Arnold Starr - US grants

We plan to study auditory evoked potentials in both clinical neurological disorders and animal experiments to define neural mechanisms of the generation of these potentials. In particular, we will study in experimental animals the role of pontine auditory structures in generating auditory brainstem components using discrete lesion methods. The generation of middle-latency, long-latency, and endogenous components will be examined using electrical recording and lesion methods in monkeys engaged in an auditory discrimination task. The application of auditory evoked potentials to patients with neurological disorders will be for 1) longlatency and endogenous components during the recovery from coma; 2) the effects of task complexity on endogenous components in dementing illnesses and 3) endogenous components during the catagorization of words in patients with aphasia.

DESCRIPTION: (Adapted from investigator's abstract) The hypotheses to be tested in this project are that the motor system is altered in patients with CFS along with cytokine production and responsiveness. The sequence of neural events intervening between stimulus presentation and motor response will be studied in patients with CFS when relatively rested and again following exercise-induced fatigue. The neuro- physiological measures to be made include sensory event-related potential (that is, auditory brainstem potentials), cognitive event- related potentials in a short-term memory task and pre- movement-related potentials. Also to be measured are excitability changes of motor cortex prior to movement, conductivity velocity of pyramidal tract and sensory- motor cortex responses to muscle afferent activity. Cytokines will be measured in the serum and the cultured supernatants of LPS-stimulated adherent cells and phytohemagglutinin (PHA)-stimulated T cells by ELISA and bioassays. Cytokine mRNA will be measured by MAPPing with polymerase chain reaction (PCR) using specific probes. Cytokine receptors will be analyzed on T cells and macrophages at the mRNA level with PCR and at the protein level by immunoblot using monoclonal antibodies. The results should provide objective measures of fatigue in CFS, localize the alteration of motor responsiveness to particular neural site(s) and to define how motor response changes correlate with cytokine production and cytokine receptor expression.

DESCRIPTION (provided by applicant): This proposal will study a recently recognized form of hearing disorder called auditory neuropathy (AN). Different from cochlear damage, AN is characterized by normal measures of cochlear outer hair cells but abnormal measures of the central auditory pathway beginning with auditory nerve. The hearing disorder typically affects speech comprehension out-of-proportion to the pure tone loss, particularly speech recognition in noise. AN is not rare and accounts for 10 percent of newborns identified as having hearing loss. The disorder occurs in children and adults. In adults the disorder is commonly associated with a peripheral neuropathy. Loss of neural synchrony is proposed as a cardinal mechanism underlying the hearing disorder. The sites of abnormality in AN could include auditory nerve and/or inner hair cells and their synapses with auditory nerve dendrites. Our long-term goals are to understand the AN mechanisms and functions in order to provide a scientific basis for alleviating the hearing deficit in AN subjects. We propose three experiments using both psychophysical and elecrophysiological techniques to characterize: (1) fundamental and complex auditory processes in AN subjects in order to explain their speech recognition difficulty, particularly in noise; (2) distinguish between the site of the disorder as being at auditory nerve or at inner hair cell/synapse complex; and (3) optimize signal processing for AN subjects with cochlear implants. The resultsof our studies could have major impact on the diagnosis, classification, and treatment of auditory neuropathy.

DESCRIPTION: (Adapted from Investigator's Abstract) Results from the prior grant period using electrophysiological recordings support the hypothesis that patients with CFS have a disorder of central motor control. Moreover, recent studies by others using transcranial magnetic stimulation also point to the central auditory pathway as being abnormal in CFS. The patients in our studies showed slowed reaction times in tasks requiring rapid responses and impaired brain activities accompanying motor response preparation. Transcranial magnetic stimulation has demonstrated a premature reduction of motor cortical output in CFS accompanying sustained motor activities. Our goals in the proposed new project are to define the time course of altered motor cortical function in CFS before and after a period of exercise-induced fatigue. The specificity of the abnormalities for CFS will be tested by comparison with a group of patients with clinical depression. The methods of study utilize neurophysiological recordings of slow brain potentials accompanying several different types of response preparation and transcranial magnetic stimulation of motor cortex to measure the extent of reduction of central motor drive.

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the changes in brain and cognitive function that take place before the onset of the clinical symptoms of Alzheimer's disease. Mild cognitive impairment (MCI) is a diagnostic term describing elderly individuals with an isolated episodic memory deficit that is often a transition state between normal aging and Alzheimer's disease (AD). Thus, the study of MCI offers insight into the changes in brain and cognitive function that occur before the widespread cognitive deficits of Alzheimer's disease are present. Neuropathological studies suggest that the degree of neuropathology in the neo-cortex is likely to be a critical difference between MCI and AD. The proposed experiments will evaluate neo-cortical function in MCI using psychological and neurophysiological methods by (1) assessing basic cognitive processes thought to reflect neo-cortical function, and (2) measuring cortical potentials directly, using non-invasive event-related potentials. The Specific Aims are: (1) to test the hypothesis that elementary cognitive functions (processing speed, attention) are impaired in MCI, (2) to test the hypothesis that cortical interactions between prefrontal cortex and sensory cortices are compromised in MCI, and (3) to determine if brain activity and behavioral measures can predict subsequent conversion to AD in individual MCI subjects, using a longitudinal study design. The proposed experiments are important because they will advance our understanding of the brain and cognitive changes that accompany the development of Alzheimer's disease. Experimental findings may also have clinical applications for determining the risk of conversion from MCI to Alzheimer's disease in individual MCI patients, and could provide objective measures of treatment efficacy.