”

As in the orphanage studies that Volkow cited, stress and deprivation slow the formation of key connections between brain regions, “compromising the ability to exercise rational responses,” she said.

Neuroscientists are beginning to explain such effects on the developing brain in terms of epigenetic modification, which is “at the very core of gene-environment interactions,” Fishbein said.

“The prevention science field is very excited about the potential of epigenetics to tell us how to help the child who’s experienced severe stress. There’s reason to believe that, with optimal rearing, enrichment experiences, and/or pharmacological intervention, we can reverse some of the damage and alter the trajectory.”

A vital aspect of this research is the attempt to characterize more clearly the “neurobiological precursors and consequences of abuse,” and to discriminate one from the other, she said. Identifying precursors and biomarkers of vulnerability, for one thing, could strengthen efforts to bring preventive services to high-risk individuals who are most in need of then.

In a prospective longitudinal study, her group found that teenagers who had much lower levels of cognitive function before they ever took drugs were the most likely to subsequently start using inhalants. Other studies suggested that precursors and consequences of substance abuse are the same, she said: Deficits in self-regulation predict its onset, and worsen as abuse continues, for example.

Brain development and alcohol abuse

Susan F. Tapert, professor of psychiatry at University of California, San Diego, focused on alcohol abuse in the context of adolescent brain development. She reported research that compared functional and structural brain features and neuropsychological measures of non- and heavy drinkers. An early study of 15-16 year olds showed a 10 percent deficit in information recall in heavy drinkers, as well as reduced cerebellar, hippocampal, and prefrontal volume, and poorer quality white matter.

Larger longitudinal studies suggested how these early outcomes reflect alterations in developmental processes. In studies that followed initially non-drinking children, some at risk (because of family history or conduct disorder symptoms) of alcohol use problems, for 3-4 years starting in early adolescence, a number of distinctive patterns emerged.

Reduction in gray matter is normal in adolescent brain development, reflecting refinement of brain circuitry, but it was accelerated, particularly in temporal and frontal lobe regions of the cortex, in the teens who began drinking heavily during the study compared with those who drank little or none. White matter growth and refinement was less-robust in heavy drinkers than the others.

Performance on tasks that measured the ability to reproduce complex visual information and to maintain vigilance improved in the non-drinking adolescents during the study period, but deteriorated in the heavy drinkers.

Repeated fMRI testing showed generally high levels of brain activation in early adolescents who were asked to perform a cognitively demanding visual exercise, which declined over time in the non-drinkers. “This is true of a lot of cognitive tasks through adolescence, as the brain becomes more efficient,” Tapert said.

“But the pattern was different in kids who transitioned into heavy drinking,” she said. “Before starting to drink, they showed less activation than others when attempting the task, which could suggest they weren’t as cognitively engaged. After drinking started, activation was higher: Their brains had to work harder to do the same tasks.”

Lindsay M. Squeglia, now at Medical University of South Carolina, reported results of an extensive analysis (in press) of baseline data from one of the longitudinal studies that Tapert described, comparing children who went on to drink heavily with those who drank little if at all.

Combining neuroimaging, demographic, and neurocognitive parameters at age 12-14 made it possible to characterize, with considerable accuracy, those who would develop problematic alcohol use in the near future.

“It was pretty surprising to me that the variables we included could predict behavior 4-5 years later,” Squeglia said.

“We’re not yet at the point where we can put kids in the scanner” to assess the likelihood of their becoming problem drinkers, she said, “but for clinicians, it seems really important to know [neurocognitive and demographic] risk factors” for alcohol abuse.