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Review Article

Effect of Psychostimulants on Brain Structure and Function in ADHD: A Qualitative Literature Review of Magnetic Resonance Imaging–Based Neuroimaging StudiesThomas J. Spencer, MD; Ariel Brown, PhD; Larry J. Seidman, PhD; Eve M. Valera, PhD; Nikos Makris, MD; Alexandra Lomedico, BA; Stephen V. Faraone, PhD; and Joseph Biederman, MD

ABSTRACTObjective: To evaluate the impact of therapeutic oral doses of stimulants on the brains of ADHD subjects as measured by magnetic resonance imaging (MRI)–based neuroimaging studies (morphometric, functional, spectroscopy).

Data Sources: We searched PubMed and ScienceDirect through the end of calendar year 2011 using the keywords (1) psychostimulants or methylphenidate or amphetamine, and (2) neuroimaging or MRI or fMRI, and (3) ADHD or ADD or attention-deficit/hyperactivity disorder or attention deficit hyperactivity disorder.

Study Selection: We included only English language articles with new data from case-control or placebo controlled studies that examined attention-deficit/hyperactivity disorder (ADHD) subjects on and off psychostimulants (as well as 5 relevant review articles).

Data Extraction: We combined details of study design and medication effects in each imaging modality.

Results: We found 29 published studies that met our criteria. These included 6 structural MRI, 20 functional MRI studies, and 3 spectroscopy studies. Methods varied widely in terms of design, analytic technique, and regions of the brain investigated. Despite heterogeneity in methods, however, results were consistent. With only a few exceptions, the data on the effect of therapeutic oral doses of stimulant medication suggest attenuation of structural and functional alterations found in unmedicated ADHD subjects relative to findings in controls.

Conclusions: Despite the inherent limitations and heterogeneity of the extant MRI literature, our review suggests that therapeutic oral doses of stimulants decrease alterations in brain structure and function in subjects with ADHD relative to unmedicated subjects and controls. These medication-associated brain effects parallel, and may underlie, the well-established clinical benefits.

J Clin Psychiatry 2013;74(9):902–917© Copyright 2013 Physicians Postgraduate Press, Inc.

Submitted: November 15, 2012; accepted April 19, 2013 (doi:10.4088/JCP.12r08287).Corresponding author: Thomas J. Spencer, MD, Massachusetts General Hospital, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, 55 Fruit St–WRN 705, Boston, MA 02114 (Spencer@helix.mgh.harvard.edu).

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobiological disorder estimated to affect up to 10% of chil-

dren and 5% of adults worldwide.1,2 Across the lifecycle, it is associated with high levels of morbidity and disability and exerts an enormous toll in all areas of functioning, including academic, occupational, and interpersonal.3 Neurobiological evidence supports a brain basis for ADHD, with alterations in widespread neural regions.4–7

Stimulants (methylphenidate and amphetamine compounds) are the mainstay of treatment for ADHD because of their robust clini-cal efficacy.8,9,10 The therapeutic effects of stimulants are most likely mediated by increases in activity of dopamine and norepinephrine in fronto-striatal circuitry, with downstream effects throughout the brain.11

Although animal studies suggested that stimulants may have detrimental effects on the rodent brain, these studies have generally used very large doses—up to 50 mg/kg—administered parenterally (intraperitoneally), whereas therapeutic doses range from 0.5 to 2.0 mg/kg/d and are administered orally in humans.12,13 Moreover, since animal studies often rely on “normal” wild-type rodents not affected by ADHD-related brain alterations, it is impossible to assess whether medication-related plasticity in these animals is neurotoxic or neuro-protective and whether the observed effects would be the same on an abnormally developing human brain. As a consequence, the relevance of these animal studies to humans taking therapeutic doses has been challenged.13–15

Structural magnetic resonance imaging (MRI) and functional MRI (fMRI) respectively allow examination of detailed anatomy and dynamic functional processes in the brain. Because MRI does not involve exposure to ionizing radiation, it can be used both as a technique to examine the effects in children and also as a repeated measure to investigate baseline and posttreatment effects. Because of these strengths, a number of studies have investigated the effects of stimulants on the ADHD brain.

Yet, to the best of our knowledge, there have been only 2 integra-tive, quantitative meta-analytic reviews16,17 examining the extant MRI literature on the effects of stimulants on the brain. Moreover, these reviews limited their analysis to (mostly) voxel-based morphom-etry studies, and only 1 included adults.17 More specifically, these 2 previous quantitative analyses examined the effect of the propor-tion of medicated subjects in ADHD groups on gray matter volumes largely measured by voxel-based morphometry.16,17 Nakao et al16 reported that stimulant medication is associated with “normaliza-tion” of basal ganglia abnormalities in ADHD. Similar results were reported by Frodl et al,17 who showed that stimulant treatment was associated with fewer ADHD-associated brain abnormalities (basal

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Spencer et alCl

inic

al P

oint

s Stimulant treatment for attention-deficit/hyperactivity ■disorder (ADHD) is known to be efficacious, but concerns about effects on the developing brain remain.

Our review of structural and functional neuroimaging studies ■finds no evidence that stimulant treatment negatively impacts brain development or function. In contrast, these studies suggest that stimulant treatment attenuates the brain abnormalities that have been associated with ADHD.

ganglia in children and anterior cingulate cortex [ACC] in adults) compared with controls. However, since these studies were limited to morphometric studies and did not include either fMRI, including functional connectivity and perfusion studies, or spectroscopy, additional work on the subject is needed. As stimulant medications are widely and chroni-cally prescribed in children, adolescents, and adults with ADHD, a better understanding of the effects of therapeutic oral doses of stimulants on brain structure and function in individuals with ADHD of all ages is an area of high clinical, scientific, and public health relevance.

The main aim of this qualitative review, therefore, was to summarize the findings from the extant morphomet-ric, functional, and spectroscopic MRI literature to assess the current state of knowledge of the effect of stimulants on brain structure, function, and biochemistry in child and adult subjects with ADHD. Our overall question was whether stimulants improve (attenuate), worsen, or have no effect on brain structure and function in ADHD subjects. We operationalized improvement and worsening through examination of the imaging values for the medicated and unmedicated groups in relation to the non-ADHD control group or in relation to each other in a crossover design (ie, testing the same subjects both on and off medication). If, in relation to the control group, the medicated group had values that tended to be closer to the control group than were the values for the unmedicated group, we argue that this result suggests a relative improvement or an attenuation of abnor-mality in brain structure or function. If, on the other hand, the medicated group had values that were more different than the unmedicated group in relation to the control group, we argue that this result would suggest a worsening effect. If the medicated and unmedicated groups were the same rela-tive to the controls, we argue that this result would suggest no effect. Thus, our conceptual framework was to examine the results of each published study in regards to treatment effects resulting in worsening, neutrality, or improvement in neural structure and function relative to controls. To the best of our knowledge, this is the first examination of effects of stimulants on both brain structure and brain function and the only review to integrate findings from articles that used either placebo- or case-control designs.

DATA SOURCESA systematic search strategy was used to identify relevant

studies. First, we carried out PubMed and ScienceDirect

searches of articles through the end of calendar year 2011 using a union of the following keywords: (1) psychostimulants or methylphenidate or amphetamine, and (2) neuroimaging or MRI or fMRI, and (3) ADHD or ADD or attention-deficit/hyperactivity disorder or attention deficit hyperactivity disorder.

STUDY SELECTION AND DATA EXTRACTIONThese searches yielded a combined 116 studies. From

these, we reviewed titles and abstracts and pared down those reports in the English language that were published as articles or letters in peer-reviewed journals and that contained new data (resulting in 49 articles). We manually reviewed the refer-ence list of all these 49 articles as well as the 5 relevant review articles we found. In order to limit the scope of our review, we included only those studies that utilized MRI-based mea-surements and included subjects with ADHD. We therefore excluded articles that used non-MRI methods (eg, positron emission tomography, electrophysiology) or studies with animal subjects, which resulted in a remaining 33 articles.

To ensure quality and interpretability of results, we included only case-control or placebo-controlled studies. For case-control studies, we required that a non-ADHD control group was used. This resulted in the exclusion of 3 additional studies.18–20 From the 30 articles that remained, we included the 29 studies that reported quantitative comparisons between ADHD subjects on and off psychostimulant medications (1 study described results only qualitatively21). The resulting 29 articles included 6 structural MRI studies,22–27 20 fMRI stud-ies,28–46 and 3 magnetic resonance spectroscopy studies.49–51 We combined details of study design and medication effects in each imaging modality. Below, we review the methods and findings of these 29 published studies.

RESULTSEffect of Psychostimulants on Brain Structure in ADHD

In Table 1, the methods, principal findings, and summary of medication effects from the 6 structural MRI studies are listed. These are summarized below.

Summary of methods used in structural neuroimaging studies.

Sample characteristics. All available structural studies included child and/or adolescent subjects (ages range from 4 to 20 years) of both sexes. The ADHD group sample sizes for the studies varied widely, with groups as small as 12 to as large as 103.

Diagnosis and comorbidity. All ADHD subjects included in the 6 structural MRI studies met criteria for DSM-IV combined type, as assessed with structured interviews or with review of clinic records. Exclusion criteria for all stud-ies included Tourette’s and any Axis I disorders, with varying additional exclusions, such as oppositional defiance disorder, learning disabilities, or both. Medication-related exclusions also varied across studies, with some studies excluding medi-cated ADHD subjects if they were concurrently taking other psychiatric medications, while many publications did not report any exclusion relating to medication.

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Effect of Psychostimulants on the Brain in ADHD

Tabl

e 1.

Eff

ect o

f Psy

chos

timul

ants

on

Brai

n St

ruct

ure

in C

hild

ren

and

Ado

lesc

ents

With

AD

HD

Stud

ySu

bjec

ts, n

Sex

Age

, Ra

nge

(mea

n), y

Des

ign

Mea

sure

Regi

ons o

f Int

eres

tPr

inci

pal F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sBl

edso

e et a

l,27

2009

18 A

DH

D-R

X13

AD

HD

-TN

15 H

C

Mal

e/ fem

ale

(11)

Cro

ss-s

ectio

nal,

case

-con

trol

Nat

ural

istic

dos

ing

with

“s

timul

ants”

for >

1 y

Are

aTo

tal c

ereb

ella

r ver

mis,

an

terio

r ce

rebe

llar

verm

is, p

oste

rior

supe

rior

cere

bella

r ve

rmis,

pos

terio

r in

ferio

r cer

ebel

lar

verm

is

(1) H

C, A

DH

D-R

X >

AD

HD

-TN

for

poste

rior i

nfer

ior c

ereb

ellar

verm

isTr

eatm

ent a

ssoc

iate

d w

ith

norm

aliz

atio

n of

pos

terio

r in

ferio

r cer

ebel

lar v

erm

is;

no o

ther

regi

ons o

f int

eres

t w

ere

smal

ler i

n A

DH

D-T

N

Cas

tella

nos

et a

l,26 2

002

103

AD

HD

-RX

49

AD

HD

-TN

139

HC

Mal

e/ fem

ale

4–19

(10)

Cro

ss-s

ectio

nal,

case

-con

trol

Nat

ural

istic

dos

ing

with

“s

timul

ants”

Volu

me

Tota

l cer

ebra

l vol

ume;

to

tal,

fron

tal,

parie

tal,

tem

pora

l, an

d oc

cipi

tal

gray

mat

ter;

tota

l, fr

onta

l, pa

rieta

l, te

mpo

ral,

and

occi

pita

l w

hite

mat

ter;

caud

ate,

cere

bellu

m

(1) H

C >

AD

HD

-TN

, AD

HD

-RX

for g

ray

mat

ter v

olum

es, c

auda

te,

cere

bellu

m, t

otal

cere

bral

volu

me

(2) H

C, A

DH

D-R

X >

AD

HD

-TN

for

all w

hite

mat

ter v

olum

es

Trea

tmen

t ass

ocia

ted

with

w

hite

mat

ter n

orm

aliz

atio

n,

but n

o ef

fect

in to

tal

cere

bral

vol

ume

or in

gra

y m

atte

r vol

umes

, inc

ludi

ng

cere

bellu

m a

nd c

auda

te

Sem

rud-

Clik

eman

et

al,24

200

6

16 A

DH

D-R

X14

AD

HD

-TN

21 H

C

Mal

e/ fem

ale

9–15

(13)

