Mark S. Mennemeier, PhD - US grants

The goal of this research is to add a quantitative element to contemporary theories of spatial neglect and to combine disparate theories into one model. Theoretical development can lead to improved treatment. Neglect affects a large number of stroke patients each year, and current treatments are of limited benefit. Contemporary theories of neglect view the disorder in terms of mental representations of space, spatial attention, and spatially- directed movements. They cannot address a number of recent empiric observations related to magnitude estimation -- misperceiving size, loudness, weight, and the like. We propose that mental representations of stimulus intensity are constructed by neural systems in the brain, in addition to mental representations of space, and that both types of representations are altered in neglect. Further, we propose that representations of stimulus intensity are developed in accordance with the psychophysical principle of ratio scaling, which is the basis for magnitude estimation. Representations of stimulus intensity add the quantitative element that is missing in contemporary theories of neglect. We anticipate this new concept will significantly advance theories concerning neglect and lead to new directions in research. It is also directly applicable to treatment, e.g., rehabilitating representations of stimulus intensity through direct training in ratio scaling. Six experiments are proposed. Subjects will be patients with right and left hemisphere lesions . following ischemic stroke who are selected for (1) clinical signs of neglect and (2) damage to a specific, neural system associated with neglect. Non-patient control subjects will be matched for age, gender, and race. Experiment I tests the hypothesis that representations of stimulus intensity are altered in multiple sensory modalities among patients with neglect. Experiment II tests the hypothesis that attention binds representations of space and stimulus intensity together. Experiment III tests the hypothesis that representation of stimulus intensity are constructed in each cerebral hemisphere. Experiments IV-VI examine alternative explanations for altered ratio scaling among patients with neglect. Finally, we propose to develop and test a mathematical model of ratio scaling during the course of this proposal.

DESCRIPTION (provided by applicant): Spatial neglect (neglect), a common, disabling condition following stroke, predicts poor rehabilitation outcome. Contemporary theories of neglect, predicated on spatial representations through which attention and movement are directed, cannot explain a number of recent empirical findings.Treatment may be of limited benefit because the theories are incomplete. Research in this proposal will investigate a new concept in neglect and apply this concept in treatment. The investigators want to broaden the framework of neglect theory. They propose that some aspects of neglect behavior reflect altered representations of space, whereas others reflect altered representations of stimulus intensity. The hypothesis of this proposal is that representations of stimulus intensity are derived in accordance with the Power-Law in psychophysics. The Power-Law describes a quantitative relationship between the physical intensity of a stimulus and its perceived intensity, and it applies across sensory modalities. It is predicated on the concept of ratio scaling -- equal ratios of stimulus intensity produce equal ratios of perceived intensity. Ratio scaling is operationalized in this proposal through use of power functions. The investigators' preliminary work shows that empirical constraints on neglect theory can be explained by a theory that combines the concepts of spatial representations with representation of stimulus intensity. Aim 1 is to extend the investigators preliminary work by examining ratio scaling in 8 perceptual continua. Aim 2 is to compare ratio scaling among patients with and without neglect following unilateral ischemic strokes of the left and right hemispheres and non-patient controls. Aim 3 is to compare patients with neglect trained vs. those untrained in ratio scaling on outcomes related to neglect and activities of daily living. Maintenance of treatment benefits over time will be assessed. Results will either support or modify the investigators' central hypothesis. The investigators anticipate this proposal's studies will lead to a comprehensive theory of neglect and a comprehensive interpretation of the Power-Law. They will advance understanding of the multi-faceted nature of mental representation and the cortical contributions to ratio scaling. The investigators anticipate Aim 3 will yield a treatment approach that can be widely applied in rehabilitation and can improve performance on real-life tasks in real-life settings.

