Omega-3, Mood, Seafood Consumption, and Neuroimaging in Kids Robert K. McNamara, Ph.D.
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1 Omega-3, Mood, Seafood Consumption, and Neuroimaging in Kids Robert K. McNamara, Ph.D. Department of Psychiatry and Behavioral Neuroscience Division of Bipolar Disorders Research University of Cincinnati College of Medicine
2 Disclosure Statement Research Support Inflammation Research Foundation Royal DSM Nutritional Products, LLC Martek Biosciences Corporation Kyowa Hakko Bio Co., LTD Ortho-McNeil-Janssen Eli Lilly and Company strazeneca NRSD NIH/NIMH NIH/NIDDK NIH/NI Consulting Inflammation Research Foundation (Scientific dvisory Board) VY Pharma Inc. Omthera Pharmaceuticals, Inc. Vifor Pharma Inc.
3 Fish/seafood are primary dietary sources of DH which is the most abundant n-3 PUF in the mammalian brain MUF Oleic acid (18:1n-9) 19% Omega-9 % RMDR 5% Stearic (18:) 18% Palmitic (1:) 17% Myristic (1:) <1% SF Saturates 3% Omega-7 8% Palmitoleic acid (1:1n-7) 3% Vaccenic acid (18:1n-7) 5% Omega- 17% L (18:n-) 1% (:n-) 9% DT (:n-) 5% DP (:5n-) % PUF * Omega-3 1% L (18:3n-3) <1% EP (:5n-3) <1% DP (:5n-3) <1% DH (:n-3) 1%
4 DH levels increase sharply in the human and rat frontal cortex during adolescent development DH (wt % total) +% +15% -% DH (wt % total) B GE (YERS) P1 P5 P9 Docosanoids ipl 7% <1 years Eicosanoids COX/LOX DH cpl
5 The frontal cortex regulates attention, executive function, and mood, and undergoes rapid maturational changes during adolescence Males ttention & Executive Function Superior longitudinal fasciculus PFC Females Uncinate fasciculus C mygdala Hippocampus Mood & Memory mygdala GE (Years) Geidd et al. (9) J m cad Child dolesc Psychiatry. 8:5-7
6 Robust frontal amygdala pruning during adolescence in rats PFC mygdala Cressman et al. () J Comp Neurol. 518:93-79
7 Rat neuroimaging: P1 P9 Control n-3 (L+) Deficient n-3 (L-) Fish Oil (EP+DH) n= n= n= DTI DTI 1 H MRS phmri Table 1. Diet Compositions Control Deficient Fish Oil Ingredient 1 (TD.85) (TD.8) (TD.1837) 18 1 * DH 7 Tesla Brucker mg/ mg g/ g diet wt % of total fatty acids nd = not detected FO CON DEF
8 dult forebrain white matter integrity is reduced by dietary omega-3 fatty acid deficiency during adolescent development B p=.1 p=.5 RD: DEF>CON RD: DEF>FO McNamara et al. (18) Dev Neurosci. :8-9
9 Frontal glutamate homeostasis is modified by dietary omega-3 fatty acid intake during peri-adolescent development B C D DH 5 3 RBC B PFC C Thalamus DH * DH E F FO CON DEF FO CON DEF FO CON DEF B C DH r = -.3, p= DH r = +.9, p= Glutamate r = -.5, p= Glutamate 8 FO ## * CON DEF B Glutamine 8 C Gln/Glu * # FO CON DEF FO CON DEF Glutamate GLST GLST McNamara et al. (17) Psychiatry Res. 7:39-5
10 9 dolescent omega-3 fatty acid deficiency impairs frontostriatal recruitment following repeated amphetamine treatment RBC DH FO 5 CON DEF. Saline-Pretreated ICj CON Cg M1 CPu ICj Nc ICj VP my VP FO LH my S1 Thal LH Sub LH Sub SNR mg/ mg 3 1 B. MPH-Pretreated DEF CON p=.1 r = +.95, p.1 PFC D mg/ mg SLINE DH MPH C. MPH > SL FO DEF CON FO p=.5 DEF SLINE MPH + mm mm McNamara et al. (18) Nutr Neurosci. [Epub ahead of print]
