Deterioro neuropsicológico asociado al consumo de alcohol y cocaína

Resumen

8. SUMMARY OF THE THESIS This report is a summarized version of the doctoral dissertation of the candidate Isabel Senabre, entitled: NEUROPSYCHOLOGICAL DEFICITS IN COCAINE USE AND COCAINE AND ALCOHOL USE. According to Spanish national regulations, in order to achieve the International PhD. title in Spain, a part of the doctoral dissertation must be written in English for external evaluation. The full version of this doctoral thesis is written in Spanish and contains more information and details that have been omitted in this report for brevity purposes. 8.1. JUSTIFICATION OF THE STUDIES In the last decade, there has been much evidence to suggest that people abusing substances show neuropsychological deficits. Processes of attention, memory, psychomotor abilities, response inhibition, flexibility and making-decision processes are the most affected by the chronic use of cocaine. (Jovanovski et al., 2005; Fernández-Serrano et al., 2010). Alcohol use has also been related to a series of neuropsychological stable disorders (i.e. processing speed deficit, visual-perceptual and psychomotor skills, memory and executive functions) as well as to a decline in the making-decision process and perceptual-motor impulsivity. There is little research into the neuropsychological effects of cocaine and alcohol co-use, and the studies report contradictory results. On the one hand, some studies confirm that the concurrent use of cocaine and alcohol has more serious effects than the use of each drug separately (Goldstein et al., 2004 y Bolla et al., 2000). However, there is also evidence suggesting a lower level of achievement in those people using only cocaine compared to those using cocaine and alcohol together (Robinson et al., 1999, Abi-Saab et al., 2005) or there is no reciprocal effect of each condition but there is an effect of both conditions altogether compared to controls (Di Sclafani et al., 2002). This study arises from this conceptual framework in order to evaluate neuropsychological deficits in patients using alcohol and patients using alcohol and cocaine. We think that the concurrent use of both substances is becoming a common practice and evidence in the last years upon this specific user profile is limited and contradictory. 8.2 INTRODUCTION 8.2.1 Neuropsychological impairments related to substance use 8.2.1.1 Neuropsychological impairment in alcohol users Alcohol abuse has been consistently related to high levels of self-reported impulsivity. Alcohol-dependent subjects reach a high score in the urgency subscale (a tendency to respond impulsively to negative events) (Whiteside y Lynam, 2003), Sensation Seeking scale (Bjork et al., 2004a, see meta-analysis in Hittner 2006), in the UPPS38 Impulsive Behaviour Scale and in the Barratt Impulsiveness Scale (Mitchell et al., 2005). 8.2.1.1.1 Effects of alcohol on attention and executive functions There are many studies on how alcohol affects the working memory in abusers. In a study a test was designed to evaluate the working memory (Delayed Alternation Task). Its authors came to the conclusion that these patients showed an alteration in the memory temporal storage, even showing no evidence of other serious cognitive disorder (Ambrose et al., 2001). A similar study, along the same line, carried out with alcoholic women (Sullivan et al., 2002) highlighted that the working memory, whether verbal or non verbal, is one of the most affected functions, especially when it involves visuospatial processing. These findings have been recently corroborated in a study where there was found an alteration in the visual, verbal and multimodal span in alcoholic subjects (Pitel et al., 31). However, some studies applying the Digit Span subtest of the Wechsler Adult Intelligence Scale (Wechsler, 1981), which is considered to be a good measure of the phonological loop, concluded that the level of achievement was normal (Landa et al., 2006; Eckardt et al., 1995). Likewise, research strategies have been evaluated as well as the access to semantic material, through verbal fluency tasks. Most studies show a worse performance in this test (Pitel et al., 2007; Le Berre et al., 2010; Nöel et al., 2001) even though some authors do not observed any relevant difference (Landa et al., 2006). 