Virginia E. Sturm, Ph.D. - US grants

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Virginia Sturm, a neuropsychology fellow at the University of California, San Francisco Memory and Aging Center (MAC). Dr. Sturm is establishing herself as a young investigator who conducts patient-oriented clinical research on emotion in neurodegenerative disease. This K23 will provide Dr. Sturm with the support necessary to accomplish the following goals: (1) to gain expertise in neurodegenerative disease, differential diagnosis, and behavioral neurology; (2) to advance her knowledge of psychophysiology by learning a new method, facial electromyography; (3) to become proficient in structural and functional neuroimaging analyses; (4) to obtain experience with clinical measures of real-world behavior; (5) to learn advanced statistical techniques; and (6) to develop an independent research career. To achieve these goals, Dr. Sturm has assembled a mentoring team that includes two primary mentors: Drs. Howard Rosen (a neurologist with expertise in neurodegenerative disease, psychophysiology, and structural neuroimaging) and William Seeley (a neurologist with expertise in neuropathology, functional neuroimaging, and resting state network connectivity analyses); two co-mentors: Drs. Bruce Miller (a neurologist with expertise in behavioral neurology, neurodegenerative disease, and clinical research) and Robert Levenson (a psychologist with expertise in psychophysiology, emotion, and empathy); and three consultants: Drs. James Gross (a psychologist with expertise in psychophysiology, facial electromyography, and emotion), John Neuhaus (a biostatistician with expertise in advanced multivariate statistical analyses), [and Gary Glover (an MRI physicist with technical expertise in functional magnetic resonance imaging methodologies)]. The proposed research project focuses on emotional empathy, an automatic affective reaction to others that occurs via physiological and behavioral mirroring mechanisms. Dr. Sturm will use laboratory-based measures of emotion to measure two forms of emotional empathy (i.e., facial mimicry and autonomic reactivity) in patients with behavioral variant frontotemporal dementia (bvFTD), patients with Alzheimer's disease (AD), and healthy control subjects (Aim 1). Dr. Sturm will integrate laboratory measures of emotional empathy with neuroimaging and clinical data in order to identify the neural systems that are related to emotional empathy impairment in bvFTD and preservation in AD (Aim 2) and to determine the real-world behavioral impact of emotional empathy deficits (Aim 3). Data collection will take place at the MAC and at the University of California, Berkeley. [By detailing specific, empathy-relevant, bvFTD-vulnerable neural network, these studies will inform disease models of bvFTD and suggest imaging biomarkers for measuring disease progression and treatment response. Dr. Sturm's K23 training will prepare her to conduct interdisciplinary studies of emotion in neurodegenerative disease and to conduct future studies that detail the neuroanatomical bases of emotional dysfunction in various clinical disorders.]

ABSTRACT Frontotemporal dementia (FTD) is a neurodegenerative disease that is characterized by progressive decline in social behavior, emotion, and language. In behavioral variant FTD (bvFTD), the most common FTD subtype, impairment in emotion and empathy are hallmark features that arise due to degeneration of emotion circuits. Although bvFTD begins in frontoinsula and anterior cingulate cortex, brain regions with known roles in visceromotor emotion generation and autonomic integration, the earliest signs of emotion system dysfunction are unknown. Approximately 40% of FTD cases are genetic and due to mutations in C9ORF72, GRN, and MAPT. Gene-positive mutation carriers offer a novel inroad into early emotion alterations in FTD because these individuals can be identified, studied, and followed during the asymptomatic, preclinical phase of disease and in the early symptomatic clinical phase. Changes in emotion physiology and behavior may occur early in the disease, reflect decline in emotion-relevant brain networks, and relate to affective symptoms. The proposed studies will help to characterize preclinical emotion deficits and their underlying circuitry and to determine whether these deficits are early indicators of decline in FTD. Anatomically-specific markers could be used to monitor symptom progression or to track disease-related dysfunction in clinical trials of asymptomatic or mildly symptomatic individuals. This proposal integrates laboratory measures of autonomic nervous system reactivity and facial expression with multi-modal neuroimaging techniques to identify how emotion systems change in the earliest stages of FTD. We will study 100 asymptomatic gene-positive subjects (50 C9ORF72+, 30 GRN+, and 20 MAPT+), 50 healthy controls (age-matched, gene-negative family members), 40 patients with bvFTD, and 40 older age-matched healthy controls at two annual research visits. Subjects will undergo laboratory testing of emotion in addition to a clinical work-up and structural and functional connectivity magnetic resonance imaging. The central hypothesis of this proposal is that objective measures of emotion physiology and behavior are direct readouts of vulnerable brain systems that can be measured noninvasively and track progression in the in preclinical and early symptomatic phase of FTD. We will address three key aims. In Aim 1, we will isolate the domains of emotional dysfunction in early FTD and determine how specific emotional deficits relate to behavioral and affective symptoms. In Aim 2, we will delineate the neural circuitry underlying identified emotional deficits in bvFTD and preclinical FTD. In Aim 3, we will identify laboratory measures that track emotion network decline over time in early FTD. This project has the potential to advance current models of the biological basis of emotion dysfunction in FTD and other clinical disorders that have similar emotional symptoms but lack obvious brain lesions.

