“Abnormal Brain Structure Implicated in Stimulant Drug Addiction” Sibling Study

Abnormal Brain Structure Implicated in Stimulant Drug Addiction (excerpted from Science mag.)

Abstract — Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual’s health and social and personal life.

We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.
Drug dependence is increasingly recognized as a “relapsing brain disorder” and, in support of this view, marked structural changes in striatal and prefrontal brain regions have been reported in people dependent on stimulant drugs.

These reports, however, raise the question of whether these brain abnormalities may have predated drug-taking, rendering individuals vulnerable for the development of dependence.

Individuals at risk for drug dependence typically have deficits in self-control , which may reflect a diminished ability to recruit prefrontal networks for regulating behaviorStimulant drugs are highly reinforcing, because they directly affect brain systems implicated in motivated behavior, such as the basal ganglia and the limbic system, and they modulate control systems in the prefrontal cortexMalfunction of these circuitries may increase the susceptibility for stimulant-induced neuroadaptive changes and facilitate the development of drug dependence.

As brain structure is, to a large extent, inherited and drug dependence runs in families (9), a genetic or epigenetic influence on addictive behaviors seems plausible. Yet, we know very little about the mechanisms through which risks for drug dependence might be inherited.

Endophenotypes are quantitative traits, mediating between the predisposing genes (genotypes) and the clinical symptoms (phenotypes) in complex disorders . As heritable traits, endophenotypes can be measured objectively in both patients and their unaffected first-degree relatives.

  • The brains of the sib-pairs showed distinct abnormalities relative to the healthy control volunteers.  Specifically, key structures previously implicated in addiction, such as the medial temporal lobe and the basal ganglia, were significantly enlarged in the sib-pairsWe also identified a significant reduction of gray matter volume in the posterior postcentral gyrus and adjacent areas, such as the superior temporal gyrus and the posterior insula, in both drug-dependent individuals and their siblings compared with healthy volunteers
  • The within-pair variability of the gray matter volume increase in the putamen and of the volume decrease in the posterior insula were both significantly smaller in biological siblings than in randomly paired siblings, which indicated that this abnormality is shared between members of the same family
  • Moreover, gray matter regions associated with the duration of stimulant drug exposure differed clearly in location from the regions identified as markers of familial risk for stimulant drug dependence.

The involvement of the putamen is consistent with its implication in fronto-striatal circuits for stop-signal performance and proposed antecedent problems in response control. However, the additional regions identified as showing changes in the sib-pairs may be related to other psychological processes underlying addiction.

Thus, brain abnormalities observed in the sib-pairs in neural systems underlying learning and memory [such as the medial temporal lobe, and habit formation [such as the putamen are intriguing, given that some forms of drug addiction are thought to develop through maladaptive acquisition and control of habits.

Enlargement of limbic and striatal structures has been reported previously in patients with obsessive-compulsive disorder (OCD), and like addiction, OCD is characterized by dysfunctional habits and “out-of-control” behavior.

Our findings may indicate markers of neural vulnerability for pathological habit formation, which could further facilitate the effects of drugs of abuse by interfering with limbic-striatal functions. Pathological habits in drug addiction typically result in compulsive drug-taking behaviors when prefrontal control fails to regulate behavior. Our data are also in keeping with preclinical research indicating that impairments in response control are predictive of cocaine reinforcement and dopamine receptor dysfunction in the striatum. Deficits in inhibitory prefrontal control were evident in both drug-dependent individuals and their siblings who do not abuse drugs, which may reflect an increased risk for out-of-control drug-seeking or drug-taking behaviors, which could pave the way for the development of drug dependence.

The identified profile of familial abnormalities remarkably resembles the developmental changes of brain structure during adolescence, i.e., limbic-striatal structures mature before prefrontal brain systems. This developmental asynchrony has been suggested to create an imbalance between mesolimbic reward and prefrontal control systems, which predisposes adolescents to sensation-seeking and impulsive behavior, rendering them potentially vulnerable to drug-taking. Our previous data on biological siblings of stimulant-dependent individuals indicated a propensity for increased impulsivity, as measured on the Barratt Impulsivity Scale, contrasting with normal scores on measures of sensation-seeking traits. The present findings show that even stronger effects in the sib-pairs are observed with an objective measure of impulse control, the SSRT. These findings are also related to changes in brain structure, including the inferior frontal cortex and putamen, which are key nodes in a neural network that mediates response regulation.
Our findings thus indicate that gray matter changes in the dorsal striatum, together with abnormal inferior prefrontal cortical connectivity, underlie an increased risk for developing stimulant drug dependence.

… The identification of these brain and behavioral biomarkers for familial risk of drug dependence demonstrates that an individual’s predisposition to become addicted to stimulant drugs may be mediated by brain abnormalities linked to impaired self-control.

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