nutrition's impact on

Tuesday, October 15th 1 pm ET/10 am PT

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Aron Barbey, PhD Professor of Psychology Director of the Center for Plasticity Director of the Intelligence, , & Plasticity Initiative University of Illinois at Urbana-Champaign

Affiliations Beckman Institute Bioengineering Program Division of Nutritional Sciences Institute for Genomic Biology Medical Scholars Program Program disclosures

Financial Relationship Commercial Interest

Center for Nutrition, Learning, and , Grant / Research Support Abbott Nutrition, USA

Institute of Inflammation and Ageing, Scientific Advisory Board University of Birmingham, UK

Speakers Bureau

Stock Shareholder

Employee

Other objectives

1. Introduction to research in Nutritional

2. Review advances in nutritional epidemiology: The application of biomarker pattern analysis

3. Learn about methods from neuroscience that enable an investigation of brain health through the application of high-resolution MRI

4. Discuss current directions of research in nutritional cognitive neuroscience on the nature and mechanisms of cognitive aging Cognitive Aging

Hertzog et al., (2008) Cognitive Aging

HertzogHertzog et et al., al., (2008) (2008) How malleable are biologically defined boundaries of cognitive aging and to what extent can diet and nutrition enhance performance across the lifespan? Nutritional Cognitive Neuroscience is an emerging interdisciplinary field of research that seeks to understand nutrition’s impact on human cognition and brain health across the lifespan

Zamroziewicz & Barbey (2016)

University of Illinois at Urbana-Champaign Nutritional Cognitive Neuroscience

•Lutein and Crystallized Intelligence •Omega-3 PUFAs and General Zamroziewicz et al., (2016; Frontiers in Aging Neuroscience) Intelligence Talukdar et al., (2019; Mapping) •Mediterranean Diet and Healthy Zamroziewicz et al., (2017; NeuroImage) Brain Aging Key et al., (2019; Molecular Nutrition and Food Research) •Omega-3/6 Balance and Memory Zwilling et al., (2019; NeuroImage) Zamroziewicz et al., (2017; Aging and ) Zamroziewicz & Barbey (2017; Role of Medi Diet in the Brain) •Omega-3 PUFAs and Traumatic •Omega-3 PUFAs and Executive Brain Injury Hasadri et al., (2013; Journal of Neurotrauma) Functions Zamroziewicz et al., (2015; Frontiers in Aging Neuroscience) Bowman et al., (2013; Frontiers in Aging Neuroscience) • and Executive Functions •Omega-3 PUFAs and Fluid Zamroziewicz et al., (2016; Frontiers in Aging Neuroscience) Intelligence Talukdar et al., (2018; Human ) Zamroziewicz et al., (2017; ) Age-Related Cortical Thinning

Fjell et al., (2009) Aging of Brain Networks

Fjell et al., (2013) Nutrient Biomarkers of Healthy Brain Aging

Anterior cingulate cortex structure

Inferior prefrontal cortex structure

Parahippocampal cortex structure

Frontoparietal cortex structure

Fornix white matter integrity

Dorsal network connectivity

Cognitive flexibility Omega-3 polyunsaturated fatty acids The beneficial effects of nutrition on

Phosphatidylcholine cognitive performance are mediated Crystallized intelligence by specific brain mechanisms Lutein Fluid intelligence Precursor omega-3 polyunsaturated fatty acids

Balanced Memory polyunsaturated fatty acids Monounsaturated fatty acids General intelligence To what extent can diet and nutrition promote healthy brain aging and target specific brain networks that selectively decline with age? Yogurt and

• Yogurt contains beneficial bacteria that are known to have positive health outcomes

• Advances have recently been made in understanding their beneficial effects on mood and the reduction of stress

• A recent study observed significant reductions in self-reported negative mood and distress for individuals randomly assigned to a probiotics condition (compared to placebo) over 30 days (Messaoudi et al., 2011)

Sarkar et al., (2016)

An Interdisciplinary Approach

Explore the relationship between nutrient profiles and indices of brain health

1. Health status: Physical fitness, daily exercise, social function, mental health 2. Cognitive function: Executive control, learning, and memory 3. Functional brain connectivity: Resting-state functional connectivity 4. Structural brain connectivity: Diffusion tensor imaging of white matter fiber tracts 5. Cortical thickness and brain volume: Voxel-based morphometry 6. Cerebral biochemistry and : MR Spectroscopy 7. Cytoarchitecture integrity: MR Elastography 8. Molecular genetics: Genetic risk factors for cognitive impairment (ApoE4) Nutrient Biomarkers of Healthy Brain Aging Nutrient Biomarkers of Healthy Brain Aging Does the functional organization of brain networks depend on diet and nutrition? Network Organization Specificity and Modularity of Brain Function

To minimize the cost of information processing, the cortex is divided into anatomically localized modes, composed of densely interconnected regions Network Organization Global Integration of Brain Function

Coordinated, system-wide function requires a network architecture that also enables global information processing Small World Architecture Optimal Balance of Segregation and Integration

Small world connections are critical to brain organization and known to decline as a function of age

(Deco et al., 2015; Geerlings et al., 2015) Are specific dietary patterns associated with optimal brain network efficiency?

