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

Primary Purpose

Brain Injury

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Methylphenidate

Memory and Attention Training

Placebo as both treatments

About this trial

This is an interventional treatment trial for Brain Injury focused on measuring TBI, Memory, Methylphenidate, Ritalin, Memory and Attention Training

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age: Individuals aged 18-65 who sustained a mild to severe TBI 4 months prior to study entry.
TBI: Subjects must sustain a traumatic blow to the head, resulting in either alteration of level of consciousness (manifested by being dazed and confused or having amnesia for the event) or loss of consciousness (LOC). Duration of LOC will be estimated by using all available information including patient and witness reports, emergency personnel records and Dartmouth Hitchcock Medical Center (DHMC) medical records. Post traumatic amnesia (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.
Cognitive Deficits: Subjects will have either 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 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.

Exclusion Criteria:

The following factors will exclude otherwise eligible subjects from participation:

a history of other neurologic disorders (such as epilepsy, cerebrovascular disease, mental retardation, neurodegenerative disorders)
significant systemic medical illness such as clinically significant liver disease, renal disease, atherosclerotic coronary vascular disease, or hypertension requiring medication management
current Diagnostic and Statistical Manual (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 (MINI) will be used to screen for psychiatric illness
women currently pregnant or lactating. Female participants will be asked to take a pregnancy test to confirm they are not currently pregnant.

Sites / Locations

University of Colorado at Denver
Indiana University
Dartmouth-Hitchcock Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Arm Description

Placebo Capsule and Placebo Memory and Attention Training (Placebo as both conditions)

Methylphenidate capsules and Memory and Attention Training (Active Med/Active therapy)

Methylphenidate capsules and Placebo Memory and Attention Training (Active Med/Placebo therapy)

Placebo capsules and Memory and Attention Training (Placebo Med/Active therapy)

Outcomes

Primary Outcome Measures

Neuropsychological Assessment, CVLT-II

Memory measure: California Verbal Learning Test, 2nd edition (CVLT), Total, trials 1-5 (range: 0-80). Higher scores are better outcome.

Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time)

Continuous Performance Test, Distractibility Condition (Reaction Time in msecs) (range: 0-800). Higher score is worse performance.

Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment)

Change in performance (percent correct,adjusted for guessing) from pre-(baseline) to post-treatment (approximately 7 weeks) for in-scanner n-back working memory task (Range: 0-100). Higher scores means better performance.

Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention

Change from pre- to post-treatment in brain activation in the anterior cingulate region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.

Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention

Change from pre- to post-treatment in brain activation in the left middle/inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.

Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention

Change from pre- to post-treatment in brain activation in the right inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.

Secondary Outcome Measures

Self Report Questionnaire - MASQ

The Multiple Abilities Questionnaire (self rating) is a questionnaire in which participants can identify deficits/complaints in the areas of language, visual perception, verbal memory, visual memory and attention and concentration. A total score is calculated; range is 30-130. Higher scores indicate greater level of complaints (worse outcome). For the purposes of this study, a score one standard deviation above the mean (102.7) indicated significant reported cognitive complaints.

Full Information

NCT ID

NCT00453921

First Posted

March 27, 2007

Last Updated

June 11, 2018

Sponsor

Dartmouth-Hitchcock Medical Center

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

1. Study Identification

Unique Protocol Identification Number

NCT00453921

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2018

Overall Recruitment Status

Completed

Study Start Date

February 2007 (undefined)

Primary Completion Date

May 2013 (Actual)

Study Completion Date

May 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Dartmouth-Hitchcock Medical Center

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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 mild traumatic brain injury (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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Brain Injury

Keywords

TBI, Memory, Methylphenidate, Ritalin, Memory and Attention Training

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

76 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Placebo Comparator

Arm Description

Placebo Capsule and Placebo Memory and Attention Training (Placebo as both conditions)

Arm Title

Arm Type

Active Comparator

Arm Description

Methylphenidate capsules and Memory and Attention Training (Active Med/Active therapy)

Arm Title

Arm Type

Active Comparator

Arm Description

Methylphenidate capsules and Placebo Memory and Attention Training (Active Med/Placebo therapy)

Arm Title

Arm Type

Active Comparator

Arm Description

Placebo capsules and Memory and Attention Training (Placebo Med/Active therapy)

Intervention Type

Drug

Intervention Name(s)

Methylphenidate

Intervention Description

Dosage dependent on weight

Intervention Type

Behavioral

Intervention Name(s)

Memory and Attention Training

Intervention Description

Weekly Memory and Attention Training with at home practice.

