Introduction
Alcohol is considered to be a contributive factor in more than 200 health conditions (World Health Organization, 2018) and a risk factor for premature death (Rehm, Shield, Gmel, Rehm, & Frick, Reference Rehm, Shield, Gmel, Rehm and Frick2013). Much of the burden of disease is due to the persistent effects of alcohol on the central nervous system (Sachdeva, Chandra, Choudhary, Dayal, & Anand, Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016; Soler González, Balcells Oliveró, & Gual Solé, Reference Soler González, Balcells Oliveró and Gual Solé2014). One out of 10 dementia cases is alcohol-related (Harper, Reference Harper2009) with a dose–response relationship (Xu et al., Reference Xu, Wang, Wan, Tan, Li, Tan and Yu2017). Indeed, alcohol is the main modifiable risk factor for dementia (Schwarzinger et al., Reference Schwarzinger, Pollock, Hasan, Dufouil, Rehm, Baillot and Group2018). Alcohol-related dementia mortality is also a concern. Up to 50% of patients affected by Wernicke–Korsakoff Syndrome die due to infectious diseases and cancer in the 8 years after diagnoses (Sanvisens et al., Reference Sanvisens, Zuluaga, Fuster, Rivas, Tor, Marcos and Muga2017).
Alcohol can lead to structural and functional changes in the brain (Bates, Buckman, & Nguyen, Reference Bates, Buckman and Nguyen2013; Harper, Reference Harper2009; Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016). These brain abnormalities imply global atrophy (Bates et al., Reference Bates, Buckman and Nguyen2013) as well as region-specific neuronal loss in the superior frontal association cortex, hippocampus, limbic system, cerebellum, thalamus and hypothalamus and the connections between them (Harper, Reference Harper2009; Oscar-Berman & Marinković, Reference Oscar-Berman and Marinković2007; Pitel, Segobin, Ritz, Eustache, & Beaunieux, Reference Pitel, Segobin, Ritz, Eustache and Beaunieux2015; Ridley, Draper, & Withall, Reference Ridley, Draper and Withall2013; Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016). White-matter loss occurs in the prefrontal cortex, corpus callosum and cerebellum (Hayes, Demirkol, Ridley, Withall, & Draper, Reference Hayes, Demirkol, Ridley, Withall and Draper2016; Ridley et al., Reference Ridley, Draper and Withall2013). These structural changes lead to impairments in attention, memory and learning, executive functions and fluid abilities such as concept formation, visuospatial processing, abstraction or problem solving, among others (Bernardin, Maheut-Bosser, & Paille, Reference Bernardin, Maheut-Bosser and Paille2014; Manning, Verdejo-Garcia, & Lubman, Reference Manning, Verdejo-Garcia and Lubman2017; Moerman-van den Brink et al., Reference Moerman-van den Brink, van Aken, Verschuur, Walvoort, Egger and Kessels2019; Ros-Cucurull et al., Reference Ros-Cucurull, Palma-Álvarez, Cardona-Rubira, García-Raboso, Jacas, Grau-López and Roncero2018; Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016; Stavro, Pelletier, & Potvin, Reference Stavro, Pelletier and Potvin2013; Wanmaker et al., Reference Wanmaker, Leijdesdorff, Geraerts, van de Wetering, Renkema and Franken2018; Woods et al., Reference Woods, Porges, Bryant, Seider, Gongvatana, Kahler and Cohen2016).
The concept of alcohol-related brain damage becomes increasingly important. It encompasses a spectrum of disorders, including alcohol-related dementia and Wernicke–Korsakoff Syndrome (Bates, Bowden, & Barry, Reference Bates, Bowden and Barry2002; Hayes et al., Reference Hayes, Demirkol, Ridley, Withall and Draper2016; Ros-Cucurull et al., Reference Ros-Cucurull, Palma-Álvarez, Cardona-Rubira, García-Raboso, Jacas, Grau-López and Roncero2018). It has been estimated that among patients with a heavy drinking pattern, dementia is present in 10–24% of the patients (Ridley et al., Reference Ridley, Draper and Withall2013). Despite those severe forms, mild to moderate neurocognitive deficits are prevalent among patients with alcohol use disorder, with an estimated proportion of 50–70% presenting some degree of impairment (Bates et al., Reference Bates, Buckman and Nguyen2013). Even though for most of the patients many of the neuropsychological deficits related to heavy alcohol use are minimal or transient (Bates et al., Reference Bates, Buckman and Nguyen2013) and improve with sustained abstinence (Mulhauser, Weinstock, Ruppert, & Benware, Reference Mulhauser, Weinstock, Ruppert and Benware2018; Ridley et al., Reference Ridley, Draper and Withall2013; Ros-Cucurull et al., Reference Ros-Cucurull, Palma-Álvarez, Cardona-Rubira, García-Raboso, Jacas, Grau-López and Roncero2018; Stavro et al., Reference Stavro, Pelletier and Potvin2013), in some cases, deficits are clinically severe and can persist (Hayes et al., Reference Hayes, Demirkol, Ridley, Withall and Draper2016; Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016). Nevertheless, the different cognitive functions do not recover homogeneously (Ioime et al., Reference Ioime, Guglielmo, Affini, Quatrale, Martinotti, Callea and Janiri2018; Mulhauser et al., Reference Mulhauser, Weinstock, Ruppert and Benware2018; Ros-Cucurull et al., Reference Ros-Cucurull, Palma-Álvarez, Cardona-Rubira, García-Raboso, Jacas, Grau-López and Roncero2018). Among other factors, the amount of recent alcohol use and duration of abstinence have an influence on the recovery of cognitive skills (Ridley et al., Reference Ridley, Draper and Withall2013). The accumulation of repeated episodes of binge drinking followed by periods of abstinence leads to a slower and less complete recovery (Florez, Espandian, Villa, & Saiz, Reference Florez, Espandian, Villa and Saiz2019).
