Attention-deficit/hyperactivity disorder predominantly inattentive (ADHD-PI) and combined (ADHD-C) presentations are likely distinct disorders that differ neuroanatomically, neurochemically, and neuropsychologically. However, to date, little is known about specific white matter (WM) regions differentiating ADHD presentations. This study examined differences in WM microstructure using diffusion tensor imaging (DTI) data from 20 ADHD-PI, 18 ADHD-C, and 27 typically developed children. Voxel-wise analysis of DTI measurements in major fiber bundles was carried out using tract-based spatial statistics (TBSS). Clusters showing diffusivity abnormalities were used as regions of interest for regression analysis between fractional anisotropy (FA) and neuropsychological outcomes. Compared to neurotypicals, ADHD-PI children showed higher FA in the anterior thalamic radiations (ATR), bilateral inferior longitudinal fasciculus (ILF), and in the left corticospinal tract (CST). In contrast, the ADHD-C group exhibited higher FA in the bilateral cingulum bundle (CB). In the ADHD-PI group, differences in FA in the left ILF and ATR were accompanied by axial diffusivity (AD) abnormalities. In addition, the ADHD-PI group exhibited atypical mean diffusivity in the forceps minor (FMi) and left ATR and AD differences in right CB compared to healthy subjects. Direct comparison between ADHD presentations demonstrated radial diffusivity differences in FMi. WM clusters with FA irregularities in ADHD were associated with neurobehavioral performance across groups. In conclusion, differences in WM microstructure in ADHD presentations strengthen the theory that ADHD-PI and ADHD-C are two distinct disorders. Regions with WM irregularity seen in both ADHD presentations might serve as predictors of executive and behavioral functioning across groups. Hum Brain Mapp 37:3323-3336, 2016. © 2016 Wiley Periodicals, Inc.

Department of Counseling Educational Psychology and Special Education Michigan State University East Lansing Michigan

Department of Pediatrics University of Minnesota Minneapolis Minnesota

Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Seattle Washington

Division of Biostatistics University of Minnesota Minneapolis Minnesota

Multimodal and Functional Neuroimaging Research Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Alexander AL, Lee JE, Lazar M, Field AS (2007): Diffusion tensor imaging of the brain. Neurotherapeutics 4:316–329. PubMed PMC

American Psychiatric Association (2000): Diagnostic and Statistical Manual of Mental Disorders, 4th text rev. ed. Washington, DC: American Psychiatric Association; 943 p.

American Psychiatric Association (2013): Diagnostic and Statistical Manual of Mental Disorders, 5th ed Arlington, VA: American Psychiatric Publishing; 947 p.

Anderson MJ, Robinson J (2001): Permutation tests for linear models. Aust NZ J Stat 43:75–88.

Ashtari M, Kumra S, Bhaskar SL, Clarke T, Thaden E, Cervellione KL, Rhinewine J, Kane JM, Adesman A, Milanaik R, Maytal J, Diamond A, Szeszko P, Ardekani BA (2005): Attention‐deficit/hyperactivity disorder: A preliminary diffusion tensor imaging study. Biol Psychiatry 57:448–455. PubMed

Baeyens D, Roeyers H, Walle JV (2006): Subtypes of attention‐deficit/hyperactivity disorder (ADHD): Distinct or related disorders across measurement levels? Child Psychiatry Hum Dev 36:403–417. PubMed

Barber AD, Jacobson LA, Wexler JL, Nebel MB, Caffo BS, Pekar JJ, Mostofsky SH (2015): Connectivity supporting attention in children with attention deficit hyperactivity disorder. Neuroimage Clin 7:68–81. PubMed PMC

Barkley RA (2014): Sluggish cognitive tempo (concentration deficit disorder?): Current status, future directions, and a plea to change the name. J Abnorm Child Psychol 42:117–125. PubMed

Basser PJ (1995): Inferring microstructural features and the physiological state of tissues from diffusion‐weighted images. NMR Biomed 8:333–344. PubMed