38 UPPS: Impulsive Behaviour Scale (Whiteside y Lynam, 2001, 2003) Spanish versión by Vedejo García et al. (2009). It evaluates Negative Urgency, (lack of) premeditation, (lack of) perseverance, Sensations Seeking and Positive Urgency. Another important element of the executive functions is the inhibition ability and the interference control. Most studies find, again, a deficit of the inhibition ability in alcoholic subjects (Pitel et al., 2007; Nöel et al; 2001; Le Berre et al., 2010). But others do not find any differences (Ratti et al., 2002). Studies carried out on alcohol severe effect have also proved that even moderate doses of alcohol (below the legal minimum) worsen response inhibition in Stop-Signal and Go¿No Go tasks, and those effects are dose-dependent (Fillmore y Vogel-Sprott, 1999; Marczinski et al., 2005; Reynolds et al., 2006). On the other hand, cognitive flexibility has probably been one of the functions that have been evaluated more often. Studies about alcoholic abuse have reached broad consensus in this regard. In many studies there is some evidence suggesting that this ability has been affected in alcoholic subjects (Sullivan et al., 2000, 2002; Nöel et al., 2001; Ihara et al., 2000; Ratti et al., 2002; Corral et al; 2002). Although there is, at least, one study that does not find any differences between the group of alcohol abusers and the controls in this test, it must be pointed out that this study was carried out with a group of abusers with an age average of 26 years. It was probably the youth of the sample subjects what explains the lack of cognitive deficit. The results regarding the planning process have also proved a severe impairment in the samples of alcoholic patients that have been studied (Pitter et al., 2007; Nöel et al., 2001; Ihara et al., 2000; Moriyama et al., 2002). Lastly, the making-decision process is also affected in alcoholic patients (Loeber et al., 2009; Fein et al., 2004; Noel et al., 2007; Dom et al., 2006b; Fein et al., 2004; Mazas et al., 2000). The deficit in the making-decision process can be the deciding factor in the act of drinking compulsively as well as in other risk behaviours (Goudriaan et al., 2007; Xiao et al., 2009). A group of researchers in the University of Los Angeles (California) carried out a study among adolescents of 15 and 16 years old in the city of Chengdu (China). They analysed the making-decision process as a risk factor to practise ¿binge drinking¿. The authors evaluated the making-decision process (through the Iowa Gambling Task) and the working memory (through the Self-Ordered Pointing Test). A year later they evaluated four dimensions of impulsivity ¿namely: urgency, lack of premeditation, lack of perseverance and sensation seeking,¿ through the UPPS Impulsive Behaviour Scale and the behavior of drinking compulsively. And they compared the scores. Adolescents that eventually practised ¿binge drinking¿ did not only reach worse results in the Iowa Gambling Task but they also reached a higher score in the ¿Urgency¿ dimension compared to those that never or almost never drank (Xiao et al., 2009). 8.2.1.1.2 Impairment of the visuospatial and motorperceptive skills in alcohol use Some studies show that these are the most altered functions in alcoholics (Sullivan et al., 2000, 2002; Evert, 1995; Fein et al., 1990; Fleischhacker y Kryspin-Exner, 1986; Miller, 1990; Parsons y Farr, 1981). On the other hand, there are also many studies about the impairment of the tactile recognition in these patients (Parsons y Leber, 1981; Iruarrizaga et al., 2001). Nevertheless, an inadequate execution in this area can be influenced by a pure motor deficit such as movements slowing down or a scarce muscular strength, which can bias the results (Tarter y Jones, 1971). In this respect, some authors state that the motor deficit can be more remarkable than the cognitive deficit in alcoholic patients (Sullivan et al., 2000). Dawson et al. (2000) applied Rey Complex Figure Test and they found out that alcoholics showed difficulties in analysing and reproducing a complex graphic design and used inadequate planning strategies to carry out the task. This deficit resulted in a poor-quality copy and in greater difficulties to reproduce the figure afterwards, which confirms the results of previous studies (Zinn, 2003). 8.2.1.1.3 Memory impairment in alcohol use Some studies support the evidence of verbal semantic declarative memory impairments in alcoholics. In a study with 100 subjects, to whom a wide neuropsychological battery was applied, it was found out that even though in most tests the level of achievement was normal, there were relevant differences in the repetition of stories, whether immediately repeated or not, between alcoholics and controls (Landa et al., 2006). A similar study showed evidence of inadequacy in this test, along with a preserved visual memory ability (Davies et al., 2005). 8.2.1.2 Neuropsychological impairment associated with cocaine use Results of different studies show a profile of cognitive alterations in chronic users of this substance that is characterized by a disturbance in attention and concentration processes (Ardila et al., 1991; Hoff et al., 1991; Berry et al., 1993) visual and verbal memory (Manschreck et al., 1990; O'Malley y Gawin, 1990; Ardila et al.,1991; Azrin et al.,1992; Mittenberg y Motta, 1993) and cognitive flexibility and abstraction abilities (Volkow et al., 1988). 