11 Reduced frontal connectivity in DH-deficient monkeys : CC Superior Temporal Sulcus Grayson et al. (1) J Neurosci. 3:5-7
12 Reduced frontal connectivity in children with low vs. high RBC DH RBC DH was positively correlated with weekly fish intake frequency (r=+.57, P =.). Seed: CC Table. Fish Intake Frequency and Erythrocyte LCn-3 Fatty cid Composition Variable 1 Low-DH (n=18) High-DH (n=18) P-value 1 Fatty acid values are group mean weight percent of total fatty acids ± S.D. Two-tailed t-tests B Table. Regions exhibiting reduced functional connectivity in the low-dh group relative to the high-dh group Brain region Talairach coordinates (mm) Cluster Size (Brodmann s rea) x y z (Voxels) Right CC Seed-Region Right Insula (B13) Right Inferior frontal gyrus (B5) Right Inferior frontal gyrus (B) Right Precuneus (B19) Right Superior parietal lobule (B7) Left CC Seed-Region Right Lingual gyrus (B18) Right Inferior occipital gyrus (B19) Right Middle occipital gyrus (B19) Right Inferior temporal gyrus (B) lmeida et al. (17) Nutr Neurosci. :-5
13 Reduced biochemical indices of cortical integrity in children with low vs. high RBC DH Low DH (n=19).5±. wt % TTL High DH (n=19).1±. wt % TTL B Concentration (mm) ** * Low-DH High-DH ** ** C D Cho Cr Glx mi N Reaction Time (CPT-IP) Low DH 93±13 ms High DH 38±1 ms p=.7 McNamara et al. (13) Nutr Neurosci. 1:183-19
14 Effect of algal DH supplementation on attentioninduced frontal cortex activity in healthy children Baseline 8 weeks Placebo (n=) DH mg/d (n=) DH (wt % TTL) 1 8 Baseline Endpoint DH 1, mg/d (n=1) B Placebo DH ( mg/d) DH (1 mg/d) Tesla Varian fmri (CPT-IP) McNamara et al. () m J Clin Nutr 91:-7
15 8-week DH: 1, mg/d DH > Placebo DH < Placebo P<.5 (T5) P<.1 (T5) P<.5 (T5) McNamara et al. () m J Clin Nutr 91:-7
16 15 Positive relationship between RBC DH levels and frontal cortical activity in adolescents with MDD McNamara et al. unpublished data
17 Mood symptom severity in adolescents is inversely associated with RBC EP+DH levels EP+DH # ## B C /EP+DH # HC HR UHR BP HC HR UHR BP 1 3 HC HR UHR BP YMRS Total Score +++ HC HR UHR BP B HDRS Total Score ## 1 3 HC HR UHR BP RBC EP+DH (n=13) YMRS r = -.9, p=.8 HDRS r = -.8, p=.3 McNamara et al. (1) Early Interv Psychiatry. :3-11
18 17 Risk Progression in Bipolar Disorder SSRI vs. Fish oil? Healthy Controls High-Risk Healthy Ultra High-Risk MDD First-Episode Mania (Bipolar I Disorder) Biological Parent with Bipolar Disorder dolescence
19 18 Fish oil (.1 g/d) improves global functioning and reduces emotion-induced limbic activation in high-risk youth Mean Change in CGI-S Score Placebo -1 p=.1 Fish Oil -1.8 Wt % Total Fatty cids EP+DH ** ** ** ** ## HC Pre Post Pre Post Placebo LCn-3 Placebo: -53.% Fish oil: -5.9% p=.1 CGI-I Response Rate p=. Response rates: 1% (Fish oil) vs. 55% (Placebo)(p=.) Remission rates: 5% (Fish oil) vs. 5% (Placebo)(p=.1) Placebo Fish Oil
20 19 Mediating mechanisms n-3 PUF Blood Triglycerides Platelet ggregation Platelet Thromoxane Inflammation (Cytokines) Cerebrovascular Hypoperfusion Gray Matter trophy White Matter Pathology (WMH) Subclincal Infarct McNamara et al. (18) PLEF [Epub ahead of print]
21 This is Your (child s) Brain on DH ny Questions?
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