Differences in Adolescent Cortex Related to Age and Sex: Initial Findings from the

National Consortium on Alcohol & NeuroDevelopment in Adolescence

Adolf Pfefferbaum, M.D.

Center for Health Sciences, SRI International Department of Psychiatry & Behavioral Sciences, Stanford

University School of Medicine

Research Society on Alcoholism San Antonio, TX 22 June 2015

NCANDA FUNDING: NIAAA, NIDA, NIMH, NICHD

FINANCIAL INTEREST DISCLOSURES

Adolf Pfefferbaum, M.D.

Salary and research support:

Center for Health Sciences

Differences in Adolescent Cortex Related to Age and Sex: Initial Findings from the

National Consortium on Alcohol & NeuroDevelopment in Adolescence

Research Society on Alcoholism San Antonio, TX 22 June 2015

Adolf Pfefferbaum, Torsten Rohlfing, Kilian M. Pohl, Barton Lane, Weiwei Chu, Sandra A. Brown, Susan F. Tapert, Kevin Cummins, Wesley K. Thompson, Ty Brumback, M.J. Meloy, Terry L. Jernigan, Anders Dale, Ian M. Colrain, Fiona C. Baker, Devin Prouty, Michael D. De Bellis, James T. Voyvodic, Duncan B. Clark, Beatriz Luna, Tammy Chung, Bonnie Nagel, Edith V. Sullivan

NCANDA FUNDING: NIAAA, NIDA, NIMH, NICHD

Teenage and Young Adulthood Binge drinking Drunk driving Unsafe sex

Photo courtesy of Teresa Kellerman

Prenatal Fetal Alcohol Syndrome

Life span and excessive alcohol consumption

Adulthood Hypertension Breast cancer Liver disease Job and family

Nielsen et al, IntJCancer, 2007.

Maturity Brain damage Cognitive impairment

NCANDA MRI

Age Headsize / Supratentorial Volume Sex Ethnicity Prior Alcohol Exposure

Human Brain Growth after Birth

Brain weight increases fourfold from birth to about 10 years of age

Gray matter, white matter, and CSF volumes expand but at different rates in different regions of brain

Rise and Fall of Cortical Gray Matter Volume

5 10 15 20 25 30 Age (years)

80

90

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0

Cor

tical

Gra

y M

atte

r Vol

ume

(cc)

53 years

1 Year

1 Month

2 Years 4 Years

10 Years

14 Years

21 years

71 years

18 Years

Pfefferbaum et al. Archives of Neurology 1994

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0 5 10 15 20 25 30 Age

Volu

me

(cc)

Gray Matter

Cortical Tissue Volumes

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90

100

0 5 10 15 20 25 30

Age

Male Female

White Matter

Gray to White Matter Ratio Gray : White

1

2

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4

0 5 10 15 20 25 30

Age

Volu

me

(cc)

Male Female

Development of Cortex Age Differences in PET Local Glucose Metabolism

Chugani Preventive Medicine 1998

9 mo 1.5 yr 3 yr 4 yr 12 yr 6 yr Neuropsychology Review December 2012 cover

Brain Development after Birth Heterochronicity of Structural Modeling

NCANDA Prospective Study

National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA)

5 U.S. recruitment sites 647 no/low drinking

– 334 male, 340 female 134 exceeded criteria Age 12-14, 15-17, 18-21 years Baseline + annual visits

– Clinical interview – Neuropsychological testing – 3T MRI, DTI, resting state-fMRI

NCANDA Sample

Sex Ethnicity

Basic NCANDA MRI Protocol

Anomalies Identified on Clinical Readings in 95 Adolescents*

24 mega cysterna magna 15 subarachnoid cysts (primarily temporal and frontal) 12 pineal cysts 11 white matter anomalies (primarily corpus cysts) 6 tonsilar ectopias 5 very prominent perivascular spaces 5 gray matter heterotopias 4 pituitary masses (primarily cysts) 4 abnormally large or asymmetrical lateral ventricles 4 cavum septum pellucidum 3 developmental venous anomalies (DVA) 1 severe cranio-cervical junction stenosis (10/30 mm) 1 *right parietal cortical mass (3 cm) 1 *bilateral tonsillar herniation, medullary distortion (Chiari 1 malformation) *excluded from NCANDA cohort

95/833 adolescents = 11.4% 23 excluded from parcellation *2 excluded from the study

Subependymal heterotopia Probable congenital Rathke's cleft cyst vs. craniopharyngioma

Anomalies Identified on Clinical Readings

Large ventricles with possible cyst Cranio-cervical junction stenosis

Anomalies Identified on Clinical Readings Some Precluding Automated Quantification

Mega cisterna magna in a 15.5 year old boy

Subarachnoid cyst in a 17.0 year old girl

Abnormalities on Clinical Readings Excluded from Further Study

Chiari 1 malformation

bilateral tonsillar herniation with medullary distortion

right parietal cortical mass

T1-weighted

T2-weighted

NCANDA Data Analysis Team

Torsten Rohlfing, Ph.D.

