See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/8539310 Effects of Methylphenidate on Attention Deficits After Traumatic Brain Injury ARTICLE in AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION · JUNE 2004 Impact Factor: 2.2 · DOI: 10.1097/01.PHM.0000128789.75375.D3 · Source: PubMed CITATIONS 129 READS 67 7 AUTHORS, INCLUDING: Patricia Neff 4 PUBLICATIONS 237 CITATIONS SEE PROFILE Marcia Polansky Drexel University 142 PUBLICATIONS 5,955 CITATIONS SEE PROFILE H. Branch Coslett University of Pennsylvania 226 PUBLICATIONS 8,449 CITATIONS SEE PROFILE Available from: H. Branch Coslett Retrieved on: 03 February 2016
From the Moss RehabilitationResearch Institute, Albert EinsteinHealthcare Network, Philadelphia,Pennsylvania (JW, TH, MV, PGN, AR,HBC); the Department ofRehabilitation Medicine, ThomasJefferson University, Philadelphia,Pennsylvania (JW, TH); theDepartment of Symptom Research,University of Texas, M. D. AndersonCancer Center, Houston, Texas (AR);the Department of Biostatistics,Drexel University, Philadelphia,Pennsylvania (MP); and theDepartment of Neurology, Universityof Pennsylvania School of Medicine,Philadelphia, Pennsylvania (HBC).
Disclosures:
Supported, in part, by grantR01NS39163 from the NationalInstitute on Neurological Diseasesand Stroke, National Institutes ofHealth, and grant R24HD39621 fromthe National Center for MedicalRehabilitation Research, NationalInstitute on Child Health and HumanDevelopment, National Institutes ofHealth.
Correspondence:
All correspondence and requests forreprints should be addressed to JohnWhyte, MD, PhD, Moss RehabilitationResearch Institute, 1200 West TaborRoad, Suite 213, Philadelphia, PA19141.
Effects of Methylphenidate onAttention Deficits After TraumaticBrain InjuryA Multidimensional, Randomized,Controlled TrialABSTRACTWhyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, Coslett HB: Effects of methyl-phenidate on attention deficits after traumatic brain injury: A multidimensional, randomized, con-trolled trial. Am J Phys Med Rehabil 2004;83:401–420.
Objective: To evaluate the effects of methylphenidate on a variety of aspects of attention,ranging from laboratory-based impairment measures to caregiver ratings and work productivity, inindividuals after traumatic brain injury.
Design: A total of 34 adults with moderate to severe traumatic brain injury and attention com-plaints in the postacute phase of recovery were enrolled in a 6-wk, double-blind, placebo-con-trolled, repeated crossover study of methylphenidate, administered in a dose of 0.3 mg/kg/dose,twice a day. A wide range of attentional measures was gathered weekly, including computerizedand paper-and-pencil tests of attention, videotaped records of individual work in a distractingenvironment, real-time observational scoring of attentiveness in a classroom environment, andcaregiver and clinician rating scales of attentiveness. Participants also attempted to guess theirdrug condition each week. Data from the first ten participants were used for pilot purposes, todevelop attentional factors for composite scoring, and to identify attentional dimensions sugges-tive of a treatment effect for independent replication. The remaining 24 participants’ results wereused to confirm potential treatment effects seen in the pilot sample, using Wilcoxon’s signed-rankstest on composite factor scores and individual variables.
Results: A total of 54 dependent variables were reduced to 13 composite factors and 13remaining individual variables. Of the 13 attentional factors, five showed suggestive treatmenteffects in the pilot sample. Of these, three showed statistically significant treatment effects in thereplication sample: speed of information processing (effect sizes, �0.06 to 0.48; P � 0.001),attentiveness during individual work tasks (effect sizes, 0.15–0.62; P � 0.01), and caregiverratings of attention (effect sizes, 0.44–0.50; P � 0.01). Of the individual variables, four showedsuggestive treatment effects in the pilot sample, but only one showed significant treatment effectsin the replication sample: reaction time before errors in the Sustained Attention to Response Task(effect size, 0.20; P � 0.03). No treatment-related improvement was seen in divided attention,sustained attention, or susceptibility to distraction. None of the variables showed suggestive ordefinite negative treatment effects. Effect sizes for those performance measures positively af-fected by methylphenidate were in the small to medium range and included both impairment andactivity level measures. Improvements in processing speed did not seem to come at the expenseof accuracy.
Conclusions: Methylphenidate, at 0.3 mg/kg/dose, given twice a day to individuals with atten-tional complaints after traumatic brain injury, seems to have clinically significant positive effects onspeed of processing, caregiver ratings of attention, and some aspects of on-task behavior innaturalistic tasks. Further research is needed to identify the optimal dose and to extend thesefindings to less carefully selected individuals.
June 2004 Effects of Methylphenidate After TBI 401
Research Article
Brain Injury
Attentional impairments are amongthe most common cognitive deficitsobserved after traumatic brain injury(TBI)1. Like attention itself, these im-pairments are multifaceted in nature;they can include lowered vigilance, in-creased distractibility, slowed process-ing time, and impaired ability to director allocate attention across differentfacets of the environment2. Attentionalimpairments may also contribute tomemory deficits and impairments ofexecutive functions, the two other pre-dominant neuropsychological disor-ders observed in moderate-to-severeTBI3. The importance of attention ineveryday life, its diversity in normaland defective expression, and the typi-cal mechanisms of injury sustainedduring the closed head injuries thatresult in moderate-to-severe TBI allcreate the need for comprehensive ex-aminations to specify the types of at-tentional problems that are present atany given time for an individual.4
Although moderate-to-severe TBIaccounts for only roughly 20% of alldocumented TBIs,5 survivors requiresignificant acute medical and rehabili-tation inpatient care and postacute re-habilitation services. These survivorsoften present with changes in indepen-dent daily functioning, psychosocial re-lationships, and academic and voca-tional status.6 Of course, attentionalimpairments are not alone in deter-mining functional outcome, but ad-dressing them is essential to successfulrehabilitation efforts. Attempts to im-prove acquired attentional problemshave included both cognitive-behav-ioral remediation efforts and psycho-pharmacologic intervention, but nei-ther has been conclusively shown to beof therapeutic benefit. Thus, there is acritical need for carefully controlledevaluations of treatment efficacy tosupport evidence-based approaches tointervention,7 for both cognitive-reme-diation8 and drug-based9 clinical-trialresearch.
The lack of evidence-based treat-ment recommendations stems from a
number of methodologic challenges.Although clinicians, caregivers, andsometimes TBI survivors themselvescite attention deficits as key cognitiveproblems, it has been difficult for re-searchers to reach consensus on thenature of these problems.10 Althoughit is widely agreed that TBI results inslowed information processing,11 it isnot clear that this, alone, can accountfor the range of the attention com-plaints reported.12 Other problems,including susceptibility to distrac-tion,13 inefficient attentional selec-tion,14 impaired sustained atten-tion,12 impaired divided attention,15
and increased rates of off-task behav-ior in naturalistic tasks,16 have beenreported in some but not all studies.This difficulty is not confined to theclinical study of attention after TBI.Indeed, controversy remains in cog-nitive psychology about how to defineattention, how to subdivide it, andhow best to measure its constitu-ents17. When considering attentiondeficits from the perspective of reha-bilitation, it also becomes importantto consider the level of conceptualanalysis of the attention measures ofinterest.18 That is, some researchtasks focus primarily at the impair-ment level, others assess manifesta-tions of attention in real-world tasks(activity level), and still others mayaddress the effect of attention deficitson an individual’s ability to resumepremorbid roles (participation level).Related to this point, pharmacologictreatments target the impairmentlevel, whereas approaches to cogni-tive remediation may target impair-ment, activity levels, or a combina-tion. Thus, measuring the effect ofsuch treatments may involve atradeoff between measurement sensi-tivity (which may be maximal whenusing impairment-level outcomemeasures) and clinical relevance(which is more related to activity andparticipation measures).18 Finally,shortcomings in experimental designhave limited the interpretation of theresults of a number of studies. Pre–
post designs without an untreatedcontrol group are rarely interpretablebecause of spontaneous recovery orpractice effects.19 Small parallelgroup studies run the risk of bothtype II error, due to lack of statisticalpower, and type I error, due to be-tween-group differences in patientcharacteristics, incompletely con-trolled by randomization.