Cro

ss-s

ectio

nal,

ca

se-c

ontr

olN

atur

alist

ic d

osin

g w

ith

“stim

ulan

ts” fo

r > 1

yA

DH

D-R

X: w

ashe

d ou

t, bu

t no

leng

th m

entio

ned

Volu

me

Cau

date

, AC

C(1

) HC

> A

DH

D-R

X, A

DH

D-T

N fo

r lef

t an

d rig

ht ca

udat

e(2

) HC,

AD

HD

-RX

> A

DH

D-T

N fo

r rig

ht A

CC(3

) HC

> A

DH

D-T

N fo

r lef

t ACC

(tre

nd)

Trea

tmen

t ass

ocia

ted

with

rig

ht A

CC

nor

mal

izat

ion,

bu

t no

effe

ct in

cau

date

Schn

oebe

len

et a

l,23 2

010

12 A

DH

D-R

X13

AD

HD

-TN

15 H

C

Mal

e/ fem

ale

9–16

(13)

Cro

ss-s

ectio

nal,

case

-con

trol

Nat

ural

istic

dos

ing

with

“s

timul

ants”

for >

1 y

AD

HD

-RX

: was

hed

out,

but

no le

ngth

men

tione

d

Volu

me

Ove

rall

corp

us c

allo

sum

, 5

subr

egio

ns in

clud

ing

genu

, spl

eniu

m

(1) N

o sig

nific

ant g

roup

diff

eren

ces f

or

over

all c

orpu

s cal

losu

m o

r sub

regi

ons

(2) H

C >

AD

HD

-TN

in sp

leniu

m

Trea

tmen

t hist

ory

asso

ciat

ed

with

subt

le at

tenu

atio

n of

re

duce

d sp

leni

um v

olum

e re

port

ed p

revi

ously

Shaw

et a

l,22

2009

19

AD

HD

-RX

nc 2

4 A

DH

D-R

X29

4 H

C (t

empl

ate)

Mal

e/ fem

ale

9–20

(T

1: 1

3;

T2: 1

6)

Cas

e-co

ntro

l, lo

ngitu

dina

l N

atur

alist

ic d

osin

g

Scan

s ~ 4

y ap

art

Cor

tical

th

ickn

ess

Vert

ices

acr

oss t

he w

hole

co

rtex

(1) H

C, A

DH

D-R

Xnc >

AD

HD

-RX

for

rate

of c

ortic

al th

inni

ng in

left

mid

dle

front

al g

yrus

/infe

rior f

ront

al g

yrus

, rig

ht p

rece

ntra

l gyr

us, a

nd ri

ght

parie

tal/o

ccip

ital r

egio

ns

Trea

tmen

t ass

ocia

ted

with

no

rmal

ized

rate

of c

hang

e in

thic

knes

s acr

oss s

ever

al

cort

ical

regi

ons

Sobe

l et a

l,25

2010

31 A

DH

D-R

X16

AD

HD

-TN

57 H

C

Mal

e/ fem

ale

7–18

(12)

Cro

ss-s

ectio

nal,

case

-con

trol

N

atur

alist

ic d

osin

g w

ith

“stim

ulan

ts,”

mea

n du

ratio

n =

43.3

mo

AD

HD

-RX

: no

was

hout

fo

r sca

n

(1) V

olum

e(2

) Sur

face

m

orph

olog

y

Cau

date

, put

amen

, glo

bus

palli

dus

(1) H

C >

AD

HD

-ALL

in p

utam

en(2

) No

diag

nosis

or m

edic

al ef

fect

on

conv

entio

nal v

olum

es in

caud

ate/

glob

us p

allid

us(3

) HC

> A

DH

D-R

X >

AD

HD

-TN

for

surfa

ce d

efor

mat

ions

in ca

udat

e, pu

tam

en, g

lobu

s pal

lidus

Trea

tmen

t ass

ocia

ted

with

at

tenu

atio

n of

bas

al g

angl

ia

surf

ace

defo

rmat

ions

Abb

revi

atio

ns: A

CC

= an

terio

r cin

gula

te co

rtex

; AD

HD

=atte

ntio

n-de

ficit/

hype

ract

ivity

diso

rder

; AD

HD

-ALL

= al

l AD

HD

subj

ects

, irr

espe

ctiv

e of

med

icat

ion

stat

us; A

DH

D-R

X =

AD

HD

subj

ects

trea

ted

with

a

stim

ulan

t med

icat

ion;

AD

HD

-RX

nc =

AD

HD

subj

ects

not

cur

rent

ly tr

eate

d w

ith p

sych

ostim

ulan

ts; A

DH

D-T

N =

stim

ulan

t-na

ive

AD

HD

subj

ects

; HC

= h

ealth

y co

ntro

l sub

ject

s.

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Spencer et al

Design. All structural MRI studies compared matched groups of ADHD subjects with and without a history of medication to a non-ADHD, unmedicated control group. All medicated groups had been treated with a mix of different types and doses of psychostimulants. All studies had a case-control design, and none contained a placebo group. Five of 6 studies were cross-sectional, whereas the remaining study22 imaged ADHD children at 2 time points (~ 4 years apart), and compared brain measures in groups stratified by medication status at follow-up, regardless of status at baseline. In terms of medication status at the actual time of scan, 2 studies23,24 washed out medicated subjects before the scan but did not mention the length of washout, 1 study25 did not wash out subjects for the scan, and the remaining 3 studies22,26,27 did not mention if medicated subjects were washed out for the scan.

Neuroimaging methods. Neuroimaging was executed on 1.5T or 3T scanners. Analytic methods varied, with some studies using manual segmentation routines and some using fully automated analyses. Three structural MRI studies23,24,26 looked at volumes of specific regions of interest; 1 study25 looked at volume and surface deformations of regions of inter-est, 1 study27 looked at the surface area of regions of interest, and 1 study22 looked at cortical thickness across the entire cortex. The regions of interest measured across the studies were quite varied. Only the caudate was specifically investi-gated in more than 1 study.24–26

Summary of results in structural neuroimaging studies. Alterations in brain structure were found in unmedicated ADHD versus control groups in all 6 structural MRI studies. Additionally, in all studies, medication was associated with attenuation of abnormalities in at least a portion of the regions assessed. Castellanos et al26 and Semrud-Clikeman et al24 were unable to find any association of medication to ADHD-related global volume reductions in the caudate. Likewise, Sobel et al25 were unable to find medication-related differences in overall caudate volume (similar to null findings of Castellanos et al26 and Semrud-Clikeman et al24), but did find significant regional caudate volume reductions in the treatment-naive group (measured as surface deformations), which were attenuated in the treated group. Similarly, in the cerebellum, Castellanos et al26 found no association of medication with ADHD-related total cerebellar volume reductions, whereas Bledsoe et al,27 when investigating local subregions of the cerebellum, found that chronic stimulant treatment was associated with attenu-ation of reduced posterior inferior vermis volumes.

For the many regions of interest that were measured in only 1 study, several showed medication-associated attenu-ations, including attenuation in ADHD-related volume reduction across white matter in all lobes of the brain,26 in the ACC,24 and in the splenium of the corpus callosum.23 Stimulant treatment was also associated with rate of change of the cortical thickness in right motor strip, left middle/inferior frontal gyrus, and in a right parietal-occipital region similar to controls.22

Many null effects of medication status were found across studies, such that no statistical differences were found between

volumes in ADHD-naive and ADHD-medicated groups in regions of interest. These regions included large lobular gray matter measurements across the brain,26 global cau-date volume,24,26 overall cerebellar gray matter volume,26 overall basal ganglia volumes,25 and overall corpus callo-sum volume.23 Notably, when corpus callosum, caudate, cerebellar, striatal, and frontal gray volumes had local volume rather than global volume measures,23,25,27 or were subjected to vertex-by-vertex cortical thickness analyses,22 all regions showed medication-associated attenuations. Across all structural MRI studies and all regions measured, medication was never associated with worsening of brain findings relative to controls.

Effect of Psychostimulants on Brain Function in ADHD

We found 20 published studies examining the effects of stimulants on brain function in ADHD. In Table 2, the methods, principal findings, and summary of medication effects are listed. These are summarized below.

Summary of methods used in functional neuroimaging studies. The 20 functional MRI articles varied widely in all aspects of methods, including sample characteristics, design, and analytic approach.

Sample characteristics. Fifteen of 20 articles included child and/or adolescent subjects, whereas the remaining 5 included adult subjects or youth and parent dyads. Thirteen of the 20 studies included only male subjects, whereas the remaining 7 included mixed male and female samples. The ADHD group sample sizes were modest for the functional studies, with a range of 9–19 subjects per group.

Diagnosis and comorbidity. The ADHD subjects were diagnosed on the basis of structured interviews, semi-structured interviews, or clinician assessment. Some samples included only subjects with the combined type, while others included all types. Exclusion criteria for comorbidities varied across the studies, with several studies making no mention of comorbidity exclusion, while others excluded subjects with a varying number of other DSM-IV diagnoses. Medication-related exclusions also varied across studies, with some excluding medicated ADHD subjects if they were concurrently taking other psychiatric medi-cations, while others did not report any exclusion criteria relating to medication.

Design. Design varied across the fMRI studies. Nota-bly, all but one employed either a placebo-controlled or case-control crossover design or a cross-sectional design. Only Bush et al28 included subjects randomly assigned to either drug or placebo groups. This report, however, lacked a control group. For the studies that included a medication intervention (ie, not the cross-sectional studies), designs were used that included naturalistic dosing versus treat-ment after a washout period, or intervention trials ranging from a challenge dose to a 1-year trial. Medication history of subjects upon trial entry varied, however, with only the studies from Rubia et al29–32 and Konrad et al33 requiring that subjects be treatment naive at entry.

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Effect of Psychostimulants on the Brain in ADHD

Tabl

e 2.

Eff

ects

of P

sych

ostim

ulan

ts o

n Br

ain

Func

tion

in A

DH

D

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sCh

ildre

n +

adol

esce

nts

And

erso

n

et al

,34 2

002

10 A

DH

D-R

X,PL

6 H

CM

ale

(10)

Dou

ble-

blin

d, cr

osso

ver,

plac

ebo-

cont

rolle

d, an

d ca

se-c

ontro

lN

o in

form

atio

n on

med

ical

hi

story

prio

r to

tria

l M

ethy

lphe

nida

te-I

R (1

.5 m

g/kg

BI

D) o

r pla

cebo

for 1

wk

Met

hylp

heni

date

/pla

cebo

dos

e 1–

3 h

prio

r to

scan

Scan

s 1 w

k ap

art,

in

coun

terb

alan

ced

orde

r

T2 re

laxa

tion

time

(neg

ativ

ely re

lated

to

per

fusio

n)

durin

g re

sting

sta

te

Cere

bella

r he

misp

here

s, ce

rebe

llar

verm

is

(1) A

DH

D-R

X >

AD

HD

-PL

in ce

rebe

llar v

erm

is in

hy

pera

ctiv

e sub

ject

s(2

) AD

HD

-PL

> A

DH

D-R

X in

cere

bella

r ver

mis

in

nonh

yper

activ

e sub

ject

s

Trea

tmen

t dec

reas

ed

verm

al p

erfu

sion

in h

yper

activ

e su

bjec

ts, b

ut

incr

ease

d pe

rfusio

n in

non

hype

ract

ive

subj

ects

Kobe

l et a

l,39

2009

14 A

DH

D-R

X,O

FF12

HC

Mal

e9–

13 (1

1)Cr

osso

ver,

case

-con

trol

Nat

ural

istic

dos

ing

(met

hylp

heni

date

-IR

or

met

hylp

heni

date

-ORO

S) fo

r > 3

mo

For t

reat

men

t sca

n, m

edic

atio

n gi

ven

1.5

h pr

ior t

o sc

anFo

r off

of tr

eatm

ent s

can,

wa

shou

t > 24

hSc

ans >

2 w

k ap

art,

in

coun

terb

alan

ced

orde

r

BOLD

activ

ity d

urin

g n-

back

wor

king

m

emor

y ta

sk

Who

le br

ain

(1) H

C >

AD

HD

-ALL

in le

ft fro

ntal

corte

x, le

ft an

d rig

ht p

arie

tal l

obe,

and

right

cere

bellu

m(2

) No

diffe

renc

es b

etwe

en A

DH

D-R

X an

d A

DH

D-

OFF

No

treat

men

t effe

cts

dete

cted

Konr

ad et

al,33

20

07a

9 A

DH

D-T

N,R

X11

HC

(bas

eline

sc

an),

HC

(follo

w-up

scan

)

