Dawn Bowers - US grants

The overall focus of our research is to use an ablative paradigm to learn more about the differential roles played by the left and right anterior temporal regions, particularly the amygdala, in affectively modulating behavior, including the startle eyeblink. The following questions will be asked: (a) Is valence modulation of the startle response differently impacted by right versus left temporal removals involving the amygdala? Recent evidence from humans suggests that the magnitude of the startle eyeblink reflex is augmented during negative affect states and diminished during positive affect states. Although animal studies have targeted the amygdala as a key structure in fear potentiated startle, no human data currently exist concerning which neuroanatomic regions might contribute to startle, or whether hemispheric asymmetries might exist; (b) Is there differential decoupling among other emotion response systems (heart rate, skin conductance, facial EMG, verbal report) due to the integrity of right versus left anterior temporal regions? To date, prior neurobehavioral studies of emotion have relied almost exclusively on evaluation of only one or the other of these response systems of emotion (i.e., only SCR, only HR); and (c) Are finding more consistent with a global right hemisphere versus bivalent model of emotional processing? To address these questions, unilateral right and left anterior temporal lobectomy patients will be studied prior to and following surgical resections. Eyeblink startle responses will be elicited while Ss concurrently engage in affect-eliciting tasks (i.e., viewing pictures, listening to emotional sounds and sentences, or shock-induced anticipatory anxiety) that use standardized sets of emotion-eliciting stimuli. During these tasks, multiple measures of emotional responsivity will be obtained including psychophysiological (HR, bilateral SCR), somatic (bilateral EMG), bilateral eyeblinks, and verbal report. As designed, the proposed studies will enable us to determine how removal of the left versus right anterior temporal regions differentially alter emotional reactivity, and whether their alteration is valence-specific, material-specific, modality-specific, or measure-specific.

From a neurobiological perspective, emotion involves a complex interaction between core limbic structures and overlying cortex. Recent evidence suggests that the two cerebral hemispheres play different roles in modulating the components of emotional behavior, although the precise manner by which this occurs is controversial. The global right hemisphere model posits that neural systems within the right hemisphere are crucially involved in all aspects of emotional behavior. In contrast, the bivalent model posits that anterior regions of the right hemisphere (RH) mediate the experience of negative/withdrawal emotions, whereas the left hemisphere (LH) mediates positive/approach emotions. To address this, patients with strokes of the RH or LH will be presented standardized sets of emotion-eliciting stimuli (affective slides, emotional nonverbal sounds, emotional sentences) that are positively and negatively toned. During these tasks, multiple measures of emotional responsivity will be obtained including psychophysiological (heart rate, bilateral SCR), somatic (bilateral facial EMG), startle eyeblinks, and verbal report measures. As designed, the proposed studies will enable us to determine how focal cortical lesions of the LH or RH differentially alter emotional reactivity, and whether their alteration is valence- specific, material-specific, modality-specific, or "measure" specific. The following questions will be addressed: (a) Is there differential decoupling among the emotion response systems (i.e., HR, SCR, facial EMG, eyeblink, verbal report) due to the integrity of right vs. left cortical regions? To date, prior neurobehavioral studies of emotion have relied almost exclusively on evaluation of only one response system of emotion (i.e., verbal report, or SCR) at a time; (b) Is valence modulation of the startle response differently affected by lesions within the right versus left hemisphere, and is intrahemispheric lesion site important? Recent evidence from normals suggests that the magnitude of the startle eyeblink reflex is augmented during negative affective states and diminished during positive affective states. No human data currently exist concerning which cortical area(s) might contribute to affective modulation of the startle response, or whether hemispheric asymmetries might exist; (c) Are findings more consistent with a global right hemisphere versus a bivalent model of emotional processing?

The purpose of this study is to evaluate emotional behavior before and after surgery for seizure disorders.

