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Advances in the

Neurobiology of ADHD

Joseph Biederman, M.D.

Professor of Psychiatry,

Massachusetts General Hospitaland Harvard Medical School



Disclosures 2009-2011

n Research Support:

q Eliminda, J&J, Shire, NIH, Philanthropy

n Honoraria:

q Fundacion Areces, Medice, Spanish ChildPsychiatry Association, Fundacion Cabral,

Monterey Mexico, MGH Academy



0 5 10 15 20Prevalence of ADHD (%)

Puerto Rico

New York City

Pittsburgh

Iowa

TennesseeMinnesota

Oregon

Missouri

Virginia

North Carolina

N.Y., Mich., Wis.

IndiaChina

NetherlandsNew Zealand

JapanBrazil

UkraineGermany

Netherlands/BelgiumSwitzerland

IsraelUnited Kingdom

IrelandCanada

New ZealandSpain

0 5 10 15 20Prevalence of ADHD (%)

Worldwide Prevalence of ADHD in Children

Faraone SV et al. (2003), World Psychiatry 2(2):104-113



ADHD: Etiology

ADHD is a heterogeneous behavioral disorder

with multiple possible etiologies

ADHD

Neuroanatomic

Neurochemical

CNSinsults

Genetic

origins

Environmentalfactors



Inattention

Impulsivity/Hyperactivity

ADHD: Core Symptom Areas



%

78%

Persistence of ADHD into Young Adult Years

Biederman et al. Psychological Medicine, 2006, 36, 167–179;

Biederman et al Psychiatric Research In Press 2010.

0

20

40

60

80

100

Syndromatic Remission Persistence

65%

SyndromaticRemission

8%Medicated

13%

FunctionalPersistence22%

SymptomaticPersistence

35% SyndromaticPersistence



Faraone et al. Psychol Med. 2006;36:159-165.

Full Diagnosis

Residual Diagnosis

0

10

20

30

40

50

60

70

80

90

100

12 15 17 21 26

Age at Follow-up

P e r s i s t e n c e R a t e

Loss of full diagnostic status is not equivalent to remission.

Persistence of Full and Residual Diagnoses



ADHD: Course of the Disorder

Inattention

Time

Hyperactivity

Impulsivity



Kessler et al. Am J Psychiatry 2006; 163:716-723



ADHD as a Brain Disorder:

Neuroimaging Findings



Brain Imaging and ADHD

n Magnetic Resonance Imaging (MRI) Anomalies(N= >25 studies):

q Asymmetry of the Caudate Nucleus

q Corpus Callosum size and shape

q Smaller Right Frontal area

q Smaller Right Basal Ganglia

q Cerebellum (vermis)



Regions of Interest With Large

Standardized Mean Difference Scores (N=2)

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

Prefrontal Cortex

Frontal Lobe

Total Deep FrontalWhite Matter

Left Deep Frontal

White Matter

Right Deep Frontal

White Matter

P <0.001

Standardized Mean Difference Score

P <0.001

P <0.001

P <0.001

P <0.001



Developmental Trajectories of Brain

Volume Abnormalities in Youth

w/ADHD

n Design: MRI case control studyn N=152 youth w/ ADHD and 139 controls of

both gendersn Objective: assess volumetric changes

over time in medicated vs unmedicated youthw/ADHD and controls

Castellanos et al. JAMA. 2002 Oct;288(14):1740-8



Brain Volumes and ADHD

M i l l i l i t e r s

Non-ADHD

Controls

Unmedicated Medicated

Unadjusted Total Cerebral Brain Volume for Unmedicated and

Medicated Children and Adolescents With ADHD and Controls

N=103

N=49

N=139

*p=0.001 by 2-way analysis of variance (group [medicated vs. unmedicated vs. control] by sex);

Castellanos FX et al. (2002), JAMA 288(14):1740-1748

1,000

1,020

1,040

1,060

1,080

1,100

1,120



Developmental Trajectories of Brain

Volume Abnormalities in Youth

w/ADHD

n Conclusions:

q Genetic and or early environmental influences on

brain development in ADHD are fixed,

nonprogressive and unrelated to stimulanttreatment

Castellanos et al. JAMA. 2002 Oct;288(14):1740-8



ADHD: Neurobiologic Basis

ALERTING

EXECUTIVE CONTROL

ORIENTING (SELECTIVE ATTENTION)

Posner and Raichle. Images of M ind.Scientific American Books; 1996.