Mal

e8–

12 (1

1)Cr

osso

ver,

case

-con

trol

All

subj

ects

treat

men

t nai

ve at

sta

rt o

f tria

lM

ethy

lphe

nida

te-I

R (m

ean

daily

do

se =

0.8

mg/

kg) f

or 1

yr

AD

HD

-TN

: 1-w

k wa

shou

t Sc

ans 1

y ap

art

BOLD

activ

ity

durin

g At

tent

iona

l N

etwo

rk T

est

(inclu

des a

lertin

g,

reor

ient

ing,

and

exec

utiv

e con

trol

cont

rasts

)

Who

le br

ain

Reor

ient

ing

(1) H

C sh

owed

gre

ater

incr

ease

in te

mpo

ro-p

arie

tal

junc

tion

from

bas

eline

to fo

llow-

up sc

ans t

han

AD

HD

incr

ease

from

trea

tmen

t nai

ve to

trea

tmen

t(2

) AD

HD

show

ed g

reat

er in

crea

se in

insu

la an

d pu

tam

en fr

om tr

eatm

ent n

aive

to tr

eatm

ent t

han

HC

from

bas

eline

to fo

llow-

up sc

ans

(3) A

DH

D-T

N (a

t tim

e 2) >

AD

HD

-RX

in in

sula

and

puta

men

Exec

utiv

e con

trol

(4) H

C sh

owed

gre

ater

incr

ease

in A

CC fr

om b

aseli

ne

to fo

llow-

up sc

ans t

han

AD

HD

incr

ease

from

tre

atm

ent n

aive

to tr

eatm

ent

(5) A

DH

D-R

X >

AD

HD

-TN

(at t

ime 2

) in

ACC

(tren

d)

Trea

tmen

t may

atte

nuat

e co

mpe

nsat

ory

over

activ

ity in

insu

la

and

puta

men

dur

ing

reor

ient

ing

and

in

ACC

durin

g ex

ecut

ive

cont

rol,

but s

howe

d no

sign

ifica

nt ef

fect

on

tem

poro

-par

ieta

l ju

nctio

n hy

poac

tivity

du

ring

reor

ient

ing

(con

tinue

d)

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 907 J Clin Psychiatry 74:9, September 2013

Spencer et al

Tabl

e 2

(con

tinue

d). E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n Fu

nctio

n in

AD

HD

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sCh

ildre

n +

adol

esce

nts

Pete

rson

et al

,37

2009

16 A

DH

D-R

X,O

FF20

HC

Mal

e/ fem

ale

7–18

(13)

Cros

sove

r, ca

se-c

ontro

lA

DH

D su

bjec

ts go

od tr

eatm

ent

resp

onde

rs at

star

t of t

rial

Nat

ural

istic

dos

ing

(met

hylp

heni

date

, de

xtro

amph

etam

ine,

or

dext

roam

phet

amin

e/am

phet

amin

e)Fo

r tre

atm

ent s

can,

med

icat

ion

give

n 45

–60

min

pre

viou

s to

scan

For o

ff of

trea

tmen

t sca

n,

wash

out >

72 h

Scan

s 7–6

3 da

ys ap

art

(mea

n = 25

), in

co

unte

rbal

ance

d or

der

(1) S

uppr

essio

n of

BO

LD si

gnal

du

ring

Stro

op

colo

r-wo

rd ta

sk(2

) Gra

nger

caus

ality

m

odeli

ng o

f in

ferio

r fro

ntal

gy

rus/

vent

ral A

CC

inte

ract

ion

Who

le br

ain

for

activ

atio

n,

vent

ral A

CC

and

left

LPFC

for

conn

ectiv

ity

(1) H

C, A

DH

D-R

X >

AD

HD

-OFF

in ve

ntra

l ACC

su

ppre

ssio

n(2

) AD

HD

-RX

> A

DH

D-O

FF in

PCC

supp

ress

ion

(3) H

C >

AD

HD

-RX

> A

DH

D-O

FF in

left

LPFC

(tr

end)

(4) H

C, A

DH

D-R

X >

AD

HD

-OFF

for i

nflu

ence

of

vent

ral A

CC o

n LP

FC ac

tivity

Trea

tmen

t im

prov

ed

supp

ress

ion

of

defa

ult-m

ode

activ

ity in

the v

entra

l AC

C an

d po

sterio

r ci

ngul

ate c

orte

x,

atte

nuat

ed la

tera

l pr

efro

ntal

cor

tex

unde

ract

ivity

, and

in

crea

sed

conn

ectiv

ity

betw

een

defa

ult a

reas

an

d lat

eral

pre

front

al

corte

x to

leve

ls co

mpa

rabl

e with

co

ntro

ls

Plisz

ka et

al,45

20

06 9

AD

HD

-RX

8 A

DH

D-T

N15

HC

Mal

e/ fem

ale

9–15

(13)

Cros

s-se

ctio

nal,

case

-con

trol

Nat

ural

istic

dos

ing

of

met

hylp

heni

date

or

amph

etam

ine f

or 1

–9 y

AD

HD

-RX:

was

hout

, len

gth

not

men

tione

d

BOLD

activ

ity d

urin

g St

op si

gnal

Righ

t dlP

FC,

ACC,

and

vent

rolat

eral

PF

C de

fined

by

task

-re

lated

ac

tivity

Succ

essfu

l vs u

nsuc

cess

ful i

nhib

ition

(1) A

DH

D-A

LL >

HC

in ri

ght d

lPFC

, rig

ht an

d lef

t ve

ntro

later

al P

FC(2

) AD

HD

-TN

> A

DH

D-R

X, H

C in

ACC

Trea

tmen

t ass

ocia

ted

with

atte

nuat

ion

of

over

activ

ity in

ACC

, bu

t no

effe

ct in

LPF

C

Posn

er et

al,38

20

1115

AD

HD

-RX,

OFF

15 H

CM

ale/ fem

ale

11–1

6 (1

3)Cr

osso

ver,

case

-con

trol

For t

reat

men

t sca

n, n

atur

alist

ic

dosin

gFo

r off

of tr

eatm

ent s

can,

wa

shou

t > 48

hSc

ans i

n co

unte

rbal

ance

d or

der

BOLD

activ

ity d

urin

g em

otio

nal S

troop

Who

le br

ain

Posit

ively

val

ence

d di

strac

tionb

(1) A

DH

D-O

FF >

HC

in le

ft m

ePFC

(2) N

o sig

nific

ant d

iffer

ence

s bet

ween

AD

HD

-RX

and

HC

in le

ft m

ePFC

Neg

ativ

ely v

alen

ced

distr

actio

nb

(3) A

DH

D-O

FF >

AD

HD

-RX,

HC

in le

ft an

d rig

ht

meP

FC d

eact

ivat

ion

Trea

tmen

t nor

mal

ized

alt

erat

ions

in m

edia

l pr

efro

ntal

corte

x ac

ross

diff

eren

t em

otio

nally

val

ence

d ta

sk co

nditi

ons

Posn

er et

al,41

20

1115

AD

HD

-RX,

OFF

15 H

CM

ale/ fem

ale

11–1

6 (1

3)Cr

osso

ver,

case

-con

trol

For t

reat

men

t sca

n, n

atur

alist

ic

dosin

gFo

r off

of tr

eatm

ent s

can,

wa

shou

t > 48

hSc

ans i

n co

unte

rbal

ance

d or

der

BOLD

activ

ity

and

effe

ctiv

e co

nnec

tivity

du

ring

subl

imin

al

pres

enta

tion

of

fear

ful f

aces

Who

le br

ain

for

activ

atio

ns,

LPFC

-am

ygda

la

for d

ynam

ic

caus

al

mod

eling

(1) A

DH

D-O

FF >

HC

in ri

ght a

myg

dala

and

in

bilat

eral

amyg

dala

-LPF

C co

nnec

tivity

(2) N

o sig

nific

ant d

iffer

ence

s bet

ween

AD

HD

-RX

and

HC

in ri

ght a

myg

dala

or i

n bi

later

al am

ygda

la-

LPFC

conn

ectiv

ity

Trea

tmen

t nor

mal

ized

am

ygda

la o

vera

ctiv

ity

and

over

conn

ectiv

ity

of am

ygda

la

with

LPF

C w

hile

subl

imin

ally

vie

win

g fe

arfu

l fac

es (con

tinue

d)

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 908J Clin Psychiatry 74:9, September 2013

Effect of Psychostimulants on the Brain in ADHD

Tabl

e 2

(con

tinue

d). E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n Fu

nctio

n in

AD

HD

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sCh

ildre

n +

adol

esce

nts

Preh

n-Kr

isten

sen

et

al,48

201

1

12 A

DH

D-R

X,O

FF12

HC

Mal

ec11

–17

(13)

Cros

sove

r, ca

se-c

ontro

l Fo

r tre

atm

ent s

can,

nat

ural

istic

do

sing

of m

ethy

lphe

nida

te

(mea

n da

ily d

ose =

0.8

mg/

kg)

For o

ff of

trea

tmen

t sca

n,

wash

out >

48 h

Scan

s > 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

BOLD

activ

ity d

urin

g de

layed

mat

chin

g to

sam

ple w

ith

face

dist

ract

or

Who

le br

ain

(1) H

C >

AD

HD

-OFF

in fr

onto

-cin

gulat

e, te

mpo

ro-

parie

to-o

ccip

ital r

egio

ns, a

nd in

caud

ate

(2) H

C >

AD

HD

-RX

in ca

udat

e and

tem

poro

-occ

ipita

l re

gion

s (bu

t clu

sters

wer

e red

uced

com

pare

d to

HC

> A

DH

D-O

FF co

ntra

st)(3

) AD

HD

-RX

> H

C in

righ

t ins

ula

Trea

tmen

t nor

mal

ized

un

dera

ctiv

ity in

fro

nto-

cing

ulat

e and

pa

rieta

l reg

ions

, and

at

tenu

ated

effe

ct in

ca

udat

e and

tem

poro

/oc

cipita

l lob

e reg

ions

du

ring

a dist

ract

ed

work

ing

mem

ory

task

Rubi

a et a

l,29

2009

12 A

DH

D-R

X,PL

12 H

CM

ale

10–1

6 (1

3)D

oubl

e-bl

ind,

cros

sove

r, pl

aceb

o-co

ntro

lled,

and

case

-con

trol

All

subj

ects

treat

men

t nai

ve at

sta

rt o

f tria

lM

ethy

lphe

nida

te-I

R (0

.3 m

g/kg

)/pl

aceb

o 1

h pr

evio

us to

scan

Sc

ans 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

BOLD

activ

ity

durin

g tim

e di

scrim

inat

ion

Who

le br

ain

(1) H

C >

AD

HD

-PL

in ri

ght +

left

OFC

/IFC/

meP

FC/

ACC/

caud

ate,

right

cere

bellu

m(2

) AD

HD

-PL

> H

C in

left

MFG

/STG

/occ

ipita

l lob

e/ce

rebe

llum

(3) A

DH

D-R

X >

AD

HD

-PL

in le

ft O

FC/IF

G/in

sula

, rig

ht m

ePFC

, lef

t ACC

, rig

ht ce

rebe

llum

(4) A

DH

D-P

L >

AD

HD

-RX

for r

ight

IFG

/meP

FC/

insu

la, r

ight

supe

rior f

ront

al g

yrus

, rig

ht m

edia

l te

mpo

ral l

obe,

right

hip

poca

mpu

s, rig

ht p

utam

en/

glob

us p

allid

us(5

) HC

vs A

DH

D-R

X, n

o di

ffere

nces

at le

nien

t th

resh

old

Trea

tmen

t nor

mal

ized

al

l gro

up ac

tivat

ion

diffe

renc

es o

bser

ved

in p

lace

bo co

nditi

on

durin

g tim

e di

scrim

inat

ion

task

Rubi

a et a

l,30

2009

13 A

DH

D-R

X,PL

13 H

CM

ale

10–1

6 (1

3)D

oubl

e-bl

ind,

cros

sove

r,

case

-con

trol

All

subj

ects

treat

men

t nai

ve at

sta

rt o

f tria

lM

ethy

lphe

nida

te-I

R (0

.3 m

g/kg

)/pl

aceb

o 1

h pr

evio

us to

scan

Scan

s 1 w

k ap

art,

in

coun

terb

alan

ced

orde

r

BOLD

activ

ity an

d co

nnec

tivity

du

ring

rewa

rded

Co

ntin

uous

Pe

rform

ance

Tes

t

Def

ined

by

task

-rela

ted

activ

ity

Vigi

lant

atte

ntio

n co

ntra

stAc

tivat

ion:

