Executive function, treatment, recovery and psychostimulant dependence
Significant variability exists within the literature regarding the persistence of executive deficits (Chang et al., 2002; Hoffman et al., 2006) and structural and functional differences (Chang et al., 2002; Kim et al., 2005) during abstinence from psychostimulant dependence. While this literature generally supports the persistence of executive deficits within these samples, some research suggests gross deficits in executive function may be less durable (Fernadez-Serrano et al., 2011).
The majority of the research cited above involves cross sectional comparisons between abstinent psychostimulant addicts and non-using control subjects. Longitudinal studies of executive abilities are generally lacking and show disparate results. Di Sclafani et al., (2002) reported greater executive impairment in a sample of crack-cocaine dependent subjects compared to controls at 5-6 weeks of abstinence. After 6 months of abstinence these deficits were still present. In contrast, adolescents with a diagnosis of methamphetamine abuse or dependence who showed poor neuropsychological performance compared to controls demonstrated improvements on the PEG Board Test and forward digit span task that were related to the length of abstinence (King et al., 2010).
Few studies have examined executive abilities as a function of abstinence greater than a year. Selby & Azrin, (1998) found no significant improvement in neuropsychological function following 36 months of cocaine abstinence among incarcerated adult male felons with a history of cocaine dependence, however this was not surprising as these participants’ neuropsychological performance was similar to matched control subjects. However, limited research suggests some improvement in executive abilities with prolonged abstinence. Toomey et al., (2003) examined neuropsychological function between 50 pairs of twins in which only one twin had a history of heavy stimulant abuse ending at least a year prior to assessment. Twins with a history of psychostimulant abuse performed poorly compared to those without a history of abuse on measures of attention and motor function, but better on a measure of visual vigilance. In addition, Salo et al., (2009) has demonstrated recently abstinent methamphamine addicts show augmented stroop reaction time interference compared to control participants and compared to methamphetamine addicts who initiated abstinence more than a year prior to being assessed. Stroop reaction time interference was also positively correlated with the length of participants’ abstinence suggesting that protracted psychostimulant abstinence may yield improvement in executive function.
Studies examining executive abilities among abstinent stimulant users often fail to report details of treatment that participants received in order achieve abstinence and therefore, little is known regarding the interaction between treatment modality, executive function and recovery from psychostimulant addiction. However, research employing Transcranial Magnetic Stimulation has linked decreased cocaine craving to activation of the dorsolateral prefrontal cortex (Camprodon et al., 2007).
Opiates
Executive dysfunction and vulnerability to opiate dependence
Several studies linking executive abilities and vulnerability to substance dependence have included opiate users (Najam et al., 1997; Tarter et al., 2003; Mezzich et al., 2007), however there are few studies specifically examining neurological functioning as a predictor of opiate dependence. Bauer et al., (1999) found that a family history of paternal opiate dependence was not related to P300 event related potentials during performance of the Stroop Task.
Impairment of executive function in opiate dependence
There is a relative lack of empirical studies examining deficits in executive function specific to opiate addicts (Feil et al., 2010, Gruber et al., 2007). However, a growing body of evidence has demonstrated impaired performance among opiate dependent subjects on executive measures including; the Stroop Task, Ruff Figural Fluency Test, Go/No go task, measures of impulsivity, gambling tasks, delay discounting tasks, attention, and working memory (Brand et al., 2008; Fishbein et al., 2007; Forman et al. 2004; Lee & Pau, 2002; Kirby & Petry, 2004; Mintzer & Stitzer, 2002; Ornstein et al., 2000; Rapeli et al., 2006; Pirastu et al., 2006). However, reports of executive deficits among opiate addicts are not universal (Ersche & Shakian, 2007; Pau et al., 2002), may be less significant than observed in psychostimulant addicts (Ersche & Shakian, 2007), and research suggests that some of deficts may be highly transient and reflect changes related to recent abstinence (Rapeli et al., 2006).
