Nuevas estrategias terapeúticas para el tratamiento de los trastornos por uso de alcohol

Abstract

Alcohol is a globally substance consumed, whose consumption levels are influenced by economic, social, religious, and cultural factors, and even by personal choices to follow a particular lifestyle. Nevertheless, its consumption can become pathological in some cases, leading to the development of alcohol use disorder (AUD). This disorder has become a public health problem that affects society as a whole (Hammer, Parent, Spiker, & World Health Organization, 2018; Rehm et al., 2010, 2017, 2009). The influence of psychosocial and environmental factors is determinant for the initiation of alcohol consumption, but also for its evolution towards abusive consumption and the transition to dependence. However, from the current biopsychosocial approach, there are also biological factors that we must take into account to form a complete picture of this problem. By and large, both alcohol and other drugs have the common characteristic of being psychoactive substances that act on the central nervous system despite having different mechanisms of action. Its consumption produces the activation of specific brain regions in a common way, generating changes in its functioning with higher or lesser permanence in time. These brain regions are involved in functions such as brain reward mechanisms along with learning, memory, motivation, and decision-making processes, so their alteration not only favors the transition from consumption to abuse and from abuse to dependence but also increases vulnerability to dependence maintenance (Ambrosio & Fernandez, 2011; Orio et al., 2014). Furthermore, due to the great scientific and technological advances that have taken place in recent years, there has been an exponential increase in the knowledge available on the link between substance use and the brain. Much of this progress has been due to the development of different techniques that allow us to study its anatomy and its functioning in relation to different substances. Among these techniques, one of the most widely used is the electroencephalography (EEG), allowing to obtain direct information of excitatory and inhibitory brain functioning due to its ability to record neuroelectrical oscillations in different conditions and populations (Carretié, 2001, 2011; Cohen, 2014). In general, the information obtained through this technique reflects that people with alcohol abuse seem to show altered general oscillatory functioning at different levels (e.g., oscillatory power, psychophysiological components, functional connectivity, etc.) (e.g., Kamarajan & Porjesz, 2015; Pandey et al., 2012; Rangaswamy et al., 2003, 2002). Nevertheless, the obtained results are not entirely consistent in the literature, reflecting that some variables may be masking the presence or absence of alterations in oscillatory functioning. One of these variables that is no always controlled is the brain’s recovery at the anatomical and functional levels due to its plastic capacity favored by abstinence. Therefore, the time of abstinence is a crucial aspect to take into account to perform an adequate characterization of the brain of people with AUD or any other substance use disorder (SUD) in the different stages of the recovery process (Camchong, Stenger, & Fein, 2013; Cardenas, Studholme, Gazdzinski, Durazzo, & Meyerhoff, 2007; Fein & Fein, 2013; Stavro, Pelletier, & Potvin, 2013). There are currently different psychotherapeutic treatments supported by scientific evidence to treat AUD from a specific perspective and SUD from a general perspective. Some of these approaches can modify both the addictive behavior and the different psychopathological manifestations that accompany it. Despite all these efforts, the rates of therapeutic failure associated with SUD remain very high (Ainscough, McNeill, Strang, Calder, & Brose, 2017; Burke, Arkowitz, & Menchola, 2003; Prendergast, Podus, Finney, Greenwell, & Roll, 2006; Roll et al., 2006; Rubak, Sandbæk, Lauritzen, & Christensen, 2005; Shishani, Odom-Maryon, & Roll, 2018; Vasilaki, Hosier, & Cox, 2006; Zgierska et al., 2019). One of the factors that have an important influence on this high percentage of therapeutic failure is the cognitive state of the person requesting treatment since, in many cases, these therapies require a high amount of cognitive resources that many of these individuals do not have available (Jurado-Barba, García-Fernandez, Rojo-Mota, & Pedrero-Pérez, 2014). For a correct approach to these cognitive alterations, there are currently different ways. One of these ways is cognitive training, which is aimed to improve or restore the individual’s skills in areas that require different processes, such as comprehension, planning, and other higher-level cognitive skills. In addition, several studies have shown that improving the functioning of the biological mechanisms underlying these alterations through this type of approaches increases the effects of other therapies in different aspects, such as reducing alcohol craving and increasing well-being self-perception (Pedrero-Pérez, Rojo-Mota, Ruiz Sánchez de León, Llanero-Luque, & Puerta-García, 2011; Rupp, Kemmler, Kurz, Hinterhuber, & Fleischhacker, 