(1) H

C >

AD

HD

-PL

in ri

ght I

FC/v

entro

med

ial O

FC/

hipp

ocam

pus,

left b

asal

gan

glia

, lef

t and

righ

t in

sula

/par

ahip

poca

mpa

l gyr

us/c

ereb

ellum

(2) H

C, A

DH

D-R

X >

AD

HD

-PL

in le

ft an

d rig

ht IP

L/ST

G, r

ight

supe

rior p

arie

tal

(3) A

DH

D-R

X >

HC

in ri

ght d

lPFC

, inf

erio

r cer

ebell

ar

verm

is (r

egio

ns n

egat

ive c

orre

latio

n w/

com

miss

ion

erro

rs)

Conn

ectiv

ity:

(4) H

C, A

DH

D-R

X >

AD

HD

-PL

in in

terc

orre

latio

n be

twee

n:(a

) Lef

t/rig

ht in

ferio

r fro

ntal

corte

x an

d str

iatu

m,

thal

amus

, cer

ebell

um(b

) Cer

ebell

um an

d IP

L, st

riatu

m, c

ingu

late

(c) T

hala

mus

and

PCC

Rewa

rd co

ntra

st(5

) HC

> A

DH

D-P

L, A

DH

D-R

X in

righ

t cer

ebell

um(6

) HC,

AD

HD

-RX

> A

DH

D-P

L in

left

cere

bellu

m(7

) AD

HD

-PL

> A

DH

D-R

X, H

C in

left

OFC

, lef

t and

rig

ht S

TGNo

conn

ectiv

ity a

nalys

is du

ring r

ewar

d co

ntra

st

Dur

ing

vigi

lant

atte

ntio

n,

treat

men

t inc

reas

ed

com

pens

ator

y ac

tivity

and

impr

oved

inhi

bitio

n an

d no

rmal

ized

un

dera

ctiv

ity in

pa

rieto

-tem

pora

l re

gion

s and

un

derc

onne

ctiv

ity

in fr

onto

-str

iata

l-ce

rebe

llar c

ircui

ts.

Dur

ing

rewa

rd

cont

rast,

trea

tmen

t at

tenu

ated

alte

red

leve

ls of

activ

ity in

or

bito

front

al an

d ce

rebe

llar r

egio

ns

(con

tinue

d)

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 909 J Clin Psychiatry 74:9, September 2013

Spencer et al

Tabl

e 2

(con

tinue

d). E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n Fu

nctio

n in

AD

HD

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sCh

ildre

n +

adol

esce

nts

Rubi

a et a

l,31

2011

12 A

DH

D-R

X,PL

13 H

CM

ale

10–1

5 (1

3)D

oubl

e-bl

ind,

cros

sove

r, pl

aceb

o-co

ntro

lled,

and

case

-con

trol

All

subj

ects

treat

men

t nai

ve at

sta

rt o

f tria

lM

ethy

lphe

nida

te-I

R (0

.3 m

g/kg

)/pl

aceb

o 1

h be

fore

scan

Sc

ans 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

BOLD

activ

ity d

urin

g Si

mon

odd

ball

task

Who

le br

ain

(1) A

DH

D-R

X >

AD

HD

-PL

in le

ft ce

rebe

llum

/fu

sifor

m/M

TG/in

ferio

r tem

pora

l gyr

us an

d rig

ht

IFC/

prem

otor

/STG

/IPL

(2) H

C >

AD

HD

-PL

in ri

ght I

FG/IP

L/su

pplem

enta

ry

mot

or ar

ea/A

CC/P

CC/s

uper

ior p

arie

tal l

obul

e and

lef

t vm

PFC/

basa

l gan

glia

/thal

amus

/STG

/MTG

/oc

cipita

l lob

e(3

) HC

> A

DH

D-R

X in

left

supp

lemen

tary

mot

or

area

/ACC

/pre

cune

us/M

TG/o

ccip

ital l

obe/

STG

/IPL

Trea

tmen

t had

regi

on-

spec

ific n

orm

aliz

atio

n ef

fect

s in

infe

rior a

nd

vent

rom

edia

l fro

nto-

stria

tal r

egio

ns d

urin

g in

terfe

renc

e inh

ibiti

on

Rubi

a et a

l,32

2011

12 A

DH

D-R

X,PL

13 H

CM

ale

10–1

5 (1

3)D

oubl

e-bl

ind,

cros

sove

r, pl

aceb

o-co

ntro

lled,

and

case

-con

trol

All

subj

ects

treat

men

t nai

ve at

sta

rt o

f tria

lM

ethy

lphe

nida

te-I

R (0

.3 m

g/kg

)/pl

aceb

o 1

h be

fore

scan

Sc

ans 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

BOLD

activ

ity d

urin

g St

op ta

skW

hole

brai

nU

nsuc

cess

ful i

nhib

ition

cont

rast

(1) A

DH

D-R

X >

AD

HD

-PL

in le

ft M

FG, r

ight

IPL/

pr

ecun

eus/

occip

ital l

obe a

nd b

ilate

ral I

FC/in

sula

/pu

tam

en/c

auda

te(2

) HC

> A

DH

D-P

L in

left

IFC/

PCC/

prec

uneu

s, rig

ht

prem

otor

corte

x/IP

L/IT

L/ce

rebe

llum

, and

bila

tera

l dm

PFC/

pre–

supp

lemen

tary

mot

or ar

ea/s

uper

ior

parie

tal l

obul

e/oc

cipita

l lob

e/pu

lvin

ar(3

) No

signi

fican

t diff

eren

ces b

etwe

en A

DH

D-R

X an

d H

CSu

cces

sful i

nhib

ition

cont

rast

(4) N

o sig

nific

ant d

iffer

ence

s bet

ween

med

icat

ion

cond

ition

s(5

) HC

> A

DH

D-P

L in

left

IFC,

righ

t med

ial t

empo

ral

lobe

/occ

ipita

l lob

e/lin

gual

gyr

us/IP

L/pr

ecun

eus/

PCC/

cere

bellu

m an

d bi

later

al in

sula

/ACC

/pu

lvin

ar/p

resu

pplem

enta

ry m

otor

area

(6) N

o sig

nific

ant d

iffer

ence

s bet

ween

AD

HD

-RX

and

HC

Trea

tmen

t nor

mal

ized

ac

tivat

ion

durin

g er

ror p

roce

ssin

g,

and

durin

g bo

th

erro

r pro

cess

ing

and

succ

essfu

l inh

ibiti

ons,

no d

iffer

ence

s cou

ld

be d

etec

ted

betw

een

med

icat

ed A

DH

D

subj

ects

and

HC

Shaf

ritz e

t al,43

20

0419

AD

HD

-RX,

PL14

HCd

Mal

e/ fem

ale

14–1

7 (1

5)D

oubl

e-bl

ind,

cros

sove

r, pl

aceb

o-co

ntro

lled,

and

case

-con

trol

Mix

ed m

edic

al h

istor

y pr

ior t

o tr

ial

Met

hylp

heni

date

-IR

(15–

25 m

g)

dose

For t

reat

men

t sca

n,

met

hylp

heni

date

1.5

h p

rior

to sc

anFo

r pla

cebo

scan

, was

hout

for a

t lea

st 72

hSc

ans 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

(1) B

OLD

activ

ity

durin

g di

vide

d at

tent

ion

(2) B

OLD

activ

ity

durin

g se

lectiv

e at

tent

ion

Who

le br

ain

Div

ided

atte

ntio

n(1

) HC

> A

DH

D-P

L in

MTG

(2) H

C, A

DH

D-R

X >

AD

HD

-PL

in d

orsa

l str

iatu

m(3

) AD

HD

-RX

> A

DH

D-P

L in

MTG

Trea

tmen

t nor

mal

ized

un

dera

ctiv

ity in

dor

sal

stria

tum

but

not

MTG

; ef

fect

s wer

e spe

cific

to

div

ided

but

not

se

lectiv

e atte

ntio

n

(con

tinue

d)

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 910J Clin Psychiatry 74:9, September 2013

Effect of Psychostimulants on the Brain in ADHD

Tabl

e 2

(con

tinue

d). E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n Fu

nctio

n in

AD

HD

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sCh

ildre

n +

adol

esce

nts

Teich

er et

al,35

20

0011

AD

HD

-RX,

PL 6

HC

Mal

e(1

0)D

oubl

e-bl

ind,

cros

sove

r, pl

aceb

o-co

ntro

lled,

and

case

-con

trol

No

info

rmat

ion

on m

edic

al

histo

ry p

rior t

o tr

ial

Met

hylp

heni

date

-IR

(1.5

mg/

kg

BID

) or p

lace

bo fo

r 1 w

kSc

ans 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

Met

hylp

heni

date

/pla

cebo

dos

e 1–

3 h

prev

ious

to sc

an

T2 re

laxa

tion

time

(neg

ativ

ely re

lated

to

per

fusio

n)

durin

g re

sting

sta

te

Thal

amus

, ca

udat

e, pu

tam

en

(1) A

DH

D-P

L >

HC

in p

utam

en(2

) AD

HD

-PL

> A

DH

D-R

X in

put

amen

in

hype

ract

ive s

ubje

cts

(3) A

DH

D-R

X >

AD

HD

-PL

in p

utam

en in

no

nhyp

erac

tive s

ubje

cts

Trea

tmen

t atte

nuat

ed

hype

rper

fusio

n in

hyp

erac

tive

AD

HD

subj

ects

and

hypo

perfu

sion

in

nonh

yper

activ

e A

DH

D su

bjec

ts

Vaid

ya et

al,42

19

9810

AD

HD

-RX,

OFF

6 H

C-RX

, H

C-O

FF

Mal

e8–

13 (1

0)Cr

osso

ver,

case

-con

trol

AD

HD

: nat

ural

istic

m

ethy

lphe

nida

te d

ose (

rang

e, 7.

