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This work is a major collaborative effort with the Department of Radiology at UMDNJ, and the Department of Psychology at Rutgers University, Newark. Much of the work focuses on the identification of patterns of cerebral activation in different clinical populations during the performance of working memory and information processing tasks.

Each year roughly 250,000 people are hospitalized and survive moderate and severe traumatic brain injury (TBI). As a result, a large number of individuals with TBI endure life-long impairment and disability. Acute rating scales such as the Glasgow Coma Scale have shown limited predictive validity regarding patient outcome and traditional neuroimaging techniques such as CT and MRI maintain limited correlations with brain injury severity and cognitive functioning. Continued advances in neuroimaging, however, have provided researchers with an important opportunity to study the pathophysiology of brain dysfunction following TBI. The purpose of this study is to correlate proton magnetic resonance spectroscopy (MRS), an advanced neuroimaging technique, with behavioral measures of TBI severity and cognitive outcome. MRS measures the concentration of cerebral metabolites such as N-acetylaspartate (NAA), choline (Cho), and glutamate (Glu). While MRS has shown promise in predicting brain injury severity and patient outcome, the exact protocols for using MRS with TBI remain undetermined and the purpose of the proposed study is to examine three critical areas: 1.) when in the post-injury time period MRS data should be acquired (e.g., within one week of injury, within one month of injury) 2.) how metabolites should be measured (i.e., absolute concentrations or changes in concentration over time) and 3.) brain locations best suited for MRS data acquisition (i.e., acquisition near lesion sites or acquisition at sites remote from probable brain lesion). The proposed study will make determinations in these three areas through the use of two acute MRS scans following TBI to measure concentrations of NAA, Cho and Glu and their correlation with injury severity and cognitive variables. In addition, correlation of acute MRS data with behavioral data (e.g., duration of loss of consciousness, duration of post-traumatic amnesia) will elucidate the relationship between changes in brain metabolism and changes in patient behavior during acute recovery from TBI. With an established protocol for using MRS, this instrument should prove useful for determining the effectiveness of acute interventions (e.g., hypothermia, pharmacologic intervention) and for predicting the acute course of patient recovery.

The NIH Consensus Statement on Rehabilitation of persons with traumatic brain injury (TBI) states that "the neurobiology of TBI in humans should be studied with modern imaging techniques and correlated with neuropsychological findings." Similarly, the need to integrate neuroimaging research with neuropsychological assessment has been recognized by the NCMRR as they encourage research correlating imaging and behavioral variables, such as neuropsychological assessment. Memory deficits are among the most frequently reported and most severe problems following TBI and can persist years after injury. While much research has documented the presence of memory impairments in TBI, the specific cognitive mechanisms of such impairments are not yet well understood. Work from our laboratory has shown that memory difficulties evidenced in TBI may be primarily attributable to deficits in the acquisition or encoding of information rather than retrieval of information from long-term storage. Understanding why persons with TBI experience difficulty in the acquisition or encoding of information is of critical importance. A major aim of the present study is to examine factors which influence the encoding of information. Because of its influence on the encoding of learned material, it is critical to relate behavioral data regarding organizational strategies with alterations in cerebral substrates in persons with TBI. While behavioral data from our laboratory and others clearly indicate that organization and executive control impact and may disrupt memory, the cerebral substrates are unknown. To date, there are no functional neuroimaging studies examining the impact of organizational strategies on encoding in TBI. A purpose of this study is to address this critical void. We will use BOLD fMRI to examine the effects of TBI on encoding using paradigms that have been established in healthy individuals. Participants will be 40 persons with moderate-severe TBI (20 with significant executive dysfunction; 20 with minimal dysfunction) and 20 healthy controls. It is expected that TBI subjects will show more widespread activation during encoding tasks requiring greater executive control compared with healthy controls. It is expected that this effect will be greatest in TBI subjects with significant executive dysfunction. The results of the present study will provide a better understanding of the specific mechanisms of encoding and the impact of executive control on memory and may provide tools to develop more effective intervention and rehabilitation. Given that new learning and memory have also been identified as important cognitive deficits in the Multiple Sclerosis (MS) population, the same study will be conducted in MS to examine the effect of encoding strategies in this rehabilitation population as well.