Impairments in executive functioning and memory can affect the efficacy of cognitive and behavioural treatments (Bernardin et al., Reference Bernardin, Maheut-Bosser and Paille2014; Blume & Alan Marlatt, Reference Blume and Alan Marlatt2009; Blume, Schmaling, & Marlatt, Reference Blume, Schmaling and Marlatt2005). These neurocognitive deficits may influence the patients' ability to attend and retain new information, identify goals or flexibly adapt to new environmental demands (Rupp, Reference Rupp2012). Moreover, cognitive deficits can be associated with increased impulsivity (Bates et al., Reference Bates, Bowden and Barry2002; Czapla et al., Reference Czapla, Simon, Richter, Kluge, Friederich, Herpertz and Loeber2016; Moraleda Barreno et al., Reference Moraleda Barreno, Domínguez-Salas, Díaz-Batanero, Lozano, Lorca Marín and Verdejo-García2019) that alter decision making (Domínguez-Salas, Díaz-Batanero, Lozano-Rojas, & Verdejo-García, Reference Domínguez-Salas, Díaz-Batanero, Lozano-Rojas and Verdejo-García2016; Moraleda Barreno et al., Reference Moraleda Barreno, Domínguez-Salas, Díaz-Batanero, Lozano, Lorca Marín and Verdejo-García2019; Stevens et al., Reference Stevens, Goudriaan, Verdejo-Garcia, Dom, Roeyers and Vanderplasschen2015). As a consequence, patients with alcohol-related cognitive impairment (ARCI) present lower self-efficacy (Bates, Pawlak, Tonigan, & Buckman, Reference Bates, Pawlak, Tonigan and Buckman2006; Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016), lower motivation and treatment compliance (Bates et al., Reference Bates, Buckman and Nguyen2013, Reference Bates, Pawlak, Tonigan and Buckman2006; Bernardin et al., Reference Bernardin, Maheut-Bosser and Paille2014), as well as fewer days of abstinence (Florez et al., Reference Florez, Espandian, Villa and Saiz2019; Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016), more drinks per drinking day (US SDUs, 1SDU = 14 g) (Bates et al., Reference Bates, Pawlak, Tonigan and Buckman2006) and poorer quality of life (Horton, Duffy, & Martin, Reference Horton, Duffy and Martin2015; Rensen, Egger, Westhoff, Walvoort, & Kessels, Reference Rensen, Egger, Westhoff, Walvoort and Kessels2017). Furthermore, the comorbidity of ARCI with other psychiatric disorders, depression for instance, can worsen the cognitive symptoms (Horton et al., Reference Horton, Duffy and Martin2015).
In this context, despite the potential indirect effects of cognitive impairment in treatment outcome (Bates et al., Reference Bates, Bowden and Barry2002, Reference Bates, Pawlak, Tonigan and Buckman2006; Manning et al., Reference Manning, Verdejo-Garcia and Lubman2017), ARCI is still underdiagnosed (Hayes et al., Reference Hayes, Demirkol, Ridley, Withall and Draper2016; Horton, Duffy, & Martin, Reference Horton, Duffy and Martin2014; Soler González et al., Reference Soler González, Balcells Oliveró and Gual Solé2014), under-recognised (Sachdeva et al., Reference Sachdeva, Chandra, Choudhary, Dayal and Anand2016) and undertreated (Barrio et al., Reference Barrio, Teixidor López, Gual, Moreno-España, Frías-Torres and Ortega2016; Horton et al., Reference Horton, Duffy and Martin2015; Manning et al., Reference Manning, Verdejo-Garcia and Lubman2017).
Two previous studies systematically reviewed the available treatments for ARCI (Horton et al., Reference Horton, Duffy and Martin2014; Svanberg & Evans, Reference Svanberg and Evans2013). Differently to these two previous reviews in which many of the studies were included independently of the evidence level and the vast majority were case reports or case series, the present review is aimed at the analyses of longitudinal studies that include a control group.
Hence, the aim of the present review is to examine and describe the range of neuropsychological and pharmacological interventions available for ARCI treatment.
Methods
Data for the systematic review were collected following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Moher, Liberati, Tetzlaff, Altman, & PRISMA Group, Reference Moher, Liberati, Tetzlaff, Altman and PRISMA Group2009). This protocol provides a checklist for reporting systematic reviews (online Supplementary Table S1).
Search strategy
Electronic searches were performed by two independents reviewers (EC, HL-P) using PubMed, Scopus and Science Direct databases. A combination of the following terms was used: (alcohol-related brain damage OR alcohol-related cognitive impairment OR korsakoff OR Wernicke-Korsakoff OR Korsakoff's syndrome) AND (intervention OR rehabilitation OR remediation OR treatment). No date limitations were set, so all relevant publications could be identified. The included bibliography was reviewed in order to add studies that may be relevant but did not show up on the searches.
Selection criteria
The search resulted in 804 published articles (Fig. 1). Studies were included if (1) referred to any cognitive rehabilitation or pharmacological intervention for cognitive deficits related to alcohol; (2) were prospective interventions; (3) included a control group; (4) cognitive rehabilitation interventions among other substance users were also included as long as the alcohol users group outcomes were specified. Exclusion criteria were (1) animal studies, (2) brain structural or functional studies that do not include a cognitive outcome, (3) not available in English, Spanish, Catalan or French.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart. PM, PubMed; SC, Scopus; SD, Science Direct.