8.2.1.2.1 Attention and executive functions impairment in cocaine use Hoff et al. (1996) found abstract reasoning impairment through the application of the Booklet Categories Test (Hoff et al., 1996; DeFilippis and McCampbell, (1979, 1991)). Other authors have also obtained these results about concepts abstraction and categorization deficit (Grant and Judd, 1976). Studies applying the Wisconsin Card Sorting Test (WCST, (Heaton, 1981) have shown how addicts, whether cocaine users or poliusers, reach lower levels of achievement (Rosselli and Ardila, 1996b). These differences in the cognitive flexibility of the participants have also been reported by (Strickland et al., 1993), (Beatty et al., 1995) and (Kouri et al., 1996). Di Sclafani et al. (2002) obtained lower scores in attention, spatial processing and executive function in cocaine users six weeks after abstinence but not six months. It has also been proved how cocaine users show longer latencies and a greater number of mistakes in the inhibition of automatic responses, especially in Stroop-like tasks (Stroop, 1935). Thus, in different works, (Bolla et al., 2000a) relevant differences have been found between the users group and the controls. That response inhibition has also shown differences in Go / No Go tasks (Bolla et al., 2000a). Some works have shown that cocaine addicts have problems in making decisions based upon the feedback in the Iowa Gambling Task (Bartzokis et al., 2000). And with regard to phonological verbal fluency (FAS) in the Controlled Oral Word Association Test (COWAT) (Benton and Hamsher, 1976), the works by Strickland, Beatty y Kouri, in the late 90s, showed that cocaine addicts had greater difficulties in accessing and fluent production of words. In the last decade, studies on response inhibition evaluated through laboratory tasks have become more and more relevant. Animal models have showed some evidence suggesting that patients repeatedly exposed to cocaine also present a cognitive flexibility impairment, specifically in the perseverance and the ¿reversal learning¿ associated with the activity in the orbitofrontal cortex (Jentsch, 2002; Schoenbaumet al., 2004; Stalnaker et al., 2006, 2009). Other authors have found an increase in impulsivity, specifically in the delayed reinforcement paradigm in rats that have been exposed to cocaine (Paine et al., 2003; Santucci et al., 2004; Simon et al., 2007). Acute cocaine administration (observed on functional magnetic resonance imaging) produce alterations in brain regions involved in reward processing, executive functions and emotional regulation, including mesolimbic and mesocortical regions, prefrontal cortex, and orbitofrontal cortex (Kufahl et al., 2005). Contradictory results have been found regarding the effects of acute cocaine administration on response inhibition, some studies showing detrimental effects on inhibition (Fillmore et al., 2002), while others found paradoxical improvements (Fillmore et al., 2005), mainly as a function of the dose (Fillmore et al., 2006). A recent fMRI study showed that acute cocaine-induced performance improvements were associated with increases in activation in the medial and lateral prefrontal regions, which may be chronically dysregu lated in chronic users (Garavan et al., 2008). Acute administration of methamphetamine has been associated with transient improvements in psychomotor functioning, attention and perceptual speed, as well as an increase in risky decision-making (Johnson et al., 2000; Silber et al., 2006). 8.2.1.2.2 Memory impairment in cocaine addiction Animal models showed the existence of impairments in short-term and long-term memory and an increase in impulsivity, specifically in the delayed reinforcement paradigm, in rats exposed to cocaine (Paine et al., 2003; Santucci et al., 2004; Simon et al., 2007). In rats, methamphetamine produces various types of alterations, including alterations in time perception, time- based prospective memory, reversal learning, and spatial working memory (Cheng et al., 2007; Nagai et al., 2007). In humans, the first studies on memory suggested that cocaine caused visual and verbal short-term memory impairments (Grant and Judd, 1976; Manschreck et al., 1990; Azrin et al., 1992; Mittenberg and Motta, 1993). Ardila et al. (1991) but there was no evidence of long-term memory impairments. Later works have pointed out that memory is one of the most altered functions in cocaine use, even causing mnestic deficits, remaining the rest of cognitive processes unaltered (Gillen et al., 1998). On the other hand, while works by Beatty et al.(1995) and Kouri (1996) have shown that cocaine severe addicts keep all their mnesic deficits at least within the first six months of abstinence, one of the most important conclusions drawn from the study by (Selby and Azrin, 1998a) is that cocaine use related deficits can drop, at least, after three years of abstinence. In the last decade the studies by Volkow et al. (2001) and Moon et al., (2007) have been relevant. Volkow et al. (2001) conducted a neuropsychological and dopamine-transporter-binding PET imaging study that retested five methamphetamine-abusing individuals after a 12¿17-month period of abstinence. Their imaging results showed significant increases in basal ganglia dopamine transporters availability at follow-up. However, re-test of cognitive performance showed only mild (non-significant) improvements in gross motor skills and episodic memory, but persistent deficits on fine-grained psychomotor function and executive-based interference during memory encoding. Moon et al. (2007) studied verbal and visual episodic memory in 19 methamphetamine dependent subjects with a mean abstinence of 1.79 years (although with a high variability) and 18 non-drug users. The results showed that long-term abstinent methamphetamine users had intact performance on verbal memory, but impaired performance on the visual memory task (an adaptation of the Rey Complex Figure Test). 