DESCRIPTION (Adapted from applicant's abstract): In the neurology literature it is widely known that central nervous system damage can produce forms of psychopathology (e.g., depression, "denial" of illness, acquired psychopathy) that are virtually indistinguishable from their "functional" psychiatric counterparts. The overall focus of our research is to use an ablative paradigm in order to learn more about the role of cortical sites in the affective modulation of behavior. Recent evidence from humans suggests that startle eyeblinks are enhanced during negative affective states and reduced during positive affect. Although animal studies have targeted the amygdala as a key structure in fear potentiated startle and anxiety states, lesions at some cortical sites that relay information to the amygdala appear to attenuate fear potentiated startle in rodents of completely eliminate them following others. No human data currently exist concerning which cortical sites might contribute to affect modulation of startle, or whether hemispheric asymmetries might exist. This is the focus of the investigator's present research. In the proposed studies, the investigator wishes to extend her ongoing funded research in humans with amygdala damage to more broadly encompass individuals with cortical lesions that interact prominently with the amygdala. She hypothesizes that disruption of those cortical systems (e.g., orbitofrontal) that are most closely linked with amygdala will dramatically alter valence modulation of startle and other aspects of emotional behavior. To address this hypothesis, patients with discrete lesions involving orbitofrontal, dorsolateral frontal, or posterior temporal sites within the right or left hemisphere will be evaluated. Eyeblink startle responses will be elicited while subjects concurrently engage in affect eliciting tasks (shock induced anticipatory anxiety, viewing emotional scenes, listening to affective sounds). During these tasks, multiple measures of emotional reactivity will be obtained including verbal report and psychophysiologic measures sensitive to arousal (skin conductance), valence (startle eyeblink, facial EMG), and processing demands. As designed, she hopes to learn whether: a) there is differential decoupling among these emotion response systems due to integrity of particular cortical sites; b) whether valence modulation of the startle response is differently affected by lesions involving frontal or posterior temporal sites; c) whether obtained patterns of findings are more consistent with one of several neuropsychological laterality models of emotion processing (bivalent, right hemisphere, etc.). Hopefully, the obtained data will provide useful information about emotional disorders and psychopathology that occur following dysfunction of specific neural systems within the brain.

Parkinson's disease; face expression; brain mapping; neurosurgery; pathologic process; clinical research; human subject;

DESCRIPTION: (provided by applicant) Facial expressions are complex signals caused by rapid changes in facial muscular activity that are brief and last only a few seconds. Humans typically decode these signals during dynamic interactions in which the face moves. The present proposal aims to fulfill a gap in the literature regarding a well documented, but poorly explained phenomenon. Over the years, numerous studies have shown that the left side of the face is more emotionally expressive than the right. This asymmetry is more predominant for right- than left-handers and seems to occur for both negative and positive expressions. Even nonhuman primates such as the rhesus monkey have been reported to display more intense expressions over the left side of the face. The basis for these asymmetries is unclear. The most popular neuropsychological interpretation has been that this left hemi-face asymmetry is a consequence of a right hemisphere advantage in processing emotional material. Unfortunately, little progress has been made since the late 1970?s to more clearly articulate this position or to evaluate alternative explanations for observations that the left hemi-face is more intensely expressive than the right. The overall purpose of the proposed research is to examine three hypotheses that might contribute to our understanding of hemi-facial movement asymmetries and assess their viability using contemporary state-of-the-art methodologies. The specific aims of this project are: (a) to use trans-cranial magnetic stimulation (TMS) to learn whether the left lower hemi-face receives more cortical influence (either contra-lateral or ipsilateral) and determine whether this relates to behavioral asymmetries in dynamic facial expression; (b) to test the hypothesis of material specific (linguistic, emotion) hemispheric priming of contra-lateral motor systems; and (c) to test the hypothesis of lateralized inhibition of contra-lateral motor systems. A series of 6 studies are planned using cognitive priming, trans-cranial magnetic stimulation, and computer-based systems for digitizing dynamic facial signals. Either singly, or in combination, an increased understanding of these hypothesized mechanisms will likely contribute to our knowledge of expressive asymmetries and provide information that will ultimately be useful for examining emotional communication disturbances associated with psychiatric and neurologic disease in humans.

DESCRIPTION (provided by applicant): The overall goal of this research is to improve understanding of nonverbal communication disorders among patients with neurologic disease. Facial expressions are complex signals that are brief, last only a few minutes and important for communicating intention, motivation, and emotional states. In humans a variety of neurologic and psychiatric conditions alter the propensity to use facial signals. In fact, diminished facial expressivity, or the "masked face" is one of the cardinal features of Parkinson's disease, a neurodegenerative basal ganglia disorder that primarily affects older adults. Classically, it has been held that Parkinson's disease represents a "model system" for impairing spontaneous (limbic) facial emotions, whilst leaving intentionally posed (cortical) facial expressions intact. Preliminary data, using computer imaging methods to quantify dynamic movement changes over the face, tentatively suggests that this dissociation may be unfounded (Bowers et al., in press). The purpose of the proposed research is to apply computing imaging methods to learn: (a) whether diminished facial expressivity among Parkinson patients involves modulatory defects that influence both volitional and spontaneous emotions; (b) whether these modulatory defects are related to dopaminergic deficiency, and (c) which parameters of facial expressivity (timing, frequency, entropy) are improved by a behavioral intervention for treating respiratory strength in PD. Taken together, the findings from this study may facilitate understanding of the mechanisms underlying diminished facial expressivity in Parkinson's disease and provide information that may ultimately be useful in the treatment of nonverbal communication disturbances.

