Sweitzer et al.

ADHD, smoking withdrawal and inhibitory control: Results of an fMRI study with methylphenidate challenge

Supplementary Information

Supplemental Methods and Materials

Psychiatric Evaluation

Diagnostic criteria for ADHD and other psychiatric disorders were determined by a

comprehensive psychiatric evaluation conducted by a Ph.D.-level psychologist. The evaluation

included administration of a structured, computerized psychiatric screening measure, Conners’

Adult ADHD Rating Scale (CAARS; Conners et al., 1998), Conners’ Adult ADHD Diagnostic

Interview for DSM-IV (CAADID; Epstein et al, 2000), and clinical interview. ADHD

participants met all diagnostic criteria for ADHD and had age- and sex-adjusted T-scores on

relevant CAARS subscales ≥ 65. Control participants reported no history of ADHD and had T-

scores on relevant CAARS subscales ≤ 55.

Exclusion Criteria

Exclusion criteria for both groups were current significant health problems; estimated IQ

scores of < 80 measured using the Kaufman Brief Intelligence Test (K-BIT 2; Kaufman and

Kaufman, 2004), current primary Axis I disorder other than ADHD or nicotine dependence;

current use of psychoactive medications (other than ADHD pharmacotherapies among ADHD

diagnosed participants); use of smokeless tobacco; drug or alcohol abuse within the past year;

positive urine drug screen; current use of nicotine replacement therapy or other smoking

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cessation treatment; presence of conditions contraindicated for MRI or methylphenidate; and

pregnancy among females.

Study Drug and Medication Safety

Methylphenidate (MPH) was administered via 40 mg capsules provided by two

manufacturers over the course of the study (Mallinckrodt and Watson). Placebo capsules

contained Dextrose, USP Anhydrous (provided by Medisca). Over-encapsulation of MPH and

placebo was conducted by Duke Investigational Drug Service, which also provided blinded kits.

All participants completed a 4-hr MPH safety session prior to scanning. In this session,

participants were administered 40 mg MPH and self-reported symptoms and vitals were acquired

every 30 minutes. The study physician (RD) reviewed the results of this session and cleared

participants for participation.

Participants Excluded from Analyses

A total of 633 participants were telephone screened for the study, resulting in 101 in-

person screens. Of these, 67 were enrolled in the study, and 35 were included in analyses. Of

participants not included in the analysis, 9 (n=6 ADHD, n=3 control) were lost to contact or had

scheduling difficulty; 8 exhibited a lack of MPH tolerance at the medication safety session (n=4

ADHD; n=4 control); 10 were noncompliant with study requirements (e.g. did not abstain from

smoking; tested positive for drugs; quit or substantially reduced smoking; n=6 ADHD;

4=control). An additional two ADHD participants were found to have tattoos or metal implants

post enrollment but prior to scanning. Finally, three control participants were excluded from

analysis due to excessive head motion.

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CO and Self-Report Withdrawal

Consistent with abstinence/smoking requirements, CO levels in the SAT+PLAC,

ABS+PLAC, and ABS+MPH conditions were 17.1 (SD=8.2), 2.9 (SD=2.1), and 3.0 (SD=1.8)

ppm, respectively. On the SJWS, main effects of condition were observed for Negative Affect,

F(2,72)=8.62, p<.001, Craving, F(2,72)=87.58, p<.0001, Habit Withdrawal, F(2,72)=40.52,

p<.0001, and Appetite, F(2,72)=4.27, p<.05, with these effects being largely driven by symptoms

that were greater in the ABS as compared to SAT conditions (see Supplementary Figure S1).

MPH did not affect symptom levels differentially between the two groups compared with

ABS+PLAC.