Data extraction
Data were independently extracted by four reviewers, grouped in pairs (EC and HL-P extracted data from half of the articles and LN and CO from the other half), and in case of disagreement, advice from a senior researcher was asked (MB and AG). From the selected studies, the following information was extracted: authors’ names, year of publication, country where the intervention was carried, study design (randomised control trial, RCT v. non-RCT v. cohort) blinding (double blind v. single blind v. not blind), sociodemographic data of included patients (sample size, gender, age), control group (matched controls or not, and sociodemographic characteristics), main cognitive domain studied, outcome measure, main and secondary results, source of funding and limitations. Quality of the included articles was also assessed, using Jadad Scale for randomised controlled trials (Jadad et al., Reference Jadad, Moore, Carroll, Jenkinson, Reynolds, Gavaghan and McQuay1996), which assesses if randomisation has been conducted appropriately (items 1–3), the method of blinding (items 4–6) and if the fate of all the participants in the trial has been specified (item 7). The scoring anchors range from 0 to a maximum of 5.
The effect size for the findings in the included studies will be offered in the Results section. If these data are not offered in the article and enough data are available, the Cohen's D will be computed, using the online calculator from the University of Colorado Springs (https://lbecker.uccs.edu/). The effect sizes of the interventions presenting statistically significant results will be summarised in Table 3, together with data regarding the quality of the studies (Jadad Scale scores).
Results
From the 804 resulting articles, 26 were finally included for revision (Fig. 1). Among these, 14 were referred to neuropsychological rehabilitation interventions and 12 to psychopharmacological treatments.
Neuropsychological interventions
Intervention will be presented according to the main strategy applied (technology-based interventions, errorless learning, component method, other interventions) (Table 1).
Neuropsychological interventions for alcohol-related cognitive impairment (ARCI)
EG, experimental(training) group; CG, control group; RCT, randomised controlled trial; AUD, alcohol use disorder; AD, alcohol dependence; AAD, alcohol-induced persisting amnesic disorder; CI, cognitive impairment; WM, Working Memory; CANTAB, Cambridge Neuropsychological Test Automated Battery; WMS, Wechsler Memory Scale; DD task, Delay Discounting Rate; EFT, Episodic Future Thinking; HVLT, Hopkins Verbal Learning Test Revised; WAIS(-r), Wechsler Adult Intelligence Scale (-revised);TMT, Trail Making Test; ANAM, Automated Neuropsychological Assessment Metrics; BDI, Beck Depression Inventory; MMSE, Mini Mental State Examination; FAB, Frontal Assessment Battery; WCST, Wisconsin Card Sorting Test; CTT, Color Trail Test; IGT, Iowa Gambling Task; TPT, Toulouse Pieron Test; RBMT, The Rivermead Behavioural Memory Test; CVLT, California Verbal Learning Test; RAVLT, Rey Auditory Verbal Learning Test; MoCA, Montreal Cognitive Assessment; RTS, Rotation Span; RDS, Reading Span; ACT, Auditory Consonant Trigram; RLS, Running Letter Span; RSS, Running Spatial task; KT, Keep track Task; IMIS, Memory-focused neuropsychological assessment battery including Inpatient Memory Impairment.*p < 0.05; **p < 0.01;.
a Presence of an additional psychological and/or medical disorder as an exclusion criterion.
b Untreated psychological comorbid disorder as an exclusion criterion.
c Sample size calculation is specified.
Technology-based interventions
Technology-oriented intervention refers to cognitive stimulation treatments that have been applied through some computer or mobile phone-based system.
Working memory/executive functions: Two studies (Khemiri, Brynte, Stunkel, Klingberg, & Jayaram-Lindström, Reference Khemiri, Brynte, Stunkel, Klingberg and Jayaram-Lindström2019; Snider et al., Reference Snider, Deshpande, Lisinski, Koffarnus, LaConte and Bickel2018) were identified exploring the effect of a computer-based working memory training to strengthen working memory capacity. In these, the training was performed using the COGMED® software, which consists of 12 different verbal and visuospatial working memory exercises. The software used would adjust to the individuals' performance and progressively increase the exigency of the tasks.
COGMED® training resulted in statistically significantly greater improvement in verbal working memory but not in the spatial working memory function or in other neuropsychological tasks in 25 patients (50% male, mean age = 49.6) with the alcohol use disorder diagnoses (severity = unspecified) that were not receiving treatment (active drinking) in comparison to the matched control group (partial η 2 = 0.142) (Khemiri et al., Reference Khemiri, Brynte, Stunkel, Klingberg and Jayaram-Lindström2019). As shown by the results, working memory training using this tool enhanced performance on a near-transfer task in 20 patients (68% male with a mean age = 42.5 years old) with alcohol dependence who reported drinking during the previous 6 months (r 2 = 0.15) (Snider et al., Reference Snider, Deshpande, Lisinski, Koffarnus, LaConte and Bickel2018).
Furthermore, cognitive training was also related to behavioural changes as a trend was found between working memory training and the reduction of drinks per drinking occasion (from 7.07 drinks to 5.58 drinks in the intervention group v. 5.58 drinks to 5.73 in the control group; Swedish SDUs, 1 Standard Drink Unit = 12 g) (Khemiri et al., Reference Khemiri, Brynte, Stunkel, Klingberg and Jayaram-Lindström2019).
