Adam J. Woods, PhD - US grants

ABSTRACT: This randomized clinical trial will test whether transcranial direct current stimulation (tDCS) of frontal cortices enhances neurocognitive and functional outcomes achieved from cognitive training in older adults experiencing age-related cognitive decline. Change in well-validated measures of neurocognitive function and everyday abilities will serve as outcome measures. Functional and structural neuroimaging biomarkers of neural plasticity and learning (fMRI, GABA MRS, etc.) will measure intervention-associated alterations in specific brain regions impacted by cognitive aging. tDCS is a noninvasive brain stimulation method that facilitates neural plasticity and learning. Accordingly, when used as an adjunctive intervention, tDCS may augment cognitive training effects. This study will leverage existing multisite clinical trial infrastructure at McKnight Brain Institutes located in two of the states with the largest representation of older adults in the United States: University of Florida, University of Miami, and University of Arizona. Adults over the age of 65 represent the fastest growing group in the US population. As such, age-related cognitive decline represents a major concern for public health. Recent research suggests that cognitive training in older adults can improve cognitive performance, with effects lasting up to 10 years. However, effects are typically limited to the tasks trained, with little transfer to other cognitive abilities or everyday skills. Effects may also be reduced in people with Alzheimer's disease risk factors. A two-phase multisite randomized clinical trial will examine the individual and combined impact of pairing cognitive training with transcranial direct current stimulation (tDCS) in older adults experiencing age-related cognitive decline (n = 360; 120 per site). Participants will consist of elderly men and women 65-90 years of age with evidence of age-related cognitive decline, but not MCI or Alzheimer's disease (MoCA?25). We will compare changes in cognitive and brain function resulting from CT and CT combined with tDCS using a comprehensive neurocognitive, clinical, and multimodal neuroimaging assessment of brain structure, function, and metabolic state. Functional magnetic resonance imaging (fMRI) will be used to assess brain response during working memory, attention, and memory encoding; the active cognitive abilities trained by CT. Proton magnetic resonance spectroscopy (MRS) will assess markers of neural plasticity, GABA concentrations, and cerebral metabolism. We hypothesize that: 1) tDCS will enhance neurocognitive function, brain function, and functional outcomes from CT; 2) Effects of tDCS on CT will be maintained up to 12 months following training, and 3) Neuroimaging biomarkers of cerebral metabolism, neural plasticity (GABA concentrations) and functional brain response (fMRI) during resting vs. active cognitive tasks will predict individual response to tDCS, with certain Alzheimer's risk factors (e.g., APOE4 genotype, family history of Alzheimer's disease) predicting poorer cognitive and functional outcome. To date, no studies have comprehensively examined combined CT and tDCS intervention in the elderly. This study will provide definitive insight into the value of combating cognitive decline in a rapidly aging US population using tDCS with cognitive training.

? DESCRIPTION (provided by applicant): This project will answer important questions regarding remediation of cognitive decline in older adults and address two critical areas of training: advanced imaging (magnetic resonance spectroscopy, functional connectivity) and cognitive/clinical aging interventions (cognitive training). The PI is a cognitive neuroscientist wth a strong background in transcranial direct current stimulation (tDCS), cognition, and electrophysiology, as well as a basic understanding of magnetic resonance imaging. The K01 will provide protected time and training to focus his research career firmly in cognitive aging, specifically focusing on the development of novel non- invasive treatments for age-related cognitive decline. This training will afford the knowledge required to translate his basic science expertise into clinical translational applications in aging populations. The current study will investigate a method for enhancing cognitive training effects in healthy older adults and improving functional transfer of skills by employing a combined intervention approach targeting facilitation of neural plasticity and optimal learning state. Adults over the age of 65 represent te fastest growing portion of the US population. As such, age-related cognitive decline represents a major concern for public health. Recent research suggests that cognitive training in older adults can have lasting effects on performance, lasting up to 10 years. However, these effects are typically limited to the tasks trained, with little transfer to other cognitive abilities or evryday skills. This study will examine the impact of pairing cognitive training with tDCS. Individual effects of tDCS and cognitive training on cognitive, functional, and neuroimaging measures will be assessed. tDCS is a non-invasive brain stimulation method that directly stimulates brain regions involved in active cognitive function and enhances neural plasticity when paired with a variety of cognitive tasks. We will compare changes in cognitive and brain function resulting from cognitive training and cognitive training combined with tDCS using a comprehensive neurocognitive, clinical, and multimodal neuroimaging assessment of brain structure, function, and metabolic state. Functional connectivity from functional magnetic resonance imaging (fMRI) will be used to assess the coherence of brain response during working memory and focused attention; the active cognitive abilities trained by cognitive training. Proton magnetic resonance spectroscopy (MRS) will assess cerebral metabolites, including GABA concentrations sensitive to neural plasticity in task-associated brain ROIs. We hypothesize that: 1) tDCS will enhance neurocognitive function, brain function, and functional improvements from cognitive training; 2) Effects of tDCS on cognitive training will be maintained up to 3 months following training; and 3) Neuroimaging biomarkers of cerebral metabolism, neural plasticity (GABA concentrations) and coherence of functional brain response (fMRI) in default network and functionally relevant brain regions will predict individual response to cognitive training and tDCS.