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Table S1. Participant Characteristics

Variable N (%) ADHD

N (%) Control P Value*

Sex (% female) 9 (53%) 10 (56%) .877

Race (% non-white) 3 (18%) 9 (50%) .044

Education (% > H.S.) 15 (88%) 14 (78%) .349

Variable Mean (SD)ADHD

Mean (SD)Control P Value*

Age 31.2 (8.5) 29.8 (10.2) .651

Cigarettes per Day 16.6 (5.7) 16.2 (5.4) .823

FTND 5.1 (2.2) 5.0 (1.9) .933

Years Smoking 10.5 (7.2) 10.6 (9.5) .970

Screen CO 19.6 (8.7) 22 (9.4) .438

K-BIT 109.1 (13.5) 103.4 (14.0) .233

CAARS1-DSM-IV Inattentive 80.6 (11.0) 44.9 (10.3) .001

CAARS-DSM-IV Hyperactive 72.5 (11.7) 42.4 (11) .001

CAARS-DSM-IV Total 81.5 (10.3) 42.9 (11.8) .001

*P-value reflects statistical significance of chi-square or t-test as appropriate.

1Conners’ Adult ADHD Rating Scale for DSM-IV, Self-Report Version

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Table S2. Go/No Go task performance effects by group (ADHD and Control) and condition

(SAT+PLAC, ABS+MPH, and ABS+PLAC)

SAT+PLAC ABS+PLAC ABS+MPH

Trial Type ADHD Control ADHD Control ADHD Control

% Correct

Go Only Freq Go .93 (.06) .92 (.08) .92 (.08) .90 (.09) .90 (.13) .91 (.11)

Infreq Go .91 (.08) .91 (.09) .91 (.09) .90 (.10) .89 (.15) .90 (.12)

All Trial Freq Go .98 (.03) .94 (.11) .97 (.06) .95 (.06) .97 (.05) .95 (.07)

Infreq Go .97 (.06) .95 (.11) .97 (.07) .95 (.07) .97 (.05) .95 (.09)

NoGo .58 (.21) .58 (.16) .56 (.24) .61 (.18) .64 (.19) .62 (.20)

Reaction Time

Go Only Freq Go 192 (72) 242 (84) 239 (96) 252 (78) 199 (81) 230 (93)

Infreq Go 184 (72) 242 (87) 237 (98) 249 (82) 199 (85) 230 (94)

All Trial Freq Go 282 (46) 299 (55) 287 (60) 304 (58) 287 (52) 302 (64)

Infreq Go 315 (55) 331 (52) 322 (74) 339 (70) 315 (66) 330 (67)

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Figure S1.

SAT+PLAC ABS+PLAC ABS+MPH01234567

ADHDControl

Hab

it W

ithdr

awal

SAT+PLAC ABS+PLAC ABS+MPH01234567

Aro

usal

SAT+PLAC ABS+PLAC ABS+MPH01234567

ADHDControl

Neg

ativ

e A

ffect

SAT+PLAC ABS+PLAC ABS+MPH01234

567

App

etite

SAT+PLAC ABS+PLAC ABS+MPH0

1

2

3

4

5

6

7ADHDControl

Som

atos

enso

ry

Figure S1. Subjective ratings of withdrawal on Shiffman-Jarvik Withdrawal Scale subscales by

group (ADHD, control) and condition (SAT+PLAC, ABS+PLAC, ABS+MPH). A significant

group by condition interaction was observed for Habit Withdrawal, with SAT+PLAC >

ABS+PLAC for both groups (both p’s < .001); and ADHD > Control during ABS+PLAC, t(72)

= 2.10, p < 0.05. Main effects of condition were observed for Negative Affect (p < 0.05) and

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Appetite (p < .001); no condition or interaction effects were observed for Arousal or

Somatosensory withdrawal.

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Figure S2.

Figure S2. Main effects of task for sustained inhibitory control (No Go blocks > Go Only

blocks), collapsed across group and condition. Significant cluster of activation encompasses

102067 voxels, Z-Max = 11.1, peak voxel at 4, -26, -8.

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Table S3. Local maxima for main effects of task for sustained inhibitory control (No Go blocks

> Go Only blocks), collapsed across group and condition.

Region Location Z Maxx y z

Midbrain 4 -26 -8 11.1

Cerebellum -32 -54 -34 11

Right Insula 30 22 -8 10.2

Supplemental motor area 10 8 46 10.2

Right Insula 32 24 -2 10.2

Left insula -36 14 -2 10.1

Figure S3.