Studies have investigated structural deficits associated with chronic opiate use. Pezawas et al., (1998) using Computerized Tomography found that compared to controls opiate dependent individuals showed significant cortical volume loss and that this loss in the frontal cortex was associated with a shorter period of abstinence before relapse. Lyoo et a!., (2006) using Magnetic Resonance Imaging and voxel-based morphometry found reduced gray matter density in the bilateral prefrontal cortex and several other regions in opiate dependent subjects compared to controls. Using similar imaging methods, Liu et al., (2009) reported gray matter reductions in the right prefrontal cortex, left supplementary motor cortex, and bilateral cingulate cortex among opiate addicts.
Functional imaging research also implicates hypofrontality and executive impairment as a consequence of chronic opiate use. Forman et al., (2004) using event-related Functional Magnetic Resonance Imaging in individuals performing the Go/No go task found that relative to controls, opiate dependent subjects had reduced anterior cingulate error signal activation and poorer task performance. Using Functional Magnetic Resonance Imaging while heroin dependent subjects and controls performed the Arrow Task (which assesses cognitive regulation and impulsivity) it was found that heroin addicts had greater impulsivity and performed more errors. Neural activation of heroin dependent subjects was attenuated in the anterior cingulate cortex and augmented in the left dorsolateral prefrontal cortex, bilateral inferior parietal, and left medial temporal regions relative to controls (Lee et al., 2005). Another study combining Positron Emission Tomography with performance on the Cambridge Risk Task revealed heroin dependent subjects had significant under-activation in the lateral orbitofrontal region compared to controls and that abnormal task related activation was correlated with duration of intravenous heroin use. Being conservative following loss of points on the task was negatively associated with activation of the pregenual anterior cingulate and insula cortex in controls, but not opiate users (Ersche et al., 2006).
Executive function, treatment, recovery and opiate dependence
Abstinence from opiate dependence has been linked to persisting executive and cortical deficits. Fu et al., (2008) used functional Magnetic Resonance Imaging to examine the neural mechanisms of response inhibition while abstinent heroin addicts performed the Go/no go Task. Neural response inhibition in the anterior cingulate cortex, medial prefrontal, and inferior frontal lobe activity was linked to response inhibition and competition on the behavioural measure. Moreover, heroin dependent subjects showed impaired response inhibition that persisted several months into abstinence. These results are further supported by studies reporting heroin addicts who had been abstinent for between 3 and 18 months performed more poorly than controls on the Porteus Maze Test of impulse control (Lee & Pau., 2002) and significant deficits in episodic memory and impulsivity following three months of abstinence (Prosser et al., 2006). Other studies support executive impairment lasting as long as a year into abstinence in verbal fluency (Davis et al., 2001) and impulsivity but not attention, mental flexibility and abstract reasoning (Pau et al., 2002).
Research has also investigated the extent to which executive function changes in response to treatment and is predictive of clinical outcome. Passetti et al., (2008) found that performance on two measures of decision making (Cambridge Gambling Task and Iowa Gambling Task), but not on measures of planning, motor inhibition, reflection impulsivity or delay discounting were predictive of abstinence from illicit drug use at 3 months in opiate dependent subjects following 6 weeks of community drug treatment. Similarly, Gruber at al., (2006) examined subjects upon entering methadone maintenance therapy and again following two months of treatment. Improvements in verbal learning and memory, visuospatial memory, psychomotor performance, and decreased frequency of drug use were observed compared to baseline.
