Impulsivity, frontal lobes and risk for addiction

Abstract

Alcohol and substance abuse disorders involve continued use of substances despite negative consequences, i.e. loss of behavioral control of drug use. The frontal-cortical areas of the brain oversee behavioral control through executive functions. Executive functions include abstract thinking, motivation, planning, attention to tasks and inhibition of impulsive responses. Impulsiveness generally refers to premature, unduly risky, poorly conceived actions. Dysfunctional impulsivity includes deficits in attention, lack of reflection and/or insensitivity to consequences, all of which occur in addiction [Evenden JL. Varieties of impulsivity. Psychopharmacology (Berl) 1999;146:348-361.; de Wit H. Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addict Biol 2009;14:22-31]. Binge drinking models indicate chronic alcohol damages in the corticolimbic brain regions [Crews FT, Braun CJ, Hoplight B, Switzer III RC, Knapp DJ. Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats. Alcohol Clin Exp Res 2000;24:1712-1723] causing reversal learning deficits indicative of loss of executive function [Obernier JA, White AM, Swartzwelder HS, Crews FT. Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharmacol Biochem Behav 2002b;72:521-532]. Genetics and adolescent age are risk factors for alcoholism that coincide with sensitivity to alcohol-induced neurotoxicity. Cortical degeneration from alcohol abuse may increase impulsivity contributing to the development, persistence and severity of alcohol use disorders. Interestingly, abstinence results in bursts of neurogenesis and brain regrowth [Crews FT, Nixon K. Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol 2009;44:115-127]. Treatments for alcoholism, including naltrexone pharmacotherapy and psychotherapy may work through improving executive functions. This review will examine the relationships between impulsivity and executive function behaviors to changes in cortical structure during alcohol dependence and recovery.

Figures

Fig. 1. A Simplified Schematic of Frontal Cortical and Limbic brain region circuitry that contribute to addictive behavior

Shown is a diagram of a human brain with internal structures highlighted with projections indicated by arrows with the structure color. Frontal cortical areas are involved in reflection, attention, goal setting and planning as well as impulse inhibition. The dorsal lateral prefrontal cortex (dlPFC), projects to anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) with all 3 projecting to the ventral striatum (VS) a dopamine rich area important for expression of behaviors. Although all 3 structures are within the PFC. Recent studies have indicated that the dlPFC is a key brain region for executive functions, particularly to select attention, monitoring and planning (Abe and Hanakawa, 2009). The dlPFC receives inputs from all sensory systems and association cortex that projects to other PFC areas and premotor areas. The dlPFC appears to be sensitive to behavioral costs of attention selection of goal related information (Liu et al., 2006). Thus, the dlPFC must be activated to attend to decisions. Without the dlPFC addictive behavior can proceed as a cue induced semi-automatic learned behavioral repertoire. The dlPFC projects to ACC and OFC with all contributing to executive functions and inhibition of impulses. The ACC likely plays a key role in maintaining attention. The OFC projects to the amygdale and contributes to evaluation of outcomes and particularly unexpected outcomes, key elements for successful reversal learning (Schoenbaum et al., 2007). Once dlPFC focuses attention on activity it activates OFC to use associative information and project future outcomes (Schoenbaum et al., 2006). Limbic regions including the amygdala (AMG) and entorhinal cortex (ENT) also project to VS, which projects to globus plaidus (GP) and thalamus (Thal), which then projects to multiple brain regions for expression of behaviors. Impulsive behaviors reflect poor executive function since they include actions that are poorly conceived, prematurely expressed, unduly risky or inappropriate to the situation that often results in undesirable consequences. Expression of impulsive behaviors result from a deficit in suppressing responses, poor evaluation of consequences and an inability to forgo immediate small rewards in favor of greater delayed rewards. Thus, adolescent impulsivity due to poor development of executive functions is a risk period for addition due to the high experimentation, risk taking and active learning of associations. After initiation of drinking, progressive increased drinking may damage frontal areas leading to a progressive lose of executive function that may ultimately lead to loss of control over substance use, i.e. addiction.

Fig. 2. Naltrexone increases activation of Orbital Frontal Cortex

The left panel shows the effect of naltrexone on brain activity, as measured by fMRI, during decisions between small, immediate and larger, delayed rewards. Activity was increased following acute administration of 50 mg of Naltrexone (NTX) relative to administration of placebo (PBO; adapted from Boettiger et al., in press). Lower plot shows the mean activity in the orbitofrontal cortex (OFC) site indicated by the green circle in the image above as a function of drug condition. Right panel provides orientation as to the location of the orbitofrontal cortex within the brain. Plot reflects mean ± S.D. L, left hemisphere.

Fig. 3. Ethanol Induced Brain Damage and Inhibition of Neurogenesis

Shown are brain sections of control and alcohol treated animals. Neurogenesis as indicated by BrdU+ histochemistry (black cells on the edge of the ventricle). Top Left – Control brain, right -Ethanol-(5gm/kg). Note control on left has many black dots that represent newly forming neuroprogenitors that will migrate to the forebrain. Note one dose of ethanol completely eliminated the stem cells (Adapted from (Crews et al., 2006a). Pictures middle and bottom show binge alcohol induced brain damage. BIBD ethanol induced necrotic degeneration in hippocampus visualized by agyrophilic amino cupric silver stain (black-middle photo) or Fluoro-Jade B (green-bottom) (Obernier et al., 2002a). Note only binge treated brains shown black silver stain neuronal death and green FluroJade neuronal death stains. The neuronal cell death and loss of neurogenesis are forms of alcoholic neurodegeneration.

