Suzanne Corkin - US grants

The overall goal of the proposed research is to investigate brain mechanisms underlying normal human perception, cognition, and action; the approach will be study patterns of sparing and loss of function in patients with selected cerebral lesions. This inquiry, grounded both in neuroscience and in cognitive science, relates the specific deficits that follow brain injury to theories of brain organization and to the interplay of cognitive systems. The aspects of behavior that we have selected include memory, cognitive functions other than memory, and sensory and sensorimotor capacities ranging from simple to complex. Two groups of subjects will be studied: men with cerebral injuries sustained during World War II or the Korean Camgaign; and men and women with amnesias of several different etiolgies, resulting from damage to various discrete brain structures. Control subjects will include World War II veterans with peripheral nerve injuries, healthy Korean Campaign veterans, and normal civilian subjects. All of the veterans previously participated in neuropsychological studies in our laboratory or its predecessor, H.-L. Teuber's laboratory at Bellevue Hospital in New York. The proposed work represents 15-year to 40-year follow up studies in these men. The amnesic patients, many of whom have already been identified, are referred regularly by our consultants at local hospitals. All veterans, amnesic patients, and control subjects will be admitted to the MIT Clinical Research Center for extensive neuropsychological examination.

Investigations of amnesia have contributed to our understanding of the neurology of memory. Amnesia occurs in a variety of neurological conditions following damage to either of two regions of the brain: the diencephalic region surrounding the third ventricle and the medial temporal-lobe region. There appear to be important differences between the amnesic syndromes produced in these two cases, both with respect to the presence of concomitant deficits that interact with the expression of the memory disorders and with respect to the nature of the memory disorders themselves. There are other etiologies of amnesia in which the link to diencephalic or temporal-lobe regions is less clear. Notable among these is the amnesic syndrome that sometimes occurs following successful surgery for anterior communicating artery aneurysm. The neuroanatomical substrate of this amnesic syndrome has not been described; little is known about its relationship to diencephalic and temporal-lobe amnesias. The proposed research will address these issues by providing the first comprehensive neurological, psychiatric, and neuropsychological characterization of the sequelae of surgery for anterior communicating artery aneurysm. The protocol will include both patients who do and patients who do not develop an amnesic syndrome. The findings will permit us to compare and contrast this syndrome anatomically and behaviorally to other amnesic syndromes, and thereby to determine the nature of this amnesic disorder. We shall administer tests of memory and other cognitive capacities in order to evaluate the effects of non-mnemonic deficits (e.g., linguistic or attentional deficits) on the expression of this form of amnesia. Such findings will contribute to our knowledge of the neurological foundations of memory. Furthermore, the assessment of behavioral capacities outside the domain of memory permits us for the first time to evaluate the syndrome as a whole. This approach should contribute substantially to the clinician's ability to provide a more informed prognosis and program of care for such patients.

We propose to study the long-term safety and efficacy of bilateral cingulotomy, a brain operation performed to relieve severe chronic pain and certain psychiatric disorders that are intractable to more standard therapies. The unique population that we shall study consists of 179 patients who underwent cingulotomy and participated in a prospective study conducted in our laboratory independently of the neurosurgeon. Patients were given rigorous psychiatric evaluations, neurological examinations, and neuropsychological assessments before and soon after operation. Early results indicated therapeutic benefits for a substantial proportion of patients in some diagnostic categories, without significant intellectual impairments. Considerable caution is desirable, however, in drawing conclusions about the value of a psychosurgical procedure. A meaningful evaluation requires a controlled, prospective study of the long-term benefits and dangers of the operation. The proposed follow-up study will permit such an evaluation by documenting, over the next 5 years, the long-term consequences of cingulotomy. We shall readminister all procedures given before and soon after operation in order to quantify changes in psychiatric, chronic pain, neurological, and neuropsychological status. In addition, we shall give new tests that tap the unknown contribution of the cingulate gyrus to human behavior. The combination of repeated and new methods of evaluation will allow us to answer in detail certain questions about the long-term safety and efficacy of cingulotomy and about the limbic system.

cognition; phosphatidylcholines; dietary supplements; nutrition related tag; Alzheimer's disease; neuropharmacology; aging; human subject;

