Gray Matter Alterations in Adults with Attention-Deficit/Hyperactivity Disorder Identified by Voxel Based Morphometry

Larry J. Seidman, Joseph Biederman, Lichen Liang, Eve M. Valera, Michael C. Monuteaux, Ariel Brown, Jonathan Kaiser, Thomas Spencer, Stephen V. Faraone, and Nikos Makris
Background: Gray and white matter volume deficits have been reported in many structural magnetic resonance imaging (MRI) studies of children with attention-deficit/hyperactivity disorder (ADHD); however, there is a paucity of structural MRI studies of adults with ADHD. This study used voxel based morphometry and applied an a priori region of interest approach based on our previous work, as well as from well-developed neuroanatomical theories of ADHD. Methods: Seventy-four adults with DSM-IV ADHD and 54 healthy control subjects comparable on age, sex, race, handedness, IQ, reading achievement, frequency of learning disabilities, and whole brain volume had an MRI on a 1.5T Siemens scanner. A priori region of interest hypotheses focused on reduced volumes in ADHD in dorsolateral prefrontal cortex, anterior cingulate cortex, caudate, putamen, inferior parietal lobule, and cerebellum. Analyses were carried out by FSL-VBM 1.1. Results: Relative to control subjects, ADHD adults had significantly smaller gray matter volumes in parts of six of these regions at p Յ .01, whereas parts of the dorsolateral prefrontal cortex and inferior parietal lobule were significantly larger in ADHD at this threshold. However, a number of other regions were smaller and larger in ADHD (especially fronto-orbital cortex) at this threshold. Only the caudate remained significantly smaller at the family-wise error rate. Conclusions: Adults with ADHD have subtle volume reductions in the caudate and possibly other brain regions involved in attention and executive control supporting frontostriatal models of ADHD. Modest group brain volume differences are discussed in the context of the nature of the samples studied and voxel based morphometry methodology. Key Words: Attention-deficit/hyperactivity disorder, caudate, cerebellum, prefrontal cortex, structural MRI, voxel based morphometry ical features, comorbidities (6,7), neuropsychological dysfunctions (8 –10), and functional impairment with ADHD children (1,11–15). The persistence of ADHD into adulthood in two thirds of childhood cases (16) supports the hypothesis that structural brain abnormalities present in childhood will persist to adulthood (17,18). Little is known about the neuroanatomy of adult ADHD (19,20). Whereas there are more than two dozen quantitative reports of structural neuroimaging using magnetic resonance imaging (MRI) in ADHD children from more than a dozen research groups (reviewed in [17]) and summarized in two meta-analyses (21,22), there are only a few structural imaging studies of adults with ADHD: two articles from one research group (23,24), an article by another group (25), and a number of articles from our group (18,26 –28). Hesslinger et al. (23) and Perlov et al. (24) reported a significant reduction of the left fronto-orbital cortex (FOC) (23) in a small sample, and after specifically testing for hippocampus and amygdala volume differences in a subsequent analysis with a larger sample, they reported a null finding compared with control subjects (24), similar to our negative results (18). Frodl et al. (25) reported no significant differences in hippocampus but found a bilateral reduction in amygdala compared with healthy control subjects. We found significant gray matter volume reductions in ADHD in dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC), and the cerebellum (18,28) compared with healthy control subjects. We also found significant cortical thinning in ADHD involving the inferior parietal lobule (IPL), DLPFC, and ACC in the sample (26) used in the Seidman et al. (18) volumetric study. We evaluated the structural connectivity network underlying attention and executive functions (EFs), demonstrating white matter abnormalities measured by fractional anisotropy in the cingulum bundle and the superior longitudinal fasciculus II in a completely independent sample of ADHD adults (27). These findings largely emphasize cortical circuits (DLPFC, ACC, and IPL) and subcortical circuits with BIOL PSYCHIATRY 2011;69:857– 866 © 2011 Society of Biological Psychiatry

A

ttention-deficit/hyperactivity disorder (ADHD) in adults has gradually become recognized as a valid and reliable disorder, sharing many features with the childhood syndrome (1). A substantial percentage of individuals diagnosed with ADHD in youth have symptoms persisting into adulthood (2,3) and epidemiologic data indicate that approximately 4% of adults in the United States suffer from ADHD (4,5). Adults with ADHD share similar clin-

From the Department of Psychiatry (LJS, JB, EMV, MCM, AB, TS, SVF, NM), Harvard Medical School, Massachusetts General Hospital, Boston; Massachusetts Mental Health Center Public Psychiatry Division (LJS), Beth Israel Deaconess Medical Center, Boston; Neuroimaging Program (LJS, JB, EMV, MCM, AB, TS, SVF, NM), Clinical and Research Programs in Pediatric Psychopharmacology and Adult Attention-Deficit/Hyperactivity Disorder, Massachusetts General Hospital, Boston; Martinos Center for Biomedical Imaging (LJS, EMV, NM), (Massachusetts Institute of Technology, Harvard Medical School, and Massachusetts General Hospital), Charlestown; Departments of Neurology and Radiology Services (LL, JK, NM), Harvard Medical School, Center for Morphometric Analysis, Massachusetts General Hospital, Boston; and Department of Brain and Cognitive Sciences (AB), Massachusetts Institute of Technology, Cambridge, Massachusetts; and Departments of Psychiatry and of Neuroscience and Physiology (SFV), The State University of New York Upstate Medical University, Syracuse, New York. Address correspondence to Larry J. Seidman, Ph.D., Massachusetts General Hospital, Clinical and Research Program in Pediatric Psychopharmacology, Fruit Street, Warren 7, Boston, MA 02114; E-mail: lseidman@bidmc. harvard.edu. Received Mar 22, 2010; revised Aug 10, 2010; accepted Sep 29, 2010.

