The use of brain imaging to elucidate neural circuit changes in cocaine addiction

Abstract

Within substance abuse, neuroimaging has experienced tremendous growth as both a research method and a clinical tool in the last decade. The application of functional imaging methods to cocaine dependent patients and individuals in treatment programs, has revealed that the effects of cocaine are not limited to dopamine-rich subcortical structures, but that the cortical projection areas are also disrupted in cocaine dependent patients. In this review, we will first describe several of the imaging methods that are actively being used to address functional and structural abnormalities in addiction. This will be followed by an overview of the cortical and subcortical brain regions that are most often cited as dysfunctional in cocaine users. We will also introduce functional connectivity analyses currently being used to investigate interactions between these cortical and subcortical areas in cocaine users and abstainers. Finally, this review will address recent research which demonstrates that alterations in the functional connectivity in cocaine users may be associated with structural pathology in these circuits, as demonstrated through diffusion tensor imaging. Through the use of these tools in both a basic science setting and as applied to treatment seeking individuals, we now have a greater understanding of the complex cortical and subcortical networks which contribute to the stages of initial craving, dependence, abstinence, and relapse. Although the ability to use neuroimaging to predict treatment response or identify vulnerable populations is still in its infancy, the next decade holds tremendous promise for using neuroimaging to tailor either behavioral or pharmacologic treatment interventions to the individual.

Figure 1

Number of original research publications using neuroimaging to study addicted populations users. The graph above demonstrates the results of a PubMed Central literature search for all original human research published between 1990 and 2011 containing addiction related keywords* and either “neuroimaging” (blue) or connectivity-related (red) keywords^#. Notes: *Addiction, substance dependence, cocaine, alcohol, marijuana, opiate, methamphetamine, nicotine; ^#neural circuit, connectivity, network.

Figure 2

Cortical and subcortical brain areas frequently cited in cocaine addiction literature. Brain regions which are frequently investigated in both clinical and preclinical cocaine neuroimaging studies: orbital prefrontal cortex (OPFC), medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC), insula, caudate (Cau), putamen (Put), ventral tegmental area (VTA), nucleus accumbens (N.Acc), amygdala (Amyg). The substantia nigra is not frequently assessed in cocaine literature but included here because of its dopaminergic relevance (S Nig). These regions are highly interconnected with some level of functional and structural organization.

Figure 3

A representative cortical neuron projecting to a subcortical neuron. Information in the brain is processed via neural circuits like these which rely on both intact functioning of the neurons and the structural integrity of the axons and myelin which will transmit the electrical potential. Both functional and structural connectivity of cortical–subcortical circuits appear to be compromised in chronic cocaine users. Notes: This figure of two pyramidal neurons is for display purposes only. It is not to scale. There are also reciprocal subcortical–cortical projections.

Figure 4

Cortical–striatal connectivity deficits during a simple sensorimotor integration task in cocaine users. Reprinted from Drug and Alcohol Dependence. Hanlon CA, Wesley MJ, Stapleton JR, Laurienti PJ, Porrino LJ. The association between frontal-striatal connectivity and sensorimotor control in cocaine users. Drug Alcohol Depend. 2011;115(3):240–243. Copyright 2011, with permission from Elsevier. (A) During a simple finger tapping task (which requires frontal and striatal coordination including the dopamine system) controls have a significant functional coupling between both cortical–cortical regions and cortical–subcortical regions. (B) In cocaine users however, cortical–subcortical coupling was impaired despite intact cortical–cortical coupling.

Figure 5

Measuring functional connectivity via simultaneous brain imaging and brain stimulation. Through the use of transcranial magnetic stimulation in the magnetic resonance environment, we are able to selectively stimulate cortical brain regions and measure the BOLD response or changes in blood flow secondary to the stimulation. Abbreviation: BOLD, blood-oxygen level dependent.

Figure 6

Integrating impaired structural integrity in cocaine users with functional activity. (A) Cocaine users (n = 26) have lower structural integrity of transcallosal fibers than controls (n = 36) (fractional anisotropy values, P < 0.001). (B) Loss of structural integrity (blue) overlain with abnormal functional activity (orange) in chronic cocaine users during a basic finger tapping task. Notes: As described in Hanlon et al, cocaine users have a loss of typical functional laterality during a simple finger tapping task. These data demonstrate that cortical areas of abnormally elevated BOLD signal are coincident with areas of decreased corpus callosum fiber integrity (blue). This suggests that the loss of typical laterality may be due to a loss of typical transcallosal inhibition via corpus callosal fibers. Abbreviation: BOLD, blood-oxygen level dependent.