The Research Plan for the National Center for Medical Rehabilitation Research (NCMRR) points to the need to "evaluate the efficacy of neuroimaging techniques," and to "develop new and precise quantitative measures of impairment" after traumatic brain injury (TBI). The present proposal will address these goals by applying functional fMRI to study the effects of executive control impairment on episodic memory (i.e., encoding and recall) after TBI. Memory distubance is one of the most disabling consequences of TBI, but there has been little focused research on the cerebral mechanisms of impaired memory. In response to this need, the present proposal will apply an innovative approach to the study of episodic memory in TBI through the use of MRI. Our pilot data demonstrate that TBI subjects s how altered cerebral representation of episodic and working memory relative to controls. What is not known, however, are the cerebral substrates of impaired encoding and recall after TBI, and the impact of impaired executive control processing on functions. We will use BOLD fMRI to examine the effects of TBI on episodic memory tasks using paradigms that have been established in healthy individuals. Participants will be 40 persons with moderate-severe TBI (20 with significant executive dysfunction and 20 with minimal executive dysfunction) and 20 healthy controls. Because cognitive effort underlies fMRI activations during memory tasks, it is expected that as task demands increase, individuals with TBI will show more widespread cerebral activations than healthy controls. This effect is expected to be greatest in TBI subjects with significant executive control impairments. It is expected that individuals with TBI will show greater intensity and dispersion of cerebral activation, even at simpler levels of memory processing, suggesting altered reorganization of the cerebral substrates of episodic memory following TBI. The results of the present study will provide a better understanding of specific mechanisms of episodic memory and may provide the tools to develop and improve behavioral and pharmaceutical interventions.

Given that episodic memory is also a major cognitive deficit in MS, the same study will be conducted in MS to examine the relationship between episodic memory and executive control functions in MS as well.

Cognitive performance of Multiple Sclerosis (MS) patients is characterized by reduced processing speed compared to controls. To examine the neural substrates of this phenomenon, we compared BOLD activation patterns of MS-diagnosed patients with that of healthy control subjects using event-related functional magnetic resonance imaging (fMRI). During scanning, both groups were asked to perform a modified version of the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale, a test with known sensitivity to individual differences in processing speed. On each trial subjects saw an "answer key," a set of digit-symbol pairings, across the top of the screen. In the answer key, the digits 1-9 appeared with a set of nonsense figures below them. A single digit-symbol pairing appeared below the answer key. The subject's task was to determine whether the pairing that appeared below the answer key matched (right-thumb button press) or did not match (left-thumb button press) one of the entries in the answer key. Preliminary results suggest equivalent activation in early visual (cuneus, precuneus and lingual gyrus) and parietal regions between MS patients and controls. In middle frontal regions, we observed more intense and more widespread activation in patients relative to controls. In superior prefrontal regions, greater activation was observed in controls relative to patients. Thus, there were greater activation differences in anterior compared to posterior regions between patients and controls. These results suggest that differences in prefrontal function may mediate processing speed reductions observed in MS patients relative to controls.

The present study evaluates working memory in Multiple Sclerosis (MS) through the application of functional Magnetic Resonance Imaging (fMRI). Estimates of cognitive dysfunction in MS range from 35-60% and a deficit in working memory or information processing abilities is one of the most frequently identified problems in MS. Interestingly, despite the fact that neuroimaging has revolutionized the study of cognition, the documentation of impaired working memory in MS remains strictly behavioral.

The present proposal applies fMRI to study the patterns of cerebral activation on two working memory tasks designed to specifically assess the subsystems theorized to underscore working memory (e.g. central executive system, phonological loop). One of the most consistently identified cognitive deficits in MS is in working memory, yet there have been few efforts to identify the source of the deficit (e.g. phonological loop or central executive system). In addition, no studies have yet examined these deficits at the level of the cerebral substrate. To address this void in the literature, the present proposal will apply an innovative approach to the study of working memory in MS through the use of BOLD fMRI. Our pilot data demonstrates that MS subjects show altered cerebral representation of working memory relative to controls. However, it is not yet known which aspect of working memory is impaired in MS. This study will examine the central executive system and the phonological loop in MS, both at a behavioral level and at the level of the cerebral substrate. We will examine 40 MS subjects (20 with working memory impairment and 20 without working memory impairment) and 20 age and education matched healthy control subjects. Based on our pilot data, we expect the MS working memory impaired group to show more widespread cerebral activations than healthy controls and the MS nonimpaired group on the central executive system tasks. In contrast, the groups are expected to show similar patterns of activatin on the phonological loop tasks. Results will increase our understanding of the specific mechanisms of working memory impairment in MS and may advance the development of behavioral and pharmacological interventions for working memory dysfunction in MS. In this manner we hope to eventually be able to improve the quality of life of individuals with MS through the improved management of their working memory deficits.

Modafinil for Improving New Learning and Memory in Multiple Sclerosis

Deficits in new learning and memory in MS are a major complaint of patients, and have been noted to be a significant contributor to disability by numerous researchers. Modafinil is a psychostimulant medication, FDA approved for the treatment of Narcolepsy, with potential application for the treatment of learning and memory dysfunction in MS. This randomized clinical trial tests the efficacy of Modafinil for the treatment of new learning and memory deficits in MS.