5–30

mg)

HC:

10-

mg

chal

lenge

dos

e of

met

hylp

heni

date

For t

reat

men

t sca

n,

met

hylp

heni

date

1–2

h

prev

ious

to sc

anFo

r AD

HD

-OFF

scan

, > 36

-h

wash

out

Scan

s > 1

wk

apar

t, in

co

unte

rbal

ance

d or

der

(1) B

OLD

exte

nt

durin

g sti

mul

us-

cont

rolle

d G

o/N

o-G

o(2

) BO

LD ex

tent

du

ring

resp

onse

-co

ntro

lled

Go/

No-

Go

Stria

tum

, fro

ntal

lobe

s (in

cludi

ng

ACC)

Stim

ulus

-con

trolle

d G

o/N

o-G

oIn

stria

tum

: (1

) HC-

OFF

> H

C-RX

(2

) AD

HD

-RX

> H

C-RX

(3

) HC-

OFF

> A

DH

D-R

X >

AD

HD

-OFF

In fr

onta

l lob

es:

(4) H

C-RX

> H

C-O

FF

(5) A

DH

D-R

X >

AD

HD

-OFF

Trea

tmen

t ass

ocia

ted

with

incr

ease

d fro

ntal

activ

atio

n in

co

ntro

ls an

d A

DH

D

subj

ects;

inte

ract

ion

in st

riatu

m, w

here

tre

atm

ent a

ttenu

ated

str

iata

l und

erac

tivity

in

AD

HD

, and

de

crea

sed

activ

ity

in co

ntro

ls du

ring

stim

ulus

-con

trolle

d ta

sk. N

o sig

nific

ant

effe

cts i

n re

spon

se-

cont

rolle

d G

o/N

o-G

o Ad

ults

Bush

et al

,28

2008

10 A

DH

D-T

N,R

X11

AD

HD

-TN

,PL

Mal

e/ fem

ale

18–5

1 (3

2)D

oubl

e-bl

ind,

rand

omiz

ed,

plac

ebo-

cont

rolle

d 3

of 2

1 tre

atm

ent-n

aive

su

bjec

ts ha

d pr

evio

us

unsu

cces

sful t

rial w

ith

met

hylp

heni

date

M

ethy

lphe

nida

te-O

ROS

(titra

ted

from

36

mg

to

optim

al re

spon

se) f

or 6

wk

Scan

s 6 w

k ap

art

BOLD

sign

al ch

ange

an

d sp

atia

l va

riabi

lity

durin

g M

ulti-

Sour

ce

Inte

rfere

nce T

ask

Def

ined

by

task

-rela

ted

activ

ity

(1) A

DH

D-R

X >

AD

HD

-PL

in ch

ange

from

bas

eline

in

left

and

right

dor

sal a

nter

ior m

idci

ngul

ate

corte

x/in

sula

(2) A

DH

D-R

X >

AD

HD

-PL

in A

CC, r

ight

dlP

FC,

left a

nd ri

ght s

uper

ior p

arie

tal

(3) A

DH

D-R

X re

spon

ders

(N =

7) >

AD

HD

-RX

nonr

espo

nder

s (N

= 4)

, pla

cebo

(N =

11) i

n do

rsal

an

terio

r mid

cing

ulat

e cor

tex

Trea

tmen

t ass

ocia

ted

with

incr

ease

d ac

tivat

ion

in ci

ngul

o-fro

nto-

parie

tal

netw

ork,

dor

sal

ante

rior m

idci

ngul

ate

corte

x ef

fect

s gr

eate

r in

treat

men

t re

spon

ders (c

ontin

ued)

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 911 J Clin Psychiatry 74:9, September 2013

Spencer et al

Tabl

e 2

(con

tinue

d). E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n Fu

nctio

n in

AD

HD

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sAd

ults

O’G

orm

an

et al

,36 2

008

9 A

DH

D-R

X,O

FF11

HC

Mal

e20

–48

(30)

Cros

sove

r, ca

se-c

ontro

l N

atur

alist

ic d

osin

g (in

clude

s m

ethy

lphe

nida

te-O

ROS,

m

ethy

lphe

nida

te-I

R, an

d de

xtro

amph

etam

ine)

> 1

mo

For t

reat

men

t sca

n, IR

giv

en

1 h

prev

ious

to sc

an, s

usta

ined

re

lease

giv

en 5

h p

revi

ous t

o sc

anFo

r off

of tr

eatm

ent s

can,

wa

shou

t > 1

wk

Scan

s in

coun

terb

alan

ced

orde

r

Resti

ng-s

tate

pe

rfusio

n m

easu

red

by

cont

inuo

us ar

teria

l sp

in la

belin

g

Who

le br

ain

(1) A

DH

D-O

FF >

HC

in le

ft ca

udat

e, IF

G, c

ingu

late,

prec

uneu

s, M

FG, p

ostc

entra

l gyr

us(2

) AD

HD

-OFF

> A

DH

D-R

X in

left

IFG

, pa

rahi

ppoc

ampa

l gyr

us, p

ostc

entra

l gyr

us,

supr

amar

gina

l gyr

us(3

) AD

HD

-OFF

> A

DH

D-R

X, H

C in

left

caud

ate

(4) A

DH

D-R

X >

HC

for r

ight

pre

cent

ral g

yrus

, ci

ngul

ate,

IPL

Trea

tmen

t ass

ocia

ted

with

atte

nuat

ion

of re

gion

al

hype

rper

fusio

n in

fron

tal a

nd

parie

tal r

egio

ns, a

nd

norm

aliz

atio

n of

hy

perp

erfu

sion

in

caud

ate

Schl

ocht

erm

eier

et al

,44 2

011

10 A

DH

D-R

Xnc

10 A

DH

D-T

N10

HC

Mal

eCa

se-c

ontro

l, cr

oss-

sect

iona

lA

DH

D-R

Xnc w

ere m

edic

ated

in

child

hood

, and

med

icat

ion-

free f

or >

1 y

BOLD

sign

al d

urin

g ne

utra

l and

ne

gativ

e pic

ture

s, so

me w

ith

emot

iona

l va

lence

cued

Am

ygda

la,

ACC,

vent

ral

stria

tum

Une

xpec

ted

posit

ive v

s neu

tral p

ictu

res

(1) H

C >

AD

HD

-TN

in b

ilate

ral v

entra

l str

iatu

m an

d sA

CC(2

) AD

HD

-RXn

c > A

DH

D-T

N in

left

vent

ral s

tria

tum

Une

xpec

ted

nega

tive v

s neu

tral p

ictu

res

(3) H

C >

AD

HD

-TN

in ri

ght v

entra

l str

iatu

m an

d sA

CC(4

) AD

HD

-RXn

c > A

DH

D-T

N in

bila

tera

l ven

tral

stria

tum

Expe

cted

vs u

nexp

ecte

d ne

gativ

e pic

ture

s(5

) HC

> A

DH

D-T

N in

sACC

Trea

tmen

t in

child

hood

as

soci

ated

with

no

rmal

izat

ion

of

unde

ract

ivity

in sA

CC

and

vent

ral s

tria

tum

in

resp

onse

to em

otio

nal

stim

uli

Stoy

et al

,40

2011

12 A

DH

D-R

Xnce

11 A

DH

D-T

Nf

12 H

C

Mal

e(2

8)Ca

se-c

ontro

l, cr

oss-

sect

iona

lA

DH

D-R

Xnc w

ere m

edic

ated

in

child

hood

, and

med

icat

ion-

free f

or >

1 y

BOLD

sign

al

durin

g M

onet

ary

Ince

ntiv

e Dela

y Ta

sk

Vent

ral s

tria

tum

du

ring

rewa

rd

antic

ipat

ion

and

OFC

du

ring

rewa

rd

outc

ome,

expl

orat

ory

who

le-br

ain

anal

ysis

(1) N

o gr

oup

effe

cts f

or ve

ntra

l str

iatu

m o

r OFC

re

gion

s of i

nter

est

Gai

n an

ticip

atio

n(2

) HC

> A

DH

D-T

N in

left

IFG

(3) H

C >

AD

HD

-RXn

c in

right

IFG

Loss

antic

ipat

ion

(4) H

C >

AD

HD

-RXn

c in

right

MFG

(5) N

o sig

nific

ant d

iffer

ence

bet

ween

trea

tmen

t gro

ups

Gai

n ou

tcom

e(6

) No

effe

cts o

f gro

upLo

ss o

utco

me

(7) H

C, A

DH

D-R

Xnc >

AD

HD

-TN

in in

sula

(8) H

C >

AD

HD

-TN

in ri

ght p

rece

ntra

l gyr

us

Effe

ct o

f AD

HD

no

t sig

nific

ant i

n re

gion

s of i

nter

est,

but t

reat

men

t had

lat

eral

izat

ion

effe

ct in

in

ferio

r fro

ntal

gyr

us

durin

g an

ticip

atio

n of

a re

ward

, and

no

rmal

izat

ion

of in

sula

but

not

pr

ecen

tral g

yrus

hy

poac

tivity

dur

ing

nega

tive f

eedb

ack

(con

tinue

d)

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 912J Clin Psychiatry 74:9, September 2013

Effect of Psychostimulants on the Brain in ADHD

Tabl

e 2

(con

tinue

d). E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n Fu

nctio

n in

AD

HD

Stud

ySu

bjec

ts, N

Sex

Age,

Rang

e (m

ean)

, yD

esig

nM

easu

re/T

ask

Regi

ons o

f In

tere

stPr

incip

al F

indi

ngs

Sum

mar

y of

M

edic

atio

n Ef

fect

sO

ther

Epste

in et

al,46

20

07g

13 A

DH

D-R

X,PL

(y

outh

)15

AD

HD

-RX,

PL

(par

ent)

Mal

e/ fem

ale

Yout

h: (1

7)Pa

rent

: (49

)D

oubl

e-bl

ind,

cros

sove

r, pl

aceb

o-co

ntro

lled,

and

case

-con

trol

Mix

ed m

edic

al h

istor

y pr

ior t

o tr

ial

Met

hylp

heni

date

-IR

(0.3

mg/

kg)

or p

lace

boTr

eatm

ent o

r pla

cebo

dos

e giv

en

60–1

20 m

in p

revi

ous t

o sc

anSc

ans 1

d ap

art,

in

coun

terb

alan

ced

orde

r

BOLD

activ

ity d

urin

g G

o/N

o-G

oSt

riatu

m,

pref

ront

al

corte

x, p

ost

parie

tal

lobe

gyr

i, ce

rebe

llum

From

acco

mpa

nyin

g stu

dy(1

) HC-

YOU

TH >

AD

HD

YO

UTH

-PL

in b

ilate

ral

MFG

/cau

date

, rig

ht IF

G/IP

L/AC

C(2

) HC-

PARE

NT

> A

DH

D P

ARE

NT-

PL in

bila

tera

l IF

G, l

eft c

auda

te(3

) AD

HD

PA

REN

T-PL

> H

C-PA

REN

T in

left

IPL,

AC

CFr

om m

edic

atio

n stu

dy(4

) AD

HD

YO

UTH

-RX

> A

DH

D Y

OU

TH-P

L fo

r lef

t M

FG, l

eft I

FG, r

ight

IPL,

ACC

, rig

ht ca

udat

e, an

d lef

t cer

ebell

um(5

) AD

HD

PA

REN

T-RX

> A

DH

D P

ARE

NT-

PL fo

r lef

t cau

date

(6) A

DH

D P

ARE

NT-

PL >

AD

HD

PA

REN

T-RX

for

right

IPL

and

left M

FG

Met

hylp

heni

date

as

soci

ated

with

in

crea

sed

front

o-str

iata

l and

cere

bella

r ac

tivat

ion

in

yout

h; ad

ults

on

met

hylp

heni

date

sh

owed

sim

ilar

incr

ease

s in

activ

atio

n fo

r str

iatu

m an

d ce

rebe

llum

, but

not

pr

efro

ntal

corte

x

a All

com

paris

ons i

nclu

ding

AD

HD

-TN

(fol

low

-up

scan

) wer

e fr

om a

n ex

plor

ator

y fix

ed-e

ffect

s ana

lysis

of 5

subj

ects

who

refu

sed

med

icat

ion

durin

g tr

ial:

thes

e an

alys

es co

mpa

red

AD

HD

-TN

(at b

asel

ine

and

follo

w-u

p sc

ans)

and

HC

(at b

asel

ine

and

follo

w-u

p sc

ans,

N =

11).

b Ana

lyse

s of g

roup

× va

lenc

e in

tera

ctio

n co

ntro

l for

the

effe

cts o

f cog

nitiv

e di

stra

ctio

n.c Pe

r per

sona

l ele

ctro

nic c

omm

unic

atio

n w

ith A

. Pre

hn-K

riste

nsen

, PhD

, in

April

201

3.d Sh

afrit

z et a

l44 a

lso in

clud

ed a

gro

up o

f rea

ding

diso

rder

ed su

bjec

ts w

ithou

t AD

HD

, but

thos

e re

sults

are

not

pre

sent

ed.

e Five

of 1

2 cu

rren

tly fu

lfille

d A

DH

D d

iagn

osis;

oth

ers w

ere

rem

itted

.f Fi

ve o

f 11

curr

ently

fulfi

lled

AD

HD

dia

gnos

is; o

ther

s wer

e re

mitt

ed.

g Epst

ein

et a

l47 co

ntai

ned

2 st

udie

s in

one

publ

icat

ion.