2012). In the last 10 years, several researchers in the field of SUD have paid special attention to a specific type of focused cognitive training, which is the cognitive bias modification, and more specifically, the modification of the approach bias towards alcohol and/or other substances (Kakoschke, Kemps, & Tiggemann, 2017; Lindgren et al., 2019; Loijen et al., 2018; Manning et al., 2016; Rinck, Wiers, Becker, & Lindenmeyer, 2018; R. W. Wiers, Eberl, Rinck, Becker, & Lindenmeyer, 2011). The literature on this type of intervention shows that it seems to positively affect cognitive, brain, and consumption level by reflecting that it can help improve people’s prognosis with alcohol dependence (Kakoschke et al., 2017; Manning et al., 2016; Rinck et al., 2018; C. E. Wiers, Ludwig, et al., 2015; C. E. Wiers, Stelzel, et al., 2015; R. W. Wiers et al., 2011). Nevertheless, aiming to enhance this positive effect of the procedure, in recent years, we are also trying to find out what its combined effect is with other types of training (e.g., working memory, attentional bias modification) (Manning et al., 2019; Rinck et al., 2018) and techniques (e.g., transcranial magnetic stimulation) (Claus, Klimaj, Chavez, Martinez, & Clark, 2019; den Uyl, Gladwin, Rinck, Lindenmeyer, & Wiers, 2017). Even though no significant improvements have been found to emerge from these combinations for now. Following this methodology of combining alcohol approach bias modification training with other procedures, we consider another possible way that has not been studied in-depth. This way consists of combining the cognitive bias modification procedure with mnesic modification strategies, such as the recovery-extinction process (Martínez-Maldonado, Jurado-Barba, et al., 2020). This process has been widely studied in the treatment of irrational fear with very positive results (Baldi & Bucherelli, 2015; Feng, Zheng, & Feng, 2015, 2016; Kaag et al., 2016; Lesting et al., 2013; Monfils, Cowansage, Klann, & LeDoux, 2009; Mueller, Panitz, Hermann, & Pizzagalli, 2014). Monfils et al. (2009) developed a retrieval-extinction procedure to study memories associated with irrational fear. These authors demonstrated that the re-consolidation of memories related to irrationally feared stimuli after being retrieved from memory together with other response pattern prevents the spontaneous retrieval from the fear of these stimuli, the renewal of fear in the original context, and the restoration after re-exposure. Monfils et al. (2009) even indicated that this procedure could produce a permanent erasure of the irrational fear of certain types of stimuli. Due to the good results obtained in the treatment of irrational fear using this retrieval-extinction procedure and the mnesic processes that share the memory of irrational fear and reward associated with drugs (Liu, Tian, & Li, 2019), in recent years, there have been attempts to apply this procedure in the area of the consumption of different substances such as heroin (Xue et al., 2012), cocaine (Sartor & Aston-Jones, 2014), morphine (Ma, Zhang, & Yu, 2012), nicotine (Germeroth et al., 2017) and alcohol (Millan, Milligan-Saville, & McNally, 2013). The results obtained from these studies show that the retrieval of substance-associated memories before extinction training can reduce the subsequent reinstatement of substance-seeking behaviors (Germeroth et al., 2017; Ma et al., 2012; Millan et al., 2013; Sartor & Aston-Jones, 2014; Xue et al., 2012). In addition, this recovery-extinction process also produces significant changes in the functioning of brain structures with a central role in motivational behavior, such as the prefrontal cortex and the ventral striatum (Kaag et al., 2016; Mueller et al., 2014). This recovery-extinction process applied to substance use consists of two fundamental phases. In the first phase, the destabilization of the substance-related memories is carried out through its activation, facilitating the re-consolidation of the modified memory after extinction training in the second phase (Millan et al., 2013). The activation of alcohol-related memories before cognitive training would facilitate counter-conditioning of automatic responses to alcohol-related stimuli. Therefore, it would allow both the disruption of the association between alcohol and the automatic approach response and establish or strengthen the association between alcohol and the automatic avoidance response. Based on the information that has been presented, we propose the following objectives and hypotheses in this work: ● Phase I of the research: o Objective 1. To study neuroelectrical oscillations in individuals with AUD with long-term and short-term abstinence compared to healthy individuals. ▪ Hypothesis 1. We expect people with AUD to have higher power levels in the theta and beta bands but lower in the alpha band, being these differences more pronounced in those with AUD with shorter abstinence time. ▪ Hypothesis 2. Individuals with AUD are expected to show higher synchronization in the theta band and lower synchronization in the alpha and beta bands. These differences will be more pronounced in those with AUD with shorter abstinence time. ● Phase II of the