Basser PJ, Pierpaoli C (2011): Microstructural and physiological features of tissues elucidated by quantitative‐diffusion‐tensor MRI. 1996. J Magn Reson 213:560–570. PubMed

Biederman J, Petty CR, Fried R, Kaiser R, Dolan CR, Schoenfeld S, Doyle AE, Seidman LJ, Faraone SV (2008): Educational and occupational underattainment in adults with attention‐deficit/hyperactivity disorder: A controlled study. J Clin Psychiatry 69:1217–1222. PubMed

Biederman J, Petty CR, Ball SW, Fried R, Doyle AE, Cohen D, Henderson C, Faraone SV (2009): Are cognitive deficits in attention deficit/hyperactivity disorder related to the course of the disorder? A prospective controlled follow‐up study of grown up boys with persistent and remitting course. Psychiatry Res 170:177–182. PubMed PMC

Bonath B, Tegelbeckers J, Wilke M, Flechtner HH, Krauel K: Regional gray matter volume differences between adolescents with ADHD and typically developing controls: Further evidence for anterior cingulate involvement. J Atten Disord (in press). PubMed

Catani M, Jones DK, Donato R, Ffytche DH (2003): Occipito‐temporal connections in the human brain. Brain 126:2093–2107. PubMed

Chen L, Huang X, Lei D, He N, Hu X, Chen Y, Li Y, Zhou J, Guo L, Kemp GJ, Gong QY (2015): Microstructural abnormalities of the brain white matter in attention‐deficit/hyperactivity disorder. J Psychiatry Neurosci 40:280–287. PubMed PMC

Chiang HL, Chen YJ, Lo YC, Tseng WY, Gau SS (2015): Altered white matter tract property related to impaired focused attention, sustained attention, cognitive impulsivity and vigilance in attention‐deficit/hyperactivity disorder. J Psychiatry Neurosci 40:325–335. PubMed PMC

Chuang TC, Wu MT, Huang SP, Weng MJ, Yang P (2013): Diffusion tensor imaging study of white matter fiber tracts in adolescent attention‐deficit/hyperactivity disorder. Psychiatry Res 211:186–187. PubMed

Delis DC, Kaplan E, Kramer JH (2001): Delis‐Kaplan Executive Functioning System: Examiner's Manual. San Antonio, TX: The Psychological Corporation.

Dennis M, Francis DJ, Cirino PT, Schachar R, Barnes MA, Fletcher JM (2009): Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders. J Int Neuropsychol Soc 15:331–343. PubMed PMC

Duering M, Gesierich B, Seiler S, Pirpamer L, Gonik M, Hofer E, Jouvent E, Duchesnay E, Chabriat H, Ropele S, Schmidt R, Dichgans M (2014): Strategic white matter tracts for processing speed deficits in age‐related small vessel disease. Neurology 82:1946–1950. PubMed PMC

de Zeeuw P, Mandl RC, Hulshoff Pol HE, van Engeland H, Durston S (2012): Decreased frontostriatal microstructural organization in attention deficit/hyperactivity disorder. Hum Brain Mapp 33:1941–1951. PubMed PMC

Edel MA, Enzi B, Witthaus H, Tegenthoff M, Peters S, Juckel G, Lissek S (2013): Differential reward processing in subtypes of adult attention deficit hyperactivity disorder. J Psychiatr Res 47:350–356. PubMed

Ellison‐Wright I, Ellison‐Wright Z, Bullmore E (2008): Structural brain change in Attention Deficit Hyperactivity Disorder identified by meta‐analysis. BMC Psychiatry 8:51. PubMed PMC

Fair DA, Nigg JT, Iyer S, Bathula D, Mills KL, Dosenbach NU, Schlaggar BL, Mennes M, Gutman D, Bangaru S, Buitelaar JK, Dickstein DP, Di Martino A, Kennedy DN, Kelly C, Luna B, Schweitzer JB, Velanova K, Wang YF, Mostofsky S, Castellanos FX, Milham MP (2012): Distinct neural signatures detected for ADHD subtypes after controlling for micro‐movements in resting state functional connectivity MRI data. Front Syst Neurosci 6:80. PubMed PMC