Met

hods

repo

rted

are

from

the

med

icat

ion

stud

y, w

here

as p

lace

bo v

ersu

s HC

resu

lts a

re fr

om a

ccom

pany

ing

stud

y th

at a

naly

zed

the

subs

et o

f dya

ds th

at w

ere

rand

omly

ass

igne

d to

get

pla

cebo

firs

t (N

= 9

dyad

s) a

nd a

mat

ched

gro

up o

f 9 H

C d

yads

.A

bbre

viat

ions

: AC

C =

ante

rior c

ingu

late

cort

ex; A

DH

D =

atte

ntio

n-de

ficit/

hype

ract

ivity

diso

rder

; AD

HD

-ALL

= al

l AD

HD

subj

ects

, irr

espe

ctiv

e of

med

icat

ion

stat

us; A

DH

D-O

FF =

subj

ects

trea

ted

with

stim

ulan

t m

edic

atio

n bu

t was

hed

out f

or sc

an; A

DH

D-P

L =

plac

ebo-

trea

ted

AD

HD

subj

ects

; AD

HD

-RX

= A

DH

D su

bjec

ts tr

eate

d w

ith a

stim

ulan

t med

icat

ion;

AD

HD

-RX

nc =

AD

HD

subj

ects

not

cur

rent

ly tr

eate

d w

ith

psyc

host

imul

ants

; AD

HD

-RX

,OFF

= on

e sc

an p

erfo

rmed

whe

n A

DH

D su

bjec

t was

on

psyc

host

imul

ant,

one

perf

orm

ed a

fter s

ubje

ct w

as w

ashe

d ou

t; A

DH

D-R

X,P

L =

one

scan

per

form

ed w

hen

AD

HD

subj

ect

was

on

psyc

host

imul

ant,

one

perf

orm

ed w

hen

on p

lace

bo; A

DH

D-T

N =

psyc

host

imul

ant-

naiv

e A

DH

D su

bjec

ts; A

DH

D-T

N,P

L =

one

scan

per

form

ed w

hen

subj

ects

wer

e tr

eatm

ent n

aive

, one

per

form

ed w

hen

on p

lace

bo; A

DH

D-T

N,R

X =

one

scan

per

form

ed w

hen

subj

ects

wer

e tr

eatm

ent n

aive

, one

per

form

ed w

hen

on st

imul

ants

; BID

= tw

ice

a da

y; B

OLD

= bl

ood

oxyg

enat

ion

leve

l-dep

ende

nt; d

lPFC

= d

orso

late

ral

pref

ront

al co

rtex

; dm

PFC

= d

orsa

l med

ial p

refr

onta

l cor

tex;

HC

= h

ealth

y co

ntro

l sub

ject

s; H

C-R

X =

one

scan

per

form

ed w

hen

cont

rol s

ubje

ct w

as o

n ps

ycho

stim

ulan

t; H

C-R

X =

one

scan

per

form

ed w

hen

cont

rol s

ubje

ct w

as m

edic

atio

n fr

ee; I

FC =

infe

rior f

ront

al co

rtex

; IFG

= in

ferio

r fro

ntal

gyr

us; I

PL =

infe

rior p

arie

tal l

obul

e; IR

= im

med

iate

rele

ase;

ITL

= in

ferio

r tem

pora

l lob

e; m

ePFC

= m

edia

l pre

fron

tal c

orte

x;

MFG

= m

iddl

e fr

onta

l gyr

us; M

RI =

mag

netic

reso

nanc

e im

agin

g; M

TG =

mid

dle

tem

pora

l gyr

us; O

FC =

orbi

tofr

onta

l cor

tex;

ORO

S = os

mot

ic re

leas

e or

al sy

stem

; PC

C =

pos

terio

r cin

gula

te co

rtex

; PFC

= pr

efro

ntal

co

rtex

; sA

CC

= su

bgen

ual a

nter

ior c

ingu

late

cort

ex; S

TG =

supe

rior t

empo

ral g

yrus

; vm

PFC

= ve

ntra

l med

ial p

refr

onta

l cor

tex.

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Spencer et al

Neuroimaging methods. Neuroimaging was executed on 1.5T, 2T, or 3T scanners. Of the 20 publications, 17 investigated neural response during a cognitive task (and 3 additional studies of connectivity between regions); however, the cognitive tasks used were different in each article despite testing overlapping processes such as attention and interfer-ence control (eg, attentional network task [ANT], continuous performance test, multisource interference task47), cogni-tive control (eg, the Stroop color-word task, Simon oddball task), working memory (eg, n-back task, delayed matching to sample), emotional processes (eg, emotional Stroop), and inhibition (eg, stop signal task, Go/No-Go). The remaining studies derived measures of local blood perfusion during a resting state by using T2-relaxometry34,35 or continuous arterial spin labeling.36

Regions of interest investigated across the studies were also varied: some studies examined activity across the whole brain, some examined regions of interest functionally defined by regions active during task, and some examined regions of interest defined independently of the data based on a priori hypotheses. For the connectivity analyses, coupling was examined either between 2 a priori regions of interest37,38 or across 11 regions that were activated during the task.30 Two34,35 of the 3 resting state perfusion studies each analyzed an a priori region of interest (cerebellum and basal ganglia), and the remaining perfusion study36 examined the whole brain.

Summary of results in functional neuroimaging studies.Effect of stimulants on task-elicited activation. Alterations

in functional activation were found in all studies comparing ADHD to control subjects, and, in all but one of these stud-ies,39 stimulant medication was associated with attenuation of control versus ADHD activation differences in at least a portion of the regions found to be altered. Three brain regions were almost universally included in analyses because they have been found previously to be involved in ADHD or were activated by the specific task assessed. These regions were the striatum (including caudate and putamen), ACC, and prefrontal cortex (PFC).

Of the 15 task-based studies investigating medication effects on activity in the striatum versus a control com-parison group (Pliszka et al45 used only frontal regions of interest, Bush et al28 had no control group), 6 studies found no ADHD-related abnormalities in striatal activation while performing executive,32,37,39 reward,40 or emotional tasks.38,41 Of the 9 studies that did show alterations in striatal activity in the medication-naive versus control groups, all found that medication attenuated ADHD-related striatum dysfunction.

The ACC was examined in all 16 task-based fMRI studies with control comparison groups. Six of these studies found no ADHD-related abnormalities in ACC activation while performing executive/attentional30,39,42,43 or emotion-eliciting38,41 tasks. Of the 10 studies that did show alterations in ACC activity in the medication-naive versus control groups, all but two32,44 found that medication attenuated abnormal ACC function.

The PFC was examined in 15 of the 16 task-based fMRI studies with control comparisons. Three of these studies found no ADHD-related alterations in PFC activation while performing executive/attentional33,43 or emotion-eliciting38 tasks. Of the 12 studies that did show alterations in PFC activity in medication-naive versus control groups, results were somewhat mixed. Two studies39,45 showed no medi-cation effect on ADHD-related activity alterations during executive/attentional tasks, whereas 9 studies29–32,37,38,40,46,48 showed that medication attenuated dysfunction in regions of the PFC. In 4 studies,30,40,42,46 medication was associated with greater differences than medication-free control sub-jects in regions of the PFC.

Non–fronto-striatal regions were not consistently exam-ined across the task-based fMRI studies, although 11 of the 16 task-based studies with control comparison groups did examine whole brain effects. Results followed the general pattern that when unmedicated ADHD subjects showed an abnormality, medication was associated either with no effect in a particular region or with attenuation of this abnormality. For instance, temporal lobe regions were measured in 12 studies, 7 of which showed abnormalities in activation in the unmedicated ADHD group. Four of these 7 showed that medication attenuated temporal lobe dysfunction,29,30,32,48 whereas 3 of the 7 showed a lack of effect of the medication on activity.31,33,43 Patterns of results were similar across pari-etal lobe, occipital lobe, insula, cerebellum, and subcortical regions (see Table 2 for details).

Across all studies and all regions of the brain (aside from PFC, ACC, and striatum), only 4 regions indicated that medication in ADHD subjects was associated with greater differences than control subjects. These were greater PFC activation in medicated ADHD subjects versus non-ADHD control subjects during executive/attentional30,42,46 and reward40 tasks, greater inferior parietal lobule activation during a Go/No-Go task,46 greater activity in the cerebellar vermis during rewarded continuous performance test,30 and greater insula activity during a distracted working memory task. No differences were found in these regions in the unmedicated ADHD subjects versus controls.

Effect of medication on functional connectivity. Func-tional connectivity was investigated along with task-related activity in 3 studies. Rubia et al30 showed that during a vigilant attention task, hypoconnectivity found between multiple brain regions in the ADHD treatment–naive group was attenuated after a challenge dose of methylphenidate. Peterson et al37 showed that, during a Stroop task, hypocon-nectivity between ventral ACC and lateral PFC found after a washout period was attenuated when youth with ADHD were taking their naturalistic dose. Finally, Posner et al38 found that decreased connectivity between amygdala and lateral PFC after a washout was attenuated in ADHD when subjects were taking their naturalistic dose.

Effect of psychostimulants on resting-state perfusion. Anderson et al34 and Teicher et al35 reported effects of a placebo-controlled trial of methylphenidate (for 1 week) on perfusion values in the cerebellum and basal ganglia,

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Effect of Psychostimulants on the Brain in ADHD

respectively. Both studies found an interaction effect between baseline levels of hyperactivity in ADHD children and changes in perfusion in the respective region of interest. Together, these articles suggest that methyl-phenidate has an effect on brain perfusion in a region-specific manner and that these effects were mediated by baseline values of hyperactivity. In the third perfusion study, O’Gorman et al36 showed that stimulants attenuated hyperperfusion in frontal and parietal regions and attenuated hyperperfu-sion in the caudate. No information was given on baseline measures of hyperactivity in O’Gorman et al.36

Effect of Psychostimulants on Brain Biochemistry in ADHD (magnetic resonance spectroscopy studies)

In Table 3, the methods, principal findings, and summary of medication effects on brain biochemistry in ADHD are listed. These are summarized below.

Of the 3 identified magnetic resonance spectroscopy studies, 2 were conducted in pediatric samples49,50 and 1 in an adult sample.51 The studies excluded comorbidity (Carrey et al49 allowed oppositional defiance disorder and learning disabilities). They ranged in size from 7 to 14 (ADHD) sub-jects. All compared the same subjects before and after treatment, but 1 study (adult) had no controls and the other 2 studies (pediatric) compared ADHD subjects before and after treatment to historical controls. Of the studies with controls, 1 reported stimulant- (and nonstimulant-) associated attenuation of glutaminergic tone in the striatum49 and the other50 stimulant-associated attenuation of glutaminergic tone in the ACC.

DISCUSSIONDespite great variability in study methods in terms of design, neuro-

imaging technique, and regions of interest studied, results of this qualitative review of the extant MRI literature on ADHD were strikingly consistent and suggest that treatment of ADHD with therapeutic oral doses of stimulants is associated with findings in persons with ADHD that are more similar to non-ADHD controls than were findings of unmedicated ADHD individu-als. This conclusion is supported by the consistent direction of all structural and connectivity findings, and nearly all functional activation findings: brain measures in medicated groups of persons with ADHD were closer to control measures than were unmedicated ADHD groups. These qualitative results confirm and extend the findings of 2 recent meta-analyses16,17 of the voxel-based morphometry MRI literature.