8.2.1.3 Neuropsychological impairment in alcohol and cocaine use Cocaine and alcohol are a combination of substances frequently consumed by drug users. Numerous studies have tried to investigate the neuropsychological effects of each substance separately. However, given the high frequency of their combined consumption, many authors have recently examined whether the concurrence of both substances can produce combined effects on neuropsychological performance. Several studies have revealed that the combination of cocaine and alcohol produces a metabolite called cocaethylene, that produces further deterioration than the use of each substance separately (Andrews, 1997; Carroll et al., 1993; Jatlow et al., 1996). There is little research into this matter and some studies are contradictory. Some studies show that (i) the impairment caused by the use of both substances together is more toxic than the impairment caused by the use of both substances taken separately; other studies suggest that (ii) using alcohol and cocaine together can diminish neuropsychological deficits caused by cocaine use and (iii) some studies do not find any differences between the specific use of cocaine or the combination of cocaine and alcohol. Goldstein et al. (2004) contrasted the neuropsychological performance of three groups: a group of crack/cocaine users who also used alcohol (n = 42; average abstinence of 22.9 days), a group of alcohol users (n = 40;average abstinence of 16.9 days),and a group of non drug users (n = 72).The cocaine/alcohol groups were formed by community and residential treatment participants. The results showed that the cocaine group had significantly generalized neuropsychological impairments, although of a moderate nature, in the neuropsychological domains studied: verbal knowledge, episodic memory, including visual and verbal memory, attention and executive functions, specifically on cognitive flexibility measures. The specific analysis of the performance associated with cocaine use (controlling the use of alcohol) showed an association of this substance with verbal memory impairments. In contrast, alcohol use was associated with a greater effect on attention and executive functions; cocaine users who also used alcohol performed worse on these measures than those who did not use alcohol. Bolla et al. (2000) used regression techniques in a non treatment seeking sample including cocaine users who did not consume alcohol (n = 29) and cocaine users who did (n = 27), in order to dissociate the effects of the two substances on the different neuropsychological functions. Subjects were assessed twice, after 1¿3 days of abstinence and after 28¿29 days of abstinence. After 1¿3 days of abstinence, they found dose related associations between cocaine dose and alcohol dose and neuropsychological performance. Specifically, processing speed and executive function, including cognitive flexibility and planning, were affected by the use of alcohol, while episodic memory, verbal learning and attention were affected by cocaine. The authors observed that these alterations persisted after 4 weeks of abstinence, although with somewhat different results depending on the dose. Specifically, they found a decline in the Stroop test relative to baseline in participants who reported mid-range cocaine use together with mid-range alcohol use. This decline was not found in those who reported using small amounts of cocaine in conjunction with heavy drinking or those who used heavy amounts of cocaine together with light drinking (Fernández-Serrano et al., 2010). A second group of studies have found evidence of the opposite notion, i.e. alcohol co co-abuse may decrease cocaine-induced neuropsychological deficits. Two studies supporting this notion met criteria for inclusion, one conducted during short-term abstinence and one carried out during mid-term abstinence. Abi-Saab et al. (2005) investigated the effects of co-abuse during short-term abstinence. Participants were 22 cocaine users and 71 cocaine and alcohol users, both groups¿ non-treatment seekers, with an average abstinence of 4.82 days. These authors observed that the two groups presented alterations on measures of episodic memory, attention and manual dexterity. The magnitude of alterations in both groups was quite similar, although it was slightly higher in the cocaine group for all the measures and considerably higher on the memory tests. When considering mid-term abstinence duration, Robinson