DESCRIPTION (provided by applicant): The overarching goal of the current project is increased understanding of emotional processes in Parkinson's disease. Parkinson's disease (PD) is one of the most common neurodegenerative disorders of late life. It is caused by progressive dopaminergic depletion with motor, cognitive, and emotional changes. While advances have been made with respect to motor symptoms, emotional and neuropsychiatric changes (depression, apathy, anxiety) are prevalent and can be the some of the most disturbing, disabling, and complex aspects of the disorder. Findings from four recent studies of emotional responding have found that non-demented Parkinson patients without psychiatric co-morbidities exhibited blunted physiologic reactivity to aversive pictures as indexed by the startle eyeblink response (Bowers et al., 2006; Miller et al., 2009; Zahodne et al., 2011) or an event related potential component of motivated attention, the late positive potential, LPP (Dietz et al., 2011a). This reduced reactivity to unpleasant stimuli was not due to medication, depression, perceptual difficulties, or failure to generate basic startle or electrocortical activity. One interpretation of this emotional blunting relates to dopaminergic gating and inhibition of the amygdala, a key limbic structure in the emotion processing cascade. In light of these findings, the aims of the present study are to learn whether Parkinson patients can upregulate their responses to emotional stimuli and whether success in doing so is related to integrity of frontal-executive function. To address this aim, two approaches for amplifying emotional reactivity will be taken, one that is more active and self-directed (auto-evoked) and another that is more passive (exo-evoked). Both approaches have been associated with increased physiologic reactivity in healthy controls, as indexed by electrocortical responses (Moser et al., 2009, 2010; Foti & Hajcak, 2008; McNamara et al., 2009). In the current research, non-demented, non-depressed Parkinson patients and healthy controls will participate in two separate studies. Parkinson patients will be psychometrically classified into two cognitive subgroups based on neurocognitive measures: executively impaired (PD-exec) and cognitively normal (PD). During testing, participants will view standardized sets of neutral and emotional pictures while startle eyeblink responses and EEG are recorded. One study will involve use of self-directed regulation strategies to increase reactivity to emotional pictures, and the other study will involve passive listening to narratives that alter subsequent semantic meaning. Primary dependent variables will be amplitude of LPP, startle eyeblink and verbal ratings of valence and arousal. The major hypothesis is that effective regulation of physiologic reactivity to emotional stimuli by PD patients will depend on the integrity of frontal-executive systems. Parkinson patients in the cognitively normal subgroup will show changes in emotional reactivity regardless of active or more passive regulation approaches, whereas PD patients with executive disturbance will benefit only in the passive condition. Relationship to disease variables and neuropsychiatric factors (apathy, anxiety) will be examined. The proposed research will be the first to test whether Parkinson patients can benefit from techniques for bolstering their physiological and emotional reactivity. If predictions are met, the obtained findings may have broad implications for emotional enhancement in Parkinson disease.

? DESCRIPTION (provided by applicant): Movement disorders such as Parkinson's disease, dystonia, and ataxia strip away the ability to act on our environment. Each disease causes unwanted movements, makes desired movements more difficult to perform, and also affects how we think and process our emotions. To be effective, research into movement disorders must cross disciplines, and enhance the translation of basic science discoveries to help humans move more effectively. This Movement Disorders and Neurorestoration Training (MDNR) program confronts this problem head on by bringing together an outstanding group of mentors with a rich infrastructure and resources to train predoctoral Trainees focused on movement disorders. This program combines a critical mass of well-trained scientists prepared to conduct research focused on the ABC'S of translational research: an etiology, biomarkers/end phenotypes, and causative and symptom based therapies. To do so, the program will encompass three areas with a central theme of movement disorders: a) molecular biology and animal models; b) translational neuroscience and physiology, and c) human motor and cognitive neuroscience. Specific approaches within these themes can range from genetics to molecular to neuroimaging to neurorestoration to behavioral, but the central focus is movement disorders. Trainees are selected from a pool of outstanding students with diverse backgrounds and are admitted by one of five graduate programs. A key feature is that Trainees experience laboratories that cross areas, and dissertation committee members must come from each of the three scientific areas. The MDNR program capitalizes on existing strengths and strategic investments at the University of Florida (UF) including well-established investigators in ataxia, Parkinson's disease, atypical parkinsonism, and dystonia, outstanding animal research facilities for basic science, world class animal and human imaging facilities, three privately endowed and foundation supported Centers of Excellence for Parkinson's disease, dystonia, and ataxia, and the UF Center for Movement Disorders and Neurorestoration. This patient-centered clinical research facility maintains the largest, comprehensive clinical research database in the world. Upon entering the program, each trainee prepares an individualized career development plan that consists of a structured didactic program, specialized courses, seminars, and laboratory research. The mentor to mentor interaction that crosses levels of analysis sets up a unique learning environment that will prepare Trainees for a strong future as biomedical scientists that can make a difference in movement disorders. This training program in Movement Disorders and Neurorestoration provides an interdisciplinary training environment that is fundamental to the advancement of research in the etiology and treatment of movement disorders.