Verbal learning and verbal memory: One study assessed the effect of a computerised training tool (Posit Science software®) for the enhancement of verbal learning and memory (Bell, Vissicchio, & Weinstein, Reference Bell, Vissicchio and Weinstein2016). The tool is designed to improve several cognitive functions including attention, memory and sensory processing through visual and auditory tasks that progress from elementary to more complex and demanding games. The sample consisted of 31 patients with alcohol use disorder that were in their first 30 days of sobriety and were receiving outpatient treatment. Severity of the diagnoses was not specified. The participants were mainly male (97%) in their 50s. Patients (n = 15) that practiced 5 h a week for 13 weeks presented a statistically significant increase in verbal learning and verbal memory at 3 months follow-up in comparison to the patients that received work therapy only (Cohen's D 1.01 for verbal memory and 1.09 for verbal learning). Although these effects tended to diminish, condition effects remained statistically significant at 6 months follow-up for both verbal learning and verbal memory, with Cohen's D = 1.31 and 1.18, respectively.
General cognitive function: Four studies found mixed results regarding the effect of technology-oriented interventions for the improvement of general cognitive function (Gamito et al., Reference Gamito, Oliveira, Lopes, Brito, Morais, Silva and Deus2014; Oliveira et al., Reference Oliveira, Gameiro, Gamito, Morais, Lopes, Brito and Bento2015; Peterson, Patterson, Pillman, & Battista, Reference Peterson, Patterson, Pillman and Battista2002; Rupp, Reference Rupp2012). On the one hand, a 15 one-hour sessions' programme was not significantly effective to speed up the cognitive recovery process in a group of seven recently detoxified male inpatients (mean age = 45 years) in comparison to two matched control groups (a placebo task and no treatment) (Peterson et al., Reference Peterson, Patterson, Pillman and Battista2002). On the other hand, after a 12 sessions programme consisting of 62 computerised exercises, a group of 20 patients (55% male, mean age = 45.2 years) with alcohol dependence and at least a mild cognitive impairment that were entering inpatient treatment, presented statistically significant improvements in several attention/executive functions measures: alertness, divided attention, digit-span backward; working memory measures; some memory outcomes: digit-span forward, memory long delay recall; Mini Mental State Examination (MMSE) Scores and Complex Figure Test (CFT) copy. These results presented η 2 values of about 0.1. Furthermore, the cognitive remediation intervention was related to a statistically significant decrease in psychological distress, the number of psychological symptoms and compulsive behaviour associated with craving (Rupp, Reference Rupp2012). These secondary results presented partial η 2 between 0.1 and 0.15.
Serious games are games that aim to produce changes in patients' health, cognition, physical activity or wellbeing, among others (Mccallum, Reference Mccallum2012). A cognitive stimulation treatment delivered through a mobile phone serious game was designed to train memory, attention, decision making, language and processing speed in patients with alcohol dependence that were undergoing an abstinence treatment in a therapeutic community (Gamito et al., Reference Gamito, Oliveira, Lopes, Brito, Morais, Silva and Deus2014; Oliveira et al., Reference Oliveira, Gameiro, Gamito, Morais, Lopes, Brito and Bento2015). When an intervention using this tool was added to the general treatment for alcohol dependence and compared to the group that only received treatment as usual, an improvement in cognitive ability from pre-to-post treatment was observed irrespective of the group. However, statistically significant improvements in the Frontal Assessment Battery scores were shown in the experimental group (η 2 = 0.16) (Gamito et al., Reference Gamito, Oliveira, Lopes, Brito, Morais, Silva and Deus2014) as well as a statistically significant higher improvement in cognitive flexibility as indicated by an increase in the number of correct responses in the Wisconsin Card Sorting Test (Oliveira et al., Reference Oliveira, Gameiro, Gamito, Morais, Lopes, Brito and Bento2015). This improvement presented a Cohen's D = 0.026.
Procedural learning: One study (Swinnen, Puttemans, & Lamote, Reference Swinnen, Puttemans and Lamote2005) explored the acquisition of a manual coordination task in a group of 11 patients with Korsakoff Syndrome, under different conditions of feedback information (external feedback in the form of information in the computer screen; normal vision with the lack of this information in the screen; or blindfolded condition) in comparison to 11 matched healthy controls. The participants were abstinent during the study period, 90% were male and the mean age was 50 years old. Results highlight a lower performance in the acquisition and retaining of the task in the KS group when compared to healthy controls. Augmented feedback allowed for a higher coordination performance in the KS group, whereas no learning was achieved 1 week after the training in the absence of feedback (normal vision or blindfolded condition) (Cohen's D = −0.65).
Errorless learning v. trial and error learning
Three studies assessed the efficacy of errorless learning and trial and error learning in patients with alcohol-induced persisting amnesic disorder (Kessels, Van Loon, & Wester, Reference Kessels, Van Loon and Wester2007; Oudman et al., Reference Oudman, Nijboer, Postma, Wijnia, Kerklaan, Lindsen and Van Der Stigchel2013; Rensen et al., Reference Rensen, Egger, Westhoff, Walvoort and Kessels2017). Errorless learning refers to a learning approach that consists of preventing learners from making mistakes by using feed-forward instructions (verbal cues that guide the actions of the learner) (Oudman et al., Reference Oudman, Nijboer, Postma, Wijnia, Kerklaan, Lindsen and Van Der Stigchel2013), breaking down the task in smaller steps and modelling them (Rensen, Egger, Westhoff, Walvoort, & Kessels, Reference Rensen, Egger, Westhoff, Walvoort and Kessels2019).
The same improvement in procedural learning was found irrespective of the learning condition (Kessels et al., Reference Kessels, Van Loon and Wester2007; Oudman et al., Reference Oudman, Nijboer, Postma, Wijnia, Kerklaan, Lindsen and Van Der Stigchel2013). Nonetheless, 4 weeks after the practice concluded, the performance was still high in the errorless learning condition (eight inpatients with alcoholic amnesia disorder, 88% male, mean age = 58.9 years old), while for the trial and error condition (eight matched patients), it remained similar to baseline (η 2 = 0.5) (Oudman et al., Reference Oudman, Nijboer, Postma, Wijnia, Kerklaan, Lindsen and Van Der Stigchel2013). Furthermore, it was suggested that a better explicit memory function relates to a larger-trial-and-error advantage in a group of 10 inpatients with Wernicke–Korsakoff (70% male with a mean age of 56.8 years old) (Kessels et al., Reference Kessels, Van Loon and Wester2007).