0006-3223/$36.00 doi:10.1016/j.biopsych.2010.09.053

Based on this prior work and conceptual model. To the www. 5 had been prescribed antidepressants. Second. including volume reduction in specific regions of the vermis. The likely persistence of structural abnormalities is supported by the continued deficits in attention and EFs in adults with ADHD. only the difference for the cerebellar volume remained significant (45). Thus. Durston et al. it is possible that this region normalizes over time.J. During the study. ACC. 23 control subjects). handedness. this is the first VBM study of the brain in adults with ADHD. It is also possible that the absence of caudate differences in our sample of 24 adults with ADHD compared with 18 control subjects (18) was due to small samples sizes. and 9 had received a combination of other psychotropic medications. We conducted direct interviews with all subjects. with childhood onset and persistence into adulthood. many investigators have conceptualized the neurobiology of ADHD as involving structural and functional brain abnormalities in frontal-striatal circuitry that governs attention and EFs (37– 42).18. Our empirical work has been guided by a conceptual model of the core neurocognitive deficits in ADHD. Middleton and Strick (51) demonstrated cerebellarcortical connections that provide an anatomical substrate for a possible cerebellar-prefrontal dysfunction in ADHD (17. Many researchers studying the cerebellum in ADHD children have observed structural abnormalities. and we have utilized this model to guide our work. One of the most replicated alterations in ADHD in childhood is a significantly smaller volume in the caudate (43– 45) and a smaller putamen-pallidum region. somatotopically distributed circuits essential for EFs. and all participants received an honorarium for participating. they are appropriate for directional hypothesis testing. cerebellar gray matter is hypothesized to be an important part of the brain affected in ADHD. A preliminary imaging study of 32. Attention-deficit/hyperactivity disorder (n ϭ 74) and control (n ϭ 54) adults were group matched to be comparable on age. Finally. and the functional neuroanatomy of neural circuits hypothesized to underlie these functions (17. blind to ascertainment status. inadequate command of the English language. including the caudate.3%) subsample (26 ADHD. increase synaptic dopamine by blocking the dopamine transporter in striatum (49). Damage to the striatum has been hypothesized to be associated with ADHD (47). who formed the Diagnostic Committee. Because these a priori regions of interest (ROIs) have strong theoretical and empirical support. 18 control subjects) has been previously published (18. of the cerebellar vermis have been found for ADHD boys (43– 45. we addressed the cerebellum. IPL. and the striatum has one of the highest densities of dopaminergic synapses in the brain (48). . 47 had never been prescribed psychotropic medications. putamen.69:857– 866 reciprocal connections to DLPFC. ACC. written informed consent was obtained. After a complete description of the study. interviewed all adults with the Structured Clinical Interview for DSM-IV (59) supplemented with modules from the Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiological Version (60) to cover ADHD and other childhood disorders. For control participants.8% of these subjects (24 ADHD.org/journal L. caudate. Striatal lesions in animals produce hyperactivity and poor working memory and response inhibition performance (46). and a slightly larger (38. we conducted exploratory analyses on these ROIs to assess whether any of these regions were significantly larger in ADHD and on other ROIs not specifically predicted to be part of ADHD.33) and growing numbers of functional MRI studies in ADHD adults showing abnormalities in prefrontal cortex. VIII to X. including all those in the original sample. (18) and excluding subjects with bipolar disorder comorbidity previously reported (28). Finally. sensorimotor handicaps. (45) demonstrated that significant differences in caudate volume between children with ADHD and control subjects diminished by the oldest age studied (19 years). sex. lay interviewers. identified by voxel based morphometry (VBM) meta-analysis (22). and other regions of the network for attention and EFs (34 –36).31). Patients with ADHD who were currently being treated with stimulants underwent a 24-hour washout period before scanning (n ϭ 21). Methods and Materials Subjects Male and female subjects between the ages of 18 and 59 participated in the study. The caudate. 23 had never been prescribed psychotropic medications. 