Effects of a Theta/Sensorimotor Rhythm Neurofeedback Training Protocol on Measures of Impulsivity, Drug Craving, and Substance Abuse in Forensic Psychiatric Patients With Substance Abuse: Randomized Controlled Trial

Background Forensic psychiatric patients are often diagnosed with psychiatric disorders characterized by high levels of impulsivity as well as comorbid substance use disorders (SUD). The combination of psychiatric disorders and SUD increases the risk of future violence. Chronic substance abuse can lead to a structural state of disinhibition, resulting in more drug taking and eventually loss of control over drug intake. When treating SUD, it is crucial to address high levels of impulsivity and lack of inhibitory control. Objective This study set out to investigate the effects of a theta/sensorimotor rhythm (SMR) neurofeedback training protocol on levels of impulsivity, levels of drug craving, and actual drug intake in a population of forensic psychiatric patients with a diagnosis of SUD. Methods A total of 21 participants received 20 sessions of theta/SMR neurofeedback training in combination with treatment-as-usual (TAU). Results of the intervention were compared with results from 21 participants who received TAU only. Results SMR magnitude showed a significant (P=.02) increase post training for patients in the neurofeedback training group, whereas theta magnitude did not change (P=.71). Levels of drug craving as well as scores on the motor subscale of the Barratt Impulsivity Scale-11 decreased equally for patients in the neurofeedback training group and the TAU group. Other measures of impulsivity as well as drug intake did not change posttreatment (P>.05). Therefore, neurofeedback+TAU was not more effective than TAU only. Conclusions This study demonstrated evidence that forensic psychiatric patients are able to increase SMR magnitude over the course of neurofeedback training. However, at the group level, the increase in SMR activity was not related to any of the included impulsivity or drug craving measures. Further research should focus on which patients will be able to benefit from neurofeedback training at an early stage of the employed training sessions. Trial Registration Dutch National Trial Register: NTR5386; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5386 (Archived by WebCite at http://www.webcitation.org/6nXLQuoLl).

The current study demonstrated evidence that forensic psychiatric patients are able to increase SMR magnitude over the course of neurofeedback training. However, at the group level, the increase in SMR activity was not related to any of the included impulsivity or drug craving measures. Further research should focus on which patients will be able to bene¡t from neurofeedback training at an early stage of the employed training sessions."  METHODS 3a) Description of trial design (such as parallel, factorial) including allocation ratio 3b) Important changes to methods after trial commencement (such as eligibility criteria), with reasons 4a) Eligibility criteria for participants Does your paper address CONSORT subitem 2b? * We hypothesized that patients receiving neurofeedback training and TAU would show reduced levels of impulsivity post-training, as well as a reduction in levels of drug craving and in amount of drug use in comparison to patients receiving TAU only." Does your paper address CONSORT subitem 3a? * "Out of all participants that met the requirements, a random sample was drawn and randomly assigned to one of the two study conditions (neurofeedback training + TAU or TAU only)" Does your paper address CONSORT subitem 3b? * 3b-i) Bug fixes, Downtimes, Content Changes Does your paper address subitem 3b-i? Does your paper address CONSORT subitem 4a? * Inclusion criteria were the presence of at least one DSM-IV-TR [32] diagnosis of SUD, positive drug testing in the past 24 months before inclusion, and sufficient knowledge of the Dutch language to understand training instructions. All patients had at least one comorbid axis I and/or II diagnosis. Exclusion criteria were a state of acute psychosis, in which patients experienced severe delusions and/or hallucinations and could possible become a threat to themselves or others (a diagnosis of schizophrenia, as well as disorders in the schizophrenia spectrum (e.g., schizoaffective disorder) were not considered exclusion criteria). A comorbid diagnosis of epilepsy; and visual and/or auditory impairments, which would hamper patients' ability to follow instructions and adhere to the neurofeedback training were also exclusion criteria. Medication intake was not restricted. Patients were allowed to continue the use of medication over the course of the study. Treatment supervisors were informed that, during the course of the study, prescribed medication should preferably remain stable, and that a change in type as well as dosage of medication should not be made during the course of the study unless absolutely necessary. Treatment supervisors were asked to inform researchers in case a change in type or dosage of medication did occur. 4a-i) Computer / Internet literacy Does your paper address subitem 4a-i? 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: Does your paper address subitem 4a-ii? * Out of all participants that met the requirements, a random sample was drawn and randomly assigned to one of the two study conditions (neurofeedback training + TAU or TAU only). Patients were approached through treatment supervisors for participation and informed about the general outline of the study.