Attention Networks



Seidman et al, Biological Psychiatry. 2006; In Press

MRI findings in Adult with ADHD



Volume Reductions in Adult ADHD

Biederman, Makris, Valera et al. Psychol Med. In Press.

Volumetric reductions

in light blue (frontal and

cerebellar regions)

Superior frontal

gyrus Anteriorcingulate

gyrus

Cerebellar cortex



Smaller Dorsal and Rostral ACC in ADHD

Seidman et al, Biological Psychiatry. 2006; 60: 1071-1080



Cortical Volume

Cortical Thickness

Vogt, 2005

Cerebral Cortex



•Dorsolateral FrontalCortex (BA 8, 9)

•Supramarginal Gyrus

(BA 40)

•Superior Temporal Gyrus

(BA 22)

•Angular Gyrus

(BA 39)

•Middle Temporal Gyrus

(BA 21)

Makris et al. Cerebral Cortex June 2007; 17:1364-1375



•Anterior CingulateGyrus (BA 24)

•Orbital Frontal Cortex

((BA 11, 12, 13, 14)•Orbital Frontal Cortex((BA 11, 12, 13, 14)

Makris et al. Cerebral Cortex June 2007; 17:1364-1375



Reproduced from Makris N, et al. Cerebral Cortex. 2007; doi:10.1093/cercor/bhm156.

A DT-MRI Study of Connections in

ADHD



Makris et al. Cerebral Cortex 2008 in press



cccc

70 60 50 40 30 20 10 070

60

50

40

30

20

10

0

10

20

30

COGNITIVE TASK

EMOTIONALTASK

Counting Stroop(Bush et al. 1998)

Counting Stroop

(Bush et al. 1999)Emotional Counting

Stroop(Whalen et al.

1998)

Cognitive

Division

Affective

Division

Bush,

Luu &

Posner

(2000)

Trends in

Cognitive Sciences

4:215-222

Anterior Cingulate Cortex: Increases



MGH-NMR Center & Harvard- MIT CITP Bush et al, Biological Psychiatry 1999

1 x 10-3

1 x 10-2y = +21 mm

Normal Controls

1 x 10-2

1 x 10-3

y = +21 mm

ADHD

Dorsal Anterior Cingulate Cortex (Cognitive

Division) Fails to Activate in ADHD



Methylphenidate Activates Dorsal

Anterior Midcingulate Cortex

Bush et al. Arch Gen Psychiatry. 2008:65:102-114.

0

0.5

1

1.5

2

2.5

Baseline 6 Weeks

OROS MPH

Placebo

• fMRI at baseline and again at week 6• OROS MPH group showed higher daMCC activation at 6 weeks vs placebo

• N=21 adults with ADHD; dosing to 1.3 mg/kg/day OROS MPH or placebo

P = 0.02 vs PBO



Cortical Thickness Differences

Functional ROI

DTI ROI

Volumetric ROI

Dorsal ACC (dACC)

“Cognition”

Perigenual ACC (pACC)

“Emotion”



Makris et al. Dev Neurosci 2009;31:36-49



ADHD

Imaging Studies Summary

• Neuroimaging studies confirm that brainabnormalities in fronto-subcortical networksare associated with ADHD

• But neuroimaging techniques are not valid

tools for ADHD diagnosis; imaging measuresare not sensitive or specific enough to be usedfor diagnostic purposes



Directed Attention Fascination

Executive circuit

§ Inhibitory deficits

§ Executive dysfunction

Reward circuit

§ Reduce time to reward

§ Delay aversion

ADHD

Toward a Dual Pathway Model

Sonuga-Barke. Neurosci Biobehav Rev. 2003;27:593.