Intervention Type

Other

Intervention Name(s)

Placebo as both treatments

Intervention Description

Placebo capsules and Placebo Memory and Attention Training

Primary Outcome Measure Information:

Title

Neuropsychological Assessment, CVLT-II

Description

Memory measure: California Verbal Learning Test, 2nd edition (CVLT), Total, trials 1-5 (range: 0-80). Higher scores are better outcome.

Time Frame

post-intervention (at least 7 weeks)

Title

Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time)

Description

Continuous Performance Test, Distractibility Condition (Reaction Time in msecs) (range: 0-800). Higher score is worse performance.

Time Frame

post-intervention (at least 7 weeks)

Title

Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment)

Description

Time Frame

pre- to post-6 week treatment intervention (at least 7 weeks)

Title

Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention

Description

Time Frame

pre- to post-intervention (at least 7 weeks)

Title

Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention

Description

Time Frame

pre- to post-treatment (at least 7 weeks)

Title

Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention

Description

Time Frame

pre- to post-treatment (at least 7 weeks)

Secondary Outcome Measure Information:

Title

Self Report Questionnaire - MASQ

Description

Time Frame

post-intervention (at least 7 weeks)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age: Individuals aged 18-65 who sustained a mild to severe TBI 4 months prior to study entry. TBI: Subjects must sustain a traumatic blow to the head, resulting in either alteration of level of consciousness (manifested by being dazed and confused or having amnesia for the event) or loss of consciousness (LOC). Duration of LOC will be estimated by using all available information including patient and witness reports, emergency personnel records and Dartmouth Hitchcock Medical Center (DHMC) medical records. Post traumatic amnesia (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. Cognitive Deficits: Subjects will have either 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 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. Exclusion Criteria: The following factors will exclude otherwise eligible subjects from participation: a history of other neurologic disorders (such as epilepsy, cerebrovascular disease, mental retardation, neurodegenerative disorders) significant systemic medical illness such as clinically significant liver disease, renal disease, atherosclerotic coronary vascular disease, or hypertension requiring medication management current Diagnostic and Statistical Manual (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 (MINI) will be used to screen for psychiatric illness women currently pregnant or lactating. Female participants will be asked to take a pregnancy test to confirm they are not currently pregnant.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Thomas W McAllister, MD

Organizational Affiliation

Dartmouth-Hitchcock Medical Center, Dartmouth Medical School

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Colorado at Denver

City

Denver

State/Province

Colorado

ZIP/Postal Code

80291-0238

Country

United States

Facility Name

Indiana University

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46266-6057

Country

United States

Facility Name

Dartmouth-Hitchcock Medical Center

City

Lebanon

State/Province

New Hampshire

ZIP/Postal Code

03753

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

17020482

Citation

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. doi: 10.1089/neu.2006.23.1450.

Results Reference

background

PubMed Identifier

17020483

Citation

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. doi: 10.1089/neu.2006.23.1468.

Results Reference

background

PubMed Identifier

16135640

Citation

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. doi: 10.1176/appi.ajp.162.9.1749.

Results Reference

background

PubMed Identifier

14742148

Citation

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. doi: 10.1080/02699050310001617370.

Results Reference

background

PubMed Identifier

12547983

Citation

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

Results Reference

background

PubMed Identifier

12547977

Citation

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

Results Reference

background

PubMed Identifier

12547976

Citation

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

Results Reference

background

PubMed Identifier

12547975

Citation

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.

Results Reference

background

PubMed Identifier

11910544

Citation

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. doi: 10.1076/jcen.23.6.775.1026.

Results Reference

background

PubMed Identifier

11697932

Citation

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. doi: 10.1006/nimg.2001.0899.

Results Reference

background

PubMed Identifier

10522888

Citation

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. doi: 10.1212/wnl.53.6.1300.

Results Reference

background

PubMed Identifier

10085209

Citation

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

Results Reference

background

PubMed Identifier

10085208

Citation

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

Results Reference

background

PubMed Identifier

10085203

Citation

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.

Results Reference

background

PubMed Identifier

9250431

Citation

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. doi: 10.1023/a:1025055426260.

Results Reference

background

PubMed Identifier

9017537

Citation

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. doi: 10.1176/jnp.9.1.102. No abstract available.

Results Reference

background

PubMed Identifier

1603732

Citation

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

Results Reference

background

Links:

URL

http://www.bianh.org

Description

Brain Injury Association of New Hampshire

URL

http://www.biavt.org/

Description

Brain Injury Association of Vermont

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

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