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Figure S3. Main effects of methylphenidate (ABS+MPH vs ABS+PLAC) for sustained

inhibitory control (All Trial blocks > Go Only blocks), collapsed across group. A single

significant cluster of activation was observed encompassing bilateral superior parietal cortex,

superior frontal gyrus, occipital cortex, and bilateral insula (50270 voxels, Z-Max = 4.99, peak

voxel at -22, -50, 68). Effects are in the direction of ABS+MPH > ABS+PLAC

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Table S4. Local maxima for main effects of methylphendiate (ABS+MPH vs ABS+PLAC) for

sustained inhibitory control (No Go blocks > Go Only blocks).

Region Location Z Maxx y z

Left Superior Parietal -22 -50 68 4.99

Postcentral gyrus -50 -14 52 4.88

Right Superior Parietal 32 -46 64 4.83

Right Superior Frontal 16 -8 72 4.74

Right Orbital Frontal 36 36 -14 4.72

Left Lateral Occipital -28 -90 20 4.68

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Table S5. Whole-brain correlations between abstinence-induced changes (ABS+PLAC –

SAT+PLAC) in No Go trial accuracy (NoGo percent correct) and sustained inhibitory control

(All Trial > Go Only block effects). Table presents overall activation clusters and local maxima.

Region (and Local Maxima) Location Z Max Voxelsx y Z

Left Lateral Occipital -18 -84 40 4.65 13980

Left Lateral Occipital -18 -84 40 4.65

Right Lateral Occipital 24 -80 44 4.41

Right Superior Parietal 34 -48 58 4.34

Precuneus -4 -44 56 4.16

Postcentral gyrus 0 -36 58 3.97

Precentral gyrus -34 -8 52 3.96

Left planum polare/central opercular cortex

-56 -8 4 3.85 2541

Precentral gyrus -34 -8 52 3.96

Left Insula -40 6 -8 3.56

Left Superior Temporal -56 -24 -2 3.51

Left Middle Temporal -52 -22 -12 3.42

Left Insula -38 2 -6 3.42

Left Planum Polare -46 -2 -2 3.42

Right Insula 32 12 2 4.83 1269

Right Putamen 32 0 8 3.47

Right Pallidum 22 -6 6 2.97

Right Orbital Frontal 12 26 -22 2.5

Right Orbital Frontal 12 24 -18 2.46

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Figure S4.

Figure S4. Main effects of task for transient inhibitory control (No Go trials > Rare Go trials),

collapsed across group and condition. Significant clusters of activation encompass 83743 voxels

including parietal lobe, frontal lobe, and basal ganglia (Z-Max = 9.29, peak voxel at 52, -40, 48)

and 1935 voxels including cerebellum and temporal lobe (Z-Max = 6.08, peak voxel at -40, -60, -

38).

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Table S6. Regions of activation and local maxima for main effects of task for transient inhibitory

control (No Go trials > Rare Go trials), collapsed across group and condition.

Region Location Z Max Voxels x y Z

Parietal 52 -40 48 9.29 83743

Intraparietal 38 -44 42 9.25

Inferior parietal 46 -40 42 9.12

Superior temporal sulcus 52 -34 -4 8.97

Putamen 24 14 -6 8.69

Putamen 20 6 10 8.47

Cerebellum -40 -60 -38 6.08 1935

Cerebellum -28 -62 -36 5.61

Cerebellum -28 -40 -42 3.31

Temporal lobe -26 -12 -36 2.88

Temporal lobe -28 -16 -34 2.88

Cerebellum -24 -28 -34 2.84

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Figure S5.

Figure S5. Main effects of methylphenidate (ABS+MPH vs ABS+PLAC) for transient

inhibitory control (No-Go trials > Rare-Go trials), collapsed across group. Significant clusters of

activation encompass 11546 voxels, including medial PFC, orbitofrontal cortex, subgenual ACC

and left hippocampus (Z-Max = 4.08, peak voxel at 14, 34, -6), and 1286 voxels including

precuneus/posterior cingulate cortex (Zmax=3.76, peak voxel at -20, -50, 22). Effect is in the

direction of ABS+MPH > ABS+PLAC.

x=-8 z=6x = -12x = -6