Eric Granholm - US grants

DESCRIPTION (provided by applicant): Identifying treatments to reduce the negative symptoms associated with schizophrenia is of high public health significance, due to the relationship between negative symptoms and poor functioning and quality of life, and the lack of effective treatments for negative symptoms. There is also a need for treatments of cognitive impairment to improve daily functioning in schizophrenia. Pharmacologic treatments for negative symptoms and cognitive/functional impairment have largely failed, but psychosocial treatments have been moderately effective. Two interventions, Cognitive Behavioral Social Skills Training (CBSST) and Compensatory Cognitive Training (CCT), show promise for treating negative symptoms (Granholm et al., 2005, 2007, 2012; Twamley et al., 2008, 2012), along with other symptoms, cognition, and functioning. Because of the significant effects of both CBSST and CCT on negative symptoms, we aim to develop a combined CBSST-CCT intervention specifically targeted toward negative symptom reduction, and to gather pilot data regarding its efficacy. CBSST (Granholm) and CCT (Twamley) are both manualized, group-based interventions that can be delivered in community settings to enhance generalization of training effects. CBSST combines elements of Cognitive Behavioral Therapy with Social Skills Training, two of the evidence-based treatments for schizophrenia. CCT uses compensatory strategy training and habit learning to improve cognition and everyday functioning. Both interventions have significant but moderate effects on negative symptoms (e.g., .4 at follow-up). The proposed project will bundle and refine a combined CBSST-CCT intervention to strengthen their impact on negative symptoms in schizophrenia and will test this combined intervention in a pilot randomized controlled trial comparing CBSST-CCT with a goal-focused supportive contact (SC) control group. We propose to randomly assign 64 participants with schizophrenia with persistent negative symptoms to one of the two treatments for 9 months, and follow them for 3 months after treatment. The primary goal of this project is to obtain feasibility and effect size data regarding this new intervention in order to plan a larger trial of CBSST-CCT. The primary outcome is negative symptom severity, and secondary outcomes include cognitive performance and everyday functioning. We will also examine mechanisms that mediate reduction in negative symptom severity in CBSST- CCT, including defeatist beliefs, cognitive and social skills, and pupillary responses during cognitive and social tasks (a biomarker of goal-directed effort allocation).

? DESCRIPTION (provided by applicant): Schizophrenia is one of the most devastating diseases known to humankind and is one of the top 10 causes globally of profound functional disability. Negative symptoms of schizophrenia account for much of the poor functional outcome in schizophrenia and are an unmet treatment need in a large proportion of patients. We propose to use an experimental therapeutics approach to test a novel psychosocial intervention that combines in-person and smartphone-based cognitive behavior therapy (CBT) for experiential negative symptoms in schizophrenia called, Mobile-assisted CBT for Negative symptoms (mCBTn). mCBTn is a novel extraction and integration of the CBT components that target defeatist attitudes from our cognitive behavioral social skills training (CBSST) group therapy and mobile smartphone interventions from our prior clinical trials research. The primary aim of the project is to test whether mCBTn can reduce severity of a novel treatment target: defeatist performance attitudes. In a promising new model, Beck and colleagues proposed that defeatist attitudes (e.g., Why bother, I always fail, It's not worth the effort) contribute to experientil negative symptoms like amotivation and asociality, and ultimately poor functioning in schizophrenia, because defeatist attitudes lead to avoidance of effortful goal-directed activities. Our approach centers on the hypothesis that defeatist attitudes contribute to experiential negative symptoms, including diminished motivation and effort, which ultimately leads to poor functioning in schizophrenia. In addition, the field currently relies on symptom rating scales and subjective patient reports to measure motivation and effort; more objective measures are needed. The proposed project will determine whether pupillary responses can provide an objective psychophysiological biomarker of effort that is sensitive to change in a clinical trial fr negative symptoms. Greater pupil dilation indicates greater task effort allocation. We propose two sequential clinical trials of mCBTn in consumers with schizophrenia spectrum disorders with persistent moderate-to-severe experiential negative symptoms. In the R61 phase, we propose an open trial to determine whether mCBTn changes the defeatist attitude target and will identify the optimal dose to engage the target. In the R33 phase, we propose an RCT comparing mCBTn with a supportive contact control and will determine whether mCBTn produces greater reduction in defeatist attitudes that mediates improvement in experiential negative symptoms. Pupillary responses will be recorded as a secondary outcome in both trials to determine its potential as an end point in clinical trials of motivation and effort.

Project Summary/Abstract Dementia represents one of the most important public health concerns to affect us in the coming decades. Among the most important research goals will be to identify the earliest, most reliable and easily obtainable markers of degeneration, because early identification of individuals most likely to decline now represents the most promising window for therapeutic interventions. We propose to examine pupillary responses as a novel early biomarker of Alzheimer's disease (AD) pathogenesis and staging. Unlike neuroimaging and cerebrospinal fluid (CSF) biomarkers, pupillary responses can be measured in as little as 5 minutes using a minimally-invasive, inexpensive, simple handheld device that could potentially enjoy widespread utility for screening in the context of a typical doctor's office visit. Pupil dilation recorded during simple cognitive tasks (e.g., digit span) provides a biomarker of the extent of cognitive effort or resource allocation required to achieve a given test score. Pupillary responses may be more sensitive to cognitive decline, because clinically meaningful declines in test scores become manifest only when the capacity to compensate is exceeded. If one person requires more effort to achieve the same score as another, that person is likely to be closer to maximum compensatory capacity and, therefore, is at higher risk for decline. Equally important, pupillary responses reflect locus coeruleus (LC) functioning, and postmortem studies implicate the LC as an early site of AD pathogenesis and degenerative changes with disease progression. Thus, pupillary responses may serve as a specific biomarker of functional alterations in a brain system affected by the earliest manifestations of AD. The proposed study will evaluate a model of LC system alterations across the aging-mild cognitive impairment (MCI)-AD continuum using (1) an innovative pupillometric evaluation of the functional integrity of the LC system, (2) examination of the structural integrity of the LC using recently-developed novel MRI methods, (3) a panel of CSF AD biomarkers (A?, P-tau, and total tau) anchoring participants to the existing pathophysiology involved in AD progression, and (4) innovative diagnostic and staging approaches to characterize the timeline of changes across the aging-MCI-AD continuum. Specifically, we propose to record pupillary responses during cognitive tasks, collect gold-standard CSF biomarkers of AD, and use an innovative MRI methodology to visualize neuromelanin-containing LC nuclei in 128 cognitively-normal (CN) individuals, 64 participants with amnestic MCI (aMCI), and 20 with AD. The specific aims are to determine whether pupillary responses are associated with early risk and staging of AD and whether pupillary responses are associated with LC neuronal degeneration on MRI across the aging-MCI-AD continuum. We predict that the relationship between pupillary responses and risk and progression of AD will be curvilinear following an inverted-U function, such that preclinical individuals at greater risk for AD and aMCI individuals will show compensatory effort (greater pupil dilation), but with advancing disease and greater LC dysfunction, compensatory capacity will be overloaded, resulting in decline in pupil dilation in AD.