Faraone SV, Sergeant J, Gillberg C, Biederman J (2003): The worldwide prevalence of ADHD: Is it an American condition? World Psychiatry 2:104–113. PubMed PMC

Frodl T, Skokauskas N (2012): Meta‐analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand 125:114–126. PubMed

Greicius MD, Krasnow B, Reiss AL, Menon V (2003): Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proc Natl Acad Sci USA 100:253–258. PubMed PMC

Goth‐Owens TL, Martinez‐Torteya C, Martel MM, Nigg JT (2010): Processing speed weakness in children and adolescents with non‐hyperactive but inattentive ADHD (ADD). Child Neuropsychol 16:577–591. PubMed PMC

Hamilton LS, Levitt JG, O'Neill J, Alger JR, Luders E, Phillips OR, Caplan R, Toga AW, McCracken J, Narr KL (2008): Reduced white matter integrity in attention‐deficit hyperactivity disorder. Neuroreport 19:1705–1708. PubMed PMC

Hoeft F, Barnea‐Goraly N, Haas BW, Golarai G, Ng D, Mills D, Korenberg J, Bellugi U, Galaburda A, Reiss AL (2007): More is not always better: Increased fractional anisotropy of superior longitudinal fasciculus associated with poor visuospatial abilities in Williams syndrome. J Neurosci 27:11960–11965. PubMed PMC

Holzapfel M, Barnea‐Goraly N, Eckert MA, Kesler SR, Reiss AL (2006): Selective alterations of white matter associated with visuospatial and sensorimotor dysfunction in turner syndrome. J Neurosci 26:7007–7013. PubMed PMC

Hong SB, Zalesky A, Fornito A, Park S, Yang YH, Park MH, Song IC, Sohn CH, Shin MS, Kim BN, Cho SC, Han DH, Cheong JH, Kim JW (2014): Connectomic disturbances in attention‐deficit/hyperactivity disorder: A whole‐brain tractography analysis. Biol Psychiatry 76:656–663. PubMed

Hughes EJ, Bond J, Svrckova P, Makropoulos A, Ball G, Sharp DJ, Edwards AD, Hajnal JV, Counsell SJ (2012): Regional changes in thalamic shape and volume with increasing age. Neuroimage 63:1134–1142. PubMed PMC

Jarratt KP, Riccio CA, Siekierski BM (2005): Assessment of attention deficit hyperactivity disorder (ADHD) using the BASC and BRIEF. Appl Neuropsychol 12:83–93. PubMed

Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM (2012): FSL. Neuroimage 62:782–790. PubMed

Jepsen JR, Fagerlund B, Mortensen EL (2009): Do attention deficits influence IQ assessment in children and adolescents with ADHD? J Atten Disord 12:551–562. PubMed

Jones DK, Knösche TR, Turner R (2013): White matter integrity, fiber count, and other fallacies: The do's and don'ts of diffusion MRI. Neuroimage 73:239–254. PubMed

Kaiser ML, Schoemaker MM, Albaret JM, Geuze RH (2014): What is the evidence of impaired motor skills and motor control among children with attention deficit hyperactivity disorder (ADHD)? Systematic review of the literature. Res Dev Disabil C 36:338–357. PubMed

Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997): Schedule for affective disorders and schizophrenia for school‐age children‐present and lifetime version (K‐SADS‐PL): Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988. PubMed

Kessler D, Angstadt M, Welsh RC, Sripada C (2014): Modality‐spanning deficits in attention‐deficit/hyperactivity disorder in functional networks, gray matter, and white matter. J Neurosci 34:16555–16566. PubMed PMC

Kubicki M, Westin CF, Nestor PG, Wible CG, Frumin M, Maier SE, Kikinis R, Jolesz FA, McCarley RW, Shenton ME (2003): Cingulate fasciculus integrity disruption in schizophrenia: A magnetic resonance diffusion tensor imaging study. Biol Psychiatry 54:1171–1180. PubMed PMC