This study will be the first systematic neuropharmacological approach to the monoaminergic system in dementia. The primary goal of this project is to determine the dependence upon monoaminergic systems of specific cognitive abilities and mood in patients with Alzheimer's disease. Accordingly, in separate protocols, we will examine the effects of administering single drugs that increase and decrease noradrenergic turnover; the drugs are yohimbine and clonidine respectively. A related goal of this project is to improve cognitive capacities in patients with Alzheimer's disease by administering drugs that alter monoaminergic neurotransmission. Although the cholinergic hypothesis of memory dysfunction in Alzheimer's disease remains compelling, the finding of multiple neurotransmitter deficits in the Alzheimer's disease brain militates against the success of simple cholinergic replacement therapy. We therefore propose to extend our current studies with cholinergic drugs by combining lecithin (phosphatidylcholine, or PC) with clonidine or yohimbine and, in a separate protocol, PC with tryptophan (TRY), a drug that increases the synthesis and release of serotonin (5-HT). Patients with Alzheimer's disease will be selected according to strict inclusion and exclusion criteria. The protocols call for measurements of neurological signs, psychiatric state, neuropsychological test performance, and neurotransmitter markers in plasma and cerebrospinal fluid (CSF). Special emphasis will be placed upon the development and implementation of new tests that improve the characterization of specific cognitive deficits in Alzheimer's disease, and on the use of these tests as measures of change induced by drugs. Tests of forgetting, attentional focusing, and praxis will be highlighted. The results of this research will provide new information regarding the biochemical substrates of cognition.

learning; disease /disorder; aging;

somesthesis; sensory mechanism; olfactions; auditory discrimination; visual perception; sensory disorder diagnosis; neurophysiology; brain disorder diagnosis; sign /symptom; neurologic manifestations; neuroanatomy; neurofibrillary tangles; neural degeneration; human subject; Alzheimer's disease;

Obtain multiple measures of fact-learning, skill learning and priming effects in patients with Alzheimer's Disease, Parkinson's Disease and age- matched control subjects.

The proposed research has four Specific Aims: Specific Aim 1: To administer in each of four sensory modalities (olfaction, vision, somatosensory systems, and audition) tests that sample functions of primary sensory and modality-specific cortical areas. Specific Aim 2: To perform within-subject and group comparisons across the four sensory modalities in order to determine whether AD impairs all senses equally or differentially. Further, we shall determine whether individual subjects show the same pattern of deficit in all modalities, and whether the patterns are uniform across subjects. Specific Aim 3: To assign probability scores indicating the likelihood that a proband has familial AD (FAD) or sporadic AD (SAD), and to describe the relation between the presence, nature, and severity of sensory disorders and the probability of FAD or SAD. Specific Aim 4: To determine at autopsy the neuropathological substrates that could account for patterns of sparing and loss in sensory functions noted in the living patient. In collaboration with the Neuropathology Core of the Massachusetts Alzheimer's Disease Research Center (ADRC) we shall explore case-by-case correlations between the magnitude of specific sensory deficits and the regional and laminar neuropathological changes in each of the four sensory systems. In order to achieve these Specific Aims, we shall assess 90 AD patients, 60 elderly control subjects, and 60 young control subjects over a 3-year period, examining a range of sensory capacities in four modalities: olfaction, vision, somatosensory systems, and audition. We shall examine each sensory modality in each subject. We shall achieve a full sampling of sensory capacities by administering tests from the old and new protocols. This multidisciplinary study draws upon expertise in psychophysics, behavioral neuroscience, neurology, neuro-ophthalmology, genetic epidemiology, and neuropathology. The research takes advantage of components of the Massachusetts ADRC, including its AD patient population, Data Management Facility, and Brain Tissue Resource Center.

The hypothesis that phantom limb results from the reorganization of central neural structures will be evaluated. The investigators will examine whether somatosensory perception is altered following deafferentation.

One hundred normal subjects and one hundred subjects with focal cortical and subcortical lesions in different visual association areas will be studied. Administration of a spectrum of psychophysical tests to assess specific visual capacities at basic and intermediate levels of visual function to document the deficits that focal lesions produce. This will also delineate homologies between human and monkey brains.

This study is designed to examine the safety, tolerability, and preliminary efficacy of a single intravenous dose of CNS 1102 in patients with Parkinson's disease.

To use novel high-speed fMRI methods to (a) obtain clues about the neural substrates ofspecific cognitive changes in aging and AD, (b) document individual differences in those changes, and (c) identify neurophysiological markers that may signal very early AD. In order to achieve these goals, we shall perform 60 fMRI studies per year over a 5- year period in subjects with AD, older control subjects, and young control subjects. We shall examine correlations between fMRI signal and behavior in three cognitive domains that are vulnerable to the effects of aging and AD: long-term explcit memory, visual perception, and motor control.