Healthy Older Adults Nutrient Biomarkers Nutrient Biomarkers Patterns Functional Brain Networks Does optimal efficiency within specific brain networks predict high-level cognitive function? Small World Organization and High-Level Cognition Small World Organization and High-Level Cognition

Efficiency within the following networks was associated with high-level cognition: 1. Dorsal attention network (Selective attention) 2. Frontoparietal network (Cognitive control) High-Level Cognition

General Intelligence

Barbey et al., (2012; Brain) Barbey et al., (2011; Cerebral Cortex)

Barbey et al., (2012; Neuropsychologia) Barbey et al., (2012; Cortex)

Barbey et al., (2014; Plos One) Barbey et al., (2013; Brain Structure and Function) Barbey (2017; Trends in Cognitive Sciences) Koenigs et al., (2009; Journal of Neuroscience)

Fluid Intelligence Frontoparietal Network

Barbey et al., (2013; NeuroImage)

Nikolaidis et al., (2016; Cerebral Cortex)

Paul et al., (2016; NeuroImage)

Ponsoda et al., (2016; Human Brain Mapping)

Watson et al., (2016; NeuroImage) Do nutrient biomarker patterns moderate the observed association between network efficiency and cognitive performance? Nutrient Biomarker Patterns Lycopene Moderates the Association between Dorsal Attentional Network Efficiency and Executive Functions Nutrient Biomarker Patterns

Lycopene-9-cis trans-Lycopene Lycopene-13-cis Lycopene

• Literature on lycopene's effect on brain and cognition in humans suggests that lycopene may serve a protective role in brain aging and cognitive decline (Min & Min, 2014; Johnson et al., 2013)

• Higher serum levels of lycopene are associated with lower incidences of Alzheimer's mortality (Min & Min, 2014; Johnson et al., 2013)

• A lycopene supplement in mice reduced age-related memory loss and cognitive decline, reversed age-related neuronal degradation, reduced amyloid-beta brain plaques, and reduced neuroinflammation (Zhao et al., 2018)

• Other animal studies have shown similar benefits of lycopene, by reducing oxidation and inflammation and promoting the release of inhibitory (e.g., GABA), which confer protective effects on the brain (Yang et al., 2018; Prakash & Kumar, 2014) ω-6 PUFAs Moderate the Association between Dorsal Attentional Network Efficiency and Executive Functions ω-6 PUFAs Moderate the Association between Dorsal Attentional Network Efficiency and Executive Functions ω-3 PUFAs Moderate the Association between Frontoparietal Network Efficiency and General Intelligence Nutrient Biomarker Patterns ω-6 and ω-3 PUFAS

• Evidence suggests that ω-6 and ω-3’s may have beneficial effects on cognitive aging (Parletta et al., 2013; Cunnane et al., 2009)

• ω-6 and ω-3’s PUFAs are known to contribute to: • Structural integrity of neuronal membranes • Control inflammation and oxidation • Promote energy metabolism

• PUFAs enable the myelination of white matter (Fields, 2005), which is critical for information transmission and synaptic response across long fiber tracks underlying small-world networks

• Long chain fatty acids may be critical for healthy composition in and therefore may support information transfer in small-world brain networks Nutrition and Brain Network Efficiency

• Findings motivate a multidisciplinary approach that applies methods from nutritional epidemiology and cognitive neuroscience to characterize the impact of nutrition on functional brain network efficiency in health, aging, and disease. Do ω-3 PUFA’s shape individual differences in functional brain network organization?

Multivariate Distance-Based Matrix Regression (MDMR) Shedzad et al., 2014; Talukdar et al., 2017, 2018

Step 1: The functional connectivity network due to a ROI/voxel is mapped for each subject.