While the 2 previous meta-analytic studies16,17 provided useful infor-mation summarizing the main anatomic regions affected in subjects with ADHD and the impact of medication on these regions, their analyses were largely limited to voxel-based morphometry studies and did not include fMRI, functional connectivity, and perfusion studies in both children and adults with ADHD.34–36

The structural MRI studies we reviewed here were quite consistent in design: all included only children and adolescents, all ADHD subjects were of the combined type, and all but 1 study compared volumes at 1 time point between a group of naturalistically medicated ADHD subjects, a group of treatment-naive ADHD subjects, and a non-ADHD control group. Like-wise, results of the structural studies were also consistent in many ways. First, when any medication-associated effect was present, it was always in the direction of attenuation of ADHD-control differences. Second, stud-ies that examined local volumes (specifically in frontal, striatal, cerebellar, and corpus callosum regions) were more successful at finding medica-tion effects than the studies that examined volume averaged over larger regions. Together, the structural findings suggest that chronic naturalistic Ta

ble

3. E

ffec

ts o

f Psy

chos

timul

ants

on

Brai

n M

etab

olite

s in

AD

HD

Stud

ySu

bjec

ts, n

Sex

Age

, Ran

ge

(mea

n), y

Des

ign

Mea

sure

Regi

on o

f Int

eres

tPr

inci

pal F

indi

ngs

Sum

mar

y of

Med

icat

ion

Effe

cts

Car

rey

et a

l,49 2

003

14 A

DH

D 9

Hist

oric

al

cont

rols

Mal

e/fe

mal

e7–

13Pr

etre

atm

ent v

s po

sttr

eatm

ent;

aver

age

13 w

k of

trea

tmen

t w

ith st

imul

ants

or

nons

timul

ants

Glu

tam

iner

gic t

one,

chol

ine

and

NA

APr

efro

ntal

cort

ex

and

stria

tum

Dec

reas

ed g

luta

min

ergi

c ton

e in

th

e st

riatu

m w

ith tr

eatm

ent

appr

oxim

atin

g fin

ding

s in

cont

rols

Trea

tmen

t ass

ocia

ted

with

at

tenu

atio

n of

glu

tam

iner

gic

tone

Kro

nenb

erg

et a

l,51

2008

7 A

DH

DN

o co

ntro

lsM

ale/

fem

ale

> 18

Pret

reat

men

t vs

post

trea

tmen

t;

5–6

wk

of tr

eatm

ent

with

met

hylp

heni

date

Cho

line

and

NA

AA

CC

Dec

reas

ed ch

olin

e co

mpo

unds

; in

crea

sed

NA

A le

vels

in A

CC

Abs

ence

of c

ontr

ols p

recl

udes

co

nclu

sions

Ham

mer

ness

et

al,50

201

210

AD

HD

12 H

CM

ale/

fem

ale

12–1

8Pr

etre

atm

ent v

s po

sttr

eatm

ent;

6–

8 w

k of

ORO

S m

ethy

lphe

nida

te

trea

tmen

t

Glu

tam

iner

gic t

one

AC

CD

ecre

ased

glu

tam

iner

gic t

one

in th

e A

CC

with

trea

tmen

t ap

prox

imat

ing

findi

ngs i

n co

ntro

ls (t

rend

)

Trea

tmen

t ass

ocia

ted

with

at

tenu

atio

n of

glu

tam

iner

gic

tone

Abb

revi

atio

ns: A

CC

= an

terio

r cin

gula

te co

rtex

, AD

HD

= at

tent

ion-

defic

it/hy

pera

ctiv

ity d

isord

er, H

C =

hea

lthy

cont

rol s

ubje

cts,

NA

A =

N-a

cety

lasp

arta

te, O

ROS =

osm

otic

-rel

ease

ora

l sys

tem

.

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Spencer et al

stimulant treatment is likely to be associated with attenu-ation of ADHD-related brain structure abnormalities, but in a targeted manner, affecting specific small regions of the brain. Although there was a range of findings across the structural studies, the more consistent findings in frontal, striatal, cerebellar, and corpus callosum regions suggest that these regions are most relevant. Consistent with our conclu-sion, the recent meta-analysis of voxel-based morphometry studies in ADHD, a meta-regression showed that percentage of ADHD subjects with a medication history included in each study group was associated with attenuation of volume reductions in the right basal ganglia.16

The fMRI studies we reviewed were also quite varied in terms of methods. For instance, some studies included only youth, some included only adults, and 1 included both adults and youth. Studies also varied on diagnostic methods, ADHD subtype inclusion, comorbidity inclusion, medica-tion history, sex of subjects, and length of the treatment trial. The regions most frequently examined in the functional studies, given their known role as targets for stimulants and involvement in ADHD pathology, were striatum, ACC, and PFC. As regards to stimulant-associated attenuation effects, the most consistent findings were for striatum and ACC.

Results were somewhat more mixed in the PFC. In fact, regional effects in 4 studies30,40,42,46 showed that stimulant treatment was associated with greater activity relative to con-trols in a parietal, a cerebellar, and an insula region. Notably, all of these findings were from fMRI studies that measured brain response to performance on a specific task. No such effects were found in any analyses of functional connectivity. Although the reasons for these findings are not entirely clear, one explanation for greater activity in medicated ADHD subjects may be that the activations were compensatory and associated with improved task performance, functioning in place of deficient regions that were not targeted by the medi-cation. In fact, Rubia et al30 examined the relationship of activity in hypoactive regions to behavior on a rewarded con-tinuous performance test and found that greater activity in both of these frontal and cerebellar regions was significantly correlated with reduced error rates. In the remaining studies that found less regional activity, no correlation between the regions and behavior was conducted, but, in the studies with relevant task performance data, the medicated group showed significantly better scores than the unmedicated group.42,46,48 Finally, none of these regions were found to be altered in the comparisons between unmedicated versus control groups. Therefore, it cannot be concluded that medication effects on these regions are increasing ADHD-related alterations, only that some detectable change in activity is associated with medication that may not be associated with ADHD itself.

Our results have several clinical implications. For par-ents, patients, and clinicians who have been concerned that the use of stimulants could harm the developing brain, our data indicate that these concerns are unfounded and that treatment with stimulants should be considered if appropri-ate for the clinical presentation of the patient. Our results also raise the possibility that brain changes associated with

stimulant treatment might account for stimulant-associated improvements in neurocognition and other areas. Of par-ticular interest is the possibility that, given the wide range of brain areas affected, stimulants could improve several neurocognitive functions. Because such effects have not been consistently observed in short-term treatment stud-ies, this idea requires future, long-term studies that assess changes in both brain and clinical parameters over time during treatment.

Although the available 29 MRI studies we identified in the extant literature generally suggest attenuation of ADHD versus control differences in the ADHD brain with stimu-lant treatment, even across vastly varied methods, there are several limitations to these studies that temper our ability to form firmer conclusions. For example, none of the struc-tural studies included medication intervention as a variable wherein causation could be inferred. All of the structural studies were naturalistic in that groups of subjects were recruited based on their medication status. It is therefore possible that the medicated group may have had qualities or characteristics different from the unmedicated group that led them to pursue treatment.52 Another issue is that fMRI studies can only inform about brain physiology, and only in association with a given task. Also, in the functional studies, only 1 study was a randomized control trial in which groups of subjects were blindly assigned to either medication or pla-cebo, but, unfortunately, this study lacked a control group, and so it has limited interpretability in terms of the direction of the results and whether they represent improvement or worsening of function.28 Further, group sample sizes were quite modest by today’s standards. Additional limitations include the fact that studies were not uniform for presence of psychiatric comorbidities, medication status, the use of automated versus manual segmentation routines, or the length of time that subjects were receiving medications or were washed out from medications.

In addition, both structural and functional studies varied in terms of the presence and length of a washout period. For example, some examined the effects of chronic stimu-lant treatment after washing out subjects for varying lengths of time, and, therefore, short-term withdrawal effects may have been present in some of these studies. Many studies included previously medicated subjects in their “unmedi-cated” groups, which may have confounded the results due to the possibility of long-term effects of stimulants. In order to examine the effect of stimulants on the natural course of the disorder, and to answer the important question of long-term brain effects of previous medication, future stud-ies should image treatment-naive subjects at multiple time points, including baseline, during acute treatment, and after a substantial period of discontinuation.

In addition, we cannot rule out the possibility that stimulants do not attenuate brain structure and function but produce changes different from what is seen in healthy subjects that nonetheless improve function. Forty percent of the fMRI studies did not find differences between ADHD subjects and controls in striatal activation that could be due

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Effect of Psychostimulants on the Brain in ADHD

to the task used, or to the large variability in altered striatal activation in ADHD subjects and controls (as suggested by Nakao et al16). As already mentioned, because previously treated subjects were included in some studies, uncertainty remains as to whether the differences between ADHD sub-jects and control findings reflect pathophysiology related to ADHD or its treatment, thereby limiting the ability to inter-pret movement toward what is seen in controls under those circumstances. Finally, adequate controls should be in place both for sex and comorbidity effects, each of which could mediate the expression of ADHD in the brain.53,54 Only a blocked design, randomized control trial with these factors in place will more definitively identify acute and chronic effects of therapeutic intervention.

Despite the limitations and heterogeneity of the avail-able MRI studies, our qualitative review supports the notion that therapeutic oral doses of stimulants are associated with attenuation of abnormalities in brain structure, function, and biochemistry in subjects with ADHD. We suggest that these are medication-associated brain changes that most likely underlie the well-established clinical benefits of these medications.Drug names: methylphenidate (Focalin, Daytrana, and others).Author affiliations: Clinical and Research Program in Pediatric Psychopharmacology (Drs Spencer, Brown, Seidman, Valera, and Biederman and Ms Lomedico); Harvard Medical School Department of Psychiatry (Drs Spencer, Seidman, Valera, Makris, and Biederman); Neuroimaging Program, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD (Drs Spencer, Brown, Seidman, Valera, Makris, and Biederman); Harvard Medical School Departments of Neurology and Radiology Services, Center for Morphometric Analysis (Drs Seidman and Makris), Massachusetts General Hospital; Department of Psychiatry, Harvard Medical School, Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center (Dr Seidman), Boston; Massachusetts General Hospital/Health Sciences and Technology, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown (Drs Seidman, Valera and Makris); and Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York (Dr Faraone).Potential conflicts of interest: Dr Spencer receives research support from royalties and licensing fees on copyrighted ADHD scales through Massachusetts General Hospital (MGH) corporate-sponsored research and licensing and has a US patent application pending (provisional number 61/233,686) through MGH corporate licensing on a method to prevent stimulant abuse. In the past 2 years, he has been an advisor or on an advisory board of Alcobra, Ironshore, US Department of Defense, and National Institute of Mental Health (NIMH); and has received research support from Shire, Cephalon, Eli Lilly, Janssen, McNeil, Novartis, and US Department of Defense. In previous years, he has received research support from, has been a speaker or advisor to, or has been on speakers bureaus or advisory boards of Shire, Eli Lilly, GlaxoSmithKline, Janssen, McNeil, Novartis, Cephalon, Pfizer, and NIMH. Dr Valera has received honoraria for talk at MGH Psychiatry Academy for a tuition-funded CME course and for related consulting, and she receives funds from NIMH grant R01 HD067744. Dr Biederman is currently receiving research support from ElMindA, Janssen, McNeil, and Shire. In 2012, he received an honorarium from the MGH Psychiatry Academy and The Children’s Hospital of Southwest Florida/Lee Memorial Health System for tuition-funded continuing medical education (CME) courses. In 2011, he gave a single unpaid talk for Juste Pharmaceutical Spain, received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course, and received honoraria for presenting at an international scientific conference on ADHD; received an honorarium from Cambridge University Press for a chapter publication; received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Eli Lilly, Shire, and AstraZeneca to the Department of Psychiatry at MGH. In 2010, he received a speaker’s fee from a single talk given at Fundación Dr Manuel Camelo AC in Monterrey, Mexico; provided single consultations for Shionogi Pharma and Cipher Pharmaceuticals, for which honoraria were paid to the Department of Psychiatry at the MGH; and received honoraria

from the MGH Psychiatry Academy for a tuition-funded CME course. In previous years, he has received research support, consultation, or speakers fees from Abbott, Alza, AstraZeneca, Boston University, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Esai, Fundacion Areces (Spain), Forest, Glaxo, Gliatech, Hastings Center, Janssen, McNeil, Medice (Germany), Merck, MMC Pediatric, NARSAD, National Institute on Drug Abuse, New River, National Institute of Child Health and Human Development, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, Prechter Foundation, Quantia Communications, Reed Exhibitions, Shire, Spanish Child Psychiatry Association, Stanley Foundation, UCB Pharma, Veritas, and Wyeth. Drs Brown, Seidman, Makris, Faraone, and Ms Lomedico report no conflicts of interest.Funding/support: This study was supported in part by the Pediatric Psychopharmacology Council Fund, Massachusetts General Hospital, Boston.Role of the sponsor: The sponsor had no role in the design and conduct of the study; no role in the collection, management, analysis, and interpretation of the data; and no role in the preparation, review, or approval of the manuscript.