17 had received stimulants and antidepressants. current alcohol or substance abuse or dependence defined by DSM-IV or a chronic history of abuse or dependence as defined by clinician review.26) utilizing volumetric and cortical thickness analyses.26 –29. Clinical Assessment Attention-deficit/hyperactivity disorder adults were included if they met full criteria for ADHD according to the DSM-IV. putamen. including attention and EFs (30). commonly used to treat ADHD. given its involvement in a number of cognitive and affective processes beyond simple motor functions (50). Trained. was used in a volumetric analysis of the effects of comorbidity of bipolar disorder and ADHD (28). using subjects in which we extend matching of cases and control subjects on the same characteristics as in the first sample by Seidman et al. Regarding lifetime medication history for ADHD participants. We recruited ADHD subjects from referrals to psychiatric clinics at the Massachusetts General Hospital (MGH) and advertisements in the greater Boston area and control subjects through advertisements in the same geographic areas. stimulant medications. they were supervised in weekly meetings by board-certified child and adolescent psychiatrists and experienced licensed psychologists.sobp. and 1 had received other psychotropic medications. In a study of 152 children and adolescents with ADHD and 139 control subjects. and cerebellum (29).32. including prefrontal– basal ganglia–thalamic loops (46). neurological disorder.858 BIOL PSYCHIATRY 2011. 22 had received stimulants. reductions in the posterior inferior lobules.53–56). or a full-scale IQ less than 80 as measured by the Wechsler Adult Intelligence Scale-Third Edition (57). we hypothesized that ADHD adults would have smaller volumes in DLPFC. Socioeconomic status was assessed with the Hollingshead Four Factor Index of Social Status scale (58). Thus. and race. Throughout the study. Because Castellanos et al. The study was approved by the MGH Human Subjects committee. and cerebellar gray matter. 3 had received antidepressants only. best of our knowledge. Exclusion criteria were deafness. reflected in many neuropsychological studies (8 –11. respectively. all interviews were audiotaped for random quality control assessments. The interviewers’ data were reviewed by the Diagnostic Committee so that a DSM-IV consensus diagnosis (61) could be made.52). For example. along with the putamen. psychosis. (56) found smaller overall right cerebellar volumes in a group of 30 ADHD children. This is the first report of the complete dataset of adults 18 or older. Seidman et al. and globus pallidus are part of discrete. after adjusting for total cerebral volume. 1 had received both stimulants and antidepressants. This suggests that larger studies of ADHD adults are needed to determine whether there are persistent caudate or other striatal alterations. blindness.

For this article. simplex. rates of LDs.64) carried out with FSL tools (65). Statistical maps were thresholded at p Ͻ . the rates of these comorbidities were very low in both groups at the most recent interview.org/journal .g.73 sec/ 3.. a VBM style analysis (63. There were no significant differences between groups on rates of major depressive. and all nondiagnostic (e. board-certified child and adult psychiatrists diagnose subjects from audiotaped interviews. After whole-brain analysis. 4) caudate—an area involving the head and body in the left hemisphere. BA 32). adults with ADHD were not significantly different than control subjects on the matching variables of age. 3) IPL—an area in the left hemisphere corresponding to BA 40 (supramarginal gyrus).5 Tesla scanner (Siemens Medical Systems. Global Assessment of Functioning scores. We computed kappa coefficients of diagnostic agreement by having experienced. Voxel-based thresholding. 9. and 6) the cerebellum. The ROI VBM is more sensitive than the whole-brain VBM used for testing a priori hypotheses. Results Demographic Characteristics. and cognitive factors. based on the CMA adaptation of the MNI atlases.95]). Next. MRI Protocol Whole-brain magnetic resonance images were collected on a Siemens 1. adults with ADHD had at least one area of significantly smaller gray matter volumes (Table 2.98.01. Oxford University. A sagittal localizer scan was performed for placement of slices. psychiatric. Intellectual Functioning and Symptoms As Table 1 shows. These smaller regions included the 1) DLPFC—an area corresponding to lateral BA 8 in the left and right hemispheres. 5) putamen—left hemisphere. gender. Erlangen. or race. and 46.69). BA 8.0). and Figures 1.39 msec/1.fmrib. BA 40) gyri. Germany) at the MGH Martinos Center (Charlestown. The significance level with the familywise error (FWE) corrected was set at p Ͻ . They were also statistically comparable on IQ. The only significant differences were in social class. BA 39) and supramarginal (supramarginal gyrus. both uncorrected and corrected. (26). United Kingdom).L. we performed ROI VBM analysis by creating a mask for each of the six a priori ROIs. The IQ was estimated from the block design and vocabulary subtests of the Wechsler Adult Intelligence Scale-Third Edition (57). represented by parcellation units F1 (superior frontal gyrus. structural images were brain-extracted using the Brain