Lawrence KE, Levitt JG, Loo SK, Ly R, Yee V, O'Neill J, Alger J, Narr KL (2013): White matter microstructure in subjects with attention‐deficit/hyperactivity disorder and their siblings. J Am Acad Child Adolesc Psychiatry 52:431–440.e4. PubMed PMC

Lei D, Ma J, Du X, Shen G, Jin X, Gong Q (2014): Microstructural abnormalities in the combined and inattentive subtypes of attention deficit hyperactivity disorder: A diffusion tensor imaging study. Sci Rep 4:6875. PubMed PMC

Lebel C, Walker L, Leemans A, Phillips L, Beaulieu C (2008): Microstructural maturation of the human brain from childhood to adulthood. Neuroimage 40:1044–1055. PubMed

Li Q, Sun J, Guo L, Zang Y, Feng Z, Huang X, Yang H, Lv Y, Huang M, Gong Q (2010): Increased fractional anisotropy in white matter of the right frontal region in children with attention‐deficit/hyperactivity disorder: A diffusion tensor imaging study. Neuro Endocrinol Lett 31:747–753. PubMed

Ling J, Merideth F, Caprihan A, Pena A, Teshiba T, Mayer AR (2012): Head injury or head motion? Assessment and quantification of motion artifacts in diffusion tensor imaging studies. Hum Brain Mapp 33:50–62. PubMed PMC

Makris N, Buka SL, Biederman J, Papadimitriou GM, Hodge SM, Valera EM, Brown AB, Bush G, Monuteaux MC, Caviness VS, Kennedy DN, Seidman LJ (2008): Attention and executive systems abnormalities in adults with childhood ADHD: A DT‐MRI study of connections. Cereb Cortex 18:1210–1220. PubMed

Mamah D, Conturo TE, Harms MP, Akbudak E, Wang L, McMichael AR, Gado MH, Barch DM, Csernansky JG (2010): Anterior thalamic radiation integrity in schizophrenia: A diffusion‐tensor imaging study. Psychiatry Res 183:144–150. PubMed PMC

Mandonnet E, Nouet A, Gatignol P, Capelle L, Duffau H (2007): Does the left inferior longitudinal fasciculus play a role in language? A brain stimulation study. Brain 130:623–629. PubMed

Masterman DL, Cummings JL (1997): Frontal‐subcortical circuits: The anatomic basis of executive, social and motivated behaviors. J Psychopharmacol 11:107–114. PubMed

McBurnett K, Pfiffner LJ, Frick PJ (2001): Symptom properties as a function of ADHD type: An argument for continued study of sluggish cognitive tempo. J Abnorm Child Psychol 29:207–213. PubMed

McLeod KR, Langevin LM, Goodyear BG, Dewey D (2014): Functional connectivity of neural motor networks is disrupted in children with developmental coordination disorder and attention‐deficit/hyperactivity disorder. Neuroimage Clin 4:566–575. PubMed PMC

Metin B, Krebs RM, Wiersema JR, Verguts T, Gasthuys R, van der Meere JJ, Achten E, Roeyers H, Sonuga‐Barke E (2015): Dysfunctional modulation of default mode network activity in attention‐deficit/hyperactivity disorder. J Abnorm Psychol 124:208–214. PubMed

Mori S, Zhang J (2006): Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron 51:527–539. PubMed

Mostofsky SH, Rimrodt SL, Schafer JG, Boyce A, Goldberg MC, Pekar JJ, Denckla MB (2006): Atypical motor and sensory cortex activation in attention‐deficit/hyperactivity disorder: A functional magnetic resonance imaging study of simple sequential finger tapping. Biol Psychiatry 59:48–56. PubMed

Nagel BJ, Bathula D, Herting M, Schmitt C, Kroenke CD, Fair D, Nigg JT (2011): Altered white matter microstructure in children with attention‐deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 50:283–292. PubMed PMC