REFERENCES

1. Centers for Disease Control and Prevention (CDC). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep. 2010;59(44):1439–1443. PubMed

2. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716–723. doi:10.1176/appi.ajp.163.4.716 PubMed

3. Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005;57(11):1215–1220. doi:10.1016/j.biopsych.2004.10.020 PubMed

4. Krain AL, Castellanos FX. Brain development and ADHD. Clin Psychol Rev. 2006;26(4):433–444. doi:10.1016/j.cpr.2006.01.005 PubMed

5. Dickstein SG, Bannon K, Castellanos FX, et al. The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry. 2006;47(10):1051–1062. doi:10.1111/j.1469-7610.2006.01671.x PubMed

6. Seidman LJ, Valera EM, Makris N. Structural brain imaging of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57(11):1263–1272. doi:10.1016/j.biopsych.2004.11.019 PubMed

7. Valera EM, Faraone SV, Murray KE, et al. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61(12):1361–1369. doi:10.1016/j.biopsych.2006.06.011 PubMed

8. Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. Eur Child Adolesc Psychiatry. 2010;19(4):353–364. doi:10.1007/s00787-009-0054-3 PubMed

9. Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 2010;71(6):754–763. doi:10.4088/JCP.08m04902pur PubMed

10. Kaplan G, Newcorn JH. Pharmacotherapy for child and adolescent attention-deficit hyperactivity disorder. Pediatr Clin North Am. 2011;58(1):99–120, xi. doi:10.1016/j.pcl.2010.10.009 PubMed

11. Arnsten AF. Stimulants: therapeutic actions in ADHD. Neuropsychopharmacology. 2006;31(11):2376–2383. doi:10.1038/sj.npp.1301164 PubMed

12. Grund T, Lehmann K, Bock N, et al. Influence of methylphenidate on brain development—an update of recent animal experiments. Behav Brain Funct. 2006;2(1):2. doi:10.1186/1744-9081-2-2 PubMed

13. Berman SM, Kuczenski R, McCracken JT, et al. Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol Psychiatry. 2009;14(2):123–142. doi:10.1038/mp.2008.90 PubMed

14. Volkow ND, Insel TR. What are the long-term effects of methylphenidate treatment? Biol Psychiatry. 2003;54(12):1307–1309. doi:10.1016/j.biopsych.2003.10.019 PubMed

15. Hyman SE. Methylphenidate-induced plasticity: what should we be looking for? Biol Psychiatry. 2003;54(12):1310–1311. doi:10.1016/j.biopsych.2003.10.003 PubMed

16. Nakao T, Radua J, Rubia K, et al. Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry. 2011;168(11):1154–1163. PubMed

17. Frodl T, Skokauskas N. Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand. 2012;125(2):114–126. doi:10.1111/j.1600-0447.2011.01786.x PubMed

18. Sheridan MA, Hinshaw S, D’Esposito M. Stimulant medication and prefrontal functional connectivity during working memory in ADHD: a preliminary report. J Atten Disord. 2010;14(1):69–78. doi:10.1177/1087054709347444 PubMed

19. Lee JS, Kim BN, Kang E, et al. Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment. Hum Brain Mapp. 2005;24(3):157–164. doi:10.1002/hbm.20067 PubMed

20. Lee YS, Han DH, Lee JH, et al. The effects of methylphenidate on neural substrates associated with interference suppression in children with ADHD: a preliminary study using event related fMRI. Psychiatry Investig. 2010;7(1):49–54. doi:10.4306/pi.2010.7.1.49 PubMed

21. Zang YF, Jin Z, Weng XC, et al. Functional MRI in attention-deficit

© 2013 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. 917 J Clin Psychiatry 74:9, September 2013

Spencer et al

hyperactivity disorder: evidence for hypofrontality. Brain Dev. 2005;27(8):544–550. doi:10.1016/j.braindev.2004.11.009 PubMed

22. Shaw P, Sharp WS, Morrison M, et al. Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. Am J Psychiatry. 2009;166(1):58–63. doi:10.1176/appi.ajp.2008.08050781 PubMed

23. Schnoebelen S, Semrud-Clikeman M, Pliszka SR. Corpus callosum anatomy in chronically treated and stimulant naïve ADHD. J Atten Disord. 2010;14(3):256–266. doi:10.1177/1087054709356406 PubMed

24. Semrud-Clikeman M, Pliśzka SR, Lancaster J, et al. Volumetric MRI differences in treatment-naïve vs chronically treated children with ADHD. Neurology. 2006;67(6):1023–1027. doi:10.1212/01.wnl.0000237385.84037.3c PubMed

25. Sobel LJ, Bansal R, Maia TV, et al. Basal ganglia surface morphology and the effects of stimulant medications in youth with attention deficit hyperactivity disorder. Am J Psychiatry. 2010;167(8):977–986. doi:10.1176/appi.ajp.2010.09091259 PubMed

26. Castellanos FX, Lee PP, Sharp W, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002;288(14):1740–1748. doi:10.1001/jama.288.14.1740 PubMed

27. Bledsoe J, Semrud-Clikeman M, Pliszka SR. A magnetic resonance imaging study of the cerebellar vermis in chronically treated and treatment-naïve children with attention-deficit/hyperactivity disorder combined type. Biol Psychiatry. 2009;65(7):620–624. doi:10.1016/j.biopsych.2008.11.030 PubMed

28. Bush G, Spencer TJ, Holmes J, et al. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry. 2008;65(1):102–114. doi:10.1001/archgenpsychiatry.2007.16 PubMed

29. Rubia K, Halari R, Christakou A, et al. Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate. Philos Trans R Soc Lond B Biol Sci. 2009;364(1525):1919–1931. doi:10.1098/rstb.2009.0014 PubMed

30. Rubia K, Halari R, Cubillo A, et al. Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task. Neuropharmacology. 2009;57(7–8):640–652. doi:10.1016/j.neuropharm.2009.08.013 PubMed

31. Rubia K, Halari R, Cubillo A, et al. Methylphenidate normalizes fronto-striatal underactivation during interference inhibition in medication-naïve boys with attention-deficit hyperactivity disorder. Neuropsychopharmacology. 2011;36(8):1575–1586. doi:10.1038/npp.2011.30 PubMed

32. Rubia K, Halari R, Mohammad AM, et al. Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011;70(3):255–262. doi:10.1016/j.biopsych.2011.04.018 PubMed

33. Konrad K, Neufang S, Fink GR, et al. Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: results from a longitudinal functional MRI study. J Am Acad Child Adolesc Psychiatry. 2007;46(12):1633–1641. doi:10.1097/chi.0b013e318157cb3b PubMed

34. Anderson CM, Polcari A, Lowen SB, et al. Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD. Am J Psychiatry. 2002;159(8):1322–1328. doi:10.1176/appi.ajp.159.8.1322 PubMed

35. Teicher MH, Anderson CM, Polcari A, et al. Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry. Nat Med. 2000;6(4):470–473. doi:10.1038/74737 PubMed

36. O’Gorman RL, Mehta MA, Asherson P, et al. Increased cerebral perfusion in adult attention deficit hyperactivity disorder is normalised by stimulant treatment: a non-invasive MRI pilot study. Neuroimage. 2008;42(1):36–41. doi:10.1016/j.neuroimage.2008.04.169 PubMed

37. Peterson BS, Potenza MN, Wang Z, et al. An FMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry.

2009;166(11):1286–1294. doi:10.1176/appi.ajp.2009.08050724 PubMed38. Posner J, Maia TV, Fair D, et al. The attenuation of dysfunctional emotional

processing with stimulant medication: an fMRI study of adolescents with ADHD. Psychiatry Res. 2011;193(3):151–160. doi:10.1016/j.pscychresns.2011.02.005 PubMed

39. Kobel M, Bechtel N, Weber P, et al. Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder. Eur J Paediatr Neurol. 2009;13(6):516–523. doi:10.1016/j.ejpn.2008.10.008 PubMed

40. Stoy M, Schlagenhauf F, Schlochtermeier L, et al. Reward processing in male adults with childhood ADHD—a comparison between drug-naïve and methylphenidate-treated subjects. Psychopharmacology (Berl). 2011;215(3):467–481. doi:10.1007/s00213-011-2166-y PubMed

41. Posner J, Nagel BJ, Maia TV, et al. Abnormal amygdalar activation and connectivity in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(8):828–837, e3. doi:10.1016/j.jaac.2011.05.010 PubMed

42. Vaidya CJ, Austin G, Kirkorian G, et al. Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci U S A. 1998;95(24):14494–14499. doi:10.1073/pnas.95.24.14494 PubMed

43. Shafritz KM, Marchione KE, Gore JC, et al. The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. Am J Psychiatry. 2004;161(11):1990–1997. doi:10.1176/appi.ajp.161.11.1990 PubMed

44. Schlochtermeier L, Stoy M, Schlagenhauf F, et al. Childhood methylphenidate treatment of ADHD and response to affective stimuli. Eur Neuropsychopharmacol. 2011;21(8):646–654. doi:10.1016/j.euroneuro.2010.05.001 PubMed

45. Pliszka SR, Glahn DC, Semrud-Clikeman M, et al. Neuroimaging of inhibitory control areas in children with attention deficit hyperactivity disorder who were treatment naive or in long-term treatment. Am J Psychiatry. 2006;163(6):1052–1060. doi:10.1176/appi.ajp.163.6.1052 PubMed

46. Epstein JN, Casey BJ, Tonev ST, et al. ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD. J Child Psychol Psychiatry. 2007;48(9):899–913. doi:10.1111/j.1469-7610.2007.01761.x PubMed

47. Mantanus H, Ansseau M, Legros JJ, et al. Relationship between dexamethasone suppression test and contingent negative variation in major depressive patients. Neurophysiol Clin. 1988;18(4):345–353. doi:10.1016/S0987-7053(88)80091-1 PubMed

48. Prehn-Kristensen A, Krauel K, Hinrichs H, et al. Methylphenidate does not improve interference control during a working memory task in young patients with attention-deficit hyperactivity disorder. Brain Res. 2011;1388:56–68. doi:10.1016/j.brainres.2011.02.075 PubMed

49. Carrey N, MacMaster FP, Fogel J, et al. Metabolite changes resulting from treatment in children with ADHD: a 1H-MRS study. Clin Neuropharmacol. 2003;26(4):218–221. doi:10.1097/00002826-200307000-00013 PubMed

50. Hammerness P, Biederman J, Petty C, et al. Brain biochemical effects of methylphenidate treatment using proton magnetic spectroscopy in youth with attention-deficit hyperactivity disorder: a controlled pilot study. CNS Neurosci Ther. 2012;18(1):34–40. doi:10.1111/j.1755-5949.2010.00226.x PubMed

51. Kronenberg G, Ende G, Alm B, et al. Increased NAA and reduced choline levels in the anterior cingulum following chronic methylphenidate: a spectroscopic test-retest study in adult ADHD. Eur Arch Psychiatry Clin Neurosci. 2008;258(7):446–450. doi:10.1007/s00406-008-0810-2 PubMed

52. Surman CB, Monuteaux MC, Petty CR, et al. Representativeness of participants in a clinical trial for attention-deficit/hyperactivity disorder? comparison with adults from a large observational study. J Clin Psychiatry. 2010;71(12):1612–1616. doi:10.4088/JCP.09m05344pur PubMed

53. Biederman J, Makris N, Valera EM, et al. Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder: a MRI study of brain volumes. Psychol Med. 2008;38(7):1045–1056. doi:10.1017/S0033291707001791 PubMed

54. Valera EM, Brown A, Biederman J, et al. Sex differences in the functional neuroanatomy of working memory in adults with ADHD. Am J Psychiatry. 2010;167(1):86–94. doi:10.1176/appi.ajp.2009.09020249 PubMed