[unreadable] DESCRIPTION (provided by applicant): This R03 application examines how perception of strength and balance is altered by decreased arousal following stroke. Stroke affects 600,000 patients annually in the United States. Perception of limb strength may be altered in half of all stroke patients. One-third of all stroke patients fall during stroke rehabilitation. Falling is related to altered strength and balance. The long term goal of this study is to improve the outcome of stroke rehabilitation by treating arousal-related deficits that impede progress in therapy and lead to complications. Whereas the neglect syndrome following right hemisphere stroke is known to be associated with altered arousal and perception, this project aims to show that altered perception of strength and balance is much more common than neglect and that rehabilitation is complicated by deficits in arousal even in patients without neglect. Aim I will validate the constructs of altered strength and balance perception by demonstrating their relationship to functional limitations. Aim II will test the link between altered arousal, perception and function by using caloric stimulation to temporarily increase arousal in stroke patients. Aim III examines whether patients with the capacity to respond to caloric stimulation have better functional outcomes three months after rehabilitation than those who do not. This research is intended to lay the ground-work for pharmacological studies that use arousal-enhancing medications to treat perceptual deficits in stroke patients during rehabilitation. [unreadable] [unreadable] This proposal aims to improve public health in the US by rehabilitating altered perception of contralateral limb strength following stroke. Altered perception of strength may be a significant contributor to poor participation and frustration in rehabilitation therapy and it increases the risk of orthopedic injury due to falls. Stroke affects 600,000 patients annually in the United States. Half of all stroke patients in rehabilitation may have altered strength perception. There is no pharmacological treatment at the present time. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This R21, exploratory application will apply insights gained from studies of unilateral neglect to the investigation and treatment of dsyphagia. The long term goal is to establish a pharmacological treatment for both disorders that can be applied during the subacute stage of stroke when neglect and dysphagia are most problematic for rehabilitation. The specific aims are to investigate how perception of stimulus intensity (magnitude estimation) is altered by hypoarousal and how an alteration of magnitude estimation accounts for aspects of neglect and dysphagia. A final specific aim is to determine whether a pharmacological agent approved to treat sleep disorders (modafinil, Provigil) can be used to improve arousal-related deficits in neglect and dsyphagia. This research is significant and it can have a direct and immediate impact on public health. Both neglect and dysphagia are common, disabling conditions associated with stroke that affect up to 300,000 patients annually in the United States. Both disorders impede rehabilitation and they place patients at increased risk for additional injury and hospitalization due either to falls or aspiration pneumonia, respectively. There is no widely effective form of pharmacological treatment for either disorder. We plan to test our aims by measuring arousal, magnitude estimation, neglect and dysphagia in unilateral stroke patients both before and after caloric stimulation;shown to temporarily increase arousal and improve neglect. We will also examine, using a placebo-controlled study design with treatment-reversal, whether temporary improvement can identify patients who respond chronically to modafinil (Provigil) therapy. This research can produce breakthrough discoveries both for understanding swallowing impairment in dysphagia and for the management of literally thousands of stroke patients in the US who suffer from neglect and dysphagia during rehabilitation therapy. PUBLIC HEALTH RELEVANCE: Project Narrative This proposal aims to improve public health in the US by establishing a pharmacological treatment standard for neglect and dysphagia that could be made available to stroke patients immediately. Stroke affects 600,000 patients annually in the United States. Between 20 and 45% of stroke patients have either neglect, dysphagia or both disorders. Neglect is a leading predictor of poor rehabilitation outcome and a major cause of additional injury due to falls. Dysphagia can lead to respiratory complications, aspiration pneumonia, and even death. There is no widely effective pharmacological treatment for either disorder at the present time.

DESCRIPTION (provided by applicant): Subjective tinnitus is perception of sound like ringing, buzzing, or hissing in the absence of external stimulation. Tinnitus is a significant neurological disorder that affects 51 million US citizens. There is no cure. Twelve million patients seek treatment for disturbances of sleep, affect and concentration and 3 million are unable to function occupationally. Current treatments do little to actually reduce tinnitus perception. In contrast, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of regional brain stimulation that can significantly reduce subjective tinnitus in 50% of patients; however, the treatment effect is temporary, lasting 1 to 2 weeks after a week-long course of standard treatment. Our preliminary work indicates that this limitation can be overcome by changing the way rTMS is applied. We have observed that the rTMS effect on tinnitus is very reliable among persons who respond positively to a standard course of treatment (i.e., treatment responders) and that reapplying rTMS when tinnitus returns (i.e., maintenance treatment) produces added benefits that are sustained over time. We hypothesize that maintenance rTMS works by reversing pathological processes which are set in motion by a loss of normal sensory input (i.e., a thalamocortical dysrhythmia) and we will test this hypothesis using high density EEG recordings before and after treatment. We expect that maintenance treatment will improve tinnitus in an additive fashion and that it will impede relapse relative to standard treatment and to a sham-treatment control. We will focus the study on 30 treatment responders who will receive sham and active maintenance rTMS using a blinded study design with treatment crossover. Thirty non responders will be studied to learn what patient characteristics predict a treatment response. Maintenance treatment will consist of four, 3-day courses of rTMS separated by fixed 3-week intervals. Primary outcome measures will include a questionnaire of tinnitus severity, visual analogue ratings of tinnitus loudness and annoyance, forced- choice measures of improvement/worsening, a physically anchored measures of tinnitus frequency and loudness and the spectral power and coherence of EEG frequency bands. The timing and duration of maintenance treatment effects will be assessed by counting the number of days between the end of a course of treatment and the return of tinnitus. Follow-up assessment will be conducted at 3 months to evaluate change in the primary outcome measures and in the baseline assessments of clinical, behavioral, emotional, and perceptual aspects of tinnitus related to quality of life. Analyses will compare change scores from baseline on the primary outcome measures between standard and active maintenance treatment and between active and sham maintenance treatment. Attrition and missing data will be treated with subject replacement. This project is significant because it has potential to produce a treatment that decreases tinnitus perception chronically. Our innovative approach of using maintenance rTMS can shift current paradigms and models of how rTMS is applied in other clinical disorders treated with rTMS. We expect maintenance rTMS to benefit half of patients with tinnitus. We anticipate that these findings will support larger, multisite trials that can establish rTMS as a frst line treatment approach for tinnitus and gain FDA approval for this use.