Methylphenidate (MP) and otherpsychostimulants have been used totreat attention deficit hyperactivitydisorder (ADHD) at least since 1938,when it was discovered that benze-drine led to increased interest andeffort in school for affected chil-dren20. A recent review and meta-analysis covering 40 yrs of researchon MP treatment in ADHD concludedthat despite great variability acrossmethodology and quality of studies,MP consistently affects the inatten-tion, excessive behavior, and impul-sivity that constitute the core clinicalfeatures of the disorder21. Stimulantssuch as MP decrease hyperactivityand increase on-task behavior inADHD22. Compared with the amphet-amines to which it is chemically re-lated, MP may affect mental functionsmore prominently than motor activ-ity23. Recent studies have sought toisolate the cognitive functions mostaffected by MP in children with atten-tion disorders. For example, on theStroop Color Word Task, MP does notseem to improve interference control(e.g., ability to suppress prepotentword naming responses in the inter-ference condition)24,25, but the drugdoes affect speed of “effortful” pro-cessing (e.g., color-naming alone) ina highly positive way.25
MP has also been used to treatADHD in adults, although the re-search on this use is far less exten-sive. Variations in treatment responseamong adults may relate to differ-ences in diagnostic criteria used,presence of co-morbidities, anddoses. However, a rigorously de-signed crossover study showed highly
402 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
significant treatment effects amongadults with ADHD.26
The success of MP in childrenwith attention and behavior disordershas prompted researchers and clini-cians to use the drug for similar dis-orders seen in TBI and other acquiredbrain injuries. Other types of post-traumatic problems also have beenaddressed with MP. For example, thedrug has been reported to be effectivefor the treatment of posttraumaticnarcolepsy27 and difficulties with an-ger control28. Less conclusive effectshave been suggested for overall ad-justment29 and behavior30. However,the majority of published studieshave tested the effects of MP on cog-nition. Recently, we published a de-tailed review and critique of studieson MP and other psychostimulants inTBI,9 including a previous random-ized, controlled trial from our labo-ratory.31 As discussed in more detailin that review, studies are difficult tocompare because they vary widely indegree of experimental rigor, statisti-cal power, acuity and severity of TBIin the sample, age of the sample,number and type of dependent mea-sures, and other key factors that af-fect the interpretation of results. Theweight of the evidence thus far, how-ever, seems to indicate that MP doesnot have a very strong effect on as-pects of attention such as maintain-ing vigilance over time (sustained at-tention)29,31,32 or resistance todistraction.29,31 MP does seem tohave a beneficial effect on processingspeed, as measured in tasks of reac-tion time and speeded decision-mak-ing.31–34 In our previous controlledinvestigation,31 we demonstratedthat this effect of MP was due to aspecific effect on cognitive speedrather than speed of motorperformance.
The purpose of this study was toextend previous research findings onthe effect of MP on attention deficitsresulting from TBI. Because of themultifaceted nature of attention, asdiscussed above, we chose to study
the effects of MP on a wide range ofattention measures, including thoseat impairment and activity levels, as-sessed over a 6-wk period of intensivedata collection. Recognizing that theneed to conduct statistical testing ofthe drug’s effect in each of many ar-eas increases the risk of type I error,we sought to develop compositescores reflecting several differentvariables. We also designed the studyto include a pilot phase, followed byan independent replication in a largersample, of any drug effects thatseemed promising. This complex de-sign was undertaken to achieve twobroad research objectives. One was toexamine the clinical efficacy of MPfor attention-related deficits associ-ated with TBI in a more systematicand controlled fashion than has beenundertaken in previous research. Theother, equally important, objectivewas to clarify which attentional do-mains are responsive to MP treat-ment in this population so that fu-ture clinical trials can focus on asmaller number of empirically vali-dated primary outcomes.
METHODS
Participants
Participants were recruited froma variety of sources, with most refer-rals coming from the outpatient clin-ical programs at the Drucker BrainInjury Center at MossRehab Hospitaland the research registry maintainedat MossRehab, of inpatients fromMossRehab Hospital, Magee Rehabil-itation Hospital, and Bryn Mawr Re-habilitation Hospital, all located inthe Philadelphia area. We also adver-tised the study through the local pub-lic transportation system, a freenewspaper distributed in a variety ofplaces in the area, and with the braininjury associations of Pennsylvaniaand New Jersey.
Participants who were interestedin the study were interviewed andtheir medical records reviewed. To be
included, participants had to be be-tween the ages of 16 and 60 yrs and tohave a history of nonpenetrating TBIof at least moderate severity at least 3mos before enrollment. Severity levelwas defined by significant and welldocumented loss or alteration of con-sciousness after injury (i.e., lowestGlasgow Coma Scale score of �12[Although many of the GlasgowComa Scale scores used to determineeligibility were postresuscitationscores, in some instances, the initialGlasgow Coma Scale score was ob-tained from later secondary recordsin the absence of the acute care flowsheets, such that the exact timing ofthe score was unclear.] or prospec-tively documented posttraumatic am-nesia of �1 hr) or focal abnormalityon a neuroimaging study that wasattributable to traumatic injury. Par-ticipants needed to be able to performtasks for 10–15 mins semi-indepen-dently and be available to attend theproject five full days per week for 6wks. A subjective complaint of atten-tion difficulties by the participant,treating clinician, or caregiver wasalso required.
Potential participants were ex-cluded if they were currently hospi-talized; if they were pregnant or likelyto become pregnant; if they had ahistory of premorbid neurologic dis-ease, psychosis, major affective disor-der, mental retardation, or ADHD; ifthey were taking psychotropic medi-cations other than anticonvulsants; ifthey were currently abusing alcoholor recreational drugs, or if their his-tory of using these substances wassignificant enough to place them atrisk of long-term neurologic effects.Individuals were also excluded for be-havioral problems or for impairmentsin vision, hearing, or motor functionthat were severe enough to precludeparticipation in the research tasks.Participants or their involved care-givers (depending on the partici-pant’s cognitive capacity) providedinformed consent.
During a period of several years,
June 2004 Effects of Methylphenidate After TBI 403
we reviewed �1,500 individuals forpossible participation in this study, asshown in Figure 1. Possible partici-pants who were involved in clinicalprograms could often be excludedbased on the available records. Thosewho were encountered as a result ofpublic advertising were generally in-terviewed first to obtain releases fortheir medical records if they seemedeligible through interview. However,ascertainment of some of the eligibil-ity criteria (e.g., history of ADHD orsubstance abuse, availability for 6wks) generally required an interview,and this, in turn, required explainingthe basics of the study as an intro-duction. Thus, there were a numberof potential participants whose finaleligibility could not be ascertainedeither because they did not returntelephone calls or because they de-clined after hearing about the studybut before answering the interviewquestions. A total of 39 participantsconsented to the study and were ran-domized to a drug order (see below).Two subsequently withdrew due tosubjective adverse effects (one whilereceiving placebo), and one wasdropped because of possible exacerba-tion of baseline hypertension. Thesethree participants had insufficientdata for analysis. Two additional par-ticipants were dropped because ofsuspected substance abuse duringdata collection. Although one of thesewas dropped near the end of data col-lection, the data were not included inthe analysis because of the potentialconfounding effects of the substanceabuse. Thus, the sample of 34 indi-viduals who completed the study wasclearly a highly selected subgroup ofthose who were theoretically eligible.
Participants who met all eligibilitycriteria and provided informed consentunderwent additional data collection tocharacterize the sample and establishbaseline levels of function. Duration ofposttraumatic amnesia, as an addi-tional indicator of injury severity, wasassessed retrospectively using themethod developed by McMillan et al.35
In brief, this involved comparing par-ticipants’ memory for events aftertrauma against temporal milestonesabstracted from the medical record. Sixparticipants were unable to provide rel-evant information, either because theirinjury was so long before the assess-ment that they could not adequatelyrecall relevant events or because theyhad communication impairments thatprecluded participating effectively inthe interview. For all participants, theDisability Rating Scale36 was scored byproject staff based on participant andfamily interview at the time of enroll-ment as a measure of the level of cur-rent disability. Premorbid intellectual
status was estimated using demo-graphic and occupational history da-ta.37 Before starting the trial, partici-pants also underwent a battery ofneuropsychological tests focused pri-marily on attention and frontal/execu-tive function; these results will be pre-sented separately.
Table 1 summarizes the demo-graphic, injury and disability charac-teristics of the 34 participants. As istypical of research on moderate to se-vere TBI, the majority were male. Ex-cept for the exclusion of elderly partic-ipants, the distributions of age,education level, and ethnicity were typ-ical of TBI samples in metropolitan ar-
Figure 1: Flowchart detailing the 1,500 individuals reviewed for possibleparticipation in the study. MP, methylphenidate; P, placebo.
404 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
eas. In keeping with the exclusion forpremorbid cognitive limitations, esti-mated premorbid intellectual statusesall fell within the average to high-aver-age range. It may be seen in Table 1that the typical participant was severalyears postinjury, exhibited a moderatelevel of functional disability, and re-ported a significant degree of posttrau-matic amnesia. Table 1 also shows theproportion of participants for whomobjective records verified at least mod-erate neurologic severity by significantalteration of consciousness or neuro-imaging abnormalities. For two partic-ipants, medical records were not avail-
able for documentation of severity.However, their histories, levels of dis-ability, and motor impairment (onehad spastic quadriparesis, one a densehemiparesis) left no doubt as to theseverity of injury.