Extraction Tool (66). culmen inferior. which uses a B-spline representation of the registration warp field (72).05 for both whole brain and six ROI analyses and the uncorrected significance level was set at p Ͻ . agoraphobia [1. conduct disorder (1. handedness. The registered partial volume images were then modulated.88). we include estimates of IQ and academic achievement tests to demonstrate comparability of the two groups on overall intellectual potential and achievement. field of view ϭ 256 ϫ 256 mm. VBM Methods. which is consistent with the ADHD association with underachievement (76). which is commonly abnormal in ADHD and considered to be an effect of the disorder (77. and whole brain volume. using the chi-square test and t test for categorical and dimensional variables.M. and panic disorder [.sobp.78). anxiety. Kappa coefficients for individual diagnoses included: ADHD (. Data Analyses We compared the ADHD and control groups on demographic.0 sec/7. tissuetype segmentation was carried out using FAST4 (67). to which the native gray matter images were then nonlinearly reregistered using FNIRT (70.uk/fsl/fslvbm/index. BA 24) and paracingulate gyri (paracingulate cortex. 3. Learning disability (LD) was defined by a score less than or equal to 85 on the WRAT-III reading and/or arithmetic scaled scores.J. F2 (middle frontal gyrus. followed by a coronal T2-weighted sequence to rule out unexpected neuropathology. 5) the putamen. or antisocial disorders. to correct for local expansion or contraction. and presence/absence of lifetime psychotropic medications as covariates. analysis of covariance). and on the WRAT-III arithmetic test. reading achievement. 2) ACC—an area corresponding to BA 24/32 in the right hemisphere. sampling matrix ϭ 256 ϫ 192 pixels. BA 9). all data collected from other family members. Academic achievement was assessed with the reading and arithmetic tests of the Wide Range Achievement Test-Third Edition (WRAT-III) (62). Total intracranial volume was calculated as the sum of gray matter. and F3 (inferior frontal gyrus. The mask was then inserted as an explicit mask into VBM analysis. only t test results are reported. As we did not see a difference between the two models (t test vs. The resulting gray-matter partial volume images were then aligned to Montreal Neurological Institute (MNI) 152 standard space using the affine registration tool FLIRT (68. We also used BIOL PSYCHIATRY 2011. A priori ROI predictions for VBM included volume reductions in: 1) DLPFC—Brodmann areas (BAs) 8. combined substance use. Based on 500 assessments from interviews of children and adults. for preliminary identification of gray matter volume reductions or increases. First. www.html. and cerebrospinal fluid volumes.0]. nonselective inversion-prepared spoiled gradient echo pulse) sequences were collected (repetition time/echo time/T1/flip ϭ 2.1 (http://www. and 6) cerebellum—areas in the left cerebellum corresponding to regions culmen superior.0). Diagnoses were made for two points in time: lifetime and the month before the interview. bandwidth ϭ 190 Hz/pixel. for multiple comparisons was adopted. major depression (1. respectively.05 mm). the median kappa coefficient was . The clusters of significance were localized using a CMA adaptation of the MNI and Talairach atlases and reviewed by N. and 4). Anatomical localization was defined by the CMA parcellation unit system for cortex (74) and cerebellum (75). Oxford. 3) the IPL.71). comprising the angular (angular gyrus.ac. Seidman et al. Two sagittal three-dimensional magnetization-prepared rapid gradient-echo imaging (T1-weighted. Both groups had above average IQ. 4) the caudate— head and body of the caudate nucleus. effective slice thickness ϭ 1. Massachusetts). Structural data were resampled to 2 * 2 * 2 mm and were analyzed with FSL-VBM 1. Structural scans were transferred to the CMA and coded and catalogued for blind analysis using VBM. compared with control subjects. VBM Results in A Priori ROIs In all six ROIs.0]. The resulting images were averaged to create a study-specific template. sex distribution. 2) the ACC (anterior cingulate cortex. BA 46).33 mm on a 170 mm slab of 128 partitions) and used for analyses conducted at the MGH Center for Morphometric Analysis (CMA). 9). Threshold free cluster enhancement (73) was used to control FWE.01 (uncorrected) using a minimum cluster size of three or more voxels.69:857– 866 859 analysis of covariance with the total intracranial volume (TIV). by dividing the Jacobian of the warp field.ox. brain imaging) data. The modulated segmented images were then smoothed with an isotropic Gaussian kernel with a sigma of 3 mm (full width at half-maximum ϭ 7. from FSL Brain Extraction Tool segmentations. and multiple anxiety disorders (separation anxiety [1. Voxelwise general linear model was applied using permutationbased nonparametric testing (5000 permutations). The Diagnostic Committee was blind to the subject’s ascertainment group. white matter.