If they expressed interest in participating in the study, they were approached by one of the researchers to explain the study design and randomization procedure. All patients signed the informed consent. Randomization was done by a random number generator. " "Participants in both conditions underwent pre-treatment measurements (T0), consisting of the measurements described below. [...] After 10 weeks, participants in the control group underwent post-treatment measurements (T1), identical to pre-treatment measurements. [...] Measures Electroencephalography (EEG) A 5 minute 21-channel EEG resting-state measurement with eyes closed was conducted with Nexus-32 hardware and Biotrace software (MindMedia BV). EEG measurements were collected from 19 standard 10/20 positions [..., and the right and left mastoid with a sampling rate of 512 samples per second. The left mastoid served as the online reference. Flat type electrodes were placed above and below the left eye and at the outer canthi of each eye to correct for vertical and horizontal eye movements. EEG magnitude across delta (0.5-3.5 Hz), theta (3.5-7.5 Hz), alpha (7.5-12 Hz), beta (12-20 Hz), SMR (12-15 Hz), high beta (20-32 Hz), and gamma (32-49 Hz) frequency bands was assessed. Only magnitude changes in theta and SMR frequency were used for analysis. For analysis, custom-made Matlab scripts (version R2012b) were used. First, data from the resting-state measurements were imported into EEGLAB, bandpass ¡ltered between 1-40 Hz, and inspected for gross movement artifacts which were then manually removed. Subsequently, epochs of 4 s length were created. Epochs containing amplitudes exceeding ±100 μV at any scalp electrode and/or epochs containing abnormally distributed data (i.e., joint probability or kurtosis >5 SD from expected mean values) were rejected. From the remaining epochs, the ¡rst The short form of the DAQ-SF is a self-report questionnaire which measures levels of craving for alcohol among 14 items scored on a seven-point Likert scale (ranging from 1= strongly disagree to 7= strongly agree). The DAQ-SF has been shown to be a reliable measure to assess craving in a substance-dependent population (Cronbach's α = .70) [...]. For the purpose of this study, items from the Dutch version of the questionnaire [...] were modi¡ed to measure desire for drugs in general, as opposed to being restricted to measure desire for alcohol only. An example of a modi¡ed item is 'All my tension would completely disappear if I drank now' into 'All my tension would completely disappear if I used drugs now'. The modi¡cation was made due to the fact that alcohol use is very rare in an inpatient setting, whereas use of other drugs (e.g., cannabis or cocaine) is more common. 6b) Any changes to trial outcomes after the trial commenced, with reasons 7a) How sample size was determined NPT: When applicable, details of whether and how the clustering by care provides or centers was addressed 6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed Does your paper address subitem 6a-i?
No online questionnaires were used 6a-ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored Does your paper address subitem 6a-ii?
See above 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained Does your paper address subitem 6a-iii?
Does your paper address CONSORT subitem 6b? * No changes were made. 7b) When applicable, explanation of any interim analyses and stopping guidelines 8a) Method used to generate the random allocation sequence NPT: When applicable, how care providers were allocated to each trial group 8b) Type of randomisation; details of any restriction (such as blocking and block size) 9) Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned 7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size Does your paper address subitem 7a-i? See flow diagram. In this study, a pre-post-test design was used. A power analysis calculation for the RCT using G*Power 3 based on a 1-tailed alpha value of .05, a power value of 0.80, and an effect size (f) of 0.80 yielded a recommended sample size of 21 participants each in the control and intervention conditions. Does your paper address CONSORT subitem 7b? * Not applicable.
Does your paper address CONSORT subitem 8a? * Randomization was done by a random number generator.