Procedure
The data collection for this studywas integrated into a day activitiesprogram infrastructure, provided freeof charge to participants. A rehabili-tation clinician ran a “research class-room” for three to four participantsat a time, from approximately 9:30a.m. to 3:30 p.m., Monday through
Friday. Figure 2 shows a schematicdiagram of the weekly schedule, in-cluding daily/weekly data collectionelements described below. This class-room environment served severalpurposes. It provided a positive groupenvironment to help maintain partic-ipation for the required 6 wks, whichwas an incentive for both participantslacking other productive activity andfor their caregivers, who were fre-quently seeking structured activityfor their family members. It also pro-vided a standardized environment forbehavioral ratings of attentiveness inindividual work and group activities.Finally, it provided a milieu for par-ticipants when they were not beingtested individually in the laboratoryand allowed assessment of vital signs,side effects, and behavioral self-rat-ings. The classroom was a single,large room with a small office for theclassroom clinician attached. Theroom was filled with large work ta-bles, a whiteboard, and materials foreducational and recreational activi-ties. The clinician designed activitiesthat could be tailored to the func-tional levels of individual participantsand that required attention for theirperformance. These activities werenot designed to meet individual clin-ical goals but were intended to beengaging and functionally relevant.The clinician was trained not to in-tervene to increase attentivenessthrough cueing or reinforcement be-cause the intent of this study wasspecifically to assess drug effects.
Participants were involved in thestudy for six consecutive weeks. Theyreceived a participant fee of $50/wkplus transportation expenses. Duringhalf of this time, they received MP,the study medication; during theother half, they took an identical-ap-pearing placebo, with the two condi-tions alternating weekly. Half of theparticipants started with MP followedby placebo and the other started withplacebo followed by MP (i.e., MP, pla-cebo, MP, placebo, MP, placebo orplacebo, MP, placebo, MP, placebo,
TABLE 1Characteristics of participants (n � 34)Demographic characteristics
Age, yrsMean 37Range 20–55
Sex, n (%)Male 29 (85)Female 5 (15)
Ethnicity, n (%)White 22 (65)African American 10 (29)Hispanic 2 (6)
Education, yrsMean 12.7Median 12Range 9–18
Estimated premorbid intelligencequotient
Mean 101Range 85–119
Injury and disability characteristicsParticipants with medical recorddocumentation of, n (%):
Loss/alteration of consciousness 22 (65)Abnormality on neuroimaging 23 (68)
Estimated duration of posttraumaticamnesia (n � 28), n (%)
�2 wks 1 (4)2 wks to �1 mo 4 (14)1 mo to �3 mos 7 (25)3 mos to �6 mos 10 (36)�6 mos 6 (21)
Disability Rating ScaleMean 4 (moderate)Range 1 (mild) to 8
(moderate to severe)Time postinjury
Median 3.2 yrsRange 4 mos to 34.2 yrs
June 2004 Effects of Methylphenidate After TBI 405
MP). A pharmacist who did not haveday-to-day involvement in the studyprepared the medications weekly andrandomly determined the order of ad-ministration so that the conditionswere balanced and concealed fromthe research staff, participants, andcaregivers. Randomization occurredin blocks of four participants (two toeach treatment order). The dose ofMP was 0.3 mg/kg/dose, rounded tothe nearest 2.5 mg, administeredtwice a day at approximately 8:30a.m. and 12 noon, Monday throughSaturday. The average dose of MP(given twice a day) was 24.4 mg(range, 15–40). Sunday was a wash-out day before the crossover to theopposite condition (Fig. 2).
Participants were screened forchanges in vital signs for the first 2wks of the study and for the occur-rence of adverse events throughoutthe study. The screening procedureand the effects of the study drug onvital signs and adverse events havebeen reported separately.38 Once aweek, each participant also guessedwhat drug he or she was receivingand provided a certainty rating for
this judgment to help ascertain thesuccess of the double-blindingprocedure.
Before receiving the medication,participants were interviewed abouttheir use of tobacco, caffeine, alcohol,prescription and over-the-counterdrugs, and recreational drugs. Be-cause of the length of the project, itwas not realistic to expect partici-pants to refrain from caffeine, to-bacco, or alcohol, so they were in-structed to maintain a consistentpattern of use of these substances.While in the study, participants filledout daily forms asking about theiruse to ensure regularity. They werealso asked about sleep, pain, illness,medications taken, and any stressfulevents they might have experiencedthat day. The intent was to determinethat the participants’ state was con-sistent enough from day to day sothat variations in performance weremost likely caused by the medicationand not some other event or state.
Research staff called participantsin the early morning, at home, toremind them to take their medica-tion. At arrival, they were asked
whether and when they had taken it.If a participant missed a dose, thetasks for that morning were skippedand made up at a later date under thecorrect medication condition. Middaydoses were self-administered by par-ticipants under the observation of re-search staff.
As depicted in Figure 2, partici-pants attended four 1-hr sessions inthe classroom each day, during whichtime observational data on on-taskbehavior were collected in both indi-vidual and group tasks. A 90-min pe-riod of unconstrained time plus alunch break occurred each day, dur-ing which no classroom data werecollected. Unconstrained time al-lowed the participants to work on ac-tivities of personal interest as a sup-plement to scheduled activities.Participants were taken from theclassroom for an hour each day to doa variety of individual attention as-sessment tasks. During each of the 6wks, the same tasks and assessmentswere performed, providing threesamples of performance on each mea-sure in the MP and placebo condi-tions and allowing a direct compari-
Figure 2: Weekly schedule for research classroom. CFQ/RSAB, Cognitive Failures Questionnaire/Rating Scale ofAttentional Behavior.
406 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
son of the participants’ performancein the two conditions. Data were col-lected using laboratory measures ofinformation processing, controlledsimulations of attentional demandsof everyday tasks, and ratings of at-tentiveness in everyday life. The orderof tasks was the same each week, andtasks were performed at the sametime each day for a given participant.Morning sessions began 90 mins afterthe morning dose, and afternoon ses-sions began 90 mins after the noondose. When participants were unableto attend on a given day, the individ-ual testing session for that day wasskipped and made up at the end of the6-wk period. The pharmacist suppliedreplacement doses of the appropriatemedication for that date. Missingclassroom data were not made up.
Attention Tasks
Several of the following tasks,marked with an asterisk (*), werepresented on an Apple PowerMac G3.All but one of these were pro-grammed in PsyScope. For thesetasks, participants were seated ap-proximately 30 inches from thescreen. Responses were recorded andtimed using a PsyScope button box.For those tasks with two asterisks(**), the duration of stimulus presen-tation was individualized before studyonset to minimize ceiling and flooreffects. Other tasks described belowused paper-and-pencil responding,rating scales, or observational data.
**Sustained Arousal and AttentionTask 50/50. The Sustained Arousaland Attention Task 50/5012 is a sim-ple go/no-go visual reaction time tasklasting approximately 20 mins. Par-ticipants were presented with 161stimuli with an average interstimulusinterval of 6 secs and instructed torespond as quickly and accurately aspossible to the targets and to ignorethe foils. The target rate for this taskwas 50%. The data derived from thistask were divided into five blocks. Theinitial block of performance defined
the vigilance level, and robust regres-sion slopes were calculated across allof the blocks to determine the vigi-lance decrements in reaction time,response bias, and accuracy.
**Sustained Arousal and AttentionTask 20/80. This modification of theabove-described task used a 20% tar-get rate, based on the hypothesis thatindividuals’ attentional lapses mightbe more frequent if fewer responseswere required. Scoring on this taskwas identical to the original sus-tained arousal and attention task.
*Speed/Accuracy Tradeoff Task. Thistask differed from the two describedabove in that the presented stimuliwere visually degraded so that it wasmore difficult to distinguish betweentargets and foils, but they remainedexposed for much longer (2000msecs), allowing participants to pri-oritize speed or accuracy of respond-ing. Specifically, we were interestedin learning whether drug-inducedimprovements in speed came at theexpense of accuracy or whether bothspeed and accuracy were positivelyaffected by treatment. This task hadthe same number of trials and inter-stimulus interval as the two listedabove and was scored in the samefashion.
Unfortunately, a technical prob-lem was identified after data collec-tion was complete. This task was suf-ficiently more difficult than thesustained attention tasks describedabove, so response times were muchslower for most subjects, but re-sponse times of �2000 msecs werenot recorded by the computer. Thus,some subjects seemed to have verylow response rates, and their re-sponse time distributions were trun-cated at 2000 msecs. Consequently,this task was not incorporated intothe overall analyses described below.However, those subjects with useabledata were selected to specifically as-sess whether any effects of the drug
on speed occurred at the expense ofaccuracy.
**Distraction Task. This task was avariation on one previously pub-lished.13 The same stimuli were pre-sented with a 50% target rate withone addition: brightly colored shapesmoved rapidly up and down eitherabove or below the stimuli. These dis-tracters occurred at various intervalsjust before or after stimulus presen-tation. There were seven intervalsranging from 200 msecs before thepresentation of the stimulus to 200msecs after stimulus presentation. Inaddition, a no-distracter conditionwas included, which allowed directcomparison of distracted and undis-tracted performance within the sametask. There were 192 trials in thistask, with an average interstimulusinterval of 6 secs, organized into 12blocks of 16 trials each (one targetand one foil at each distracter inter-val, in random order). Variables fromthis task were derived by subtractingthe scores in the no-distracter condi-tion from the participant’s meanscores achieved at five of the dis-tracter intervals at which a perfor-mance decrement was noted. Thisyielded distracter effect scores for ac-curacy, response bias, and reactiontime.
