Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI)

Condition(s) targeted: Brain Injury

Intervention: Methylphenidate (Drug); Memory and Attention Training (Behavioral); Placebo as both treatments (Other)

Phase: N/A

Status: Recruiting

Sponsored by: Dartmouth-Hitchcock Medical Center

Official(s) and/or principal investigator(s):
Thomas W McAllister, MD, Principal Investigator, Affiliation: Dartmouth-Hitchcock Medical Center, Dartmouth Medical School

Overall contact:
Mary L Hynes, RN, MPH, Phone: 603-650-7552, Email: Mary.L.Hynes@hitchcock.org

Traumatic brain injury (TBI) is a significant public health problem, with 1. 5-2. 0 million Americans injured each year. Cognitive deficits, particularly in the domains of memory and attention are frequently the source of lingering disability after TBI and a source of enormous distress to the injured individuals and their family/caregivers. To date, interventions to ameliorate chronic cognitive deficits have been directed at either pharmacological interventions or cognitive rehabilitation. We propose to (1) To compare the efficacy of three interventions: memory and attention training (MAAT), methylphenidate, and memory/attention training in combination with methylphenidate and (2) use functional MRI (fMRI) to characterize changes in activation of the neural circuitry of memory and attention due to MAAT alone, methylphenidate alone, and MAAT in combination with methylphenidate. This is a two by two design with medication (methylphenidate/placebo) and cognitive therapy (Memory and Attention Training (MAAT) or an Attention control intervention) as possible interventions. Using a randomized, placebo-controlled, double-blind design, 200 individuals with persistent cognitive deficits 6-12 months after MTBI will be randomized to receive a six week trial of either (1) MAAT and placebo, (2) MAAT and methylphenidate (0. 3 mg/kg BID), (3) attention control intervention and methylphenidate (0. 3 mg/kg BID), or (4) attention control intervention and placebo. Symptom distress, attention and memory performance, and activation patterns of the neural circuitry of attention and memory while undergoing fMRI will be characterized at baseline, and after the four treatment conditions. This study will provide important information on three interventions for the most disabling sequelae of an enormous public health problem. Further, it will help to clarify underlying neural mechanisms and suggest additional treatment possibilities.

Official title: Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI)

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Efficacy Study

Primary outcome:

Neuropsychological Testing

Self Report Questionnaires

Structural and Functional MRI

Detailed description: Summary and Gaps to be Addressed by the Proposed Study

What is known: There are two interventions of promising efficacy in ameliorating deficits in attention and memory after MTBI: (i) memory and attention training/rehabilitation, and (ii)

catecholaminergic augmentation (particularly with methylphenidate - which augments both

dopaminergic and adrenergic systems). fMRI and other functional imaging strategies are providing valuable insights into the underlying neural mechanisms of the cognitive enhancing effects of methylphenidate in some neuropsychiatric populations (individuals with ADHD), and the effects of cognitive rehabilitation efforts in some domains (e. g. speech and language in individuals after stroke).

What is not known: To date there are no studies that apply a psychopharmacological strategy of augmenting neurotransmitter systems known to modulate memory/attention (dopaminergic and adrenergic systems) in combination with a cognitive rehabilitation intervention known to improve memory/attention (memory/attention training) in individuals with MTBI. We are aware of no published studies that use fMRI to assess the neural mechanisms of memory/attention improvement from the use of catecholaminergic agents or memory/attention training in individuals with MTBI. It is important to determine the efficacy of combined memory/attention training and methylphenidate. It is equally important to begin to understand the neural mechanisms underlying effective treatment as it may help to inform the development of the next generation of interventions and perhaps lead to individually tailored treatment interventions. This proposal will start to address these gaps in our knowledge.

Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Age: Individuals aged 18-60 who sustained a mild to moderate TBI 6-12 months prior to study entry.

2. TBI: The minimum level of injury severity included will be based on the criteria established by the American Congress of Rehabilitative Medicine for mild brain injury. Specifically, subjects must sustain a traumatic blow to the head, resulting in either alteration of level of consciousness (manifested by being dazed and confused and having amnesia for the event) or loss of consciousness (LOC). The upper limit of severity will be the commonly accepted criteria for moderate traumatic brain injuries; trauma resulting in LOC of up to 60 minutes, and ED Glasgow Coma Scale (GCS) scores of 9-12. Duration of LOC will be estimated by using all available information including patient and witness reports, emergency personnel records and DHMC medical records. PTA will be estimated by careful questioning of patients to determine the time of return of continuous memory. This will be informed by review of medical records. We plan to include individuals with intracranial or skull injuries stemming from the TBI, providing they meet the inclusion criteria. Such lesions will be catalogued, and included as a factor in the data analysis. Large structural pathology with lobar deformations or midline shift will be exclusions.