Does your paper address CONSORT subitem 8b? * Out of all participants that met the requirements, a random sample was drawn and randomly assigned to one of the two study conditions (neurofeedback training + TAU or TAU only). Patients were approached through treatment supervisors for participation and informed about the general outline of the study. If they expressed interest in participating in the study, they were approached by one of the researchers to explain the study design and randomization procedure. All patients signed the informed consent. Randomization was done by a random number generator. " 10) Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions 11a) If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how NPT: Whether or not administering co-interventions were blinded to group assignment Does your paper address CONSORT subitem 9? * Not applicable. (See above) Does your paper address CONSORT subitem 10? * Out of all participants that met the requirements, a random sample was drawn and randomly assigned to one of the two study conditions (neurofeedback training + TAU or TAU only). Patients were approached through treatment supervisors for participation and informed about the general outline of the study.
If they expressed interest in participating in the study, they were approached by one of the researchers to explain the study design and randomization procedure. All patients signed the informed consent. Randomization was done by a random number generator. " 11a-i) Specify who was blinded, and who wasn't Does your paper address subitem 11a-i? * Neurofeedback training was done by a certi¡ed neurofeedback therapist. The study was not blinded, as it was clear to patients as well as the neurofeedback therapist which patients received the neurofeedback training. " 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" 11b) If relevant, description of the similarity of interventions (this item is usually not relevant for ehealth trials as it refers to similarity of a placebo or sham intervention to a active medication/intervention) 12a) Statistical methods used to compare groups for primary and secondary outcomes NPT: When applicable, details of whether and how the clustering by care providers or centers was addressed Does your paper address subitem 11a-ii? Neurofeedback training was done by a certi¡ed neurofeedback therapist. The study was not blinded, as it was clear to patients as well as the neurofeedback therapist which patients received the neurofeedback training.
Does your paper address CONSORT subitem 11b? * Neurofeedback training was additional to TAU [...] Participants in the control group received TAU only. TAU was different for every patient, as treatment modalities are based on individual diagnosis and problematic behavior of the patient, as well as the cognitive ability to undergo different treatment modalities. Examples of treatment modalities were non-verbal therapy forms (e.g., psychomotor therapy, musical therapy) and cognitive-behavioral group therapy. " Does your paper address CONSORT subitem 12a? * All participants who completed pre-and post-treatment measures were included in the statistical analysis (n = 42). For analysis of drug testing, weekly reports of two of the patients from the control group were not available, therefore the analysis of drug testing consists of data from 40 patients.
All data were analyzed with SPSS version 25 (IBM Corp).
Due to violations of statistical assumptions concerning normality and homoscedasticity of almost all dependent variables (BIS motor, BIS attentional, Bis total score, DAQ-SF, delta magnitude, theta magnitude, SMR magnitude and Cued Go/No-Go commission errors), non-parametric tests were employed. To test for differences between treatment conditions pre-treatment, Mann-Whitney U tests were performed for pre-treatment scores on BIS-11 total score, BIS-11 subscales 'motor', 'non-planning', and 'attentional', as well as scores on DAQ-SF, number of commission errors, drug testing and mean theta and SMR magnitude. A Wilcoxon signed-ranks test was performed to assess changes within groups between pre-and post-treatment for all dependent variables.
A repeated-measures ANOVA with Time as within-subject variable and Treatment condition as a between-subject variable was performed. To assess significance, a within-groups effect size was used (Eta squared η^2). Cut-off scores were used according to Cohens rules in order to assess whether effect size were small η^2= 0.02, medium η^2= 0.13 or large η^2= 0.26 [38].
Pearson's correlations were performed to test for relations between changes in delta, SMR, high beta and theta frequency magnitude pre-versus post-treatment and all behavioral measures. Only results significant at the .05 level will be reported. Patients were approached through treatment supervisors for participation and informed about the general outline of the study. If they expressed interest in participating in the study, they were approached by one of the researchers to explain the study design and randomization procedure. All patients signed the informed consent. " X26-iii) Safety and security procedures Does your paper address subitem X26-iii?
Does your paper address CONSORT subitem 13a? * Of those assessed (n= 258), 47.3% of patients (n= 136) were excluded due to not ¡tting the inclusion criteria. 52.7 % (n= 122) of patients were eligible for participation. Those eligible were randomly assigned to either the neurofeedback training group (n= 61) or TAU group (n= 61). Figure 1  17a) For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) 17b) For binary outcomes, presentation of both absolute and relative effect sizes is recommended Does your paper address subitem 16-ii?