*Choice Reaction Time Task. Theparticipant was required to press anumber key on the numeric keypadof the computer keyboard in responseto presentation of a digit on thescreen. There were three blocks inthis experiment, in which there weretwo, four, or six digits displayed. Re-sponse keys not being used during agiven block were covered to makeclear to the participants that thenumber of choices varied. The num-ber stimulus remained on the screenuntil the participant responded. Aftereach response, there was a 1000-msecblank interval, followed by an 800-msec presentation of a central fixa-tion cross. This was followed by the
June 2004 Effects of Methylphenidate After TBI 407
presentation of the potential digit setin a random array for 1000 msecs.Finally, an auditory tone signaled thesimultaneous brightening of one ofthe digits to identify it as the target. Aregression slope of mean reactiontime for correct responses vs. the nat-ural logarithm of the number ofchoices available served as the indexof processing speed, based on evi-dence that the steepness of this slopeis an index of speed of mental pro-cessing (i.e., steeper � slower).39
*Dual Task. This program, written inC by Daniel Kimberg,15 was designedto assess the ability to divide atten-tion across two concurrent tasks. Theparticipant was first asked to respondas quickly as possible, by pressing thespacebar on the computer keyboard,to dots that appeared in pseudo-ran-dom locations on the computer mon-itor. The mean response time forthese trials defined the participant’sbaseline speed. The participant wasthen asked to listen to and repeatstrings of digits read to them by theresearch assistant while respondingto the dots as before. Digit stringlength was determined for each par-ticipant by initial digit span testing.The dual task decrement score is thedifference between mean responsetime in the single vs. dual taskversions.
*Sustained Attention to ResponseTask. In this task,40 225 digits (num-bers 1–9) are presented randomly,one at a time, in the center of thecomputer monitor, during a 4.5-mininterval. The participant must press aresponse key as quickly as possiblefor all but one of the digits (3) andmust withhold a response for thatdigit. This is also a go/no-go task, butit differs from those previously de-scribed in that targets are commonand foils are rare (1:9). Measures inthis task are the number of omissionerrors, the number of commission er-rors, and the reaction time of re-sponses before errors.
Test of Everyday Attention. Thistask,41 not administered by com-puter, includes eight subtests avail-able in three equivalent forms (givenas forms A, B, C, A, B, C on successivetesting weeks). The subtests are de-signed to assess selective attention,sustained attention, and attentionalswitching by simulating naturalistictasks, such as locating items on amap, looking for phone numbers in adirectory, determining which floor toget off an elevator, and checking win-ning lottery numbers.
Inattentive Behavior Task. In thistask,42 the participant was asked toperform three tasks at a worktable,including making a collage, sortingitems into their correct bowls, andworking on a complex jigsaw puzzle,while being videotaped. During thesession, a research assistant carriedout a series of naturalistic distrac-tions (e.g., making a phone call, play-ing a noisy computer game, droppinga book) on cue from taped messagesdelivered through a concealed ear-phone. The videotapes were coded ata later time on a coding workstation,which consisted of a Dell, Windows-compatible personal computer with aPentium II processor and a Panasonicvideo cassette recorder. Observa-tional Coding Software, Version 3.2,developed by Triangle Research Col-laborative, Inc. (Research TrianglePark, NC), was installed on the per-sonal computer. This software al-lowed the beginning, end, and dura-tion of each off-task event, externaldistraction, and period of the taskduring which the research assistantgave directions to be identified. Off-task events were defined with respectto direction of eye gaze, as describedpreviously.16,42 Rates of off-task be-havior were calculated separately foreach task as events per minute of tasktime. The average duration of off-taskevents in each session was also calcu-lated by dividing the total off-tasktime by the number of off-taskevents. The number of items used in
the collage and number of items cor-rectly sorted were also recorded.
Interrater reliability was assessedusing Cohen’s Kappa for the begin-nings and endings of off-task events,external distractions, and time-outevents (e.g., direction giving). Tworesearch assistants coded videotapedrecords of inattentive behavior. Ini-tially, all videotaped records weredouble coded, until adequate agree-ment, as measured by an averageKappa of �0.8, was achieved. Thisprocess was maintained for 68records, after which records sub-jected to interrater agreement assess-ment was reduced to 33% of allrecords. At this point, two researchassistants coded one randomly se-lected record for each drug conditionfor each participant, without knowl-edge of drug condition. In all, 111 ofall videotaped records of inattentivebehavior (54%) were double coded.Whenever the agreement betweencoders on a given record fell belowthe standard (Kappa of 0.8) on any ofthe six variables included in the anal-ysis, the coders met to reconcile thedifferences. The reconciled data wereused for the final analysis of drugeffects. To minimize the potential forbias (because reconciliation typicallyincreases, rather than decreases, thenumber of events noted), whenever arecord was subjected to reconcilia-tion, another session in the oppositedrug condition was also reconciled,regardless of the level of agreementbetween the coders on that secondrecord. Mean Kappas for videotapedrecords of inattentive behavior dur-ing the posttraining phase were: 0.83,0.82, 1.0, 98, 0.91, and 0.89 for off-task begin, off-task end, distracter be-gin, distracter end, time-out begin,and time-out end, respectively.
Classroom Attentiveness. In additionto the laboratory testing, participantswere observed as they participated inclassroom activities. Data collectionoccurred during four 1-hr sessionseach day: a group activity and an in-
408 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
dividual activity in both the morningand the afternoon. During individualsessions, the participant was asked tocarry out independent work (e.g.,reading a book, working on cross-word puzzles, or individual craftprojects) in the same room withother participants. During group ses-sions, activities such as playing boardgames, discussing current events,and participating in lectures, whichrequired the interaction and involve-ment of all participants, were con-ducted. For both types of session, aset of rules that defined the appropri-ate targets of attention was laid outby the classroom therapist before theactivity began. For example, in agroup activity with structured turn-taking, responding during someoneelse’s turn or failing to respond dur-ing one’s own turn were both codedas off-task behavior. During each ses-sion, a research assistant sat in theclassroom to observe and code off-task behavior. The research assistantwore a vibrating watch that provideda silent cue once per minute. A ran-dom sequence of participant identifi-cation codes was preprinted on a datacollection sheet. Each minute, whenthe watch cued, the research assis-tant looked at the appropriate partic-ipant and coded whether, at that mo-ment, he or she was on task or offtask according to operationalizedwritten behavioral criteria. Data werecollected on off-task behavior as mea-sured by eye gaze, speaking, and be-ing out of seat. However, only theeye-gaze data are reported here be-cause scores in the other two do-mains were frequently at ceiling. On-task eye gaze was defined based onwhether the research participant waslooking at the appropriate task mate-rials (for individual tasks) or the task-relevant speaker or materials (forgroup tasks).
Two research assistants indepen-dently observed 27 classroom ses-sions (approximately 2% of all datacollection classroom sessions) usingthe same vibrating watch cue-driven
time sampling and the same randomorder of participant observation. In-terrater agreement assessment, usingboth Cohen’s Kappa and percentageof agreement, was conducted on thepresence or absence of off-task eventsas indicated by direction of eye gaze.Agreement between pairs of raterscoding attentiveness in classroom ac-tivities was high. Perfect agreementwas achieved in 23 of 27 sessions.Considering percentage of agreementacross all double-coded sessions, av-erage agreement was 99%. Kappaswere calculated for those sessions inwhich both on-task and off-taskevents were observed (n � 15) andranged from 0.65 to 1.0, with a meanof 0.95 and median of 1.0. There were12 sessions during which both codersagreed that no off-task events oc-curred, and therefore, Kappa couldnot be calculated.
Attention Ratings. Two different rat-ings of the participants’ attentivenessin everyday life were gathered on aweekly basis. Different versions of theCognitive Failures Questionnaire43
were completed weekly by the partic-ipants themselves, their chosen care-giver, and the research staff (by con-sensus). This measure assesses thefrequency of everyday lapses in atten-tion using a 5-point Likert-type scale,ranging from “very often” to “never.”The participants completed a 25-itemversion, which includes more subjec-tive questions about perceived atten-tional difficulties, whereas the care-givers and research staff filled out aneight-item version. The Rating Scaleof Attentional Behavior11 is a 14-item, 5-point Likert-type scale de-signed to assess observable attention-related behaviors, such as rest-lessness and distractibility. This wascompleted by the participant’s care-giver and the research staff.