et al. (1999) evaluated community and residential treatment groups of cocaine users (n = 30) vs. users of cocaine and alcohol (n = 30) with a mean cocaine abstinence of 95.8 days and a mean alcohol abstinence of 72.9 days. These authors observed that the individuals who consumed both substances performed better than those who only consumed cocaine on global neuropsychological functioning, including measures of psychomotor functioning and manual dexterity, where they found significant differences between the two groups. The authors suggested that this superior performance was due to the vasodilator effect produced by alcohol, which would counteract the vasoconstriction produced by cocaine. This effect would mean an improved functioning of the subject as a result of the combination of the two substances. One possible explanation for the discrepancy between the results of these studies and those previously mentioned can be the differences in parameters of severity (i.e., dose, frequency or duration) of the drugs used among these studies. When inspecting the duration of alcohol use, we observe that, while in the Bolla and Goldstein¿s study the users of cocaine and alcohol presented duration of use ranging from 15 to 23 years, those in the Robinson and Abi-Saab study ranged between 5 and 17 years. Moreover, the period of abstinence in the studies by Bolla and Goldstein varied between 1 and 29 days, while in the Robinson and Abi-Saab study the period of abstinence ranged from 1 to 95 days. Therefore, the severity of alcohol and cocaine abuse and the duration of abstinence may modulate their relative contribution to neuropsychological deficits in mixed cocaine and alcohol users In spite of these findings, other group of studies found that alcohol did not increase the cognitive performance decrements associated with cocaine, nor did it seem to attenuate its effects. Fein etal.(2002) found that the two groups of drug users, cocaine(n = 17) and cocaine +alcohol (n = 29), both following residential treatment with an average abstinence of 6 weeks, did not differ from each other in the different domains; both showed alterations in episodic memory, reasoning, flexibility, selective attention, spatial processing and processing speed. Di Sclafanietal (2002) found similar results when studying the neuropsychological performance of crack users (n = 20) vs. crack and alcohol co-users (n = 37) with different abstinence periods: 6 weeks and 6 months.The results showed that both groups had comparable alterations on episodic memory, specifically on measures of immediate and delayed recall, selective attention, spatial processing, reasoning and cognitive flexibility - set-shifting. Other studies on the combined use of alcohol and cocaine, which are not so systematic, find that alcohol do not improve the impairment caused by cocaine, but it seems that it diminishes its effects. Colzato et al. (2009) evaluated attention skills in poliusers of cocaine and alcohol vs. poliusers that did not use cocaine during a short period of abstinence (2-30 days). They came to the conclusion that poliusers using cocaine reached a lower level of achievement than poliusers using alcohol. 8.3 OBJECTIVES AND HYPOTHESIS The general purpose of this doctoral thesis is to characterize and compare the different dimensions of the impulsive personality and the neuropsychological functioning of individuals with cocaine and alcohol co-dependence, only-alcohol dependence and healthy controls. This General Purpose can be splited into the following specific objectives: I. Evaluate the different personality dimensions of cocaine and alcohol co-dependent individuals, alcohol-dependent individuals and non-consumers. II. Evaluate neuropsychological functioning domains of processing speed processing, motor skills, memory and executive functions of cocaine and alcohol co-dependent individuals, alcohol-dependent individuals and non-consumers. III. Explore the association between parameters of cocaine and alcohol severity use, impulsivity scores and neuropsychological performance. For each of these specific objectives we defined a hypothesis: I. Cocaine and alcohol co-depedendent individuals will show higher levels of impulsivity than only-alcohol dependents and non-consumers. II. Cocaine and alcohol co-dependent individuals will show a more pronounced neuropsychological performance deterioration compared with only-alcohol dependents and non-consumers. According to previous evidence, we expect differential impairment associated with cocaine and alcohol co-dependence in the domains of impulsivity and psychomotor performance, he domains of impulsivity and psychomotor performance, while memory and executive functions impairment would be similar in both groups. III. Greater cocaine and alcohol use are expected to be associated with poorer neuropsychological functioning in all the assessed domains. This will be particularly evident, in the case of cocaine, in impulsivity and motor skills and, in the case of alcohol use, in attentional performance.