research: o Objective 1. To study the effect of the cognitive bias modification procedure on the brain oscillatory activity of individuals with AUD in abstinence and in combination with activation of alcohol-related memories. ▪ Hypothesis 1. The brain oscillations of all participants completing the cognitive bias modification procedure with and without prior activation of alcohol-related memories are expected to change due to functional reorganization. Specifically, after the procedure, we expect lower power in the theta and beta bands, higher power in the alpha band, lower synchronization in the theta band, and higher synchronization in the alpha and beta bands. ▪ Hypothesis 2. The change in oscillatory functioning is expected to be higher after the cognitive bias modification procedure combined with activation of alcohol-related memories. ▪ Hypothesis 3. An absence of changes is expected in the group that does not perform the training procedure. o Objective 2. To study the impact of the cognitive bias modification procedure in combination with the activation of alcohol-related memories at the behavioral level. ▪ Hypothesis 1. An increase in the automatic avoidance tendency of alcohol-related stimuli is expected in both groups performing the cognitive bias modification procedure. ▪ Hypothesis 2. The combination of cognitive bias modification with activation of alcohol-related memories is expected to produce greater behavioral changes. ▪ Hypothesis 3. An absence of changes is expected in the group that does not perform the training procedure. o Objective 3. To perform a three-month follow-up after the procedure to study the presence or absence of relapses during that period. ▪ Hypothesis 1. It is expected that the participants of those groups that perform the cognitive bias modification procedure will show a lower number of relapses during that period of time compared to the group that does not perform the procedure. In the first phase, brain oscillatory activity at rest with eyes closed was studied in people with AUD with abstinence for more than fifteen days and less than six months [short-term abstinence (STA), n = 29], with abstinence for more than six months and less than thirteen months [long-term abstinence (LTA), n = 26], and healthy controls (HC, n = 16). The acquisition of information in this phase of the research was carried out in two different sessions after the recruitment of the participants. During the first session, informed consent, clinical, socio-demographic, and self-reported information were obtained. In the second session, the recording of resting-state EEG activity with eyes closed was carried out. Once the EEG information was obtained, power and phase synchronization analyses were performed in the theta (4 - 8 Hz), alpha (8 - 14 Hz), and beta (14 - 30 Hz) bands. In the second phase of the research, the effect of the cognitive bias modification procedure was studied at the brain, behavioral and consumption levels in individuals with AUD in abstinence, as well as in combination with the activation of alcohol-related memories. For this purpose, after the participants recruitment, they signed the informed consent, and they were randomly assigned to one of three study groups: A-CBM [activation of alcohol-related memories + cognitive bias modification (CBM), n = 13], N-CBM [activation of neutral memories + CBM, n = 13] and N-INT [no intervention, n = 13]. The protocol in this phase of the research was distributed over three weeks, with eight sessions for the A-CBM and N-CBM groups and four sessions for the N-INT group. In the first session, socio-demographic, clinical, and self-reported data were obtained, and automatic action tendencies were assessed with the modified alcohol approach/avoidance task. In the second session, a recording of resting-state EEG activity with eyes closed was performed. From the third to the sixth session, the A-CBM and N-CBM groups performed their respective training protocol. In the seventh session (third session of the N-INT group), automatic action tendencies were assessed again, and in the eighth session (fourth session of the N-INT group), another recording of resting-state EEG activity was performed. Once the EEG information was obtained, power and phase synchronization analyses were performed in the theta (4 - 8 Hz), alpha (8 - 14 Hz), and beta (14 - 30 Hz) bands. As for the behavioral information, total approach/avoidance indices (TAAI) were calculated in the different conditions of the modified alcohol approach/avoidance task. Besides, a three-month face-to-face follow-up was carried out after completing the protocol for the recording of relapses during that period. The results obtained in the first phase of the investigation revealed differences in power and phase synchronization. At the power level, the results reflected two important aspects to highlight. The first is that the STA group presented a general higher power level in the theta band than the LTA and HC groups. The second aspect relates to the alpha frequency band, where the STA group presented a general lower power level in this band than the LTA and HC groups. At the phase synchronization level, two relevant aspects were also observed. On the one hand, the STA