Data Analysis
Initial Data Reduction. Performanceon most of the computerized infor-
mation processing tasks was assessedin several dimensions: D' (a signaldetection measure of accuracy, orability to discriminate the target vs.the foil), yes rate (a measure of re-sponse bias, or tendency to press theresponse key, irrespective of accu-racy), and median response time (ameasure of speed of processing andresponding, less sensitive to outliersthan the mean, and calculated onlyon correct key presses). For the tasksassessing sustained attention, theabove three scores were calculated onthe first block (first 20% of trials) todetermine initial performance, andthe slope of a robust regressionacross the scores of all five blocks wasused to represent the ability to sus-tain performance over the duration ofthe task. The relevant scores fromeach task were averaged across thethree (or in a few cases, due to miss-ing data, two) sessions from eachdrug condition, yielding a pair ofscores representing the drug condi-tions for each participant.
Assessment of the Effects of MP. Asdiscussed above, it was thought im-portant to assess the effect of MP onnumerous aspects of attentionalfunction to avoid missing clinicallyimportant effects on unmeasured at-tentional dimensions, to evaluate thedrug’s effect at impairment and activ-ity levels of analysis, and to be able tocompare the drug’s profile of actionwith those of other drugs. This pro-duced a total of 54 separate scores foranalysis (Table 2 contains descrip-tions of the scores used in the finalanalysis). These variables assessedinitial performance in a variety oftasks, as assessed by accuracy, speed,and overall response rate; deteriora-tion in performance over time, basedon these same three performance in-dices; impulsive responding; distrac-tion by competing stimuli; the abilityto divide attention; attentiveness asjudged by ratings scales; and atten-tiveness as judged by direct observa-tion of off-task behavior.
June 2004 Effects of Methylphenidate After TBI 409
TAB
LE2
Sign
ifica
nce
test
ing
ofm
ethy
lphe
nida
teef
fect
son
perf
orm
ance
fact
ors
and
indi
vidu
alva
riab
les
Task
Scor
e
PVa
lue
Effe
cta
Size
Pilo
tSa
mpl
eR
eplic
atio
nSa
mpl
e
Com
posi
teFa
ctor
sIn
itia
lac
cura
cyPe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(50%
targ
ets)
D',
first
bloc
k0.
070.
29Pe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(20%
targ
ets)
D',
first
bloc
kAc
cura
cyde
clin
ePe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(50%
targ
ets)
Rob
ust
regr
essi
onsl
ope,
D'v
s.ta
skbl
ock
1.00
—Pe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(20%
targ
ets)
Rob
ust
regr
essi
onsl
ope,
D'v
s.ta
skbl
ock
Init
ial
spee
dPe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(50%
targ
ets)
Med
ian
RT,
first
32tr
ials
0.02
�0.
001
�0.
06Pe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(20%
targ
ets)
Med
ian
RT,
first
32tr
ials
0.07
Visu
algo
/no-
gota
sk(5
0%ta
rget
s)w
ith
salie
ntm
ovin
gdi
stra
cter
sM
edia
nR
T,no
ndis
trac
tion
tria
ls0.
48C
hoic
eR
TR
obus
tre
gres
sion
slop
e:m
ean
RT
vs.
log
(no.
ofch
oice
s)0.
32D
ual
task
Mea
nR
T,ba
selin
eco
ndit
ion
0.12
Test
ofE
very
day
Atte
ntio
nm
apse
arch
No.
ofsy
mbo
lsci
rcle
d(2
min
s)0.
18Te
stof
Eve
ryda
yAt
tent
ion
tele
phon
ese
arch
Tim
epe
rco
rrec
tly
circ
led
targ
et0.
40In
atte
ntiv
ebe
havi
orta
sk:
wor
kpr
oduc
tivi
tyN
o.of
item
sso
rted
0.48
Spee
dde
clin
ePe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(50%
targ
ets)
Rob
ust
regr
essi
onsl
ope,
med
ian
RT
vs.
task
bloc
k0.
35—
Perc
eptu
ally
sim
ple
visu
algo
/no-
go(2
0%ta
rget
s)R
obus
tre
gres
sion
slop
e,m
edia
nR
Tvs
.ta
skbl
ock
Init
ial
resp
onse
bias
Perc
eptu
ally
sim
ple
visu
algo
/no-
go(5
0%ta
rget
s)R
espo
nse
rate
,fir
st32
tria
ls0.
040.
88Pe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(20%
targ
ets)
Res
pons
era
te,
first
32tr
ials
Visu
algo
/no-
gota
sk(5
0%ta
rget
s)w
ith
salie
ntm
ovin
gdi
stra
cter
sR
espo
nse
rate
,no
ndis
trac
tion
tria
lsD
eclin
ein
resp
ondi
ngPe
rcep
tual
lysi
mpl
evi
sual
go/n
o-go
(50%
targ
ets)
Rob
ust
regr
essi
onsl
ope,
resp
onse
rate
vs.
task
bloc
k0.
85—
Perc
eptu
ally
sim
ple
visu
algo
/no-
go(2
0%ta
rget
s)R
obus
tre
gres
sion
slop
e,re
spon
sera
tevs
.ta
skbl
ock
Div
ided
atte
ntio
nD
ual
task
RT
decr
emen
t(m
ean
RT
wit
hdi
git
span
–mea
nR
Tdu
ring
base
line)
0.88
—
Test
ofE
very
day
Atte
ntio
n,el
evat
orco
unti
ngw
ith
dist
ract
ion
No.
corr
ect
Test
ofE
very
day
Atte
ntio
n,te
leph
one
sear
chw
hile
coun
ting
Tim
e/ta
rget
Test
ofE
very
day
Atte
ntio
n,vi
sual
elev
ator
Tim
e/sw
itch
Test
ofE
very
day
Atte
ntio
n,el
evat
orw
ith
reve
rsal
No.
corr
ect
Sust
aine
dAt
tent
ion
toR
espo
nse
Task
Err
ors
ofco
mm
issi
onN
o.ke
ypr
esse
sto
“3”
0.91
—E
rror
sof
omis
sion
No.
ofm
isse
sto
non-
“3”
No.
key
pres
ses
wit
hR
TIm
puls
ive
erro
rsR
T�
150
mse
cs
410 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
TAB
LE2
Con
tinu
ed
Task
Scor
e
PVa
lue
Effe
cta
Size
Pilo
tSa
mpl
eR
eplic
atio
nSa
mpl
e
Fam
ilyra
ting
sC
ogni
tive
Failu
res
Que
stio
nnai
reTo
tal
scor
e0.
040.
010.
44R
atin
gSc
ale
ofAt
tent
iona
lB
ehav
ior
Tota
lsc
ore
0.50
Staf
fra
ting
sC
ogni
tive
Failu
res
Que
stio
nnai
reTo
tal
scor
e0.
85—
Rat
ing
Scal
eof
Atte
ntio
nal
Beh
avio
rTo
tal
scor
eIn
atte
ntio
n—in
divi
dual
Mor
ning
clas
sroo
m—
indi
vidu
alac
tivi
ties
%O
n-ta
skey
ega
zeco
des
0.06
0.01
0.28
Afte
rnoo
ncl
assr
oom
—in
divi
dual
acti
viti
es%
On-
task
eye
gaze
code
s0.
62In
atte
ntiv
ebe
havi
or—
task
1Av
erag
edu
rati
onof
off-
task
epis
odes
0.22
Inat
tent
ive
beha
vior
—ta
sk2
Aver
age
dura
tion
ofof
f-ta
skep
isod
es0.
15In
atte
ntiv
ebe
havi
or—
task
3Av
erag
edu
rati
onof
off-
task
epis
odes
0.47
Inat
tent
ion—
indi
vidu
alra
teIn
atte
ntiv
ebe
havi
or—
task
1R
ate
ofof
f-ta
skep
isod
es0.
26—
Inat
tent
ive
beha
vior
—ta
sk2
Rat
eof
off-
task
epis
odes
Inat
tent
ive
beha
vior
—ta
sk3
Rat
eof
off-
task
epis
odes
Inat
tent
ion—
grou
pM
orni
ngcl
assr
oom
—gr
oup
acti
viti
es%
On-
task
eye
gaze
code
s0.
92—
Afte
rnoo
ncl
assr
oom
—gr
oup
acti
viti
es%
On-
task
eye
gaze
code
sIn
divi
dual
scor
esVi
sual
go/n
o-go
task
(50%
targ
ets)
wit
hsa
lient
mov
ing
dist
ract
ers
D�
nond
istr
acti
ontr
ials
0.70
—Vi
sual
go/n
o-go
task
(50%
targ
ets)
wit
hsa
lient
mov
ing
dist
ract
ers
D'w
ith
dist
ract
ion
�D
'wit
hout
dist
ract
ion
0.62
—Vi
sual
go/n
o-go
task
(50%
targ
ets)
wit
hsa
lient
mov
ing
dist
ract
ers
Res
pons
era
tew
ith
dist
ract
ion
�re
spon
sera
tew
itho
utdi
stra
ctio
n0.
92—
Visu
algo
/no-
gota
sk(5
0%ta
rget
s)w
ith
salie
ntm
ovin
gdi
stra
cter
sM
edia
nR
Tw
ith
dist
ract
ion
�m
edia
nR
Tw
itho
utdi
stra
ctio
n0.
49—
Dua
lta
skM
easu
red
digi
tsp
an0.
190.