In an unpublished study from our lab changes in executive function on a battery of neuropsychological tests administered an average of 47 days post-admission and then again 90 days later among 16 heroin dependent individuals undergoing Methadone Maintenance Therapy were investigated. At the time of initial testing, participants showed significant deficits in the: Stroop Color Word Test, Porteus Mazes Test, and a trend toward poorer performance on the Wisconsin Card Sorting Test compared to the normative population. Methadone maintained clients showed significant improvement in Figural Fluency Test and the Stroop Interference Score between the two test times. Six family members of the Methadone maintained participants completed the Frontal Systems Behavioral Scale and reported significantly greater levels of disinhibition and a trend towards increased apathy among study participants. Family members also reported a trend towards improvement in apathy and executive function across the three months of Methadone Maintenance Therapy. In addition, Stroop Interference Scores at both time points were predictive of opiate abstinence. Stroop Interference Scores after 4 months of treatment were also predictive of cocaine and opiate abstinence. Participants who were opiate negative after 4 months showed improved performance on the Stroop Interference Test while those testing positive for opiates did not show improvement across time. While caution in warranted when interpreting these results due to the small sample size, these results are consistent with a growing literature that suggests recovery from opiate addiction is accompanied by improved executive abilities and may be predictive of clinical outcomes. (Meil et al., 2008).
Nicotine
Executive dysfunction and vulnerability in nicotine dependence
There is a lack of research directly examining executive dysfunction as a predictive factor in the development of nicotine dependence. However, childhood attention problems were shown to be a significant predictor of adult smoking (Kahalley et al., 2010). In addition, impairment in working memory has been shown to be related to an earlier age of onset of smoking. Further, male smokers initiated smoking at an earlier age and were more impaired during tests of attention than female smokers and non-smokers, leading these authors to suggest that neurotoxic effects of nicotine are more severe when use occurs earlier (Jacobsen et al., 2005). Research has also began to link impulsivity to the development of nicotine dependence in adolescent smokers (Chase & Hogarth, 2011).
Impairment of executive function in nicotine dependence
Until recently, executive dysfunction associated with nicotine dependence has recieved relatively little attention. Impairment in nicotine dependent populations has been documented in specific aspects of executive functionins such as working memory, cognitive flexibility, emotion regulation, and inhibitory control (Billieux et al., 2010; Jacobsen et al., 2005; Kahalley et al., 2010; Razani et al., 2004). In addition, Spinella (2003) found self-reported scores on the apathy, disinhibition, and executive dysfunction subscales of the Frontal Systems Behavioral Scale were related to nicotine dependence.
Limited imaging studies have also examined deficts in prefrontal cortical function in nicotine dependent individuals. Cigarette smokers showed smaller gray matter volumes and lower gray matter densities than nonsmokers in the prefrontal cortex, along with smaller volumes in the left dorsal anterior cingulate cortex and lower gray matter densities in the right cerebellum (Brody et al., 2004). Gallin et al., (2006) reported decreases in grey matter volume and lower grey matter density were observed in smokers in the frontal regions which were inversely associated with the magnitide of lifetime exposure to tobacco smoke. Research also finds increased activation of frontal regions associated with inhibitory control (such as the left orbitofrontal cortex and dorsolateral prefrontal cortex) in response to smoking related cues, suggesting the importance of these regions in resisting the urge to smoke (Brody et al., 2002).
Executive function, treatment, recovery in nicotine dependence
Studies also found evidence of persistent deficits amongst former smokers over varying periods of abstinence. Neuhaus et al., (2006) revealed persistent fronto-striatal dysfunction in former smokers despite a mean of 11 years of abstinence from cigarette smoking. In addition to other functional differences, they reported decreased cortical activation in orbitofrontal and left dorsolateral prefrontal regions amongst previous smokers when completing an auditory oddball task. These results are grossly consistent with Dawkins et al., (2009) who found no evidence of improvement on a measure of attentional bias in a small group of successful quitters over a period of three months. The successful quitters also showed no improvement on two different indices of response inhibition.
Limited reserach has also investigated executive function and treatment outcomes for nicotine dependence. Brega et al., (2008) reported participants’ scores on the Behavioral Dyscontrol Scale was a significant predictor of whether they had achieved abstinence. Moreover, research employing brain stimulation of the dorsolateral prefrontal cortex in nicotine dependent subjects suggests this procedure may be effective in combatting nicotine dependence and further implicates executive abilities in the recovery process (Eichhammer et al., 2003).