NCANDA Data Analysis Team

Torsten Rohlfing, Ph.D.

Nolan Nichols, Ph.D.

Kilian Pohl, Ph.D.

Yong Zheng, Ph.D. Dongjin Kwon, Ph.D.

Lateral Ventricle Volume Lateral Ventricle Volume

Freq

uenc

y (N

=808

)

cc

10 Boys 14.5 to 15.5 years old

Structural MRI Quantitative Measures of Regional Brain Tissue

white matter

gray matter

CSF

Tissue Segmentation

Structural MRI

FreeSurfer Gray Matter Regions

Frontal Parietal

Temporal Occipital

Cingulate

Subcortical white matter

Corpus callosum

Pons

SRI24 White Matter Regions

Frontal Superior Frontal Rostral and Caudal Middle Frontal Pars Opercularis, Pars Triangularis, and Pars Orbitalis Lateral and Medial Orbitofrontal Precentral Paracentral Frontal Pole Temporal Superior, Middle, and Inferior Temporal Banks of the Superior Temporal Sulcus Fusiform Transverse Temporal Entorhinal Temporal Pole Parahippocampal Insula

Parietal Superior Parietal Inferior Parietal Supramarginal Postcentral Precuneus Occipital Lateral Occipital Lingual Cuneus Pericalcarine Cingulate Rostral Anterior (Frontal) Caudal Anterior (Frontal) Posterior (Parietal) Isthmus (Parietal)

Frontal Parietal

Temporal Occipital

Cingulate

Structural MRI FreeSurfer Cortical Lobar Volume, Surface & Thickness

IR-Prep SPGR vs. MPRAGE

GE GE GE Siemens Siemens

Human Phantom across Site/Scanner Harmonization Across 3 GE Sites and 2 Siemens Sites

NCANDA MRI

Linear: braini ~ 0 + 1agei + 2mfgi + 3sesi + 4ethnicityi + 5sexi + ∑i

Non-linear: braini ~ S0(agei)+ 1mfgi + 2sesi + 3ethnicityi + 4sexi + ∑i

General Additive Model (GAM)

Brain region ~ age + covariates (sex, ethnicity, SES, etc)

Cross-platform Harmonization done with GAM

NCANDA MRI

Age Headsize / Supratentorial Volume Sex Ethnicity Prior Alcohol Exposure

NCANDA Cohort Baseline MRI by Age and Sex

Pons

Adju

sted

Vol

ume

(cc)

Age (years)

Adju

sted

Vol

ume

(cc)

Age (years)

Subcortical White Matter

Adju

sted

Vol

ume

(cc)

Age (years)

Corpus Callosum

Subcortical white matter

Corpus callosum

Pons Regional White Matter Volumes

NCANDA Cohort Baseline MRI by Age and Sex

Frontal

Temporal

NCANDA Cohort Baseline MRI by Age and Sex

Frontal

Temporal

NCANDA Cohort Baseline MRI by Age and Sex

Regional Cortical Thickness Frontal Temporal

Regional Cortical Volumes Frontal Temporal

Age (years) Age (years)

Age (years) Age (years)

Frontal

Temporal

Adju

sted

Vol

ume

(cc)

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ume

(cc)

Adju

sted

Thi

ckne

ss (m

m)

Adju

sted

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ss (m

m)

NCANDA Cohort Baseline MRI by Age and Sex

Regional Cortical Thickness Frontal Temporal

Regional Cortical Volumes Frontal Temporal

Age (years) Age (years)

Age (years) Age (years)

Frontal

Temporal

Adju

sted

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ume

(cc)

Adju

sted

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ume

(cc)

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ss (m

m)

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Thi

ckne

ss (m

m)

Age (years)

Age (years)

Regional Cortical Thickness

NCANDA Cohort Baseline MRI by Age and Sex

Frontal

Temporal

NCANDA MRI

Age Headsize / Supratentorial Volume Sex Ethnicity Prior Alcohol Exposure

Sex Differences in Brain Size Ad

just

ed V

olum

e (c

c)

Supratentorial Volume

Age (years)

Sex

Size Metrics and Supratentorial Volume

Frontal Gray Matter Volume

Adju

sted

Vol

ume

(cc)