Errorless learning was found to be useful to relearn daily activities in 51 inpatients with Korsakoff Syndrome (75% male, mean age = 60) in comparison to treatment as usual (Rensen et al., Reference Rensen, Egger, Westhoff, Walvoort and Kessels2017). After errorless training, affective, psychotic symptoms as well as agitation and aggression were statistically significantly improved (Rensen et al., Reference Rensen, Egger, Westhoff, Walvoort and Kessels2019), along with the patients' quality of life (Rensen et al., Reference Rensen, Egger, Westhoff, Walvoort and Kessels2017).
Component method
Two studies specifically explored a component method to improve visuospatial problem-solving skills (Goldman & Goldman, Reference Goldman and Goldman1988) and working memory (Gunn, Gerst, Wiemers, Redick, & Finn, Reference Gunn, Gerst, Wiemers, Redick and Finn2018). This strategy consists of splitting complex tasks into more simple components that are learned gradually and eventually combined into the complex task. This method is indirectly included in many of the studies that are being reviewed as one of the main goals of rehabilitation interventions is to allow the transfer of the learning achieved during the learning to daily and more complex tasks.
There is a minimal improvement for visuospatial skills during the first month of abstinence in the absence of specific training (Goldman & Goldman, Reference Goldman and Goldman1988). Training of specific task components allowed a group of male patients with alcohol use disorder receiving inpatient treatment to reacquire more generalised and complex abilities. Nevertheless, authors state that there was a large variability among the results, as the group with the longer abstinence period benefitted less from this method (r 2 = 0.37) (Goldman & Goldman, Reference Goldman and Goldman1988). A working memory programme (Gunn et al., Reference Gunn, Gerst, Wiemers, Redick and Finn2018) positively improved several working memory transfer measures in patients with moderate-to-severe alcohol use disorder. This improvement was maintained at 30-day follow-up. A greater improvement was found for patients with higher baseline working memory and intellectual quotient levels (Cohen's D = 0.35) (Gunn et al., Reference Gunn, Gerst, Wiemers, Redick and Finn2018).
Other interventions
A programme to enhance memory capacities was designed, which included several stimulation strategies: associate-learning tasks, reality orientation training activities, visual recognition and recall of recent events (Godfrey & Knight, Reference Godfrey and Knight1985). When applied to nine patients with alcohol-related memory impairment (mean age = 57.9 years) who attended four 60 min group sessions per week for 8 weeks, it was found that patients from the control group (n = 5) increased their performance to the same level as the experimental group (n = 4) that had received specific training to improve memory skills. This improvement was maintained at 1 month follow-up for the total memory score and the practical task score. The only difference between groups was found for the orientation test, in which patients in the training group outperformed the controls. The effect size of these results could not be calculated due to lack of data in the article.
Pharmacological interventions
We cluster in four groups (antidepressants, B-complex vitamins, acetylcholinesterase inhibitor and other pharmacological treatment) the pharmacological interventions reviewed (Table 2).
Pharmacological interventions for alcohol-related cognitive impairment
EG, experimental(training) group; CG, control group; RCT, randomised controlled trial; WK, Wernicke–Korsakoff; AD, alcohol dependence; WMSMQ, Wechsler Memory Scale Memory Quotient; WMS, Wechsler Memory Scale; WCST, Wisconsin Card Sorting Test; WAIS, Wechsler Adult Intelligence Scale; MMSE, Mini Mental State Examination; BPRS, Brief Psychiatric Rating Scale; CGI-I, Clinical Global Impression Category; AVLT, Rey Auditory Verbal Learning Test; ADCS-ADL, Alzheimer's Disease Cooperative Study Group-Activities of Daily Living Scale; DGAVP, desglycinamide-arginine-vasopressin.*p < 0.05; **p < 0.01.
a Presence of an additional psychological and/or medical disorder as an exclusion criterion.
B-complex vitamins
Only one double-blind randomised controlled trial (Ambrose, Bowden, & Whelan, Reference Ambrose, Bowden and Whelan2001) exploring the effects of thiamine administration on working memory fulfilled all inclusion criteria. The administration of 200 mg/day of intramuscular thiamine to 18 patients (mean age 39.8 years) that were detoxifying from alcohol represented a statistically significant improvement in working memory (assessed by the number of trials needed to reach the learning criterion in the delayed alternation task) in comparison to lower thiamine dosages (5–100 mg/day) (Cohen's D = 0.22).
Antidepressants
Fluvoxamine effects on cognitive enhancement were assessed in three of the identified papers (Martin, Reference Martin1989; Martin et al., Reference Martin, Adinoff, Lane, Stapleton, Bone, Weingartner and Eckardt1995; O'Carroll, Moffoot, Ebmeier, & Goodwin, Reference O'Carroll, Moffoot, Ebmeier and Goodwin1994). This serotonin reuptake inhibitor was not found to have a positive influence on cognitive enhancement in comparison to placebo. Only a double-blind placebo-controlled crossover study (Martin, Reference Martin1989) found the administration of 200 mg fluvoxamine to improve episodic memory but no other cognitive areas in six patients with Korsakoff Syndrome. These results could not be replicated in further studies (Martin et al., Reference Martin, Adinoff, Lane, Stapleton, Bone, Weingartner and Eckardt1995; O'Carroll et al., Reference O'Carroll, Moffoot, Ebmeier and Goodwin1994) as they did not find statistically significant differences between placebo and the administration of 200 mg of fluvoxamine (O'Carroll et al., Reference O'Carroll, Moffoot, Ebmeier and Goodwin1994), neither when the plasma fluvoxamine concentration was maintained at 400 ng/ml (administering fluvoxamine dosages ranging from 100 to 600 mg/day) (Martin et al., Reference Martin, Adinoff, Lane, Stapleton, Bone, Weingartner and Eckardt1995).