124 ns ns ns ADHD.5 (5.63.005 ␹2 ϭ . the results were only robust with respect to the caudate. attention-deficit/hyperactivity disorder. and right thalamus were significantly smaller in ADHD at this threshold (Table S1 in Supplement 1).7 (. Results did not change when covarying sex. df). superior semilunar lobule.860 BIOL PSYCHIATRY 2011.9 df ϭ 124. Demographic Characteristics of Adults with ADHD and Control Subjects Control Subjects n ϭ 54 Mean (SD) or Percentage 34. a Socioeconomic status (58).7) 38 (51%) 65 (88%) 74 (100%) 9 (12%) 6 (8%) 0 (0%) 0 (0%) 0 (0%) L. 3rd Edition. Reading Scaled Scores and/or Arithmetic Scaled Scores. or cognitive variables used to group match. or medication status. and presence/absence of medications. More work is needed to clarify these differences. p Value. and cerebellum). socioeconomic status. a t test was significant at the FWE for the caudate (Table 3). left and right occipital cortex. GAF.2 df ϭ 126. IPL.4 df ϭ 126. Results were not significantly influenced by sex.0) 186947.5 (11.817 t ϭ Ϫ. In contrast. including a large area in FOC bilaterally and a large area in the left temporal cortex and anterior parahippocampus. A number of areas in the left and right frontal lobe.3 (12.5 (11.7) 68. [75]) and areas in the right cerebellum corresponding to culmen superior. ns. left hippocampus/parahippocampus.855 ns ␹2 ϭ 1. hemispheric zone of lobule X (X-h). 3rd Edition.6) 2. and ␹2 and p Value t ϭ Ϫ1. Moreover.0 (5. p ϭ . suggesting that reductions of FOC may be a correlate of comorbidity with mood disorders rather than a correlate of ADHD. No statistically significant differences were found at the FWE at the whole brain.8 (12. we report any nonpredicted findings in which there was smaller or larger gray matter in ADHD than control subjects in other ROIs at p Յ . Thus. p ϭ . substance or antisocial disorders.0 (1.9) 60. nor were there significant differences between ADHD individuals with versus without lifetime psychotropic medication exposure. SS.4 (9. the only ROI that met FWE threshold for significance using ROI-VBM. and tonsil. our initial morphometric ROI analysis (18) found no FOC volume reductions in adult ADHD and in prior work found volumetric reductions in FOC in a study of adults with comorbid ADHD and bipolar disorder (28). They provide support for the validity of ADHD in adults and for the syndromic continuity into adult life of biological features found in ADHD children. or learning disabilities. A number of areas were larger in ADHD than control subjects at this threshold.186 t ϭ 2. comorbidities that are typically significantly more common in adult ADHD than control subjects (20). biventer (pars paraflocculus dorsalis). The larger FOC observed in our study is notable in that Hesslinger et al. Reading Scaled Score and Arithmetic Scaled Score (62).J.0 (1. a network of structures involved in attention and EFs (cf.6) 107. No significant differences were identified at the FWE correction in these ROIs or the rest of the brain when the FWE correction (p Ͻ .3) 1. p ϭ .7/1485 115.5) 1. p ϭ .364. df ϭ 126. intelligence quotient.1 df ϭ 124.3 (11. p ϭ . b Intelligence quotient.033 t ϭ Ϫ28. there were no meaningful differences between groups on rates of mood. VBM Exploratory Results Here.8) 25 (46%) 48 (89%) 54 (100%) 3 (6%) 1 (2%) 0 (0%) 0 (0%) 0 (0%) ADHD n ϭ 74 Mean (SD) or Percentage 37. These results extend to adults with ADHD the previously reported findings in the literature on children with ADHD.585.org/journal putamen.161 t ϭ Ϫ2. the Global Assessment of Functioning. the significant structural reduction in the ADHD group can be attributed to having ADHD and not to co-occurring current psychiatric or cognitive comorbidity or medications. p Ͻ .1 df ϭ 126.6/1501 116. as the studies differ substantially in sample size and methods. www. (23) used an ROI analysis to examine the FOC and found a significant volume reduction of the left FOC. e Rates of disorders at most recent interview. right temporal cortex. c Wide Range Achievement Test. Third Edition (57). anxiety.6 (2.05) was applied to the whole brain.1) 109.2 df ϭ 123. Discussion This VBM study of brain structure in ADHD adults partially supported the hypothesis that ADHD adults have subtle brain volume reductions in a priori predicted ROIs (DLPFC. In two of the six ROIs.033. Moreover. Some areas of left and right occipital cortex were also larger in ADHD than control subjects (Table S1 in Supplement 1). Wide Range Achievement Test. The differences in social class. IQ. caudate.0 (12. p ϭ . a variable comprised of occupation and education of the participants (not of the family of origin). ACC.925 t ϭ . p ϭ . 3rd Edition. Both groups were highly educated and were above average in general intellectual ability.4 (7. psychiatric. Demographic Characteristics Age (in years) SESa ADHD Symptoms Current GAF Whole Brain Volume–Voxels/cm3 Full Scale IQ Estimateb WRAT-III Reading SSc WRAT-III Arithmetic SSc Gender (Male) Handedness (Right) Race (Caucasian) Learning Disabilityd Major Depressione Multiple (Ն 2) Anxiety Disordere Antisocial Personality Disordere Substance Use Disorderse Test Statistic (t. p ϭ . biventer (pars paraflocculus dorsalis). p ϭ .3) 101.sobp. p ϭ .69:857– 866 Table 1. WRAT-III. Using ROI-VBM for the six regions individually. d Learning disability is defined by a score less than or equal to 85 on the Wide Range Achievement Test.24 df ϭ 126. there were differences between ADHD and control groups in which the ADHD group had larger gray matter volumes at p ϭ .0) 13. p ϭ .01 (DLPFC and IPL) (Table 2 and Figure 2). SES. 29).208 ␹2 ϭ 2. scaled score. TIV.9) 187656. However.572 ␹2 ϭ .000 t ϭ 7. nonsignificant. It is notable that brain differences were detectable in the absence of significant differences in demographic. Global Assessment of Functioning.5) 107. and tonsil (Makris et al. Seidman et al. measured by Vocabulary and Block Design subtests of the Wechsler Adult Intelligence Scale. the role of the FOC in .001 t ϭ Ϫ. and WRAT-III arithmetic are strongly associated with the disorder and were not matching variables.319. TIV.001.

