Ethical approval
Approval for the study (Code 2017–00543) was granted by the intercantonal ethics committee responsible for research at the University of Basel, the Ethikkommission Nordwestschweiz. Any protocol modifications will be communicated to this organisation and the trial sponsor, and registered on ClinicalTrials.gov.
Study design
This study is a randomised controlled trial involving three conditions: moderate exercise, intense exercise, and rest. Alcohol-dependent, cocaine-dependent and healthy control subjects will undergo all three conditions in randomised order. The order will be determined using a computer-generated ordering system. The random sequence was generated by the web-based Research Randomizer (randomizer.org), which yielded 60 permutations of the order of sessions (rest, moderate exercise, intense exercise). These permutations were printed, placed in separate envelopes and given to a colleague not involved in the study to distribute upon recruitment of each participant. Due to the nature of the intervention, blinding will not take place. The funder has no role in the design, analysis or interpretation of the study.
No data monitoring committee is involved in this study as the intervention (exercise) is not untested or high risk, and as only two acute sessions are involved any adverse events will be addressed immediately by the investigative team. The study therefore meets the criteria of “non-critical indications where patients are treated for a relatively short time and the drugs [in this case, exercise] under investigation are well characterized and known for not harming patients” [41].
Participants
Twenty alcohol-dependent, 20 cocaine-dependent and 20 healthy control individuals will be recruited to take part in the study (for power calculation, please see “Statistics”). Patients from the inpatient and outpatient branches of the clinic will be informed about the study by physicians, fliers and, in the case of the inpatient clinic, periodic visits from the investigators. All individuals receiving treatment for one of the substance use disorders in question will be approached, in order to ensure that as many individuals as possible who fit the inclusion criteria are reached. The mean age and gender distribution of the cocaine-dependent and alcohol-dependent participants combined will be used as a guide for finding matched healthy controls. Alcohol-dependent and cocaine-dependent individuals will be recruited from the University Psychiatric Clinic of the University of Basel.
Inclusion criteria for these individuals are: age between 18 and 75 years; meeting three or more of the DSM-IV criteria for substance dependence (as determined by the treating physician); minimum of 20 days and maximum of 40 days abstinence from substance of dependence; able to understand and complete the informed consent; able to travel to study site independently, as confirmed by the treating psychiatrist; assessed for physical and mental fitness by the treating physician; and cleared to take part in the study.
The healthy control group will be recruited through personal contacts (the friends and family members of the investigative team and other employees of the Department for Sport, Exercise and Health) and matched for age and gender. Inclusion criteria for the healthy control group are: age between 18 and 75 years; fewer than 3 h of physical exercise or sport per week; and no history of problematic alcohol or illicit drug consumption. All participants will receive a written document outlining the requirements of the study, and informing them that withdrawal at any point will not adversely affect their medical treatment. Participants who agree with the terms will sign the adjacent consent form in the presence of a member of the investigative team, who can also answer any questions arising during the consent process.
Participants will receive a financial incentive of 150 CHF for completion of all three measurements periods, and travel costs will be refunded. Participants will continue to receive treatment as usual during the study phase. In order to optimise participant retention, participants will be contacted by telephone if any of the three scheduled sessions are missed, in order to ascertain, if possible, whether a new session can be scheduled or whether the participant wishes to cease their involvement in the study. Participants may also request telephone or text message reminders of their scheduled sessions.
Prior to the baseline session, all participants will undergo a resting echocardiogram on arrival at the test laboratory. Any participants with questionable findings will be excluded from further participation and referred to their treating physician. Further exclusion criteria include: illness during the study period; inability to complete either exercise condition; and failure to attend three sessions at a maximum of 4 days apart. Participants are not prohibited from any activities during the trial. Any adverse events occurring during the trial will be documented, submitted to the treating physician and ethical committee, and may, upon discussion with the treating physician, lead to exclusion of the participant from the trial.
Data for all participants will be stored only at the intervention site, in coded form, with the key only available to the onsite investigative team. No data from participants who do not complete the full study will be retained or analysed. A single member of the team is responsible for coding, and the code key is locked in a single office at the investigation site. Data entered electronically are not linked in any way to this code list; hard copies of questionnaires are stored in a separate archive. Data entry will be controlled by the principal investigator following entry by other investigators, comparing hard copies with electronic records. Following the trial, archived material will be kept for 10 years, in line with the requirements of the local ethics committee. An inventory of each section of the trial is visible in the SPIRIT checklist (Additional file 1).
Timeline of assessments
Figure 1 demonstrates the proposed schedule of assessments for each individual participant.
Figure 2 shows the SPIRIT figure for a single participant in the study.
Measures
Demographic data
The age and gender of all participants will be recorded. Alcohol-dependent and cocaine-dependent participants will be asked to report the year of onset of their dependence, the number of treatment attempts made to date, the number of days of the current treatment episode, the number of days of abstinence and their nicotine consumption.