Furthermore, impaired verbal fluency performance was found in eight patients with Korsakoff Syndrome after 4 weeks of 200 mg of fluvoxamine intake and two of the patients developed depressive symptoms that reverted to normal within 3 days of cessation of treatment (O'Carroll et al., Reference O'Carroll, Moffoot, Ebmeier and Goodwin1994). The sample in this study consisted of five men and three women with a mean age of 69.3 years old.
In a group of 105 patients with Wernicke–Korsakoff (76% male, mean age = 49.8), 8 mg a day of reboxetine for 4 weeks (Reuster, Buechler, Winiecki, & Oehler, Reference Reuster, Buechler, Winiecki and Oehler2003) was not found to have a positive effect on the global cognitive function in comparison to the control group, excepting for the patients with less than a year of progression of the disease, which cognitive function (assessed with the MMSE) was statistically significantly improved. Patients did not use alcohol during the study period.
Acetylcholinesterase inhibitor
Two articles described the use of acetylcholinesterase inhibitors, specifically rivastigmine (Djokic & Zivkovic, Reference Djokic and Zivkovic2009; Luykx et al., Reference Luykx, Dorresteijn, Haffmans, Bonebakker, Kerkmeer and Hendriks2008), for the treatment of alcohol-induced persisting dementia (Djokic & Zivkovic, Reference Djokic and Zivkovic2009) and Wernicke–Korsakoff Syndrome (Luykx et al., Reference Luykx, Dorresteijn, Haffmans, Bonebakker, Kerkmeer and Hendriks2008).
Treatment with rivastigmine (3–12 mg/24 h) enhanced general cognitive and clinical measures in a group of 101 patients with alcohol-induced persisting dementia after 2 and 3 months of treatment in comparison to the control group that received only conventional treatment. However, these improvements did not reach statistical significance (Djokic & Zivkovic, Reference Djokic and Zivkovic2009). In five male patients with a mean age of 46 years old presenting Wernicke–Korsakoff Syndrome that were abstinent for at least 2 months, no statistically significant differences in pre-to-post treatment changes on the memory scales were found in comparison to the control group after 6 months of treatment (Luykx et al., Reference Luykx, Dorresteijn, Haffmans, Bonebakker, Kerkmeer and Hendriks2008).
Other pharmacological treatments
Neither clonidine (Mair & McEntee, Reference Mair and McEntee1986; O'Carroll, Moffoot, Ebmeier, Murray, & Goodwin, Reference O'Carroll, Moffoot, Ebmeier, Murray and Goodwin1993) or desglycinamide-arginine-vasopressin (Laczi et al., Reference Laczi, Van Ree, Balogh, Szász, Járdánházy, Wágner and De Wied1983) were found to have a positive effect on global cognitive function (O'Carroll et al., Reference O'Carroll, Moffoot, Ebmeier, Murray and Goodwin1993), memory, attention and perception (Mair & McEntee, Reference Mair and McEntee1986) in patients with Wernicke–Korsakoff.
Memantine intake improved global cognitive function in 16 patients with moderately severe dementia (50% male, mean age = 62 years) with Wernicke–Korsakoff Syndrome (Rustembegović, Kundurović, Sapcanin, & Sofic, Reference Rustembegović, Kundurović, Sapcanin and Sofic2003). However, statistical data were not provided in the article.
The effects of the psychostimulant methylphenidate on short- and long-term memory were explored in a double-blind cross-over study with six male patients aged 55–67, suffering from alcohol amnestic disorder (O'Donnell, Pitts, & Fann, Reference O'Donnell, Pitts and Fann1986). Statistically significant improvement in long-term memory was found after 3 weeks of treatment.
Quality of the studies (Jadad Scale)
In this section, results regarding the quality of the studies included in the present review, as measured with the Jadad Scale, will be presented (Table 3). As explained in the Methods section, the anchors of the scale range from 0 to a maximum of 5, depending on how the randomisation and blinding have been conducted and whether the information is presented in the article, and also depending on if the fate of all the participants in the study has been specified.
Summary of the interventions: quality of the studies and effect size
Interpretation of the effect size values (Cohen, Reference Cohen1988; Sullivan & Feinn, Reference Sullivan and Feinn2012).
Cohen's D: Cohen's D = 0–0.20 very small effect size; 0.2–0.5 small effect size; 0.5–0.8 medium effect size; >0.8 large effect size.
η 2: 0.01 low effect size; 0.06 medium effect size; >0.14 large effect size.
Partial η 2: 0.02 low effect size; 0.13 medium effect size; 0.26 large effect size.
r 2: 0.04 small effect size; 0.25 medium effect size; 0.64 large effect size.
The quality of the studies assessing the efficacy of neuropsychological treatments is moderate for most of them, as only one scored 4, four studies scored 3, four scored 2, two scored 1 and three scored 0. The study with the higher quality score indicated the effectivity of a technology-based intervention (COGMED®) to improve verbal working memory in patients with alcohol use disorder initiating treatment. These results presented a large effect size (η 2 = 0.142) (Khemiri et al., Reference Khemiri, Brynte, Stunkel, Klingberg and Jayaram-Lindström2019).