ABSTRACT The majority of research on early Alzheimer's disease (AD) has focused on cognition and has overlooked the possibility that changes in emotion may be one of AD's first manifestations. Molecular positron emission tomography (PET) scans detect elevated uptake of beta amyloid and tau, proteins that are neuropathological hallmarks of AD, in living patients with AD and in those with mild cognitive impairment (MCI), the clinical phase that precedes AD. An amyloid positive (amyloid+) PET scan in cognitively normal adults indicates preclinical AD, a phase that may begin years or decades before cognitive symptoms emerge. In addition to cognitive deficits, alterations in emotion are also common in MCI and AD and reflect changes in the neural systems that support emotion generation and emotion regulation. Declining emotion regulation may signify a pathological aging process and the presence of incipient neurodegenerative changes. Laboratory studies of emotion physiology and behavior have the potential to uncover the biological basis of affective change in AD and to determine how and when AD emotion trajectories diverge from those of normal aging. Individual differences in biological variables including sex and genetics (AD risk factor Apolipoprotein ?4 as well as single nucleotide polymorphisms and gene expression profiles) may modify disease progression or relate to variability in emotion functioning over time. The overall goal of the proposed project is to elucidate the neural systems and genetic factors that underlie emotion change in AD. Anatomically-specific markers of emotion could be used to broaden current conceptualizations of early AD phenotypes, identify subtypes at greatest risk for affective symptoms, monitor symptom progression, or track disease-related decline in clinical trials of asymptomatic or mildly symptomatic individuals. We will conduct a longitudinal study of 200 participants: 50 amyloid negative healthy controls, 50 amyloid+ healthy controls, 50 amyloid+ patients with MCI, and 50 amyloid+ patients with AD. Participants will undergo baseline genetic analyses as well as laboratory assessments of emotion (i.e., autonomic nervous system reactivity, facial expression, and subjective experience) and magnetic resonance imaging at three annual research visits. The central hypothesis of this proposal is that emotion dysregulation is an early feature of AD that can be assessed via objective measures of physiology and behavior, direct readouts of emotion systems. We will address three key aims. In Aim 1, we will determine how early AD emotion trajectories diverge from those of normal aging. In Aim 2, we will identify how emotion circuit decline relates to decreasing emotion regulation over time. In Aim 3, we will examine how sex and genetic variation relate to individual differences in emotion across the AD continuum. This project has the potential to advance current models of the neurobiological basis of emotion change in early AD.