All participants who completed pre-and post-treatment measures were included in the statistical analysis (n = 42). For analysis of drug testing, weekly reports of two of the patients from the control group were not available, therefore the analysis of drug testing consists of data from 40 patients. All data were analyzed with SPSS version 25 (IBM Corp).
Due to violations of statistical assumptions concerning normality and homoscedasticity of almost all dependent variables (BIS motor, BIS attentional, Bis total score, DAQ-SF, delta magnitude, theta magnitude, SMR magnitude and Cued Go/No-Go commission errors), non-parametric tests were employed. To test for differences between treatment conditions pre-treatment, Mann-Whitney U tests were performed for pre-treatment scores on BIS-11 total score, BIS-11 subscales 'motor', 'non-planning', and 'attentional', as well as scores on DAQ-SF, number of commission errors, drug testing and mean theta and SMR magnitude. A Wilcoxon signed-ranks test was performed to assess changes within groups between pre-and post-treatment for all dependent variables.
A repeated-measures ANOVA with Time as within-subject variable and Treatment condition as a between-subject variable was performed. To assess significance, a within-groups effect size was used (Eta squared η^2). Cut-off scores were used according to Cohens rules in order to assess whether effect size were small η^2= 0.02, medium

18-i) Subgroup analysis of comparing only users
Does your paper address subitem 18-i? Does your paper address CONSORT subitem 19? * None of the patients in the neurofeedback training + TAU group were able to complete training within the scheduled 10 weeks. This was due to holidays and planning issues, but also because some patients were mentally unable to complete a training session, or caused aggressive incidents which resulted in temporary separation/placement on a specialized crisis unit. It sometimes also happened that patients were unmotivated to attend a training session.
Participation in the study therefore lasted for an average of 14.1 (SD = 5.32) weeks per patient.
19-i) Include privacy breaches, technical problems DISCUSSION 22) Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence NPT: In addition, take into account the choice of the comparator, lack of or partial blinding, and unequal expertise of care providers or centers in each group Does your paper address subitem 19-i? 19-ii) Include qualitative feedback from participants or observations from staff/researchers Does your paper address subitem 19-ii? 22-i) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use) 20) Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses Does your paper address subitem 22-i? * "This RCT was conducted to investigate to what extent a theta/SMR neurofeedback training protocol in combination with TAU is able to reduce impulsivity and symptoms of SUD in a population of male forensic psychiatric patients residing in a FPC. The RCT compared a neurofeedback training group of 21 patients who received neurofeedback training in addition to TAU, to a control group of 21 patients receiving TAU only. Changes in targeted frequency bands and changes in levels of impulsivity, drug craving, and drug intake posttreatment were examined in the neurofeedback training group, and compared to patients in the TAU only group. Results indicate that SMR magnitude showed a signi¡cant increase post-treatment in the neurofeedback training group, whereas theta magnitude did not show any changes. Surprisingly, patients in the neurofeedback training group had signi¡cantly higher SMR magnitude pre-treatment than patients in the TAU only group.
Levels of drug craving and motor impulsivity as assessed with the BIS-11 decreased equally for patients in the neurofeedback training group and the TAU only group. Therefore, the combination of TAU and neurofeedback training was not more effective than TAU only. Other measures of impulsivity and number of drug use did not change post-treatment. " 22-ii) Highlight unanswered new questions, suggest future research Does your paper address subitem 22-ii?
Recently, QEEG-guided neurofeedback protocols are increasingly implemented in clinical practice. With these protocols, pre-treatment EEG-deviations are first assessed and the applied neurofeedback protocol then focusses on treating these EEG-deviations, as opposed to applying a standard neurofeedback protocol to all participants. While there is also discussion in the literature about the use of QEEG approach of neurofeedback treatment (e.g., Johnson & Bodenhamer-Davis, [50]) this approach fits with the rise of personalized medicine in the past decade, where a treatment approach tailored to the individual is applied rather than a one-size-fits all approach. Especially for forensic psychiatric patients, usually presenting with a wide range of comorbidities, manifesting through various deviations in EEG-frequencies, this might be a more suitable approach than applying standardized neurofeedback protocols.

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