Twenty subjects with clinically definite MS and objectively documented new learning impairment will be included in the study. All subjects will undergo baseline neuropsychological testing and EDSS to document current levels of functioning in new learning and memory abilities. Subjects will then be randomly assigned to either group 1 or group 2. Group 1 (n=10) will first undergo treatment with Modafinil (200 mg once per day in the morning) for 2 weeks. They will then undergo follow-up neuropsychological assessment and follow-up EDSS to evaluate any medication effects. After the follow-up evaluation, there will be a washout period of one week in which no medication will be administered. Group 1 will then receive a placebo medication for 2 weeks. A second follow-up evaluation will be conducted following this latter arm of the study. Group 2 (n=10) will follow the same pattern, but will receive the placebo medication during the first arm of the study and Modafinil during the 2nd arm of the study. The subjects and the experimenter administering the neuropsychological evaluation will be blind to group membership.

This study is a double-blind, placebo-control randomized clinical trial examining the efficacy of memory retraining in Multiple Sclerosis (MS). Impairment in higher level cognitive processing, such as new learning and memory, is one of the most common deficits in individuals with MS and such deficits have been shown to exert significant negative impact on multiple aspects of everyday life, including occupational and social functioning. Despite these findings, few studies have attempted to treat these cognitive deficits in order to improve the everyday functioning of individuals with MS. Through a small randomized clinical trial, we found that individuals with MS with documented memory impairment show a significant improvement in their memory performance following a treatment protocol. The current proposal will replicate this finding and further evaluate (a) the impact of the treatment on everyday functioning, (b) the long term efficacy of the treatment and (c) the utility of booster sessions in facilitating long-term treatment effects. We will randomly assign individuals with MS, with documented impairment in new learning abilities, to a memory retraining group or a placebo control group. Both groups will undergo baseline, immediate and long-term follow-up assessment consisting of: (1) a traditional neuropsychological battery and (2) an assessment of global functioning examining the impact of the treatment on daily activities. This design will allow us to evaluate the efficacy of this particular memory retraining technique in an MS population through the assessment of cognitive function via a standard evaluation. In addition, we will be able to draw conclusions regarding the impact of this particular memory remediation program on everyday life from questionnaires completed by the participant and a significant other.

The observation that items generated by individuals are better remembered than items provided to them is referred to as the generation effect. Research on the generation effect has helped further our understanding of memory function in normal, healthy individuals, and has contributed to the design of protocols that have proved effective in helping to improve memory performance in healthy individuals. There is also some evidence that the generation effect can be useful in improving memory ability in individuals with neurological impairment, such as MS. However, no studies have attempted to apply the generation effect to daily living tasks such as cooking, or managing finances with individuals who have neurological impairments.

In the current study the generation effect will be examined with everyday functional tasks within three populations: (1) individuals who have MS, (2) individuals who have TBI, and (3) normal healthy individuals. Participants will complete two cooking tasks as well as two tasks requiring the management of finances; both cooking and managing finances are a frequent focus of rehabilitation following TBI or exacerbation of MS. We expect that the generation effect will benefit learning and memory in both functional domains (cooking and managing finances).

The laboratory has continued to conduct research in patients with TBI. Research is being carried out in an attempt to: 1) apply well-known cognitive principles to the rehabilitation of those with TBI, and 2) understand what happens in the brain of TBI patients during the memory process. This latter research is being conducted using functional Magnetic Resonance Imaging (fMRI), which allows the viewing of specific areas of the brain that are involved (or damaged) while the patient is actively performing a cognitive task (see "Functional Magnetic Resonance Imaging of Cognitive Processes").

The use of VR for the assessment of vocationally-relevant skills among adults with traumatic brain injury continues to be developed. Initial tasks designed to assess learning and memory performance are being compared to more traditional paper-and-pencil tasks. Overall, one major goal of the VR studies, is to establish the efficacy of this innovative technology to provide more "functional" representations of performance (cognitive, physical and behavioral) among individuals with brain injury. In 2003, KMRREC transitioned VR research into the new Rehabilitation Engineering Laboratory.

The laboratory has been studying the amnesic syndrome observed in individuals who have suffered aneurysms at a very specific area of the brain (anterior communicating artery). What is so intriguing about this work is that the areas of the brain that have been identified over the past 100 years as critical for amnesia are not impaired in this population. Thus, the laboratory's work is leading to a new understanding about the cerebral representation of human memory. The laboratory has been internationally recognized as a leader in this area of research.