70D
ual
task
Dig
itst
ring
sad
min
iste
red
0.56
—D
ual
task
Dig
itst
ring
sco
rrec
t,%
0.63
—C
ogni
tive
Failu
res
Que
stio
nnai
re—
self
rati
ngs
Tota
lsc
ore
0.18
0.66
Sust
aine
dat
tent
ion
tore
spon
seta
skM
ean
RT
befo
reer
ror
ofco
mm
issi
on0.
110.
030.
20Te
stof
Eve
ryda
yAt
tent
ion—
visu
alel
evat
orac
cura
cyN
o.co
rrec
t0.
120.
33Te
stof
Eve
ryda
yAt
tent
ion—
lott
ery
No.
corr
ect
0.56
—In
atte
ntiv
ebe
havi
orC
olla
gepa
per
used
0.65
—
RT,
resp
onse
tim
e.aE
ffect
size
asm
easu
red
byC
ohen
’sD
.
June 2004 Effects of Methylphenidate After TBI 411
As mentioned previously, to re-duce the risk of type I error, a two-stage analytic strategy was employed.Data gathered from the first ten par-ticipants were used only for pilot pur-poses, not in the final analysis, whichserved as an independent replicationon 24 additional participants. Datafrom the pilot sample were used intwo ways. First, the three sessions ofplacebo data from these ten partici-pants were used to develop methodsfor collapsing scores from multipleempirically or conceptually relatedtasks into fewer composite scores.Second, data from the three placeboand three MP scores for these tenparticipants were analyzed for possi-ble drug effects, using a relaxed P-value cutoff of 0.20. Only those vari-ables that seemed promising, basedon meeting this cutoff, were sub-jected to confirmatory analysis, usingdata from the next 24 participants(the replication sample). Thus, to bedefined as responsive to MP, a partic-ular variable had to show a drug ef-fect in the same direction in the pilotsample (with a P value of �0.20) andin the replication sample (with a Pvalue of �0.05). Each of these analy-ses is described in greater detailbelow.
Development of Composite Scores.The small sample size precluded for-mal factor analysis as a method toarrive at composite scores. Therefore,a combination of a priori reasoningand Spearman’s correlation was used.Scores from different tasks weregrouped together in a preliminaryfashion, based on similarities in taskdemands and scoring systems. Forexample, a number of different tasksemphasized speeded performance,suggesting that processing speedmight be a single factor to whichscores from multiple tasks could con-tribute. Spearman’s correlation ma-trices were then constructed amongthe potential members of a given fac-tor (based on the average of threeplacebo scores for each of the ten
pilot participants). The two scoresshowing the highest pair-wise corre-lation were then assigned to the fac-tor. Another score that had high cor-relations with each of the twoprevious scores was then identifiedand added to the factor if its averagecorrelation with each of the previousscores was at least 0.50. This processcontinued until no other score satis-fied this criterion. Individual scoresthat failed to “join” a factor were re-tained for individual analysis.
Once scores were assembled intofactors, composite factor scores weredeveloped. Again, a pair of scores foreach variable was computed for eachparticipant by averaging the threesessions for each drug condition.Then, the MP and placebo scoreswere ranked together for each vari-able in the factor. Because there wereoccasions in which data were missingfor a particular task for an individualparticipant, the raw ranks were di-vided by the maximal possible rankfor each variable (i.e., in most in-stances, the raw rank was divided by20 [2 drugs � 10 participants] for thepilot analysis, and 48 [2 drugs � 24participants] for the replication anal-ysis) so that the modified ranksranged from 0 to 1.0 in all instances.The composite score was then com-puted by averaging all the placeboranks for each factor variable for eachparticipant and averaging all the MPranks for each factor variable for eachparticipant, resulting in a pair ofscores (MP, placebo) for each partic-ipant for a factor. A total of 13 suchfactors were created and assessed fordrug effects.
Because average ranks were usedin the final analyses of drug effects,the raw scoring system used in anygiven task had no effect, and this dataanalytic approach implicitly weightedeach contributing score equally inthe determination of the overall rank.Participants who were missing scoresfor a given task were always missingscores for both drug conditions. Thecorrection mentioned above, dividing
by the ranks by the number of par-ticipants, ensured that tasks withfewer participants’ data would nothave excessive weighting (by assum-ing higher ranks simply because offewer possible ranks).
Preliminary Assessment of Drug Ef-fects from the Pilot Sample. Wil-coxon signed rank test was performedseparately on the pairs of compositefactor scores and on the remainingindividual scores from the initial tenpilot participants. These analyseswere done in their exact form (asopposed to their asymptotic approxi-mations) because of the small samplesize. Those factor and individualscores in which the calculated Pvalue was �0.20 were used to derivea priori hypotheses for the larger rep-lication sample.
Final Analysis of Drug Effects Usingthe Replication Sample. Compositefactor scores were computed as de-scribed above on the remaining 24participants. Drug effects were thenassessed as above, using Wilcoxonsigned rank test, limited to those fac-tors and individual scores that metthe P-value cutoff from the pilot sam-ple. Asymptotic approximations wereused for the replication analysis be-cause of the larger sample size. Ininstances in which the results werestatistically significant at an alphalevel of 0.05, the data from all 34participants were combined to calcu-late descriptive statistics and effectsizes to provide the most precise es-timates of the magnitude of the drugeffect. This combining was done onlyafter the effect in the pilot samplewas confirmed independently in thereplication sample. Note that theseeffect sizes were computed paramet-rically (Cohen’s D for within-partici-pant treatment effects � mean ofindividual differences between treat-ment conditions/standard deviationof individual differences betweentreatment conditions),44 despite ourreliance on nonparametric inferential
412 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
statistical testing. Thus, the effectsizes may not correspond precisely tothe P values, despite identical samplesizes, because data outliers have dif-ferent effects on the two calculations.
Effect of Missing Data. Missing datafrom the individual laboratory ses-sions were always because of im-pairments that prevented a partici-pant from performing a particulartask. For example, one participantwas unable to learn to perform go/no-go tasks, despite performingmany other study tasks, includingthe choice reaction time task, ade-quately. These impairments led tothe participant’s omission fromboth drug conditions. Missing datafrom classroom observation oc-curred more frequently becausemost participants performed theirindividual laboratory sessions dur-ing one of the four daily classroomdata collection sessions. Again,these participants’ data were miss-ing from both drug conditions for agiven observation time period.Some participants missed addi-tional scattered days of classroomobservation because of conflictingappointments, illness, or other con-flicts, but all participants had datafrom each study week. These ab-sences seemed to have been randomin nature. Thus, although missingdata reduced the effective samplesize and, hence, statistical power,for certain variables, it should nothave biased the results. Wheneverthe sample for analysis was incom-plete, we assessed qualitativelywhether the obtained P value wasclose to the designated thresholdand, thus, whether we might havecommitted a type II error for thatvariable. This was not a significantissue.
RESULTS
Assessment of the Effects of MP. Theprocedure described above resultedin the creation of 13 factor scores and
left 13 individual scores that were notpart of any of the calculated factors.One of the individual scores, the ele-vator counting task from the Test ofEveryday Attention, was deleted be-cause of ceiling effects in both drugconditions. The scores that were partof each factor, the results of the pilotdata analysis, and where appropriate,the results of the replication analysisand calculated effect sizes are shownin Table 2. Descriptive statistics forthose variables that showed signifi-cant drug effects are shown in Table3.
As shown in Table 2, a numberof factors showed no apparent drugeffect in the pilot analysis and werenot evaluated further. In addition,two factors that seemed promisingfrom the pilot analysis failed to rep-licate. These included the factor re-flecting initial accuracy on two ofthe computerized tasks and the fac-tor reflecting initial response rateson three of the computerized tasks.Three factors did, however, showstatistically significant drug effectsin both the pilot analysis and thereplication.
An initial speed factor, composedof the speed scores from eight differ-ent tasks, showed a statistically sig-nificant positive effect of MP in boththe pilot and replication analyses, andthis was the most robust drug effectdetected. The variables contributingto this factor included not only com-puterized reaction time tasks, butalso speeded paper-and-pencil tasks, ameasure of work productivity, and ameasure of mental processing speed,suggesting that the effects on speedare seen across a wide range of tasksand range from impairment to activ-ity levels. The effect sizes rangedfrom negligible to medium, depend-ing on the task. Only one of the eighttasks showed an effect size in thenegative direction (slower perfor-mance while receiving MP), and thiseffect size was very close to zero.
Caregiver ratings were also sig-nificantly improved by MP, despite
the fact that caregivers’ only oppor-tunity to observe participants duringpeak drug effects occurred on Satur-days. Whereas the Rating Scale of At-tentional Behavior items emphasizespeed, the items on the CognitiveFailures Questionnaire include a va-riety of types of attentional lapses,and the drug effect sizes were quitecomparable for both measures. Of in-terest, differences in the ratings onthese same measures by the projectstaff did not achieve statisticalsignificance.
