Design and Participants

Overview

This double-blind, placebo-controlled, 2 × 2 factorial design tested the efficacy of pharmacotherapy, cognitive rehabilitation, and combination therapies for persistent cognitive symptoms and/or deficits after TBI in a 6-week trial (ClinicalTrials.gov Identifier NCT00453921). Participants gave written informed consent approved by the Institutional Review Boards of Dartmouth-Hitchcock Medical Center, Indiana University School of Medicine, and University of Colorado School of Medicine.

Inclusion criteria

Inclusion criteria were: (1) age 18–65 at study entry; (2) TBI of at least mild severity (Kay et al, 1993) at least 4 months before study entry; and (3) self-report of cognitive deficits as a result of the injury of sufficient severity to interfere with social and/or occupational functioning as measured by a score at least one standard deviation above the normative mean on the multiple abilities self-report questionnaire (MASQ) (Ahles et al, 2008; Seidenberg et al, 1994), and/or objective evidence of cognitive deficits represented by either (a) score two or more standard deviations below age-adjusted normative data or estimates of premorbid function (Barona et al, 1984) on one or more tests of attention and/or memory or (b) score one or more standard deviations below either age-adjusted normative data or estimates of premorbid function on two or more tests of attention and/or memory administered as part of the screening cognitive battery.

Exclusion criteria

Exclusion criteria were: (1) history of other neurological or systemic medical disorder that was unstable, likely to need repeated medication adjustments, or likely to affect cognitive function or be a contraindication to use of MPH; (2) current DSM-IV (APA, 2000) Axis I diagnosis of psychiatric illness, other than mild-moderate depression or anxiety, screened for using the Mini-International Neuropsychiatric Interview (M.I.N.I. English Version 6.0.0, modified based on the version for attention-deficit/hyperactivity disorder (ADHD) studies) (Sheehan et al, 1998), Beck Depression Inventory-II (Beck et al, 1996), State-Trait Anxiety Inventory (Spielberger, 1983), and PTSD Checklist-Stressor Specific (PCL-S) (Weathers et al, 1993); (3) currently pregnant or lactating; (4) pre-injury diagnosis of learning disability or ADHD; (5) lack of English fluency sufficient to complete study measures; or (6) standard score below 70 on the Wide Range Achievement Test-4 Word Reading subtest (Wilkinson and Robertson, 2006), to ensure reading ability sufficient to participate in cognitive rehabilitation.

Study protocol

Eligible participants underwent a pre-treatment baseline assessment, then were randomized to receive MPH or placebo and one of two cognitive rehabilitation interventions, a metacognitive intervention, Memory and Attention Adaptation Training (MAAT, designed by R.J.F.), or Attention Builders Training (ABT), a manualized repetitive practice intervention with no active cognitive-behavioral component. This resulted in four treatment combinations: MAAT/MPH, ABT/MPH, MAAT/placebo, and ABT/placebo. Phone contacts (weeks 1, 3, and 5) assessed for side effects and monitored compliance. At in-person study visits (weeks 2 and 4) participants also engaged in their assigned therapy (MAAT or ABT). After 6 weeks of treatment, participants completed post-treatment outcome measures (see Supplementary Figure 1 for study flow).

Cognitive assessment

The test battery emphasized cognitive domains most commonly reported as impaired after TBI, including memory, attention-related and executive functions, and processing speed, and included measures of general cognitive ability for sample characterization. Cognitive eligibility screening included the California Verbal Learning Test-II (Delis et al, 2000), Delis–Kaplan Executive Function System (Delis et al, 2001) Trail Making, Verbal Fluency, and Color-Word Interference subtests, Paced Auditory Serial Addition Test (Gronwall, 1977), Wechsler Adult Intelligence Scale-III (The Psychological Corporation, 1997) Letter Number-Sequencing Test, and Gordon Diagnostic System Continuous Performance Test (Gordon et al, 1996). Assessments at the pre-treatment visit included the Vocabulary and Block Design subtests of the Wechsler Abbreviated Scale of Intelligence (The Psychological Corporation, 1999), Wechsler Adult Intelligence Scale-III Digit Symbol-Coding and Digit Span subtests, Delis–Kaplan Executive Function System Sorting Test, Craft Story Memory Test (Craft et al, 1996), Brown Location Test (Brown et al, 2007), Grooved Pegboard Test (Lafayette Instrument, 1989), Finger Tapping Test (Reitan and Wolfson, 1993), and Thumb-Finger Sequencing Test (Saykin et al, 1995). The complete neuropsychological battery and the MASQ were repeated at post-treatment, with alternate test forms used where possible.

Interventions

Memory and Attention Adaptation Training (MAAT)

MAAT is a brief cognitive-behavioral therapy aimed at enhancing skills for self-managing and coping with cognitive failures in daily life. Initially developed for use in patients experiencing post-concussive symptoms (Ferguson and Mittenberg, 1996), MAAT was later adapted for treatment of cognitive symptoms after breast cancer chemotherapy, where preliminary data showed good feasibility and acceptability and beneficial treatment outcomes (Ferguson et al, 2007; Ferguson et al, 2012). The version of MAAT used in this study consisted of four biweekly 50 min individual office visits focused on cognitive-behavioral strategy use. Briefer telephone contacts between visits were intended to reinforce use of new behaviors or modify the strategy to enhance effectiveness.