Frontosubcortical Networks and

Catecholamines

n Dopaminergic and noradrenergic dysregulation

abnormalities in fronto subcortical pathways

n Medications that are effective in ADHD are eitherdopaminergic or noradrenergic

Zametkin. J Am Acad Child Adolesc Psychiatry. 1987;26(5):676-686.

Zametkin. J Am Acad Child Adolesc Psychiatry. 1987;26(5):676-686



Brain Stem

MESENCEPHALON

PONS

MEDULLARaphe nuclei(serotonin)

Substantia nigrategmentum(dopamine)

Locus ceruleus(norepinephrine)

to cerebellum

to cord

to diencephalon and

cerebrum



GeneticBasis

of ADHD

ADHD: Genetics

Twin Studies Family Studies

Adoption Studies Molecular Genetics



Mean heritability of ADHD = .75Faraone et al. Biol Psychiatry . 2005;57:1313-23.

ADHD

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Matheny 1971

Willerman 1973

Goodman 1989

Gillis 1992

Edelbrock 1992

Stevenson 1992

Schmitz 1995

Thapar 1995

Gjone 1996

Silberg 1996

Sherman 1997

Levy 1997

Nadder 1998

Hudziak 2000

Willcutt 2000

Thapar 2000

Coolidge 2000

Kuntsi 2001

Martin 2002

Rietveld 2003

Laarson 2004

Heritability

Panic Disorder SchizophreniaHeight



Dopamine Transporter(DAT)

DopamineReceptor

(DRD4)

Presynaptic Neuron

Methylphenidate

(MPH)

Dopamine

The Dopamine Story...



Williams et al. Lancet 2010; 376 (9750): 1401-8.



ADHD Genetics

n The literature is predominated by

candidate gene studies

n Genome-wide association studies

are emerging

n These studies will lead to greater

progress as they do not assume

we know more than we do about

the etiology of ADHD



Maternal Smoking During Pregnancy:

Results in Children

0

5

10

15

20

25

H i s t o r y o f M

a t e r n a l

S m o k i n g

( % )

* P =0.04, controlling for

SES, parental ADHD, and

parental IQ

P =0.00222%

ADHD( N=140)

8%

Controls( N=120)

Milberger et al. Am J Psychiatry 1996;153:1138.



ADHD

Diagnostic Considerations

Inattention

Impulsivity/Hyperactivity



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

M D D

B P D A g o r

a p h o b i a

S o c i a l p h o b i a

S i m p

l e p h o b i a

O C D O D D

C D T i c s / T o u r e t t e ' s

E n u r e s i s

N i c o t i n e d e p e n d e n c e

A l c o

h o l d e p e n d e n c e

C u m u l a t i v e M o r b i d i t y R i s k

Control ADHD

P .009 for all categories

Biederman et al. Psychological Medicine, 2006, 36, 167–179.

Cumulative Morbidity Risks for Psychiatric

Disorders in ADHD and Control Probands



Biederman et al.

AJP. April 2010



Kessler et at. Am J Psychiatry. 2006; 163:4

Patterns of Comorbidity in ADHD Adults

0 1 2 3 4 5 6 7 8

Social phobia

PTSD

Panic disorder

Obsessive-compulsive disorder

Major depressive disorder

intermittent explosive disorder

Dysthymia

Drug dependence

Bipolar disorder

Any substance use disorder

Any mood disorder

Any anxiety disorder

Alcohol dependence

Odds Ratio



Cocaine and Methylphenidate (COC and

MPH )block the Dopamine Transporter

DA

DA

DA

DA DA

MAO A

DA

DA

signal

DA

DA

DA

DA DA

MAO A

DA

DA

signal

DA

DA

DA

DADA

DADA

DA

DA DA

DA

DA

DA

coc or MPH

Volkow, Swanson. Am J Psychiatry. 2003 Nov;160(11):1909-18



0

0.01

0.02

0.03

0.04

0.05

0.06

0 20 40 60 80 100 120

U p t a k e i n s t r i a t u m ( % / c c )

Time (min)

0

0.01

0.02

0.03

0.04

0.05

0.06

0 20 40 60 80 100 120

U p t a k e i n s t r i a t u m ( % / c c )

Time (min)

0

0.0005

0.001

0.0015

0.002

0.0025

0.003

0.0035

0 20 40 60 80 100 120

U p t a k e i n s t r i a t u m ( n C i / c c )

Time (min)

iv cocaine iv MPH oral MPH

Rate of Drug Uptake Into the Brain

RapidRapid Slow

Volkow et al. Arch Gen Psych1995;52. J Neurosci 2001.