The third factor that was posi-tively affected by MP was on-task be-havior, in both the classroom envi-ronment’s individual work sessions,and the inattentive behavior task’svideotape coding. Interestingly, thisfactor combines the frequency oftime-sampled classroom ratings thatwere coded as off task with the aver-age duration of individual off-task ep-isodes recorded on videotape. The ef-fect sizes again were in the small tomedium range. Note that MP seemedto have a larger effect on off-task be-havior in the afternoon than in themorning. This result did not seem tobe caused by ceiling effects in themorning on placebo because the af-ternoon effect was larger even in asubset of patients whose morningand afternoon off-task behavior onplacebo was matched (data notshown). The frequency of off-task ep-isodes from the videotaped recordscontributed to a separate factor thatwas not significantly affected by thestudy drug. Off-task behavior in theclassroom during group activities,similarly, did not show a significantdrug effect.
Of the 12 individual scores thatdid not contribute to the above fac-tors, four met the screening cutoff forthe pilot sample. However, only thereaction time before errors of com-mission from the Sustained Attentionto Response Task showed a signifi-cant drug effect in the replicationsample. On the one hand, this is con-sistent with the general effect of MP
June 2004 Effects of Methylphenidate After TBI 413
on speed of performance. However, ingeneral, accelerating response timesduring the Sustained Attention to Re-
sponse Task are interpreted as indi-cating an automatic, or inattentive,mode of responding.
Does MP Improve Speed at the Ex-pense of Quality? Because of thetechnical problem with the speed/ac-
TABLE 3Descriptive statistics for performance variables showing significant drug effects
aSample sizes vary from the full sample of 34 because of individual participants’ inability to perform certain tasks and thescheduling of laboratory tasks for some participants during classroom time.
414 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
curacy tradeoff task, described above,a subset of ten participants was iden-tified whose raw response time distri-butions had no more than 15% oftrials slower than 1750 msecs in ei-ther drug condition. This criterionwas based on preliminary visual in-spection of response time distribu-tions that seemed to be complete(i.e., not abruptly truncated at 2000msecs). Thus, these tended to be thefaster participants overall. For theseindividuals, the drug-effect sizes onspeed and accuracy were both small(0.26 and 0.21, respectively) but wereboth in the direction of improvementwith MP. Considering the flawed dataon the whole sample, the effect onspeed was small (0.21) and on accu-
racy was medium (0.52), but again,both effects are in the direction ofimprovement with MP. Thus, there isno evidence from this task that thefaster processing associated with MPis associated with lowered accuracyor quality. Similarly, in the SustainedAttention to Response Task, individ-uals tend to adopt an automatic orinattentive mode of processing. Asthey do so, their response times ontargets tend to become faster andfaster until they ultimately make anerror of commission to a nontarget.40
Control participants tend to slowdown on their next trial, as they rec-ognize their error. Our participantswith TBI did have faster responsetimes before their errors of commis-
sion with MP than placebo, but theydid not make more errors of commis-sion, suggesting that this more rapidresponding was not evidence of less-ened attentional monitoring.
Success of Blinding. Participants’ av-erage ratings of their drug conditionassessments during placebo and MPweeks were compared via Wilcoxonsigned rank test. The median ratingsdid differ between drug conditions(MP: median � 2.5, range � 1–4;placebo: median � 3.0, range �1–4.67; P � 0.03, where 1 � cer-tainty they were taking the activestudy drug and 5 � certainty theywere taking the placebo). Althoughthe difference between the mean MP
Inattentive behavior–task 1, average duration ofoff-task episodes in secs
34 0.42 0.47
2.72 3.691.49 1.83
14.01 26.63
Inattentive behavior–task 2, average duration ofoff-task episodes in secs
32 0.26 0.41
1.25 1.471.16 1.193.73 8.59
Inattentive behavior–task 3, average duration ofoff-task episodes in secs
30 0.25 0.72
1.52 3.481.06 1.904.74 17.14
Individualscore
Sustained Attention to Response Task, responsetime before commission error in msecs
34 259 259
400 410380 390680 713
June 2004 Effects of Methylphenidate After TBI 415
and placebo ratings is statisticallysignificant, the actual differences arequite small, and in both conditions,the average ratings were in the direc-tion of thinking that they were takingthe active study drug. Inspection ofindividual data indicated that therewas only one participant who wasconsistently accurate in his drugself-assessments.
DISCUSSION
The results of this study arelargely consistent with previous re-search from our laboratory31 andfrom research in other popula-tions,25,45–47 demonstrating that MPhas reliable positive effects on perfor-mance speed across a range of tasksin a postacute adult TBI population.This effect is probably exerted pri-marily on cognitive speed, as judgedby the improvement on the choicereaction time task, for which the mo-tor response is identical across blockswith different numbers of choices.The magnitude of this effect variedfrom task to task, with small to me-dium effect sizes. In a naturalisticwork task (i.e., object sorting), ap-proximately 6% more work was ac-complished with MP in a 15-min in-terval. Although there were technicalproblems with one of the tasks de-signed to assess speed/accuracytradeoffs, it did not seem, from thistask or from the Sustained Attentionto Response Task, that the improve-ment in speed occurred at the ex-pense of accuracy. Given that slowedprocessing is one of the most widelyreported and disabling impairmentsresulting from TBI, a positive effect ofMP in this domain may have consid-erable clinical significance. The clin-ical relevance of this aspect of MP isfurther supported by the fact thatperformance was improved on a widerange of tasks that shared demandson cognitive speed, from computer-ized laboratory tasks to simulatedwork activities. Improved speed ofprocessing with MP also may have
contributed to the higher attentive-ness ratings of caregivers.
In children with ADHD, MP isreported to improve on-task behav-ior. No such effect was identified inour previous TBI pilot study,31 andthis study provided somewhat mixedresults. To interpret these effects, onemust first consider the breakdown ofthe factors that pertain to attentive-ness in the classroom and inattentivebehavior task. As mentioned previ-ously, variables that pertain to theduration of off-task episodes in thevideotaped records did not correlatewith the frequency of such events inthe same records, but they did corre-late with the proportion of off-taskobservations in the classroom. Thevideotape coding attempted to cap-ture each off-task event that oc-curred, regardless of its duration,whereas the time-sampling methodused in the classroom merely pro-vided “spot checks” of whether par-ticipants were on task or off task atrandom moments. Thus, it is possiblethat longer off-task events occurringin the classroom were more likely tobe captured by this sampling method.If so, this factor might more accu-rately be thought of as assessing theduration of these off-task episodesrather than their frequency. Underthis account, it is quite possible thatMP’s effects are primarily on howrapidly participants return to task,once off, rather than on the numberof such events, per se. Thus, the factthat no drug effect was seen on off-task event frequency on the video-taped records would not be surpris-ing. Although MP did seem todecrease the counts (perhaps by de-creasing their duration) of off-taskbehavior in individual classroom ses-sions, no such effect was seen ingroup sessions. It is possible that theduration of off-task behaviors duringindividual work tasks is determinedprimarily by the participant’s internalgoal state, whereas those same behav-iors during group sessions may bemore related to the nature and sa-
lience of distracting behaviors pro-duced by other group members. If so,it would not be surprising for MP tohave more robust effects on theformer than the latter. It is also ofinterest that MP affected on-taskclassroom behaviors more strongly inthe afternoon than in the morningsessions. In children with ADHD, MPseems to improve cognitive speedparticularly on effortful tasks.25 Pos-sibly, maintaining one’s attentionduring a mild diurnal “slump” is par-ticularly enhanced by MP because itis more effortful than paying atten-tion to the same activity in themorning.
Of particular importance, MPproduced substantial improvementsin caregiver ratings of attentivenesson two different measures, an aspectof the drug not assessed in our pre-vious research. This is somewhat sur-prising because one would expect theeffects of MP to be waning by thetime participants returned home onweekdays, and caregivers only spent 1day/wk (Saturdays) with the partici-pants when they were at peak druglevels. It is difficult to know preciselywhat changes the caregivers observedto compose these ratings. The resultsof the laboratory studies, however,may suggest that improved process-ing speed contributes to improve-ments in a variety of domains. Alter-natively, drug effects not measured inthis study, such as improved mood ordecreased irritability, may have con-tributed to caregivers’ perceptions ofpositive drug benefits, although theassessment questions did not pertainto these dimensions. Alternatively, ifthe study was not successfullyblinded, and participants and caregiv-ers communicated about the per-ceived drug condition, this couldhave contributed to bias in the care-giver ratings. However, most partici-pants were close to chance in guess-ing the correct drug condition,making this explanation less likely.The lack of drug effects on self-rat-ings is likely attributable to some
416 Whyte et al. Am. J. Phys. Med. Rehabil. ● Vol. 83, No. 6
combination of impairment in partic-ipants’ memory for their perfor-mance over days and weeks and totheir reduced self-awareness. Regard-less of its source, however, it doessuggest that participants remainedreasonably well blinded to their drugcondition.