Polysubstance dependence
Executive dysfunction and vulnerability in polysubsubstance dependence
The genetic predisposition for drug addiction may involve impulsivity (Kreek et al., 2005). Self-reported impulsivity has been recently shown to be a predictor of current and future substance use in a 3 year longitudinal study of adolescents (Krank et al., 2011). Broader aspects of executive function have also been linked to the familial factors in the development of drug addiction. Najam et al., (1997) administered children with a high and low risk for drug abuse, based on a history of paternal diagnosis, a battery of neuropsychological tests at 10-12 years of age and a drug use measure two years later. Poorer executive function performance on the Stroop task, Memory Scan, Motor restraint, and the Wechsler Intelligence Scale for Children III, was significantly associated with subsequent substance abuse. Executive cognitive functioning discriminated between children who were at high and low risk of abuse based on familial history.
A series of longitudinal studies by Tarter and colleagues have suggested that Neurobehavioral disinhibition, a construct combining affective, behavioural, and cognitive indicators of self-regulation, is a significant predictor of substance dependence between childhood and young adulthood (Kirisci et al., 2006; Mezzich et al., 2007; Tarter et al., 2003). For example, Mezzich et al., (2007) reported that neurobehavioral disinhibition in boys, measured at age 10-12 and again at age 16 significantly predicted substance use disorders by age 19. Included in their measure of neurobehavioral disinhibition are several common test of executive function including Stroop test, Porteus Maze Test, Vigilance Test, Forbidden Toys Test, Block Design Test, and Motor Restraint Test. The executive functioning component of this composite accounted for 30% of the variance at each time point, implicating it as a major component of this trait, though it should be noted that many consider other aspects of neurobehavioral disinhibition (e.g., aspects of self-regulation) as falling under the executive function umbrella. In addition, Functional Magnetic Resonance Imaging has revealed that scores on the neurobehavioral disinhibition trait are negatively correlated with frontal cortical activation (McNamee et al., 2008). It has also been suggested that drug use itself may be related to the development of executive impairment among drug addicts as Verdejo-Garcia et al., (2006) reported that the severity of use was predictive of executive deficits in a sample of poly-substance abusers. Specifically, the severity of cannabis use predicted apathy and executive dysfunction and the severity of cocaine use was predictive of greater behavioural disinhibition.
Impairment of executive function in polysubstance dependence
A recent review comparing the specific and generalized effects of abused substances on neuropsychological performance by Fenandez- Serrano et al., (2011) concluded that drugs of abuse are commonly associated with significant impairment in multiple neuropsychological domains including episodic memory, emotional processing, including updating and decision making. However, some drugs were linked to greater impairment of certain neuropsychological abilities such as enhanced effects of alcohol and psychostimulants on impulsivity and cognitive flexibility compared to other drugs. Individual studies in which polysubstance dependent subjects are compared to controls support the idea that polysubstance dependence produces significant executive impairment (Cunha et al., 2010). Studies directly comparing neuropsychological profiles between individuals dependent on different drugs suggest widespread executive deficits, but that distinct patterns of deficits may be observed between drugs (Ershe & Sahakian, 2007; Ornstein et al., 2000). Neural imaging studies also support the idea that polysubstance use yields deficits in prefrontal cortical gray matter volume (Liu et al., 1998).
Executive function, treatment, recovery and in polysubstance dependence
Research regarding the longevity of executive deficits among polysubstance user suggests impairment may persist at least up to a year (Grant et al., 1978). Fernandez-Serrano et al., (2010) recently reported that polysubstance dependent individuals enrolled in therapeutic communities averaging 24 weeks of abstinence showed substantial deficits on multiple measures of executive function including measures of working memory, fluency, shifting, planning, multi-tasking, and interference. A second study by this author also found widespread executive impairment in a population of abstinent polysubstance abusers following an average of 32 weeks of abstinence (Fernandez-Serrano et al., 2010). A recent long-term longitudinal study by Hanson et al., (2011) examined adolescents with and without alcohol and substance dependence, who were tested repeatedly for neuropsychological performance for 10 years. Ninety-four percent of substance dependent participants met criteria for alcohol dependence and dependence on at least one other drug. At baseline and subsequently, controls performed better on neuropsychological measures than substance dependent participants. Heavy use patterns over time were associated with impaired neuropsychological functioning on measures of verbal learning and memory, visuospatial memory and verbal/attention/working memory. In addition, participants who discontinued alcohol and drug use during this period showed improvement in cognitive function.