MAAT includes four cognitive-behavioral components: (1) Education regarding ‘normal’ cognitive failures, as well as potential effects of TBI on cognitive function; (2) self-awareness training to identify ‘at-risk’ situations where cognitive failures are likely to occur; (3) self-regulation training emphasizing applied relaxation techniques and stress management; and (4) cognitive compensatory strategy training. Each participant received a MAAT workbook with detailed descriptions of compensatory strategies, educational material, and guides on how to apply compensatory strategies. Clinicians followed a detailed manual to enhance treatment fidelity. R.J.F. trained and supervised therapists in conducting the MAAT treatment protocol, reviewed recordings of treatment visits, and provided corrective feedback as necessary.

Attention Builders Training (ABT)

ABT was modeled after Berg et al, (1991). Participants were provided information about cognitive remediation techniques related to the use of repetitive cognitive tasks to build skills through ‘mental exercise’ (Tate, 1997), akin to the direct attention training approaches discussed above. Visit timing and duration were identical for ABT and MAAT. ABT also included an educational component discussing common cognitive symptoms after TBI, but did not emphasize behavioral compensatory and functional reorganization strategies, nor was instruction provided on how to implement the exercises in daily living situations.

At the initial therapy visit, participants were given an ABT manual and a packet consisting of a variety of tasks, which were carefully explained and practiced to ensure understanding. A repetitive practice regimen was assigned. Tasks were not tailored to the participant’s cognitive complaints/deficits, there was no ‘coaching’ on the tasks, and no compensatory strategy training was provided. On subsequent visits, the home-practice regimen was reviewed, refresher drills and practice sessions were performed, and new assignments were given. Phone contacts entailed evaluation of the home-practice regimen by the therapist and empathetic listening without any instructions.

Methylphenidate

Participants weighing <100 kg received MPH 0.1 mg/kg of body weight twice daily (BID) for 2–4 days, then 0.2 mg/kg BID for 2–4 days (default choice for both intervals was 2 days; study physicians could extend the titration interval to 4 days at their discretion), then 0.3 mg/kg BID for the remainder of the study. Doses were rounded to the nearest 2.5 mg increment. Those weighing ⩾100 kg received doses of 10 mg BID, then 15 mg BID, then 30 mg BID for the same intervals. Therefore, dosing did not exceed 60 mg/day total. For an average 70 kg adult, this translates into about 20 mg BID. This target dose was based on studies demonstrating efficacy in improving cognitive function in TBI populations (Plenger et al, 1996; Whyte et al, 1997; Whyte et al, 2002). Participants with modest side effects who wished to continue in the protocol were allowed dose reduction at physician discretion, but needed to be able to tolerate a dose of at least 10 mg/day to remain in the study.

Placebo

Placebo was provided in capsules indistinguishable from the MPH capsules in taste and appearance, with BID dosing and similar titration increases (ie, an increase in number of capsules of placebo).

Randomization and masking

Group assignment occurred through block randomization. Group allocation was concealed. Therapists were blind to outcome data, and staff conducting outcome assessments were blind to participant randomization. Medications were prepared and distributed by site-specific pharmacies which maintained the allocation code and ensured blinding of study medications.

Adverse events and treatment compliance were monitored via phone contacts and at in-person visits, and by inventorying study capsules at in-person visits.

Statistical analysis

Demographic and clinical covariates were assessed for group differences using ANOVA or χ2-tests as appropriate. Primary outcome variables included measures of episodic memory (California Verbal Learning Test-II initial encoding over trials 1–5 number correct: CVLT), attention (Continuous Performance Test Distractibility trial reaction time: CPT_RT), divided attention and working memory (Paced Auditory Serial Addition Test Trial 3 (1.6’ pacing) number correct: PASAT), processing speed (Wechsler Adult Intelligence Scale-III Digit Symbol-Coding number correct: DSC; Delis–Kaplan Executive Function System Trail Making Test, trial 2 completion time: DTR2), and self-reported cognitive function (MASQ total score: MASQ). Secondary outcome measures included additional measures of episodic memory (Craft Stories immediate recall total score: CRAFT; Brown Location Test initial encoding over trials 1–5 number correct: BLT), and executive function (D-KEFS Sorting Test-Free Sorting Description total score: SORT).

All analyses were conducted using the R statistical software package (v3.1.2), as follows. Main effects of MAAT, MPH, and their interaction were examined via nonparametric Kruskal–Wallis test for changes between baseline and post-treatment measurements. Linear regression models were fit for post-treatment scores for each outcome variable for the primary factors of interest, cognitive rehabilitation (MAAT vs ABT) and pharmacotherapy (MPH vs placebo), together with their interaction, adjusting for baseline performance, study site, days since injury (log transformed), and treatment adherence (percent of prescribed doses taken). Post-treatment scores adjusted for covariates are referred to as ‘predicted’ scores. For each treatment combination the estimated means were obtained at the average value of the adjustment variables. It was hypothesized that the MAAT/MPH group would show greater cognitive improvement than the other groups. A P-value <0.05 was considered to indicate statistical significance. Standardized (adjusted) coefficients and effect sizes (unadjusted) are reported. Standardized coefficients are estimated from the regression model used to predict post-treatment scores. To create comparable adjusted coefficients among outcome variables, both outcome and adjustment variables are standardized to have the mean equal to zero and standard deviation equal to one. Effect sizes (Cohen’s d) are estimated by the ratio of the difference between the post-treatment and baseline scores for each treatment combination and the pooled standard error estimate of the differences.