group presented a general lower phase synchronization in the alpha band compared to the LTA and HC groups. On the other hand, the HC group showed a general higher phase synchronization in the beta band compared to the STA and LTA groups. The results obtained in the second phase of the investigation only revealed significant changes at the level of power and phase synchronization. As for the results obtained at the power level, they showed significant differences in the theta, alpha, and beta bands. These differences were found mainly at the regional level. Nevertheless, as regards the alpha band, an increase in power level was also found in the anterior region after the procedure in the A-CBM group. As for the results obtained at the phase synchronization level, they showed significant effects in the alpha and beta frequency bands. However, the only effect associated with any of the procedures used was obtained in the alpha band. The A-CBM group showed a significant general increase in phase synchronization levels in this frequency band after the procedure. Concerning the behavioral results obtained in this research phase, although the values obtained from the modified alcohol approach/avoidance task were not significantly affected by any of the different procedures, it is imperative to mention an aspect related to these results. When analyzing how many of the participants included in each group showed an increase or reduction of the global TAAI after performing the corresponding procedure, we observed significant differences between the groups. In the A-CBM and N-CBM groups, nine participants showed a reduction in the TAAI compared to four who showed an increase in the TAAI. However, three participants in the N-INT group showed a reduction in the TAAI compared to ten who showed an increase in this index. Statistical analysis of the data obtained after following up the participants with AUD for three months after the procedure revealed no statistically significant differences between the groups. Nevertheless, it should be noted that the only group that did not include any participant who relapsed during this period was the A-CBM group, while the N-CBM and N-INT groups had two participants who relapsed during this period. Regarding the discussion of the results obtained in the first phase of the research, two important aspects were observed at the power level. On the one hand, the general higher level of power in the theta band and the general lower level of power in the alpha band shown by the group of participants with short-term abstinence compared to healthy participants reinforce previous literature showing the existence of differences in oscillatory functioning in these bands between individuals with AUD and healthy individuals. On the other hand, the general lower level of power in the theta band and the general higher level in the alpha band shown by the group of participants with long-term abstinence compared to the group of participants with short-term abstinence could be reflecting a significant normalization of oscillatory brain functioning as a consequence of maintaining abstinence. This is because the group with participants with more than six months of abstinence achieved a level of oscillatory power in both bands, which is very similar to that of the healthy participants. At the level of phase synchronization, something similar occurs, but only in the alpha band since both groups of people with AUD show a general lower phase synchronization in the beta band compared to healthy individuals. Regarding the discussion of the results obtained in the second phase of the research, the most remarkable results have been found in the A-CBM group. This group showed an increase in the alpha power level in the anterior region and a general increase of the phase synchronization level in the alpha band after the procedure. Both increases could be manifestations of the increased efficiency of resting functioning of several structures related to the processing of motivationally relevant stimuli and the modification of the neural mechanisms involved in the approach response to alcohol. Moreover, the fact that these changes in brain oscillatory activity were only found in the group with the activation of alcohol-related memories could be reflecting a facilitating effect of prior activation of memories in this functional reorganization after such a procedure. Even though we did not find enlightening results at the behavioral and follow-up levels, they suggest interesting aspects. At the behavioral level, the presence of more participants who showed an increase in the alcohol avoidance tendency or a reduction in the alcohol approach tendency after the procedure reflects the existence of a slight tendency to change towards an automatic alcohol avoidance response in those participants who performed the cognitive bias modification procedure. At the follow-up level, the fact that the A-CBM group did not show any relapse compared to the N-CBM and N-INT groups could potentially reflect a protective effect against the reinstatement of alcohol-seeking behaviors associated with the recovery-extinction procedure and a protective effect of alcohol and alcohol-related situations avoidance.