General physical exercise and activity
The SIMPAQ is a brief five-item tool, which comprehensively evaluates activity over the past 7 days including time in bed, sedentary time, time spent walking, type of and time spent in exercise, and time spent for other activities [42]. Assessed physical activity refers to all domains of activity, including leisure time, domestic, work and transport-related activities. The SIMPAQ captures a 24-h period representative for the previous week.
It is important to assess the physical activity levels of participants, as more active individuals may not experience clear changes in prefrontal activation following an acute exercise bout.
General stress
In order to assess a participant’s stress levels on each test day, a short questionnaire will be completed at the beginning of each session. High stress may increase craving for substances [43, 44], and this questionnaire will allow for this factor to be considered as a covariate. The Perceived Stress Scale will be used to measure the degree to which situations in one’s life are appraised as stressful [45]. It consists of 10 items, each of which can be rated between 0 and 4 on a Likert-type scale, assessing the perceived stress of each participant over the past 4 weeks. Items are summed to generate a single score of between 0 and 40, with higher scores indicating greater perceived stress. The 10-item version of the Perceived Stress Scale is widely reported as having good internal consistency and validity [46].
Inhibitory control
For the assessment of inhibitory control, a computer-based version of the Stroop test is administered with E-Prime 2.0 (PST, USA). During the task, participants are presented with a colour word appearing in the same colour (e.g. “blue” printed in blue) on compatible trials or in a different colour (e.g. “blue” printed in green) on incompatible trials. While the word meaning has to be ignored, participants are instructed to press a key corresponding to the ink colour. The conflict resulting from the presentation of the relevant and irrelevant dimensions of the stimuli challenges the attentional system. In this respect, a system that efficiently suppresses task-irrelevant dimensions allows fewer conflicts between the colour word and the ink colour. This indicates greater efficiency of the inhibitory control system. Similar to the original Stroop paradigm, computerised versions of this task have been found to elicit interference effects and to have a high reliability [47].
In the present study, participants complete 12 practice trials, followed by four test blocks with 54 trials each. Sufficient practice rounds are included to reduce learning effects. In each test block, only compatible or incompatible trials are presented to allow the detection of interference effects using fNIRS. The blocks are alternated and the trial type employed in the first block is counterbalanced across participants. Between blocks there is a 30-s fixation period, which allows HbO2 concentrations to return to baseline. During each trial, the stimuli are presented over 2000 ms or until a response is collected. The inter-stimulus interval is varied randomly between 200 and 400 ms to avoid guessing.
The different colour words were presented with equal probability across all trials. For the assessment of task performance, the accuracy and reaction time (on response-correct trials) are calculated for incompatible trials.
Alcohol or cocaine cue exposure
Alcohol-dependent participants will be asked to report the type of alcohol (wine, beer, schnapps) which they chiefly consume or prefer. It has been established that, in research involving substance cues, craving is more reliably elicited by cues specific to the individual and their consumption history, and is consequently not a reaction to arousing cues in general [48]. Cocaine-dependent participants will not undergo this step, as there is no variation in the substance itself. All participants will be shown a block of six 1-min films, alternating cocaine cues or alcohol cues (of the preferred substance) with neutral cues. Neutral cues have to be included to be able to associate changes in HbO2 with craving rather than visual processing alone. Each 1-min film is separated from the next by a 30-s fixation period, which allows HbO2 concentrations to return to baseline. The same film block will be shown at every time point (specifically, prior to and after every condition, for each of the three conditions) in order to ensure that there is no variation in the emotional intensity of the cue.
Each 1-min film is designed to replicate activities carried out in a real-life setting. In order to achieve this, the films are created with a small camera strapped to the head, so that the viewer sees everything from the perspective on the camera holder and can see their hands picking up objects, etc. In the alcohol-cue films, the camera holder walks through a supermarket, arrives at the aisle selling the preferred beverage of the participants, looks at the bottles, picks some up and finally puts some in a basket before moving on. In the neutral films shown following the alcohol films, this sequence is repeated but some type of cleaning product is the examined and chosen. In the cocaine-cue films, the camera holder walks to a flat surface, takes out a small bag of cocaine and begins to snort it or prepares it in lines. The neutral cues are filmed in the same environment, but another activity (making tea, writing, opening a book) is undertaken on the flat surface.
Prior to the study start, the films will be tested on 10 alcohol-dependent and 10 cocaine-dependent individuals (who will not later take part in the study) in order to ensure that the film reliably elicits craving.