IX-m. Ϫ36 56. F1. angular gyrus. flocculus (see also Figures 3 and 4). IPL. biventer (pars copularis). Ϫ24 26. parcellation units. 24 26.BA 9/LAT FP/BA 9/LAT ACC . VIIB-m VIIA_crusl-m VIIA_crusl-m VIIA_crusl-m VIIIA-m VIIIB-m VI-m IX–m/VIIIB-m Region of Interest CMA PU . ADHD. Ϫ56 20. Ϫ30 20.z) p ϭ . Ϫ74. 20. 36 Ϫ58. and .Left Hemisphere Cerebellum – Left VIIA_crusl-m IV-m. 28. 16 Ϫ16. Ϫ44.Left Hemisphere SGp – BA 40 SGp – BA 40 PO . 38 14. V-m. ADHD needs to be clarified. Cerebellar areas: IV-m.20 –22) with one major exception: our adult data indiwww. Ϫ82. MNI. VI-m. biventer (pars paraflocculus dorsalis).Left Hemisphere F1/F2 . inferior parietal lobule. Ϫ8 Ϫ14. Ϫ86. simplex. and must be viewed cautiously until replicated. Center for Morphometric Analysis. attention-deficit/hyperactivity disorder. m. supramarginal gyrus anterior. frontal pole. VIIB-m. region of interest. Parcellation units are regions of interest defined by the Center for Morphometric Analysis as in Caviness et al. culmen inferior. Ϫ32. Ϫ44. Ϫ34. Ϫ68. V-m IX-m VIIIB-m Cerebellum – Right IV-m V-m. Some clusters border on more than one region—those clusters are reported more than once with cluster size in parentheses (see also Figure 1).01 p ϭ . 12 Ϫ32. ROI. Ϫ44. parietal operculum. anterior middle cingulate cortex.Right Hemisphere Ant mACC . 50.org/journal . Ϫ40 Ϫ26. 12 Ϫ20. Our ROI findings are generally consistent with the pediatric literature (17. culmen superior. Ϫ32 38.005 p ϭ . SGa. Ϫ60.Left Hemisphere ACC/BA 24 IPL . paramedian/gracilis. 4.01.y. S-II. Voxel Based Morphometric Differences Between Adults with ADHD and Control Subjects in Six ROIs Region of Interest CMA PU – BA Volume Reduction in ADHD DLPFC . Ϫ54. require further study. Ϫ36. b All results are in the direction of larger volumes in the ADHD group than in control subjects.L. 18 12 26 — — — — FSL-voxel based morphometry results comparing differences in gray matter volume thresholded to a probability of p ϭ . Ϫ40 Ϫ14. 30. 38. Ϫ62.01 p ϭ . V-m VI-m. (75) for the cerebellum. Ϫ16 Ϫ26. superior frontal gyrus. Ϫ44. lateral.BA 24/32 ACC . ACC.005 p ϭ . Ϫ22. a All results are in the direction of smaller volumes in the ADHD group than in control subjects. PO. Local maxima are reported. F2. superior semilunar lobule.001 (uncorrected). Ϫ32. VIIA_crusI-m.J. 40 28. 32 16. Locations for statistical findings are reported in the standard Montreal Neurological Institute coordinate space (x. 64 44. middle frontal gyrus. Ϫ80. BA. y. 20 Ϫ66. hemispheric zone of lobule X. including cluster size and anatomical region. SGp. supramarginal gyrus posterior. VIIIA-m. tonsil. Seidman et al.sobp. 32 Ϫ12. CMA.BA Volume Increase in ADHD DLPFC . BIOL PSYCHIATRY 2011. 26.Right Hemisphere F2 . anterior cingulate cortex. 6.Right Hemisphere AG/BA 39 Clusters of Three Voxels or Larger at Statistical Threshold for Control Subject Ͼ ADHD (Uncorrected)a MNI Coordinates (x. 42. z). FP. The larger volumes of FOC and of other ROIs in our sample were not predicted.001 6. PU. Brodmann area. VIIIB-m.y. Ϫ54 20. . 16. X-h IV-m. Ϫ54 6.005.001 Ϫ16.II. Ϫ26. 36 44. Ϫ56. AG. LAT. (74) for the cortex and Makris et al. Ϫ20 6. Ϫ58 52 27 30 10 6 74 3 7 20 122 9 334 8 52 96 (96) 30 262 (262) 30 36 56 18 41 74 (74) 5 89 34 — 17 — — 43 12 — — — — — 3 12 60 — 215 — — — — 44 — 51 (51) — 132 (132) 3 — 28 — 17 — 21 — 17 — — 17 — — 24 — — — — — — — Clusters of Three Voxels or Larger at Statistical Threshold for ADHD Ͼ Control Subject (Uncorrected)b MNI Coordinates (x. medial. Ϫ56 Ϫ14.BA 8 F1 . Montreal Neurological Institute.BA 8/LAT F2 . 50 Ϫ60.Right Hemisphere F1 BA 8/LAT IPL .Left Hemisphere Putamen . dorsolateral prefrontal cortex. somatosensory area . 38 Ϫ64. Ϫ48. as its dysfunction in ADHD has been hypothesized by a number of investigators (30) due to its importance in task coordination and control of emotional behavior. Ant mACC.z) p ϭ . X-m.BA 9 DLPFC . X-h. VI-m. DLPFC. 38 Ϫ46.BA 40/S-II/SGa/BA 40 AG/BA 39 Caudate .69:857– 866 861 Table 2.