3. Cognitive Deficits: Subjects will have both subjective and objective evidence of persistent cognitive deficits. Subjects must report persistent memory or attention deficits as a result of their injury, which are of sufficient severity to interfere with social and/or occupational functioning. Subjects must either score more than 2 standard deviations below the age adjusted norm or estimates of baseline premorbid function (using the Barona Index) on one or more tests of attention and/or memory administered as part of the baseline screening cognitive battery (see below), or score greater than 1. 0 standard deviations below either age adjusted norms or estimates of premorbid function on 2 or more of the screening tests (see below).

Exclusion Criteria:

The following factors will exclude otherwise eligible subjects from participation:

1. a history of other neurologic disorders (such as epilepsy, cerebrovascular disease, mental retardation, neurodegenerative disorders)

2. significant systemic medical illness such as clinically significant liver disease, renal disease, atherosclerotic coronary vascular disease, or hypertension requiring medication management

3. current DSM-IV Axis I diagnosis of psychiatric illness other than substance abuse. We have given careful consideration to the inclusion of the latter group given our use of a stimulant with potential abuse properties. Because of the potential for cross-over abuse with cocaine, amphetamines, and other stimulants, individuals with such histories will be excluded from this study. Individuals with history of otherwise uncomplicated ethanol or other non-stimulant drug abuse currently in stable remission will be eligible. The Structured Clinical Interview for DSM-IV (SCID) will be used to screen for psychiatric illness

4. women currently pregnant or lactating. Female participants will be asked to take a pregnancy test to confirm they are not currently pregnant.

Mary L Hynes, RN, MPH, Phone: 603-650-7552, Email: Mary.L.Hynes@hitchcock.org

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States; Recruiting
Thomas W McAllister, MD, Principal Investigator

Brain Injury Association of New Hampshire

Brain Injury Association of Vermont

Related publications:

McAllister TW, Flashman LA, McDonald BC, Saykin AJ. Mechanisms of working memory dysfunction after mild and moderate TBI: evidence from functional MRI and neurogenetics. J Neurotrauma. 2006 Oct;23(10):1450-67.

Neurobehavioral Guidelines Working Group; Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, Drake A, Gentry T, Jagoda A, Katz DI, Kraus J, Labbate LA, Ryan LM, Sparling MB, Walters B, Whyte J, Zapata A, Zitnay G. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma. 2006 Oct;23(10):1468-501.

McAllister TW, Rhodes CH, Flashman LA, McDonald BC, Belloni D, Saykin AJ. Effect of the dopamine D2 receptor T allele on response latency after mild traumatic brain injury. Am J Psychiatry. 2005 Sep;162(9):1749-51.

McAllister TW, Flashman LA, Sparling MB, Saykin AJ. Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment -- a review. Brain Inj. 2004 Apr;18(4):331-50. Review.

McAllister TW, Ferrell RB. Evaluation and treatment of psychosis after traumatic brain injury. NeuroRehabilitation. 2002;17(4):357-68. Review.

Flashman LA, McAllister TW. Lack of awareness and its impact in traumatic brain injury. NeuroRehabilitation. 2002;17(4):285-96. Review.

McAllister TW, Arciniegas D. Evaluation and treatment of postconcussive symptoms. NeuroRehabilitation. 2002;17(4):265-83. Review.

McAllister TW. Evaluation and treatment of neurobehavioral complications of traumatic brain injury--have we made any progress? NeuroRehabilitation. 2002;17(4):263-4. No abstract available.

McAllister TW, Sparling MB, Flashman LA, Saykin AJ. Neuroimaging findings in mild traumatic brain injury. J Clin Exp Neuropsychol. 2001 Dec;23(6):775-91. Review.

McAllister TW, Sparling MB, Flashman LA, Guerin SJ, Mamourian AC, Saykin AJ. Differential working memory load effects after mild traumatic brain injury. Neuroimage. 2001 Nov;14(5):1004-12.

McAllister TW, Saykin AJ, Flashman LA, Sparling MB, Johnson SC, Guerin SJ, Mamourian AC, Weaver JB, Yanofsky N. Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study. Neurology. 1999 Oct 12;53(6):1300-8.

McAllister TW. Traumatic Brain Injury and Psychosis: What Is the Connection? Semin Clin Neuropsychiatry. 1998 Jul;3(3):211-223.

Flashman LA, Amador X, McAllister TW. Lack of Awareness of Deficits in Traumatic Brain Injury. Semin Clin Neuropsychiatry. 1998 Jul;3(3):201-210.

McAllister TW, Green RL. Traumatic Brain Injury: A Model of Acquired Psychiatric Illness? Semin Clin Neuropsychiatry. 1998 Jul;3(3):158-159. No abstract available.

McAllister TW. Evaluation of brain injury related behavioral disturbances in community mental health centers. Community Ment Health J. 1997 Aug;33(4):341-58; discussion 359-64. Review.

Silver JM, McAllister TW. Forensic issues in the neuropsychiatric evaluation of the patient with mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1997 Winter;9(1):102-13. Review. No abstract available.

McAllister TW. Neuropsychiatric sequelae of head injuries. Psychiatr Clin North Am. 1992 Jun;15(2):395-413. Review.

Starting date: February 2007
Ending date: December 2012
Last updated: August 3, 2009