Craving self-report
Current craving levels will be assessed using the Alcohol Craving Questionnaire—Short Form [49] or the Cocaine Craving Questionnaire—Brief [50]. The Alcohol Craving Questionnaire—Short Form consists of 12 questions rated on a 7-point Likert-type scale, addressing the degree to which craving is experienced by the respondent in the current moment. A general craving score is generated by summing the scores of each item (three items are reverse-scored) to produce a score between 12 and 84, with higher scores indicating greater craving. The Short Form has been shown to have good levels of reliability [51] and internal consistency [52]. The Cocaine Craving Questionnaire—Brief consists of 10 items which assess current levels of craving for cocaine. The respondent rates each item on a 7-point Likert-type scale and scores are summed to produce a final value ranging between 7 and 70, with higher scores indicative of greater craving. The questionnaire is reported to have good reliability and internal consistency [53].
fNIRS recordings
Using fNIRS (NIRSport, NIRx Medizintechnik GmbH, Germany), cerebral oxygenation is recorded during the inhibitory control task and alcohol cue exposure. Probes are applied using a flexible cap adjustable to the participant’s head size. Light sources and detectors are placed over the prefrontal region using the Fz position of the EEG as reference. Channel distances are fixed to 35 mm to allow measurements at equal depths. Offline processing of the collected data is performed with Homer 2 [54] and includes the following steps: removal of discontinuities, artefact rejection and correction using spline interpolation, band-pass filtering (0.01–0.2 Hz), conversion into haemodynamic states using the modified Beer–Lambert Law [55] and normalisation using the pre-task period as baseline. As findings of a review have indicated widespread prefrontal cortex hypoactivation during inhibitory control tasks and hyperactivation during the presentation of drug-related cues, cerebral oxygenation is examined across channels placed over the prefrontal region [7].
HbO2 is calculated as the dependent variable, because Strangman et al. [56] have shown high correlations between this parameter and the blood oxygen level. For the assessment of cue-elicited craving, difference waveforms (created by subtracting the haemodynamic response to neutral cues from alcohol/cocaine cues) are extracted for statistical analysis.
Experimental conditions
To estimate the maximal heart rate of each participant, the algorithm 211 – (0.64 × age) will be used [57].
All participants will undergo three conditions, on three separate days, in a counterbalanced order. The days on which participants participate will be separated by 2–4 days. All sessions will take place in the same laboratory room at the Department of Sport, Exercise and Health at the University of Basel. Trained members of the investigative team will oversee all conditions. Owing to the nature of the intervention, investigators will not be blinded to the conditions.
The reading condition serves as a resting state comparison. Subjects will be asked to read an article about architecture in Basel. The article is 13 pages long, excluding references.
The moderate exercise condition requires participants to train on a cycle ergometer at between 50 and 60% of their maximal heart rate. Participants will wear a heart rate monitor, which will be constantly observed by study personnel, to ensure that they exercise with the correct intensity. If the participant exceeds or fails to meet the appropriate intensity, prompts will be given. Prompts will not be recorded. This constitutes a moderate, aerobic exercise bout. The exercise will last 20 min.
The intensive exercise condition is identical to the moderate condition, but participants will exercise at a pulse of between 70 and 80% of their maximal heart rate, constituting a bout approximately at the anaerobic threshold.
Statistics
Sample size is calculated a priori using G*Power 3.1 [58]. Based on effect sizes reported in previous studies [25, 40] and an alpha level set to 0.05, the initial power analysis indicates that 17 participants per group are required to reach 85% statistical power. As drop-outs have to be expected, the sample size is increased to 20 participants per group. Note that the power analysis is based on the acute effects of moderate aerobic exercise on prefrontal cortex activity and inhibitory control. The statistical analysis of collected data is performed with SPSS 23.0 (IBM Statistics, USA) for Windows. Acute effects of exercise on inhibitory control and HbO2 concentration are examined using a 2 (group: alcohol dependent, healthy controls) × 3 (condition: control, moderate exercise, highly intense exercise) × 2 (time: pre, post) ANOVA on reaction time and the haemodynamic response to incompatible trials of the Stroop colour–word test. Additionally, effects of exercise on cue-elicited craving and HbO2 concentration (neutral cues subtracted from alcohol/cocaine cues) are investigated by applying a 2 (group) × 3 (condition) × 2 (time) ANOVA. Main effects and interactions are reported. Subsequently, Bonferroni-corrected t tests are used to decompose any significant interactions. The level of statistical significance is set to p < 0.05. Data from participants who do not complete all three measurement points will not be used.
Regarding missing data, as participants who do not complete all three sessions will be excluded from the study, it is anticipated that missing data will chiefly be due to faults in the fNIRS and Stroop programming, and thus will be missing at random. For this reason, multiple imputation will be used to address this issue.
Dissemination of results
Only the investigative team will have access to the trial dataset. Results of the trial will be communicated to participants following completion of the study upon request. Individual results will not be made available. Physicians from the clinics involved in recruiting the patients will be informed about the results, and upon request the investigators will present these at faculty meetings. Findings from the study will be published in peer-reviewed academic journals.