DESCRIPTION (adapted from investigator's abstract): Of the many components of cognition affected in Alzheimer's disease (AD), two particular cognitive domains have special clinical relevance: tests of episodic memory (delayed recall and recognition) are highly sensitive for detecting AD, and tests of semantic retrieval (naming and fluency) are best for staging the disease and tracking its progression. Documenting the anatomical and physiological correlates of these impairments in the living subject gives insights into the distribution of the underlying anatomical and functional brain lesions that produce AD. To pursue this approach, and thereby extend understanding of brain-behavior relations in aging and AD, the investigators propose to conduct a series of experiments over 3 years relating cognitive test performance in these two domains to hippocampal volume and to patterns of neural activation measured with functional magnetic resonance imaging.

This study continues two long-term projects that examine the consequences of non-penetrating and focal penetrating head injury with respect to age- related decline in cognitive, sensory and motor function.

Doctoral Dissertation Research: Effect of Attention on Memory for Negative and Neutral Words.

Abstract

With National Science Foundation support, Elizabeth Kensinger and Dr. Suzanne Corkin will conduct a one-year neuroimaging study as part of Ms. Kensinger's doctoral dissertation. The study is aimed at uniting two areas of research: the detrimental effects that divided attention has on a person's ability to learn information, and the memory enhancing effects of emotion. When our attention is divided as we attempt to learn information, memory suffers. Ample behavioral data support this conclusion, yet the changes that occur in the brain have not been fully explored. Using functional magnetic resonance imaging (fMRI) the proposed studies will investigate what network of brain regions is recruited as a person attempts to learn information while performing a difficult distractor task. The studies will also examine the neural cirtuitry involved in later retrieval the information that was learned under that attention demanding condition. It is also not known how divided attention affects memory for information that we typically remember very well, for example, emotional information. Daily experiences are often infused with an emotional richness that has typically been absent, and even actively avoided, in experimental studies of learning and memory. Although behavioral studies have shown that individuals remember emotional stimuli better than neutral, it is unclear how manipulating the attentional resources available at the time of learning affects memory for emotional stimuli. The proposed studies will examine the behavioral effect of divided attention on memory for emotional as compared to neutral stimuli. The proposed behavioral and fMRI studies together will advance knowledge about the effects of attention on memory for neutral and emotional verbal stimuli.

[unreadable] DESCRIPTION (provided by applicant): The material and memories of everyday life are often infused with an emotional relevance that is not present, and may even be avoided, in traditional studies of memory in aging. To date, few studies have investigated the cognitive and neural substrates of emotional memory in older adults, and none has investigated behavior, brain structure, and brain physiology in a single study of emotional memory in any participant group. To fill this gap, we will adopt a two-pronged approach: a series of behavioral experiments that will show the extent to which emotional valence conveys a benefit on the quantity and, significantly, the quality of information remembered by older adults; and related structural and functional magnetic resonance imaging experiments using advanced technology. These investigations will allow us to uncover the neural structures that underlie emotional memory in younger adults, and altered and preserved emotional memory circuits in older adults. In young adults, memory is typically better for emotional as compared to neutral stimuli. Evidence from our laboratory and others suggests that older adults also show enhancement based on emotional valence. It is unclear, however, whether normal aging affects the cognitive or neural mechanisms supporting a specific component of emotional enhancement: the increased ability to remember rich details of a negative event. This question is of particular interest because older adults have difficulty recalling specific details of non-emotional events (as compared to remembering the gist of the events). Recollective memory for neutral items is thought to rely on the hippocampal formation, and we predict that the recollective enhancement for emotional stimuli results from connections between the amygdala, other medial temporal lobe structures, and prefrontal cortex. In contrast to older adults' ability to show enhancement based on the arousal or valence of an item, we found that older adults do not show enhancement for neutral stimuli embedded in a negative versus a neutral context. A second goal of the proposed research is to examine whether this deficit is present across a range of stimuli, and whether the impairment is related to dysfunction of specific brain regions. Because of the particular role of prefrontal cortex in binding an item to its context, or source memory, we propose that older adults' reduced enhancement may be due to structural or functional alterations in prefrontal cortex.