Nestor PG, Kubicki M, Spencer KM, Niznikiewicz M, McCarley RW, Shenton ME (2007): Attentional networks and cingulum bundle in chronic schizophrenia. Schizophr Res 90:308–315. PubMed PMC

Nezamzadeh M, Wedeen VJ, Wang R, Zhang Y, Zhan W, Young K, Meyerhoff DJ, Weiner MW, Schuff N (2010): In‐vivo investigation of the human cingulum bundle using the optimization of MR diffusion spectrum imaging. Eur J Radiol 75:e29–e36. PubMed PMC

Nichols TE, Holmes AP (2002): Nonparametric permutation tests for functional neuroimaging: A primer with examples. Hum Brain Mapp 15:1–25. PubMed PMC

Oertel‐Knöchel V, Reinke B, Alves G, Jurcoane A, Wenzler S, Prvulovic D, Linden D, Knöchel C (2014): Frontal white matter alterations are associated with executive cognitive function in euthymic bipolar patients. J Affect Disord 155:223–233. PubMed

Oouchi H, Yamada K, Sakai K, Kizu O, Kubota T, Ito H, Nishimura T (2007): Diffusion anisotropy measurement of brain white matter is affected by voxel size: Underestimation occurs in areas with crossing fibers. AJNR Am J Neuroradiol 28:1102–1106. PubMed PMC

Peterson DJ, Ryan M, Rimrodt SL, Cutting LE, Denckla MB, Kaufmann WE, Mahone EM (2011): Increased regional fractional anisotropy in highly screened attention‐deficit hyperactivity disorder (ADHD). J Child Neurol 26:1296–1302. PubMed PMC

Pierpaoli C, Basser PJ (1996): Toward a quantitative assessment of diffusion anisotropy. Magn Reson Med 36:893–906. PubMed

Psychological Corporation (2002): Wechsler Individual Achievement Test II. San Antonio, TX: Psychological Corporation.

R Core Team (2013): R: A language and environment for statistical computing. Vienna, Austria: Foundation for Statistical Computing. ISBN 3‐900051‐07‐0.

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL (2001): A default mode of brain function. Proc Natl Acad Sci USA 98:676–682. PubMed PMC

Rossi AS, de Moura LM, de Mello CB, de Souza AA, Muszkat M, Bueno OF (2015): Attentional profiles and white matter correlates in attention‐deficit/hyperactivity disorder predominantly inattentive type. Front Psychiatry 6:122. PubMed PMC

Sagvolden T, Johansen EB, Aase H, Russell VA (2005): A dynamic developmental theory of attention‐deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci 28:397–419. Discussion 419–468. PubMed

Semrud‐Clikeman M, Fine JG, Bledsoe J, Zhu DC: Regional volumetric differences based on structural MRI in children with two subtypes of ADHD and controls. J Atten Disord (in press). PubMed

Shinoura N, Midorikawa A, Kurokawa K, Onodera T, Tsukada M, Yamada R, Tabei Y, Koizumi T, Yoshida M, Saito S, Yagi K (2011): Right temporal lobe plays a role in verbal memory. Neurol Res 33:734–738. PubMed

Silk TJ, Vance A, Rinehart N, Bradshaw JL, Cunnington R (2009): White‐matter abnormalities in attention deficit hyperactivity disorder: A diffusion tensor imaging study. Hum Brain Mapp 30:2757–2765. PubMed PMC

Smith SM, Nichols TE (2009): Threshold‐free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 44:83–98. PubMed

Smith SM, Jenkinson M, Johansen‐Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006): Tract‐based spatial statistics: Voxelwise analysis of multi‐subject diffusion data. Neuroimage 31:1487–1505. PubMed

Snook L, Paulson LA, Roy D, Phillips L, Beaulieu C (2005): Diffusion tensor imaging of neurodevelopment in children and young adults. Neuroimage 26:1164–1173. PubMed

Solanto MV, Schulz KP, Fan J, Tang CY, Newcorn JH (2009): Event‐related FMRI of inhibitory control in the predominantly inattentive and combined subtypes of ADHD. J Neuroimaging 19:205–212. PubMed PMC

Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH (2003): Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20:1714–1722. PubMed

Sowell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS (2003): Cortical abnormalities in children and adolescents with attention‐deficit hyperactivity disorder. Lancet 362:1699–1707. PubMed

Sullivan JR, Riccio CA (2007): Diagnostic group differences in parent and teacher ratings on the BRIEF and Conners' Scales. J Atten Disord 11:398–406. PubMed

Suskauer SJ, Simmonds DJ, Caffo BS, Denckla MB, Pekar JJ, Mostofsky SH (2008): fMRI of intrasubject variability in ADHD: Anomalous premotor activity with prefrontal compensation. J Am Acad Child Adolesc Psychiatry 47:1141–1150. PubMed PMC

Tamm L, Barnea‐Goraly N, Reiss AL (2012): Diffusion tensor imaging reveals white matter abnormalities in Attention‐Deficit/Hyperactivity Disorder. Psychiatry Res 202:150–154. PubMed PMC

Tuch DS, Salat DH, Wisco JJ, Zaleta AK, Hevelone ND, Rosas HD (2005): Choice reaction time performance correlates with diffusion anisotropy in white matter pathways supporting visuospatial attention. Proc Natl Acad Sci USA 102:12212–12217. PubMed PMC

van den Heuvel M, Mandl R, Luigjes J, Hulshoff Pol H (2008): Microstructural organization of the cingulum tract and the level of default mode functional connectivity. J Neurosci 28:10844–10851. PubMed PMC

van den Heuvel M, Mandl R, Kahn R, Pol H (2009): Functionally linked resting‐state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp 30:3127–3141. PubMed PMC

van den Heuvel MP, de Reus MA, Feldman Barrett L, Scholtens LH, Coopmans FM, Schmidt R, Preuss TM, Rilling JK, Li L (2015): Comparison of diffusion tractography and tract‐tracing measures of connectivity strength in rhesus macaque connectome. Hum Brain Mapp 36:3064–3075. PubMed PMC

Van der Elst W, Van Boxtel MP, Van Breukelen GJ, Jolles J (2006): The Stroop color‐word test: Influence of age, sex, and education; and normative data for a large sample across the adult age range. Assessment 13:62–79. PubMed

Wagner G, Koch K, Schachtzabel C, Schultz CC, Gaser C, Reichenbach JR, Sauer H, Bär KJ, Schlösser RG (2013): Structural basis of the fronto‐thalamic dysconnectivity in schizophrenia: A combined DCM‐VBM study. Neuroimage Clin 3:95–105. PubMed PMC

Wakana S, Caprihan A, Panzenboeck MM, Fallon JH, Perry M, Gollub RL, Hua K, Zhang J, Jiang H, Dubey P, Blitz A, van Zijl P, Mori S (2007): Reproducibility of quantitative tractography methods applied to cerebral white matter. Neuroimage 36:630–644. PubMed PMC

Wolf D, Zschutschke L, Scheurich A, Schmitz F, Lieb K, Tüscher O, Fellgiebel A (2014): Age‐related increases in stroop interference: Delineation of general slowing based on behavioral and white matter analyses. Hum Brain Mapp 35:2448–2458. PubMed PMC

Wright NF, Vann SD, Aggleton JP, Nelson AJ (2015): A critical role for the anterior thalamus in directing attention to task‐relevant stimuli. J Neurosci 35:5480–5488. PubMed PMC

Yurgelun‐Todd DA, Silveri MM, Gruber SA, Rohan ML, Pimentel PJ (2007): White matter abnormalities observed in bipolar disorder: A diffusion tensor imaging study. Bipolar Disord 9:504–512. PubMed

Zemmoura I, Herbet G, Moritz‐Gasser S, Duffau H (2015): New insights into the neural network mediating reading processes provided by cortico‐subcortical electrical mapping. Hum Brain Mapp 36:2215–2230. PubMed PMC