Supratentorial Volume (cc)

Frontal Cortical Surface Area

Adju

sted

Are

a (c

m2 )

Supratentorial Volume (cc)

Frontal Cortical Thickness

Adju

sted

Thi

ckne

ss (m

m)

Supratentorial Volume (cc)

Frontal

NCANDA MRI

Age Headsize / Supratentorial Volume Sex Ethnicity Prior Alcohol Exposure

NCANDA Cohort Baseline MRI by Age and Sex

Regional Cortical Volumes Frontal Temporal

Age (years) Age (years)

Frontal

Temporal

Adju

sted

Vol

ume

(cc)

Adju

sted

Vol

ume

(cc)

Frontal

Svol

Adj

uste

d Vo

lum

e (c

c)

Age (years)

Svol

Adj

uste

d Vo

lum

e (c

c)

Age (years)

Temporal

Supratentorial Volume -Adjusted Regional Cortical Volumes

NCANDA MRI

Age Headsize / Supratentorial Volume Sex Ethnicity Prior Alcohol Exposure

Frontal Cortex Baseline MRI by Age, Sex, Ethnicity

Frontal Thickness

Frontal Volume

Age (years)

Age (years)

Frontal Ad

just

ed V

olum

e (c

c)

Adju

sted

Thi

ckne

ss (m

m)

Frontal Cortex Baseline MRI by Age, Sex, Ethnicity

Frontal Thickness

Age (years)

Frontal Ad

just

ed T

hick

ness

(mm

)

Age (years)

Svol

Adj

uste

d Vo

lum

e (c

c) Frontal Volume

Adjusted for supratentorial volume

% Difference per Year (N=631)

Pubertal Development Ad

just

ed V

olum

e (c

c)

PDS score

Frontal Gray Matter Volume

Adju

sted

Thi

ckne

ss (m

m)

PDS score

Frontal Cortical Thickness

PDS

scor

e

Age (years)

Frontal

Are the data generalizable? Frontal

Temporal

NCANDA and PING Cortical Volume and Thickness

NCANDA: National Consortium on Alcohol & NeuroDevelopment in Adolescence PING: Pediatric Imaging, Neurocognition, and Genetics

NCANDA and PING Cortical Volume and Thickness

PING NCANDA

Parietal

Occipital

Cingulate

Parietal

Occipital

Cingulate

Adj.

Volu

me

(cc)

Ad

j. Vo

lum

e (c

c)

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Volu

me

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Adj.

Thic

k (m

m)

Adj.

Thic

k (m

m)

Adj.

Thic

k (m

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Volume Cortical Thickness

Alcohol and Drug Use Criteria No/low vs. Exceeds

0

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12 13 14 15 16 17 18 19 20 21

Other Drugs

Alcohol

Marijuana

Cigarettes

Exceeds Criteria Group (N=134)

Moderate/high Alcohol Regional Cortical Volumes and Thickness

Age (years)

Svol

Adj

uste

d Sc

ore

(cc)

Total Cortical Volume Frontal Cortical Volume

Age (years) Age (years)

Total Cortical Thickness

Age (years)

Svol

Adj

uste

d Sc

ore

(mm

)

Frontal Cortical Thickness

Age (years)

Temporal Cortical Thickness Cingulate Cortical Thickness

Age (years)

Temporal

Frontal

Binge Drinking and Cortical Thickness

Binge Episodes in Past Year

Svol

Adj

uste

d Sc

ore

(cc)

Frontal Cortical Thickness Parietal Cortical Thickness

Binge Episodes in Past Year

Svol

Adj

uste

d Sc

ore

(cc)

Parietal Frontal

NCANDA Baseline MRI Findings In 833 with MRIs, clinical readings identified structural anomalies in

95 individuals (11.4%), ~3% precluding automated quantification.

Regional volume and surface, but not thickness, measures showed sex and ethnicity effects that were minimized with adjustment for variation in supratentorial volume.

NCANDA and PING data showed similar age-related differences in regional cortical volumes and thickness.

Relative to no/low drinking youth, moderate/high alcohol drinking youth had smaller and thinner cortices in frontal, temporal, and cingulate regions.

Youth who binged had thinner frontal and parietal cortices than no/low drinking youth.

NCANDA Clinical MRI Findings Baseline

A note of caution ....

NCANDA Clinical MRI Findings Baseline

NCANDA Clinical MRI Findings 1-year Followup

NCANDA Clinical MRI Findings 1-year Followup

Even in a group of healthy highly screened participants with normal brain structure at study entry, pathology will emerge in a sample this size.