The fact that staff ratings did notshow effects of MP but that caregiverratings did may relate to the moreintimate effect on caregivers of theparticipants’ usual behaviors and,hence, their greater sensitivity to be-havioral changes. Differences in theperception of deficits and their effectby professional staff and caregiversare often noted in the literature. Thecurrent data suggest that caregiverratings may be particularly importantin assessing real-world treatmenteffectiveness.
Our previous study31 also foundthat the decline in responding seenduring a sustained attention task wasblunted by MP, an effect that was notreplicated in this study. This differ-ence may simply have occurred bychance, given the number of perfor-mance measures assessed in the pre-vious study, or may be attributable tobroader impairment across a range ofaspects of attention at a more acutestage of recovery. The previous studyalso found a reduction of the effect ofexternal distracters on measures ofaccuracy. However, it seemed thatthat result relied on faster processingof the target, before the onset of thedistracter (i.e., another manifestationof faster processing with MP). In thecurrent study, modifications in dis-tracter timing may have eliminatedthat effect.
Although MP’s effects were sta-tistically and clinically significant ina number of performance domains,the effect sizes ranged from small tomedium, with absolute improve-ments ranging from 5% to 25%. Thisis in contrast to a study of adults withADHD by Spencer et al.26 in whichrating scale improvements rangedfrom 17% to 55%. There are a num-
ber of differences between studiesthat might account for the differ-ences in magnitude of treatment ef-fects. It is certainly possible thatadults with ADHD respond more dra-matically to MP than do those withTBI, particularly because improve-ments in hyperactivity (55%) and im-pulsivity (54%), symptom clustersthat are not prominent in TBI, weregreater in the ADHD study than wereimprovements in inattentiveness(17%). It is also possible that the out-come measures used in the Spenceret al.26 study are more sensitive todrug effects than those used in thisresearch. However, because of thedifferent presentation of ADHD vs.TBI-related inattentiveness, thescales used by Spencer et al.26 wouldnot be appropriate in this population.Finally, the difference may be attrib-utable to differences in dosage. Spen-cer et al. used 1.0 mg/kg/day, dividedinto three doses, whereas we used 0.6mg/kg/day (0.3 mg/kg/dose), dividedinto two doses. Although the dailydose administered in the Spencer etal.26 study was dramatically largerthan ours, individual doses were sim-ilar (0.3 mg/kg/dose vs. 0.33 mg/kg/dose). Given the short duration ofaction of MP, one would expect thesedifferent dosing regimens to affectduration of the effect more than mag-nitude, particularly for those short-duration tasks that were assessednear the time of peak drug levels.Nevertheless, it is possible that largereffects would have been seen in therating scale data with three-times-per-day dosing. Given the absence ofserious adverse events, it would be ofinterest to assess whether larger ef-fect sizes could be obtained in pa-tients with TBI by escalating thedoses of MP used.
A number of limitations in thisstudy must be kept in mind in inter-preting its findings. The study samplemight be most accurately termed an“inconvenience sample” in the sensethat a very large number of potentialparticipants had to be screened to iden-
tify the 34 participants who met theinclusion and exclusion criteria andwho were willing to commit 6 wks oftheir time. Thus, individuals who hadreturned to employment or were tooimpaired to travel, or those with pre-morbid neurologic deficits or currentpsychoactive drug treatment, were un-derrepresented in the sample. More-over, because of the time elapsed be-tween injury and enrollment for manyparticipants, the details of their initialneuropathology were often unavail-able, making it difficult to assess vari-ations in hypoxic/ischemic injury andother factors that might have affectedtreatment response. On the otherhand, in routine clinical practice, oneis often called on to treat patients inthe chronic stage whose initial histo-ries are similarly unobtainable, requir-ing the physician to tailor treatment tothe current functional status ratherthan the original injury. Although gen-eralization to a broader population ofindividuals with TBI is limited by thisselection and data collection process,we believe that the types of drug effectsseen here can be plausibly expected inother individuals with TBI. In addition,the goal of this study was less to makedefinitive recommendations regardingclinical use of MP than to help under-stand the mechanisms by which thisdrug might modify cognitive functionafter TBI. It seems likely that the fun-damental effects of MP on attentionalprocesses are likely to be fairly general.Moreover, by identifying a smaller sub-set of domains in which MP effects arelikely to be seen, this study should fa-cilitate the conduct of a more stream-lined clinical trial in a broader sample,with data collection limited to a fewvariables likely to be responsive. Alarger clinical trial of this type will ad-dress more definitively the issue ofgenerality of treatment response andwhether individual patient characteris-tics substantially modify this response.
Another limitation is the use of asingle weight-adjusted MP dose forall participants rather than conduct-ing individualized dosage titration to
June 2004 Effects of Methylphenidate After TBI 417
the optimal dose for each participantor testing each participant fully onseveral different doses. This decisionwas made largely for practical rea-sons. In our experience, individualdosage titration is very difficult be-cause of the substantial variability inperformance at any particular doseand the presence of confoundingpractice effects, not to mention theuncertainty regarding the measureagainst which to optimize the dose.Testing each participant at two orthree different doses would havelengthened the testing protocol to aninfeasible degree. Thus, our goal herewas to establish a restricted set ofvariables that can be used to assessMP response. These variables canthen be used more efficiently to studythe response to different drug doses.This approach cannot, however, com-pletely rule out the possibility thatother behavioral domains thatshowed no treatment effect at thisdose might show such an effect at adifferent dose.
Finally, the complex statisticalmethod used may have resulted ineither type I or type II error. Cer-tainly, the fact that a given score orfactor does not meet a probabilitylevel cutoff of 0.20 in a sample of tenparticipants does not mean that itcould not show a drug effect in alarger sample. Thus, we may havesacrificed the opportunity to detectsome treatment effects (particularlysmall ones) by failing to further as-sess those variables that did not meetthe pilot screening cutoff. In addi-tion, that different factors containeddifferent numbers of raw scores mayhave caused variations in sensitivityto detect drug effects. To the extentthat the data are variable or “noisy,”collapsing more scores into a singlefactor tends to improve the signal-to-noise ratio. Thus, one might expectthis method to be slightly less sensi-tive in detecting drug effects on thosefactors that have fewer score “mem-bers.” Whereas it is true that thespeed factor had the largest number
of contributing variables and themost robust treatment effect, thecaregiver rating factor had only twomembers, yet it proved highly signif-icant. With respect to type I error,this two-stage method of analysismakes is more difficult to determineprecisely the odds that a variablecould reach statistical significance bychance. However, it is worth notingthat the direction of effect for all ofthe variables that met the screeningcutoff was in the direction of MP ben-efit (with the exception of one speedfactor that had essentially a zero ef-fect size), an occurrence that wouldbe extremely unlikely by chance.
With these limitations in mind,the current findings do support thenotion that MP has a beneficial effecton cognitive processing speed aftermoderate to severe TBI. This effect,and possibly other specific benefits ofMP, translates not only into fasterperformance on laboratory measuresof attention, but also the ability toattend to naturalistic tasks or returnmore quickly to them after lapses ofattention. Although MP did not affectseveral facets of attention measuredin the current study, there was ahighly significant effect on everydayattentional behavior as assessed byrelatives very familiar with the day-to-day effect of attention deficits onour participants with chronic TBI.
CONCLUSION
MP, in a dose of 0.3 mg/kg twicea day, seems to have clear and con-sistent positive effects on speed ofprocessing and caregiver ratings ofattentiveness in a highly selectedsample of individuals with moderateto severe TBI. The effects on inatten-tiveness are more complex and maybe traceable to shorter duration ofoff-task behaviors without a reduc-tion in their frequency. Effects onsustained attention were not evident,in contrast to our previous pilotstudy, nor did MP improve dual taskperformance, in contrast to a previ-
ous study of bromocriptine.48 Posi-tive drug effects covered a range fromimpairment to activity and participa-tion measures. Further clinical trialson larger and more representativesamples of individuals with TBI arewarranted and should benefit fromthese results in selecting their pri-mary outcomes. Similarly, studiescomparing different doses of MPcould help shed light on the optimaldose for specific target goals.
ACKNOWLEDGMENTS
We thank the many individualswho assisted in the research: JosephAlban, Natosha Bailey, ChristopherGantz, Monica Hopson, and VonettaDrakes managed participant recruit-ment, testing, and behavioral observa-tion; Adelyn Brecher, Anne Hammond,Karen Hawkey, Andrea Laborde, WalterLewis, Nathaniel Mayer, Jeanne Pelen-sky, and Rosadele Plumari all helped toidentify and refer eligible participants;Kelly Card and Vivian Ly facilitated theresearch classroom; Thouron Smithprovided volunteer assistance in thelaboratory and classroom; StephenHinshaw suggested the model for theresearch classroom and providedmethodological consultation; GuylaineGagnon, Mary Kennedy, and RonaldCharno managed the blinded random-ization code and the preparation ofstudy medications; Antonella Paveseand Tracy Veramonti programmed thecomputerized laboratory tasks; Fei Shaand Gemma Baldon programmed theresearch database; and Mary Czerniakassisted in the preparation of themanuscript; and most importantly, wethank the participants and their fami-lies for investing their time and energyin this study.
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