Project Summary/Abstract: Working memory is an essential cognitive faculty. Individual differences in working memory functioning can be quantified by working memory capacity (WMC). Higher WMC enables better performance in a diverse set of cognitive operations, including attention, reading comprehension, planning, and problem solving. There is evidence suggesting that higher WMC even confers the individual with the ability to better resist cognitive impairments in brain disorders. Despite its importance as a psychological construct, the neurophysiological underpinnings of WMC, however, remain not well understood. We will address this issue by pursuing Aim 1 in which we will investigate the individual differences in the task-related modulation of frontoparietal theta oscillations during working memory encoding and retention. Specifically, we will test the hypotheses that frontal theta power and frontoparietal theta coherence decrease with increasing working memory load during encoding and increase with increasing working memory load during retention and that theta modulation by working memory load during encoding and retention is positively correlated with working memory capacity. Research to date on the relation between neuronal oscillations and cognition tends to be correlative. Noninvasive neuromodulation provides a means to uncover the causal role of neuronal oscillations in cognition. In Aim 2 we will test the efficacy of tACS stimulation at theta frequency in enhancing task-related theta modulation and working memory capacity. Specifically, we will test the hypotheses that in-phase theta tACS stimulation of the frontoparietal network upregulates task-related modulation of theta oscillations in working memory and enhances working memory capacity and that individuals with low working memory capacity will benefit more from in-phase theta tACS stimulation than individuals with high working memory capacity.

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.

ABSTRACT: This randomized clinical trial will test whether transcranial direct current stimulation (tDCS) of frontal cortices enhances neurocognitive and functional outcomes achieved from cognitive training in older adults experiencing age-related cognitive decline. Change in well-validated measures of neurocognitive function and everyday abilities will serve as outcome measures. Functional and structural neuroimaging biomarkers of neural plasticity and learning (fMRI, GABA MRS, etc.) will measure intervention-associated alterations in specific brain regions impacted by cognitive aging. tDCS is a noninvasive brain stimulation method that facilitates neural plasticity and learning. Accordingly, when used as an adjunctive intervention, tDCS may augment cognitive training effects. This study will leverage existing multisite clinical trial infrastructure at McKnight Brain Institutes located in two of the states with the largest representation of older adults in the United States: University of Florida, University of Miami, and University of Arizona. Adults over the age of 65 represent the fastest growing group in the US population. As such, age-related cognitive decline represents a major concern for public health. Recent research suggests that cognitive training in older adults can improve cognitive performance, with effects lasting up to 10 years. However, effects are typically limited to the tasks trained, with little transfer to other cognitive abilities or everyday skills. Effects may also be reduced in people with Alzheimer?s disease risk factors. A two-phase multisite randomized clinical trial will examine the individual and combined impact of pairing cognitive training with transcranial direct current stimulation (tDCS) in older adults experiencing age-related cognitive decline (n = 360; 120 per site). Participants will consist of elderly men and women 65-90 years of age with evidence of age-related cognitive decline, but not MCI or Alzheimer?s disease (MoCA?25). We will compare changes in cognitive and brain function resulting from CT and CT combined with tDCS using a comprehensive neurocognitive, clinical, and multimodal neuroimaging assessment of brain structure, function, and metabolic state. Functional magnetic resonance imaging (fMRI) will be used to assess brain response during working memory, attention, and memory encoding; the active cognitive abilities trained by CT. Proton magnetic resonance spectroscopy (MRS) will assess markers of neural plasticity, GABA concentrations, and cerebral metabolism. We hypothesize that: 1) tDCS will enhance neurocognitive function, brain function, and functional outcomes from CT; 2) Effects of tDCS on CT will be maintained up to 12 months following training, and 3) Neuroimaging biomarkers of cerebral metabolism, neural plasticity (GABA concentrations) and functional brain response (fMRI) during resting vs. active cognitive tasks will predict individual response to tDCS, with certain Alzheimer?s risk factors (e.g., APOE4 genotype, family history of Alzheimer?s disease) predicting poorer cognitive and functional outcome. To date, no studies have comprehensively examined combined CT and tDCS intervention in the elderly. This study will provide definitive insight into the value of combating cognitive decline in a rapidly aging US population using tDCS with cognitive training.