Fig. 4. Alcohol reduces New Neuron Dendritic Growth

Progenitors in hippocampus progress from dividing progenitors that exit cell cycle to grow and differentiate into neurons that are synaptically linked and appear to become fully functional integrated neurons. Doublecortin is a structural protein only expressed in differentiating neuronal progenitors during dendritic elongation and arborization. Immunohistochemistry for doublecortin provides an index of neurogenesis, the formation of new neurons, as well as allowing analysis of the effects of ethanol on neuroprogenitor growth. Left: Representative dendritic trees from traced immunohistochemistry for doublecortin in hippocampus of control (top) or ethanol treated animal (bottom). Right: doublecortin histochemistry from control or ethanol treated animals. Note how ethanol reduced new neuron formation as well as the branching and size of dendritic trees.

Fig. 5. Perseverative repetitive behaviors due to Binge Induced Brain Damage

The Morris water maze is a round water bath with a hidden platform that tests learning the location of the hidden platform just under the water using visual cues. The experimental time line on the bottom shows tests were done long after behavioral withdrawal was complete, e.g. 5-6 days after the last dose of alcohol. Learning (decreased time to find the platform) was not altered in animals known to have binge ethanol induced brain damage. Both controls and sober binge treated rats readily learned the platform location. However, they differed in the reversal learning task of the Morris water maze. The submerged platform was placed in the quadrant opposite that in which it had been placed during the learning memory task (moved from upper left to lower right quadrant). Circles on the top represent a vertical view of the track taken by a CONTROL and BINGE ETHANOL treated rat during the first trial of the reversal learning task. Binge ethanol treated animals show deficits in relearning. Note the perseverative circling behavior shown by the binge ethanol treated animal with numerous re-entries into the original goal quadrant. The binge treated rat failed to reach the new platform location within the maximum time allowed and was removed. Thus, binge treatment induced brain damage induces cognitive deficits that mimic human alcoholism. Relearning deficits could contribute to the difficulty alcoholics have in learning to live in abstinence. (Adapted from (Obernier et al., 2002b).

Fig. 6. Representative Cortical Frequency Maps of Characteristic Frequency (CF) Defined Cortical Responses

Shown are CF maps of adult, post-natal age 50 (P50) controls or animals exposed to noise during the auditory cortex critical period (P7-P35). Note the sharply defined frequency responses of receptive fields during the maturation of the auditory cortex (control left). Noise during the critical period of auditory cortex development disrupts the sharpening of sound tone specific auditory cortex activation. The focal sharpening of cortical activation by sound likely corresponds with improved ability to identify specific tones essential for music and sequences of sounds essential for language (Chang and Merzenich, 2003; Zhou and Merzenich, 2008). The disruption of the focal sharpening of sound activation of auditory cortex represents an example of environmental disruption of normal cortical development. Adolescent binge drinking may disrupt frontal cortical sharpening resulting in loss of executive and control functions.

Fig. 7. Binge Drinking in adolescent rats damages frontal brain regions

The frontal cortex of a rat is a heterogeneous mixture of cortical layers. On the left is shown the left half of a coronal section of rat brain stained for cellular nuclei and cytoplasm (H & E) stain. The midline (right side) of the left picture is the medial part of frontal cortex. Note the rhinal fissure (RF) is an indentation from the left side (lateral) of the brain moving inside. This separates the anterior olfactory nucleus (AON) and anterior piriform cortex (PIR) from the orbital frontal cortex (OFC) and agranular insular cortex, dorsal part (Ald). Arrows show OFC medial (right) and lateral (left). The prelimbic area (PL) and anterior cingulated area (ACA) are part of medial frontal cortex. On the right are sections from 2 adolescent rats exposed to binge ethanol treatment (Crews et al., 2000) that have been stained with the neurodegeneration silver stain. The black regions in the pictures at right represent binge induced neuronal cell death. Note the degeneration looping the frontal cortex (#1-upper right) and over orbital frontal cortex, the anterior olfactory nucleus (AON) and anterior piriform cortex (PIR) (#2-lower right). These images are representative of the significant frontal cortical degeneration found following binge treatment in adolescent rats (Crews et al., 2000).

Fig. 8. Impact of Executive Functions and Impulsiveness on Stages of change associated with treatment, recovery and relapse during addiction

Psychological changes that occur during recovery from addiction likely involve alterations in frontal cortical function. Behavioral change during recovery from addiction can be modeled as “Stages of Change” (DiClemente, 2007). Addicted individuals can be in a state of precontemplation, e.g. no interest in changing behavior and likely denial of drug problems, or may enter into the first stage of change, contemplation, e.g. risk-reward analysis. Preparation, involving planning and committing are consistent with increased activation of the frontal cortex. As mentioned earlier, naltrexone, which increases orbitofrontal activation in recovering alcoholics can improve recovery. Recovery may represent frontal-subcortical activation of directed motivation and socially responsive behaviors. Increased impulsivity during maintenance of recovery could underlie relapse and return to the limbic driven behaviors of addiction. Thus, the neurobiology of the psychology of stages of recovery may represent levels of frontal cortical involvement in behavior and regulation of impulsivity.