Regarding the quality of the 12 studies on pharmacological interventions, more than half presented a good or moderate quality in the Jadad Scale (Jadad score 4 for fluvoxamine and desglycinamide-arginine-vasopressin; Jadad score 3, for thiamine, two studies on fluvoxamine, clonidine, methylphenidate). None obtained the maximum score in the Jadad Scale, one scored 2 (clonidine), two scored 1 (reboxetine and rivastigmine) and one scored 0 (rivastigmine). The two studies with higher quality scores studied fluvoxamine and desglycinamide-arginine-vasopressin, which were not found to be better than placebo to improve cognitive functions in patients with Wernicke–Korsakoff Syndrome.
Discussion
The present review was aimed at the investigation of the neuropsychological and pharmacological interventions that have been studied to improve cognitive impairment related to alcohol use.
The review revealed some strategies and interventions that had a positive effect on neuropsychological deficits. However, several concerns regarding the design of the studies included need to be considered as they interfere with the generalisation of the results to the clinical practise. Out of the 26 articles included for revision, a half (n = 12) had a sample size smaller than 30 individuals and only four included at least 100 individuals. Sample size calculation was performed in only one of the studies. Among the neuropsychological treatments, only two (14.29%) were double blinded and eight (66.66%) in the pharmacological group. It is also important to consider that from the 24 studies that reported the sample sociodemographic data, 11 had performed the training in groups with mean ages lower than 50 (n = 8, 57.14% of the neuropsychological interventions; n = 3, 30% of the pharmacological). Furthermore, three of the neuropsychological studies had mean ages lower than 40. When deploying these interventions to samples with older ages, performance could be lower, as besides the impairment related to alcohol use, it may coexist a deterioration in brain structures due to ageing (Hayes et al., Reference Hayes, Demirkol, Ridley, Withall and Draper2016); therefore, age is a confounding factor that should be controlled in further studies. Finally, in some of the studies, the diagnosis of the included sample is not sufficiently specified (for instance, the severity of the alcohol use disorder). Thus, a greater characterisation of the sample would help to a more accurate interpretation of the results.
Results from the present review show that cognitive interventions can be successfully performed through technological devices, as computer-based interventions were found to effectively improve working memory function (Khemiri et al., Reference Khemiri, Brynte, Stunkel, Klingberg and Jayaram-Lindström2019; Snider et al., Reference Snider, Deshpande, Lisinski, Koffarnus, LaConte and Bickel2018), verbal learning and verbal memory (Bell et al., Reference Bell, Vissicchio and Weinstein2016), several attention and executive functions, memory, and MMSE scores (Rupp, Reference Rupp2012), functions associated with frontal lobes (Gamito et al., Reference Gamito, Oliveira, Lopes, Brito, Morais, Silva and Deus2014), and cognitive flexibility (Oliveira et al., Reference Oliveira, Gameiro, Gamito, Morais, Lopes, Brito and Bento2015). In some studies in which abstinence was not required, these improvements were accompanied by secondary positive changes in behavioural responses such as the reduction in alcohol consumption (Khemiri et al., Reference Khemiri, Brynte, Stunkel, Klingberg and Jayaram-Lindström2019), and a decrease in psychological distress, the number of psychological symptoms and compulsive behaviour associated with craving (Rupp, Reference Rupp2012).
Digital tools allow a flexible deployment of tasks directed to specific needs adapting the difficulty level to the patients' performance. However, for most of the interventions reviewed, the training mirrored traditional interventions based on the repetition of exercises that do not resemble daily life activities, which may hinder the transferring and generalisation of the acquired abilities into the natural environment. Thus, digital tools present some distinct characteristics that can serve as a solution to this limitation by allowing the development of exercises and virtual scenarios that involve daily life activities which can potentially increase the generalisation of the outcomes trained (Rochat & Khazaal, Reference Rochat and Khazaal2019; Tuena et al., Reference Tuena, Serino, Dutriaux, Riva, Piolino, Tuena and Piolino2019). For instance, through virtual reality, patients can interact with relevant stimuli in familiar contexts that demand real-world functional behaviours (Lange et al., Reference Lange, Requejo, Flynn, Rizzo, Valero-Cuevas, Baker and Winstein2010). Also, the characteristics of serious games (e.g. interactive, offer feedback, appealing to the eye) make them motivating for the patients (Oliveira et al., Reference Gamito, Oliveira, Lopes, Brito, Morais, Caçoete and Oliveira2017). Lastly, these solutions, such as mobile-based interventions, have been suggested to be cost-effective (Soler González et al., Reference Soler González, Balcells Oliveró and Gual Solé2014), as they can be administered with minimum or even without supervision (Cameirao, Bermudez i Badia, Duarte Oller, & Verschure, Reference Cameirao, Bermudez i Badia, Duarte Oller and Verschure2010) and improve accessibility to treatment in people that would be traditionally excluded (Gamito et al., Reference Gamito, Oliveira, Lopes, Brito, Morais, Caçoete and Oliveira2017).
Several techniques other than computerised interventions have been used to cope with cognitive impairments in ARCI. For instance, errorless learning was found to be a useful approach to learn (or relearn) skills (Kessels et al., Reference Kessels, Van Loon and Wester2007; Oudman et al., Reference Oudman, Nijboer, Postma, Wijnia, Kerklaan, Lindsen and Van Der Stigchel2013; Rensen et al., Reference Rensen, Egger, Westhoff, Walvoort and Kessels2017) as well as splitting the learning material into simpler components that are learned gradually (Goldman & Goldman, Reference Goldman and Goldman1988; Gunn et al., Reference Gunn, Gerst, Wiemers, Redick and Finn2018) and adding external feedback when teaching new procedures (Swinnen et al., Reference Swinnen, Puttemans and Lamote2005).