Revised Title: Research Training in Non-Pharmacological Interventions for Cognition in Aging, MCI, and Alzheimer?s Disease Revised Project Summary/Abstract This competitive renewal application requests continuation of a 15-year predoctoral training program at the University of Florida (UF). Funds are requested for six (6) predoctoral trainees. The program focuses on research training in non-pharmacological interventions for cognitive aging (CA), mild cognitive impairment (MCI) and Alzheimer?s disease (AD) with three substantive emphases: (a) behavioral interventions (e.g., cognitive training, exercise, mindfulness); (b) multi-component compensatory interventions; and (c) neuromodulation/stimulation interventions for older adults with and without MCI- and AD-related cognitive impairment. We have three levels of preceptors: Mentors are tenured senior scientists with predoctoral training track records. Senior advisors are field leaders (often center directors, and physician-scientists) who often do not directly supervise predocs, but provide infrastructure (grants, center resources, data sets) and will serve on mentoring committees. Mentors-in-training (M-i-T) are untenured junior PhDs with research programs; they will receive mentoring training (e.g., UF Mentoring Academy) and will be coupled with a senior mentor as co-mentors for trainees, and are expected to enhance the diversity of the pipeline of future mentors. Disciplines represented in this proposal include applied physiology and kinesiology, biomedical engineering, communication sciences, geriatrics, neuroscience/neurology, nursing, occupational therapy, psychology, public health, and social epidemiology. Core program components include (1) assignment of each student to a frequently convened multi-disciplinary mentoring team (2) formation and close tracking of individual developmental goals in the areas of research, education, and service; (3) regular training director meetings to consider protection of human research participants, theory/method/past findings in cognitive interventions, rigor and reproducibility, and professional development; (4) required supplemental coursework and other didactics in interventions to be used with CA, MCI and AD, statistics/methodology, responsible conduct of research, and rigor and reproducibility. Preference is given to students who have completed doctoral qualifying examinations, thereby selectively investing resources in committed, productive students who have already completed major program milestones. Proposed changes to the program include: (a) leveraging enhanced capacity at UF to focus more strongly on interventions to be used with CA, MCI and AD; (b) increasing mechanisms for trainees to engage in collaborative team science; and (c) introducing a mentor-in-training role to create a diverse pipeline of future mentors. Progress to date: Of 37 trainees to date, 27 (73%) were women, 11 (30%) were members of under-represented racial/ethnic minorities. Twelve (12) trainees remain in training (student, intern, post-doctoral fellow). Twenty-five (25) trainees are post-training with 22 (88%) in research intensive or research related positions, including :16 (64%) associate/assistant professors, 3 (12%) research scientists and 2 (8%) administrators; 17 (68%) in Research 1, 2 (8%) in Research 2, and 3 (12%) in VA institutions.

ABSTRACT There is a pressing need for effective interventions to remediate age-related cognitive decline and alter the trajectory toward Alzheimer?s disease. The NIA Alzheimer?s Disease Initiative funded Phase III Augmenting Cognitive Training in Older Adults (ACT) trial aimed to demonstrate that transcranial direct current stimulation (tDCS) paired with cognitive training could achieve this goal. The present study proposes a state of the art secondary data analysis of ACT trial data that will further this aim by 1) elucidate mechanism of action underlying response to tDCS treatment with CT, 2) address heterogeneity of response in tDCS augmented CT by determining how individual variation in the dose of electrical current delivered to the brain interacts with individual brain anatomical characteristics; and 3) refine the intervention strategy of tDCS paired with CT by evaluating methods for precision delivery targeted dosing characteristics to facilitate tDCS augmented outcomes. tDCS intervention to date, including ACT, apply a fixed dosing approach whereby a single stimulation intensity (e.g., 2mA) and set of electrode positions on the scalp (e.g., F3/F4) is applied to all participants/patients. However, our recent work has demonstrated that age-related changes in neuroanatomy as well as individual variability in head/brain structures (e.g., skull thickness) significantly impacts the distribution and intensity of electrical current induced in the brain from tDCS. This project will use person-specific MRI-derived finite element computational models of electric current characteristics (current intensity and direction of current flow) and new methods for enhancing the precision and accuracy of derived models to precisely quantify the heterogeneity of current delivery in older adults. We will leverage these individualized precision models with state-of-the-art support vector machine learning methods to determine the relationship between current characteristics and treatment response to tDCS and CT. We will leverage the inherent heterogeneity of neuroanatomy and fixed current delivery to provide insight in the not only which dosing parameters were associated with treatment response, but also brain region specific information to facilitate targeted delivery of stimulation in future trials. Further still, the current study will also pioneer new methods for calculation of precision dosing parameters for tDCS delivery to potentially optimize treatment response, as well as identify clinical and demographic characteristics that are associated with response to tDCS and CT in older adults. Leveraging a robust and comprehensive behavioral and multimodal neuroimaging data set for ACT with advanced computational methods, the proposed study will provide critical information for mechanism, heterogeneity of treatment response and a pathway to refined precision dosing approaches for remediating age- related cognitive decline and altering the trajectory of older adults toward Alzheimer?s disease.