Subjects’ functional connectivity maps

Step 2: A correlation based distance metric is computed, which represents the dissimilarity between functional connectivity maps for a subject pair. This is repeated for every possible pairwise combination of subjects and the values of d are entered into a matrix called the ‘distance matrix’. Step 3: A pseudo-F statistic is calculated at each voxel, which provides a measure of the amount of variation in the distances that is explained by the phenotypic variable. Omega-3 Sensitive Regions Age-Related Cortical Atrophy Does the influence of ω-3 sensitive regions on global brain network connectivity predict fluid intelligence? Cognitive Aging Fluid Intelligence Adaptive Reasoning and Problem Solving Skills Fluid Intelligence Adaptive Reasoning and Problem Solving Skills Conclusions

• Findings suggest that ω-3 PUFAs are associated with optimal brain network organization, which is known to decline as a function of age

• ω-3 PUFAs account for individual differences in functional brain connectivity, specifically within the default mode network – a primary network affected by aging

• The global connectivity of ω-3 sensitive regions predicts individual differences in fluid intelligence, supporting their role in cognitive processes that are central to aging

• Motivate the design of novel intervention trials that examine the effects of omega-3 supplementation on brain network efficiency How can we enhance fluid intelligence to promote healthy cognitive aging? Army Medicine Performance Triad

“Health is personal and each of us defines it in our own way. Health is more than the absence of illness; achieving better health means taking a proactive approach to your well-being. This includes quality , regular activity, and good nutrition.” Fitness & Nutritional Intervention

A randomized controlled trial to evaluate the efficacy of a multimodal fitness & nutritional intervention on cognition performance & physical fitness conducted in active-duty Airmen at Wright Patterson Air Force Base (led by Adam Strang of the STRONG Lab) Exercise Training Placebo +

Exercise Training Nutritional Supplement + Experimental Design

• Control Group (n = 78) 1. High Intensity Interval Training (HIIT) fitness intervention 2. Nutritionally inert placebo beverage

• Experimental Group (n = 70) 1. High Intensity Interval Training (HIIT) fitness intervention 2. Experimental nutritional beverage

• Each intervention contained 60 exercise training sessions (45 minutes, once per day, M-F) & 168 beverages (two per day, seven days a week)

• Average attendance rate of 90% Intervention Protocol Fitness Training Beneficial Effects of Fitness on the Brain

Brain morphology & biochemistry

• Increased (new ) • Increased synaptic complexity • Angiogenesis (new blood vessels) Learning & Memory • Increased cerebral blood flow • Increased BDNF • Enhanced fMRI network connectivity • Increased IGF-1 uptake in brain • Enhanced structural connectivity • Increased phosphocreatine metabolism • Enhanced learning & memory

Systemic effects

• Decreased inflammation • Decreased stress • Decreased cortisol following stress • Increased insulin sensitivity • Improved self-efficacy • Improved mood Fitness Training

Weeks Monday Tuesday Wednesday Thursday Friday

Total Body Moderate Cardio Total Body Moderate Cardio High Intensity Resistance & Core Resistance & Core Cardio Intervals

2, 6 & 10 Circuit 1 Circuit 1 Circuit 2 Circuit 2 Circuit 1

3, 7 & 11 Circuit 3 Circuit 3 Circuit 4 Circuit 4 Circuit 2

4, 8 & 12 Circuit 5 Circuit 5 Circuit 6 Circuit 6 Circuit 3

5, 9 & 13 Circuit 7 Circuit 7 Circuit 8 Circuit 8 Circuit 4

Each circuit had an identical macro-structure (exercise 1 = rotational pull) but unique micro-structure (horizontal push for circuit 1 = pushup; circuit 2 = bench press) Nutraceutical

Lutein and Crystallized Intelligence Zamroziewicz et al., (2016; Frontiers in Aging Neuroscience) Omega-3 PUFAs and Executive Functions Zamroziewicz et al., (2015; Frontiers in Aging Neuroscience) Bowman et al., (2013; Frontiers in Aging Neuroscience) Omega-3 PUFAs and Fluid Intelligence Talukdar et al., (2018; Human Brain Mapping) Zamroziewicz et al., (2017; Nutritional Neuroscience) Zwilling et al., (2018; NeuroImage) Omega-3 PUFAs and General Intelligence Talukdar et al., (2019; Human Brain Mapping) Zamroziewicz et al., (2017; NeuroImage) Omega-3/6 Balance and Memory Zamroziewicz et al., (2017; Aging and Disease) Omega-3 PUFAs and Traumatic Brain Injury Hasadri et al., (2013; Journal of Neurotrauma) Phosphatidylcholine and Executive Functions Zamroziewicz et al., (2016; Frontiers in Aging Neuroscience) Nutraceutical

Ingredients

Ca-HMB DHA Folic Acid

Lutein Magnesium Phospholipid Selenium

Vitamin B1 B2 Vitamin B3 Vitamin B5

Vitamin B6 Vitamin C Vitamin D

Vitamin E

Comprised of 18 ingredients selected from research in nutritional cognitive neuroscience suggesting benefits for physical fitness & cognition Pre/Post Fitness Measures