§ Cocaine (iv) and methylphenidate (iv) produce a

“high” but methylphenidate (oral) does not

§ The slow brain uptake of oral methylphenidate

permits effective treatment without a “high”



SUD in ADHD Youth Growing Up:

Overall Rate of Substance Use Disorder

Biederman, Wilens, Mick et al., Pediatric 1999

0

5

10

15

20

25

30

35

Control(n=344)

Medicated(n=117)

Unmedicated(n = 45)

P e r c e n t o f G r o u p

p < 0.001



0 10 3020

25

50

75

100

Age

*p<0.05 vs. Controls

%

Biederman et al. Am J Psychiatry. 2008 Mar 3

Stimulant Therapy and Subsequent Risk

for Substance Dependence Disorders

No Stimulant

Therapy*

Controls

Stimulant

Therapy**p<0.05 vs. Controls



Biederman et al.

Pediatrics 2009

Jul;124(1):71-8.



Protective Effect of Stimulants on Comorbidity

Biederman et al. Pediatrics in press 2009

c2(1) =19.7, p<0.001 c2

(1) =17.8, p<0.001

c2(1) =3.5, p=0.063



Functional Impairments

Results of A Survey of 1000 Subjects with and

without ADHD



Educational Impairment in High School

*

*

*

*

* p .001

Percentage of Those Who Attended High School

52%

27%

37%

13%

37%

10%

30%

8%

"C" average or lower

Had a tutor

Had special classes

Had to repeat a grade

ADHD (N=464)

Non-ADHD (N=487)

Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524-40



Relationship Problems as AdultsPercentage of Each Group

28%

10%

15%

5%

ADHD (N=500)

No ADHD (N=501)

**

*

Percent "Strongly Agree"

47%

40%

70%

70%

**

**

Ever divorced

Ever separated

Good relationship with parents

Fits in well with peers

* P 0.01, ** P 0.001Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524-40



Current Employment Status

*

*

*

*

* p .001

Percentage of Each Group

52%

72%

34%57%

48%

27%

14%5%

Currently employed

Employed full time

Not currently employed

Looking for work ADHD (N=500)Non-ADHD (N=501)

Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524-40



Average Household Income by

Education Level Attained

$23,859

$29,577

$46,471$38,733

$66,683$63,086

$52,404

$91,316

$0

$10,000

$20,000

$30,000

$40,000

$50,000$60,000

$70,000

$80,000

$90,000

$100,000

Less than High

School

High

School/Some

College

College/Some

Post-Grad

Post-graduate

Degree

Control ADHD

Education (Highest Degree Obtained)Biederman and Faraone. Medscape General Medicine 2006; 8:12.



Traffic Accidents and Violations

0

10

20

30

40

50

60

70

P e r c e n t a g e

Drove

before

licensed

12 or more

traffic

citations

5 or more

speeding

citations

License

suspended

or revoked

ADHD (n = 105)

Control (n = 64)

3 or more

vehicular

crashes

P = 0.003

P = 0.001 P = 0.002P = 0.001

P = 0.007

Negative Driving Outcomes From Driving History Interviews

With Young Adults Aged 17-28

Barkley et al. J Int Neuropsychol Soc . 2002;8:655-672.



Summary

n ADHD is a neurobehavioral disorder with a:

q Complex etiology

q Neurobiologic basis

q Strong genetic component

n ADHD

q Affects millions of people of both gendersq Persists through adolescence and adulthood in a high

percentage of cases

q Can have negative impact on multiple areas of functioning

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