There are other rehabilitation interventions or specific strategies that did not fulfil inclusion criteria for the present review, that have also shown promising results for the rehabilitation of cognitive deficits in patients with ARCI, such as future event simulation to improve prospective memory (Platt, Kamboj, Italiano, Rendell, & Curran, Reference Platt, Kamboj, Italiano, Rendell and Curran2016), mnemonic strategies like ‘chunking’ to enhance working memory performance (Haj, Kessels, Urso, & Nandrino, Reference Haj, Kessels, Urso and Nandrino2018) or the use of salient cues to improve prospective memory (Altgassen, Ariese, Wester, & Kessels, Reference Altgassen, Ariese, Wester and Kessels2016). However, these strategies have not been evaluated in prospective controlled trials but could be considered in future studies.
Regarding the pharmacological interventions, among the treatments reviewed, three (thiamine, memantine and methylphenidate) produced a statistical significance cognitive improvement. The improvement in WK after 200 mg/day of thiamine is still preliminary due to the small sample size in each group and the short duration of the treatment (Ambrose et al., Reference Ambrose, Bowden and Whelan2001). There is still insufficient data regarding dosage and duration of the treatment with thiamine (Day, Bentham, Callaghan, Kuruvilla, & George, Reference Day, Bentham, Callaghan, Kuruvilla and George2013), however intervention with b-vitamins could help prevent dementia development or progression in patients with AUD (Chou et al., Reference Chou, Chang, Lin, Chang, Chen and Ko2018). The effect of methylphenidate on cognition was assessed in a single cross-over study with a small sample size (n = 6) (O'Donnell et al., Reference O'Donnell, Pitts and Fann1986). On the other hand, evidence regarding the effect of the N-methyl-D-aspartate, memantine (Rustembegović et al., Reference Rustembegović, Kundurović, Sapcanin and Sofic2003) on cognitive functions is weak, as information about the methodology and specific data obtained was lacking in the article, and no replication of these effects has been found. The quality of the evidence of these studies, assessed with the Jadad Scale, is moderate (3) for thiamine and methylphenidate, and low (0) for memantine.
The present review reveals an important heterogeneity among the cognitive domains in which the interventions focus on, as well as among the interventions themselves. One of the explanations for this heterogeneity could be the fact that ARCI encompasses a spectrum of disorders (Bates et al., Reference Bates, Bowden and Barry2002; Hayes et al., Reference Hayes, Demirkol, Ridley, Withall and Draper2016) in which cognitive impairments differ largely between patients, depending on the brain structures affected and the severity of the impairment. Also, it is needed to build consensus on the cognitive domains in which rehabilitation interventions should focus on, in order to produce, in turn, a higher impact on the management of addiction and psychological wellbeing. Strengthening memory and executive functioning should be preferent targets due to its influence in treatment outcome and abstinence maintenance by enhancing positive behavioural outcomes (Bates et al., Reference Bates, Buckman and Nguyen2013; Bernardin et al., Reference Bernardin, Maheut-Bosser and Paille2014; Brion et al., Reference Brion, D'Hondt, Pitel, Lecomte, Ferauge, de Timary and Lecomte2017; Houben, Wiers, & Jansen, Reference Houben, Wiers and Jansen2011). Lastly, more research is needed to clarify the association between the reduction of alcohol use and cognitive improvements in patients with alcohol use disorder, as the weight of each factor in the interaction has not been studied yet.
Although the extracted results give an in-depth analysis of how cognitive impairments in ARCI are being addressed and the need of developing ecological training to improve them, some limitations of the present review have to be taken into account. First, the number of articles (14 for neuropsychological and 12 for pharmacological interventions) included in the current revision is relatively low, because of the strict inclusion criteria we established to guarantee a minimum quality. Despite these efforts, some of the articles analysed have limitations that prevent us from extracting robust conclusions about the efficacy of the interventions. As stated earlier, sample sizes of the included studies are small and, in most of them, sample size calculations have not been conducted. Also, it was not possible to carry out a meta-analysis due to the heterogeneity of the studies. Lastly, the generalisation of the results is also hindered by the lack of replication of the studies. Despite these limitations, we have applied strong measures in order to guarantee the quality of the included studies, as data were extracted following the PRISMA guidelines, only longitudinal studies have been considered, and the quality of these studies has been assessed using the Jadad Scale.
Conclusions
Results point out how cognitive functions can be improved by using specific neuropsychological and pharmacological interventions. In some studies, these cognitive improvements happened at the same time as alcohol use reduction; however, the impact of one factor on the other is not clear and needs more research. However, methodological weaknesses of studies in this field prevent from having a gold standard treatment for ARCI. Randomised clinical controlled trials with large sample sizes are required as well as interventions that ease the transference of the acquired abilities to daily life. Considering the cost-effectiveness of digital interventions, and their promising role for the development of ecological treatments, they should be considered in future studies.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S0033291720002925.
Author contributions
Conceptualization: EC and HL-P; methodology: EC, HL-P, CO, LN; writing – original draft preparation: EC, HL-P; writing – review and editing: EC, HL-P, CO, LN, MB, AG.
Financial support
This research received no external funding. H.L.-P. received funding from the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III through a ‘Rıo Hortega’ contract (CM17/00123, to Dr López-Pelayo), with the support of the European Social Fund.
Conflict of interest
H.L.-P. has received travel grants from the laboratories honoraria and travel grants from Janssen and Lundbeck; A.G has received honoraria from Lundbeck. None of these COI is related to the current research. The rest of the authors declare no conflict of interest.