Domain Assessment

Abdominal Circumference Anthropometrics DEXA Body Fat % Aerobic Capacity VO2 max Wingate (upper & lower) Long Jump Anaerobic Power Sled Push Sled Rope Pull Rotational Ball Toss 1-min push-up Muscle Endurance Alternate pull-up 1-min sit-up Core Endurance Lateral bridge Supine bridge Balance Y-balance (upper & lower) Speed & Agility Modified Illinois Agility Pre/Post Cognitive Measures

Domain Assessment

Short Term Memory Immediate Free Words Immediate Pictures Keep Track Immediate Recall Delayed Recall Fluid Intelligence Number Series Letter Sets Working Memory Rotation Span Symmetry Span Executive Function Stroop Congruous Stroop Incongruous Processing Efficiency Executive Function Reaction Time Fluid Intelligence Reaction Time Symbol Digit Modalities Primary Results Physical Fitness Improvements

Fitness plus Nutritional Fitness plus Placebo Supplement Bayes p-value Cohen’s d Bayes factor p-value Cohen’s d factor

Strength 9.4 E -4 0.38 28.1 2.7 E -6 0.62 6.3 E 3

Endurance 2.2 E -16 1.52 9.5 E 15 4.3 E -15 1.52 1.6 E 12

Flexibility 2.0 E -7 0.64 6.2 E 4 2.3 E -8 0.73 5.5 E 5

Blood Pressure 0.19 0.1 0.29 0.004 0.33 7.9

Heart Rate 0.017 0.25 2.2 1.7 E -8 0.75 7.3 E 5 Benefits of Nutraceutical

Fitness Improvement

Strength

Endurance ✔

Flexibility

Blood Pressure ✔

Heart Rate ✔ Cognitive Improvements

Fitness plus Placebo Fitness plus Nutritional Supplement

Bayes p-value Cohen’s d p-value Cohen’s d Bayes factor factor

Short Term Memory 0.99 0.30 0.0 0.99 0.33 0.1

Paired Associates 0.009 0.32 4.3 0.01 0.30 3.0

Fluid Intelligence Acc 10 E -7 0.65 100953 10 E -7 0.68 19290

Fluid Intelligence RT 0.79 0.09 0.1 0.021 0.25 1.9

Working Memory 0.96 0.20 0.1 0.02 0.25 1.9

Executive Function Acc 0.87 0.13 0.1 .99 0.47 0.03

Executive Function RT 0.001 0.37 26.8 10 E -7 0.65 57154

Processing Efficiency 0.005 0.23 113646 10 E -6 0.40 13513 Benefits of Nutraceutical

Cognition Improvement

Episodic Memory

Paired Associates

Fluid Intelligence Acc ✔

Fluid Intelligence RT

Working Memory ✔

Executive Function Acc

Executive Function RT ✔

Processing Efficiency Conclusions

• Our randomized controlled trial provides evidence to establish the efficacy of a novel nutraceutical to enhance fluid intelligence, working memory, and executive functions Current Directions Data Fusion and Machine Learning

National Center for Supercomputing Applications

Big Data Information Knowledge Action

Raw Observation Processed Data Maps, Models Actionable Decisions

Data Aggregation Data Fusion Causal Inference Treatment Regimens

Data Scrubbing Summary Statistics Networks, Analytics Forecasts, Predictions

Semantic Mapping Derived Biomarkers Linkages, Associations Public Policy Recommendations

Translating high-dimensional, multivariate data into knowledge that guides public policy Conclusions

• By combining methods from nutritional epidemiology and cognitive neuroscience, the interdisciplinary field of nutritional cognitive neuroscience will continue to advance our understanding of the beneficial effects of nutrition on the aging brain

• Research to develop predictive nutrient patterns for healthy brain aging will provide an empirically sound foundation for developing nutritional therapies that support the targeted treatment of cognitive and neurological impairments of the aging brain BECKMAN INSTITUTE University of Illinois at Urbana-Champaign

Research Scientists Alumni RYAN LARSEN ANA DAUGHERTY HILLARY SCHWARB ROHRIG AKI NIKOLAIDIS TANVEER TALUKDAR JOACHIM OPERSKALSKI ERICK PAUL Postdoctoral Fellows JAVI ROMAN VALENTINA DI PIETRO PAUL SHARP KELSEY HASSEVOORT NICOLE VAN HOECK MATTHEW MOORE NATHAN WARD KRISOPHER POLIAKIWSKI PATRICK WATSON CHRIS ZWILLING MARTA ZAMROZIEWICZ MUDD

Graduate Students ILARIA AMATO EVAN ANDERSON GRACE GOODWIN KELLY HEWES MICKEAL KEY NIKOLAI SHEREPA RAMSEY WILCOX JISHENG WU

We thank the following agencies for their generous support: For more information, please visit: https://www.DecisionNeuroscienceLab.org/

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