The Human Electrophysiology Core Facility has the goals of providing, a) innovative services that move the field fonward, b) extensive training for research personnel in quantitative noninvasive recording as well as brain stimulation in human subjects, and c) reliable and reproducible results based on sound experimental design and standardized experimentation. This (Ziore includes pioneering Recording and Stimulation methodologies with a strong history of innovation. The P50 potential is a sleep-state-dependent midlatency auditory evoked response that provides a quantitative measure of, a) the level of arousal through the amplitude of the first response of a pair of stimuli, and b) the level of habituation, and the process of sensory gating, through the amplitude of the response to the second stimulus as a percent of the response to the first. That is, the P50 potential is a noninvasive measure of brainstem-thalamus processing of arousal/preattentional mechanisms. The P50 potential has higher amplitude and/or reduced habituation in disorders that manifest hyperarousal, e.g. schizophrenia, anxiety disorder, depression, Parkinson's disease (PD). The P50 potential has lower amplitude in disorders that manifest hypoarousal, e.g. autism, Alzheimer's disease, Huntington's disease, coma. The psychomotor vigilance task (PVT) is a test of behavioral alertness and involves a simple reaction time (RT) designed to evaluate the ability to sustain attention and respond in a timely manner to salient signals. That is, the PVT is a noninvasive measure of thalamocortical processing of attentional mechanisms. We also have capacity for electroencephalographic (EEG) and electromyographic (EMG) recordings and analysis, usually used in conjunction with TMS studies to determine motor evoked potentials. Other tests, including an operant test battery (measures timing behavior, short-term memory, learning behavior, etc.) and near infrared spectroscopy (NIRS) (measures changes in hemoglobin concentration and redox state of cytochrome oxidase, as well as the ratio of oxygenated to total tissue hemoglobin in the frontal lobes from sensors affixed to the forehead) are also available. This Core allows the rapid (<1 hr) assessment of various levels of the neuraxis, from the brainstem to the thalamus to the cortex to the frontal lobes in human subjects. This Core also supports the common goal of making transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) (both non-invasive forms of brain stimulation) tools for studying disease processes, treating symptoms, and ultimately making them available as a treatment; although, the studies themselves represent different applications and different stages of the translational research cycle. TMS is regarded by the FDA as an investigational device, and it was only recently granted limited approval for the treatment of depression. Our clinical trials using repetitive TMS (rTMS) to treat tinnitus are specifically designed to translate clinical findings into general medical practice by laying the foundation for a large-scale trial that can gain FDA approval for this application. For example, our initial efforts to apply rTMS for the treatment of tinnitus prompted this Core to develop a realistic placebo or sham rTMS technique, one of the best in the field, and described below. In general, the clinical usefulness of rTMS has outpaced knowledge of its neural mechanisms of action and there is a great need for basic science studies of rTMS. For example, we conducted a clinical trial of TMS to alter cognition and behavior in persons who are tobacco-dependent. This study examined whether and how TMS influences reward systems in smokers who are either satiated or withdrawn from nicotine. We carried out a parallel study in the Animal Electrophysiology Core of rTMS effects in rodents exposed to smoke that afforded a greater opportunity to examine neural mechanisms of action. Other ongoing studies that use brain stimulation as a clinical treatment include the use of tDCS to augment gait recovery in stroke patients by increasing cortical activation prior to training, and will inform the design of future clinical trials in human subjects that are necessary to translate TMS and tDCS into clinical practice.