VIIIA-m. a hypothesis that has some traction based on results by Shaw et al. hemispheric zone of lobule X. inferior part. posterior supramarginal gyrus. Lat.69:857– 866 cate comparability of overall cerebral volume. Lat. ventromedial prefrontal cortex. AG. pars opercularis. superior frontal gyrus. Brodmann area. somatosensory area . supracalcarine cortex. Figure 3. parietal operculum. IX-m.78). CGp. VI-m. Li. middle frontal gyrus. anterior parahippocampal gyrus. Significant differences are displayed on the flattened cerebellar surface of the Montreal Neurological Institute brain. which are considered exploratory findings outside of the predicted regions of interest. PRG. anterior supramarginal gyrus. as reflected in a meta-analysis of 137 studies (79) and in frequency of comorbid LD (77. supplementary motor cortex. with means of approximately 35 years of age in the two groups. The ADHD samples typically have lower IQs (on average by about nine points. culmen superior. Limitations This study has a number of limitations. BA. Voxel based morphometry control subjects Ͼ attention-deficit/ hyperactivity disorder (ADHD): cortical regions that are smaller in ADHD compared with control subjects. SMC. Cohen’s d ϭ Ϫ. Labels with arrows are smaller in attention-deficit/hyperactivity disorder (p Ͻ . a higher functioning subgroup of the distribution of cases than those typically seen in pediatric samples. posterior cingulate gyrus. lateral superior. Moreover. Note those regions that are smaller at this threshold. biventer (pars copularis).org/journal .J. superior frontal gyrus. We conducted a number of statistical tests on six ROIs that vary in size. F1. TP. lateral occipital area. V-m. PHp. In contrast. CALC. Another possibility requiring further research is that stimulant medications may have normalized brain volumes in ADHD (83). given the nonsignificant find- Figure 1. pars orbitalis. voxel based morphometry. superior semilunar lobule. depending on the ROI. OLs. VBM. paramedian/gracilis. L. anterior cingulate cortex. This issue can only be resolved by long-term follow-up study of children diagnosed with ADHD in childhood who retain their ADHD diagnoses and receive brain imaging in their adult years. angular gyrus. VMPF. outside of the predicted regions of interest are in Table S1 in Supplement 1. F3o. either psychiatric or LDs. F1. VIIA_crusI-m. occipital pole. lateral. OP. (82). which are considered exploratory findings. PP. F2. While the ADHD features of high IQ patients parallel those seen in lower IQ patients for both children (80) and adults (81) with the disorder. FP. culmen inferior. parietal operculum. Cerebellar regions that are smaller in attention-deficit/hyperactivity disorder compared with control subjects on a flattened brain. and thus. voxel based morphometry. BA. attention-deficit/hyperactivity disorder. VBM. cuneus. VIIIB-m. voxel based morphometry. Another explanation is that developmental differences that are present in childhood diminish in adulthood. tonsil. IV-m.61). ACC.01) and correspond to those described in Table 2 for predicted regions of interest. VIIB-m. SCLC. Labels with arrows are those regions that are larger in ADHD (p Ͻ .01) and correspond to those described in Table 2 for predicted regions of interest. in children entering their early teen years. frontal pole. SGa. Voxel based morphometry control subjects Ͻ attention-deficit/hyperactivity disorder (ADHD): cortical regions that are larger in ADHD compared with control subjects. CGp. superior part. S-II. flocculus. whereas the pediatric literature consistently reports smaller overall brain volume in ADHD than control subjects. Significant differences are displayed on the inflated surface of the Montreal Neurological Institute brain. ADHD. www. Ant mACC. OLi. and thus we are vulnerable to making a type I error. X-h. planum polare. posterior cingulate gyrus. it is possible that higher IQ in ADHD is associated with fewer structural brain differences from control subjects. Labels with arrows are those regions that are smaller in ADHD (p Ͻ . F3orb. PO. Seidman et al. frontal pole. Significant differences are displayed on the inflated surface of the Montreal Neurological Institute brain. lateral. fronto-orbital cortex. precentral gyrus. lingual gyrus. AG. SGp. are in Table S1 in Supplement 1. VBM. anterior middle cingulate cortex. whereas this adult ADHD sample did not. PP. PO. lateral inferior. FP. FOC. simplex. Figure 2. posterior parahippocampal gyrus. lateral occipital area. temporal pole.II.862 BIOL PSYCHIATRY 2011. One possible explanation for this difference is that our adult ADHD sample is relatively high functioning (mean IQ of 116) with few comorbidities.01) and correspond to those described in Table 2. inferior frontal gyrus. X-m. calcarine area.sobp. there were no meaningful sociodemographic and cognitive differences from control subjects. LS. Brodmann area. Their work demonstrated a developmental lag in cortical thickness of between 3 and 5 years. CN. Note those regions that are larger at this threshold. LG. angular gyrus. PHa. inferior frontal gyrus. our sample ranges from ages 18 to 59. biventer (pars paraflocculus dorsalis). planum polare.