Project Summary In addition to cognitive changes, aging is associated with emotional changes such as loss of interest in activities, lowered responding to emotional information, and difficulty in reading emotional cues. These emotional changes occur in normal aging and tend to be pronounced in age-related neurodegenerative disorders such as Parkinson Disease (PD). In addition to psychosocial factors (e.g., loss of spouse, declining health), there is some evidence that age-related dampening of neural response in limbic regions crucially involved in processing of emotion (i.e., anterior insula) may underlie these emotional deficits in aging. The anterior insula supports the integration of internal signals from our body with external signals in our environment and helps us simulate our own emotional states and the emotions of others to better understand how they feel. These processes contribute to successful social interaction and promote well-being. To date, processes in the brain underlying emotional deficits and particularly the extent to which they are malleable have been primarily studied in young adults, while research on older adults and in PD is scarce. The proposed study aims to fill this research gap by applying the highly innovative technology of real-time functional magnetic resonance imaging (rtfMRI) that allows for direct testing of brain-behavior links. Emotional health is relevant to people across all age groups. Thus, it is vital to understand the extent to which and why emotions change as individuals grow older, and to determine processes involved in effective regulation on the level of brain and behavior. In Aim 1, we will examine whether young and older healthy adults and PD patients can learn to up- and down-regulate brain activity in anterior insula. In Aim 2, we will test whether increasing one?s own anterior insula activity can improve the ability to recognize others? emotions and affects responding to emotional cues. In particular, we will assess participants? anterior insula activity in real time and give them continuous feedback about how active it is. We will train participants to increase or decrease activity in anterior insula (or auditory cortex activity as a control) when asked to do so. At pre- and post-training, participants will try to assess the emotions of people seen in pictures as well as regulate their emotional response to images of scenes and objects. Information gained from this project will advance scientific knowledge of the basic mechanistic chain underlying emotion processing in healthy and pathological aging. In addition, our project will implement rtfMRI as a novel neuroimaging technique for the study of brain-behavior connections in older populations.

ABSTRACT There is a great need for effective treatments and prevention therapies that can provide symptomatic and disease modifying benefits for those at risk for Alzheimer?s disease. The proposed multi-site collaborative project brings together research teams at the University of Florida (UF) and University of Arizona (UA) to test a novel, relatively low cost, low risk, and potentially high impact therapeutic intervention in older adults who are at increased risk for Alzheimer?s disease. The intervention involves transcranial and intranasal delivery of near infrared (NIR) light via light emitting diodes, aka photobiomodulation. Prior research in cellular and animal models suggest that red and infrared light are neuroprotective and thought to improve mitochondrial function by promoting increased production of intracellular ATP. Transgenic mouse models of Alzheimer?s disease demonstrate reduced beta-amyloid and neurofibrillary tangles in response to transcranial NIR versus sham stimulation. Preliminary human studies have also shown promising behavioral findings in young adults and those with TBI, aphasia, and Alzheimer?s disease. From our team, pilot phosphorous magnetic resonance spectroscopy (31P MRS) and cognitive data in older adults support this mechanism of action and provide compelling evidence for a Phase II clinical trial. To more fully determine whether this novel stimulation approach has potential for enhancing cognition in cognitively normal but ?at risk? individuals for Alzheimer?s disease, we plan to conduct a multi-site double blinded randomized sham-controlled Phase II clinical trial. Our overall hypothesis is that exposure to NIR stimulation will have beneficial effects on brain health via influence on mitochondrial function as measured by changes in 31P MRS-based markers of ATP, neural network changes in functional connectivity (rs-fMRI), and improved cognitive performance. To test this hypothesis, we plan to randomize 168 older adults with subjective cognitive complaints, and a first-degree family history of Alzheimer?s disease to sham or real treatment groups and evaluate neuroimaging and cognitive outcome measures, before and after a 12-week intervention involving transcranial and intranasal NIR-PBM. The protocol will involve ?lab? and ?home? sessions, and a 3 month post-intervention follow-up. This trial will determine: 1) whether NIR stimulation, relative to sham, improves performance on memory and executive tasks sensitive to hippocampal and frontal brain function in older adults with increased risk for Alzheimer?s disease; 2) whether NIR stimulation, relative to sham, enhances brain function and connectivity measured by changes in MRS phosphorous ATP and resting state functional connectivity; and 3) how differences in demographic, neuroimaging, and Alzheimer-related risk factors influence the brain response to NIR stimulation versus sham in older adults with increased risk for Alzheimer?s disease. Results will provide key insights into whether this novel NIR intervention can enhance cognition in older adults with increased risk for Alzheimer?s disease and will provide the necessary data for a future Phase III randomized clinical trial.