Studies investigating the effectiveness of treatment among abstinent polysubstance dependent subjects suggest the degree of neuropsychological deficits may be important in determining clinical outcomes. Fals-Stewart and Schafer, (1992) reported that in substance abusers admitted to a therapeutic community, performance on the Digit Symbol and Block Design Subtests of the Wechsler Adult Intelligence Scale were predictive of time in treatment. In another study, the decision to stop drug use following a prevention intervention during adolescence was predicted by the severity of childhood neurobehavioral disinhibition (Kirisci et al., 2006).
Conclusion
This topic is unique compared to other papers reviewing the relationship between anatomical and functional changes in the prefrontal cortex, executive abilities, and substance dependence (Feil et al., 2010; Goldstein & Volkow, 2002; Fernandez-Serrano et al., 2011; Schoenbaum et al., 2006). This topic emphasizes the breadth of this topic by describing this relationship across multiple classes of drugs and polysubstance dependence. In addition, it examines this relationship across the vulnerability to develop substance dependence, the impairment observed among addicts, and the persistence and recovery of executive functions during abstinence and as a function of treatment.
Several conclusions can be drawn from this literature review. Pre-existing variability in executive function and the effects of drug use itself are among the variables which influence an individuals’ risk of developing substance dependence. A significant body of literature shows that substance dependent individuals are impaired across multiple domains of executive functioning, and possess decreased grey matter and impaired activity within the prefrontal cortex. Moreover, multiple studies combining brain imaging and neuropsychological measures link impairment of performance on tests of executive function with anatomical and functional impairments of the prefrontal cortex. The persistence of executive deficits across time is highly variable, however research suggests that following short-term and long-term abstinence many individuals show recovery of executive functions which appears to be related to their ability to maintain abstinence across time. A growing body of research suggests specific treatments focused on augmenting activity within the prefrontal cortex or strengthening executive abilities may represent viable treatment approaches. While some differences in impairment of executive abilities have been observed across drugs, there are remarkable similarities in the executive deficits observed among drug addicts.
There are several limitations of this review. The purpose of this topic is to illustrate the role of executive dysfunction in substance dependence, however it does not represent an exhaustive review of this topic. The research described here illustrates the major findings of studies in this area but does not emphasize results that were not consistent with the premise of this review. Based on this review it is evident that specific areas of the prefrontal cortex appear to show a greater degree of impairment than others (orbitofrontal, anterior cingulate, and dorsolateral regions) and that substance dependent populations appear to show greater deficits on certain executive domains (response inhibition, impulsivity, working memory); this topic did not systematically evaluate these differences. This review focussed on the role of prefrontal cortical regions and executive dysfunction in addiction. Regions of the prefrontal cortex have also been implicated in other addiction related processes including craving, reward, and withdrawal (Goldstein & Volkow, 2002), however, a broader neural circuitry and associated behavioral dysregulation is likely involved in drug dependence.
The typical definition of a "disease" emphasizes that it involves abnormal structure and function of the body (Leshner, 1997). This topic argues that according to this broad conceptualization, substance dependence should be considered a disease given its association with deficits in cortical function and related executive abilities. Addiction also shows several similarities with other chronic conditions considered diseases, such as a similar vulnerability toward relapse (Leshner, 1997). While these deficits are not unique to drug addiction (Rogers et al., 1999), in combination with compulsive drug use and other neurobiological markers this body of research strengthens the argument for defining addiction as a disease.