these findings may not generalize to diagnoses defined using data from informants.sobp. superior semilunar lobule.7352 .05. and the Commonwealth Research Center of the Massachusetts Department of Mental Health (to LJS). Thus. the March of Dimes Foundation. Labels with arrows are smaller in attention-deficit/hyperactivity disorder (p Ͻ . voxel based morphometry. biventer (pars copularis). although presence or absence of lifetime medications did not significantly influence the results.6464 . as do other automated measures.2240 .J. and interpretation of the data. Another limitation to the generalizability of our results is that our sample was not representative of lower socioeconomic or all IQ strata and only included Caucasian participants. NIMH MH 57934 (to SVF). The diagnoses of adult ADHD relied entirely on the self-report of adult subjects. Replication of these findings in adults is necessary to establish that the particular structures found to be abnormal are core components of the neurobiology of ADHD in adults.0292 Group. assuming that brain volume differences are associated with IQ. National Research Service Award (NIMH F32 MH065040-01A1). and few psychiatric comorbidities. Finally. X-h. hemispheric zone of lobule X.0130 Group. complementing studies demonstrating persistent neuropsychological and functional brain dysfunctions.5250 . the effects on the brain of diverse medication histories are unknown.3186 .2816 . Moreover. ADHD. ings at the FWE threshold for the whole brain. a Statistically significant at familywise error rate at p Ͻ . However.0394 Group . X-m. and psychiatric comorbidities.g.4404 . and Medication . Finally. VI-m. Conclusions and Future Directions Despite these limitations. These results were observed in the context of a very tightly matched control group and an ADHD group with relatively high IQs. Total Brain Volume.1500 . and preparation. While generalizability is limited until we learn whether these results are robust across samples.1580 . V-m.6510 . Seidman et al.2094 . few LDs.4230 . VBM. to eliminate rater effects arising from manual morphometry.1300 . Total Brain Volume . anterior cingulate cortex. review.85). LDs. in part. as we noted in detail in Makris et al.7510 . simplex. Thus. Moreover. VIIIB-m. the National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award and the Johnson and Johnson Center for the Study of Psychopathology (to JB). inferior parietal lobule. analysis.5160 . significantly larger FOC). paramedian/gracilis. as this study was carried out over a 5-year period and involved a large sample. collection. biventer (pars paraflocculus dorsalis). and The National Center for Research Resources (P41RR14075). ADHD. management. Significant differences are displayed on the inflated cerebellar surface of the Montreal Neurological Institute brain. Peter Livingston Fellowship through the Harvard Medical School Department of Psychiatry. Because our sample was referred for ADHD.. Medication Status .L. DLPFC. . the current methods of registration employed in this study represent state of the art technology in this domain. IX-m. IPL. we identified a number of unpredicted results. the results provide partial support for the hypothesis that some structural brain abnormalities persist into adulthood in ADHD. Familywise Error Corrected p Values for Models Using Regions of Interest Hypothesized to be Significantly Smaller in ADHD Than Control Subjects Regions of Interest DLPFC IPL ACC Putamen Cerebellum Caudatea Group. VIIIA-m. tonsil. Sex. we have shown elsewhere that ADHD features in high IQ ADHD adults parallel those seen in other adults with ADHD (81). This work was supported in part by National Institute of Mental Health (NIMH) MH/HD 62152.1650 . We used VBM. Despite these limitations. culmen inferior. particularly the problem of co-registration. the relatively homogeneous nature of BIOL PSYCHIATRY 2011. attention-deficit/hyperactivity disorder. future studies should address these questions by studying psychotropically naïve individuals and studying the effects of substance use and medications on the brain in ADHD individuals. the Mental Illness and Neuroscience Discovery Institute.4112 . VIIA_crusI-m. Although we had a relatively high IQ sample. While VBM allows a large number of brains to be measured without the influence of raters.org/journal Figure 4. our sample and its tight matching with control subjects suggests that our findings do not result from these confounds.1110 . flocculus. culmen superior. These funders had no role in the design and conduct of the study. Sex. or approval of the manuscript. ([26] page 1372). and the Clinical Research Training Program Fellowship in Biological and Social Psychiatry MH 16259 and MH 071535 (to EMV). there were no significant differences in the opposite direction in these ROIs. it suffers from its own intrinsic limitations (84. this study may have been less likely to find significant results than many in the literature. and further work will be needed to replicate these findings (e. were consistent with a priori hypotheses and with the bulk of the literature in children with ADHD. attention-deficit/hyperactivity disorder. our main findings were in the predicted direction.69:857– 866 863 Table 3.0130 ACC. dorsolateral prefrontal cortex. www. IV-m. VIIB-m.01) and correspond to those described in Table 2. our results cannot be generalized to nonreferred samples.4300 . and were robust in the caudate at the a priori hypothesis testing FWE.2426 . Cerebellar regions that are smaller in attention-deficit/hyperactivity disorder compared with control subjects as seen on an inflated brain.

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