ABSTRACT Changes in emotion and social behavior are early yet overlooked features of Alzheimer's disease (AD). In AD, there is progressive accumulation of beta amyloid (A?) and tau proteins, a pathological process that leads to neurodegeneration and functional connectivity alterations in distributed brain networks. Episodic memory decline is a hallmark feature of typical amnestic AD presentations, but AD can also cause atypical dysexecutive/amnestic, language (i.e., logopenic variant primary progressive aphasia [lvPPA]), and visuospatial (i.e., posterior cortical atrophy [PCA]) syndromes. In typical AD, default mode network dysfunction is accompanied by elevated functional connectivity in the salience network, a system that supports emotion generation and interoception. Enhanced salience network connectivity in AD is associated with greater affective symptoms such as anxiety. Our previous studies have found that specific types of emotional empathy, a rudimentary form of affect-sharing, are elevated in typical AD and relate to default mode network atrophy. Whether emotion elevations are present in atypical AD syndromes is unknown but are suggested by clinical and neuroimaging data. There is emerging evidence that gains in emotional empathy are evident even in preclinical AD, a prodromal phase in which people have signs of AD pathology on biomarker testing but lack cognitive symptoms. A central hypothesis of this proposal is that early neuropathology and neurodegeneration in AD-vulnerable networks disinhibits the salience network and elevates emotion functioning across AD syndromes. A more detailed understanding of emotion in AD will help to improve diagnosis by broadening current conceptualizations of each syndrome, to identify emotion measures that suggest the presence of early AD, and to uncover new biomarkers that change as neuropathology affects emotion-relevant brain networks. In the proposed studies, we will conduct laboratory-based assessments of emotion (i.e., autonomic nervous system activity, facial behavior, and subjective experience) in 200 people with AD, as indicated by elevated A? (A?+) and tau deposition on molecular PET scans (110 amnestic/dysexecutive AD, 45 lvPPA, and 45 PCA), and 150 older healthy controls with and without AD pathology (75 A?+ and 75 A?-) with varying levels of tau pathology. By relating emotion measures to clinical data, structural and functional connectivity, A? and tau burden, and affective symptoms, we will address three key aims. In Aim 1, we will quantify emotion, empathy, and social behavior in AD syndromes and A?+ healthy controls. In Aim 2, we will delineate the structural and functional neural networks underlying emotion alterations across the AD spectrum. In Aim 3, we will elucidate associations among A? and tau pathology, emotion system functioning, and affective symptoms. By forging links among measures of emotion, neural network dysfunction, affective symptoms, and A? and tau deposition, the proposed research will help to broaden models of AD's earliest manifestations and to elucidate how specific neuropathological changes alter emotion systems and relate to affective symptoms.

ABSTRACT Affective symptoms are a common feature of neuropsychiatric disorders that reflect dysfunction in a distributed brain network that supports emotion. How aberrant functioning in a single emotion network underlies a wide range of affective symptoms, such as depression and anxiety, is not well understood. Anchored by the anterior cingulate cortex and ventral anterior insula, the emotion network responds to numerous affective stimuli. A more sophisticated understanding of how the emotion network produces emotions?and how atypical emotion network functioning relates to affective symptoms?will be critical for advancing current neuroanatomical models of neuropsychiatric disorders. Intracranial electroencephalography (iEEG) provides direct estimates of neuronal populations and can be used to map the spatiotemporal dynamics of the emotion network at a millisecond-level resolution. Although functional neuroimaging studies have uncovered little evidence for neural differentiation among emotions, these studies lack the spatiotemporal and spectral resolution to determine whether emotions are characterized by unique neural signatures. The overall goals of the proposed project are to elucidate how emotion network dynamics relate to the behavioral, autonomic, and experiential changes that accompany emotions and to investigate how emotion network dysfunction relates to affective symptoms. Anatomically- specific biomarkers of emotion network dysfunction could be used to guide development of novel treatments, monitor symptoms and treatment response, and improve animal models of affective symptoms. We will study 100 patients with intractable epilepsy undergoing surgery for seizure localization. Subjects with iEEG electrodes within the emotion network will undergo continuous neural and video recordings during a multi-day hospital stay. Naturalistic affective behaviors that subjects display spontaneously throughout their hospitalization, emotional reactivity in response to standardized affective stimuli, and emotional reactions following electrical stimulation of emotion network hubs will be quantified. We will examine how activity within emotion network hubs changes during emotions and how emotion network properties make some individuals more vulnerable to affective symptoms than others. We will address three key aims. In Aim 1, we will determine how emotion network activity relates to naturalistic affective behaviors. In Aim 2, we will uncover the unique neural signatures of discrete emotions and their relations to task-based measures of emotional reactivity. In Aim 3, we will probe whether electrical stimulation of emotion network hubs changes network activity and alters emotions, mood, and anxiety. By utilizing a multidisciplinary approach, the proposed project has the potential to ask novel questions about the neural origins of emotions and to advance current models of the neurobiological basis of emotions and affective symptoms.