Skip to main content Accessibility help

White matter microstructure of the extended limbic system in male and female youth with conduct disorder

  • Karen González-Madruga (a1), Jack Rogers (a2), Nicola Toschi (a3), Roberta Riccelli (a1), Areti Smaragdi (a4), Ignazio Puzzo (a5), Roberta Clanton (a2), Jesper Andersson (a6), Sarah Baumann (a7), Gregor Kohls (a7), Nora Raschle (a8), Lynn Fehlbaum (a8), Willeke Menks (a8), Christina Stadler (a8), Kerstin Konrad (a7), Christine M. Freitag (a9), Stephane A. De Brito (a2), Edmund Sonuga-Barke (a10) and Graeme Fairchild (a11)...



Previous studies of conduct disorder (CD) have reported structural and functional alterations in the limbic system. However, the white matter tracts that connect limbic regions have not been comprehensively studied. The uncinate fasciculus (UF), a tract connecting limbic to prefrontal regions, has been implicated in CD. However, CD-related alterations in other limbic tracts, such as the cingulum and the fornix, have not been investigated. Furthermore, few studies have examined the influence of sex and none have been adequately powered to test whether the relationship between CD and structural connectivity differs by sex. We examined whether adolescent males and females with CD exhibit differences in structural connectivity compared with typically developing controls.


We acquired diffusion-weighted magnetic resonance imaging data from 101 adolescents with CD (52 females) and 99 controls (50 females). Data were processed for deterministic spherical deconvolution tractography. Virtual dissections of the UF, the three subdivisions of the cingulum [retrosplenial cingulum (RSC), parahippocampal and subgenual cingulum], and the fornix were performed and measures of fractional anisotropy (FA) and hindrance-modulated orientational anisotropy (HMOA) were analysed.


The CD group had lower FA and HMOA in the right RSC tract relative to controls. Importantly, these effects were moderated by sex – males with CD significantly lower FA compared to male controls, whereas CD and control females did not differ.


Our results highlight the importance of considering sex when studying the neurobiological basis of CD. Sex differences in RSC connectivity may contribute to sex differences in the clinical presentation of CD.


Corresponding author

Author for correspondence: Karen González-Madruga, E-mail:


Hide All
Alegria, AA, Radua, J and Rubia, K (2016) Meta-analysis of fMRI studies of disruptive behavior disorders. American Journal of Psychiatry 173, 11191130.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: Washington, DC: American Psychiatric Publishing.
Andershed, HA, Kerr, M, Stattin, H and Levander, S (2002) E. Blaauw and L. Sheridan (eds.) Psychopathic traits in non-referred youths: initial test of a new assessment tool. Psychopaths: Current International Perspectives, 131158. Hague, Netherlands, Elsevier.
Andersson, JLR and Sotiropoulos, SN (2016) An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. NeuroImage 125, 10631078.
Andersson, JLR, Graham, MS, Zsoldos, E and Sotiropoulos, SN (2016) Incorporating outlier detection and replacement into a non-parametric framework for movement and distortion correction of diffusion MR images. NeuroImage 141, 556572.
Aoki, Y, Inokuchi, R, Nakao, T and Yamasue, H (2014) Neural bases of antisocial behavior: a voxel-based meta-analysis. Social Cognitive and Affective Neuroscience 9, 12231231.
Asato, MR, Terwilliger, R, Woo, J and Luna, B (2010) White matter development in adolescence: a DTI study. Cerebral Cortex 20, 21222131.
Auriat, AM, Borich, MR, Snow, NJ, Wadden, KP and Boyd, LA (2015) Comparing a diffusion tensor and non-tensor approach to white matter fiber tractography in chronic stroke. NeuroImage: Clinical 7, 771781.
Barkley, RA, Fischer, M, Smallish, L and Fletcher, K (2004) Young adult follow-up of hyperactive children: antisocial activities and drug use. Journal of Child Psychology and Psychiatry, and Allied Disciplines 45, 195211. Available at
Basser, PJ, Pajevic, S, Pierpaoli, C, Duda, J and Aldroubi, A (2000) In vivo fiber tractography using DT-MRI data. Magnetic Resonance in Medicine 632, 625632.
Blair, RJ (2008) The amygdala and ventromedial prefrontal cortex: functional contributions and dysfunction in psychopathy. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 363, 25572565.
Broulidakis, MJ, Fairchild, G, Sully, K, Blumensath, T, Darekar, A and Sonuga-Barke, EJS (2016) Reduced default mode connectivity in adolescents with conduct disorder. Journal of the American Academy of Child & Adolescent Psychiatry 55, 800808.
Casey, BJ, Jones, RM and Hare, TA (2008) The adolescent brain. Annals of the New York Academy of Sciences 1124, 111126.
Catani, M and Thiebaut De Schotten, M (2012) Atlas of Human Brain Connections. Oxford University Press. Available at
Catani, M, Dell’ Acqua, F and Thiebaut De Schotten, M (2013) Neuroscience and biobehavioral reviews a revised limbic system model for memory, emotion and behaviour. Neuroscience and Biobehavioral Reviews 37, 17241737.
Craig, MC, Catani, M, Deeley, Q, Latham, R, Daly, E, Kanaan, R and Murphy, DGM (2009) Altered connections on the road to psychopathy. Molecular Psychiatry 14, 946953, 907.
Christiansen, K, Aggleton, JP, Parker, GD, O'Sullivan, MJ, Vann, SD and Metzler-Baddeley, C (2016) The status of the precommissural and postcommissural fornix in normal ageing and mild cognitive impairment: An MRI tractography study. NeuroImage 130, 3547.
Decety, J, Yoder, KJ and Lahey, BB (2015) Sex differences in abnormal white matter development associated with conduct disorder in children. Psychiatry Research – Neuroimaging 233, 269277.
Dell'Acqua, F, Scifo, P, Rizzo, G, Catani, M, Simmons, A, Scotti, G and Fazio, F (2010) A modified damped Richardson–Lucy algorithm to reduce isotropic background effects in spherical deconvolution. NeuroImage 49, 14461458.
Dell'Acqua, F, Simmons, A, Williams, SCR and Catani, M (2013) Can spherical deconvolution provide more information than fiber orientations? Hindrance modulated orientational anisotropy, a true-tract specific index to characterize white matter diffusion. Human Brain Mapping 34, 24642483.
Dunst, B, Benedek, M, Koschutnig, K, Jauk, E and Neubauer, AC (2014) Sex differences in the IQ-white matter microstructure relationship: a DTI study. Brain and Cognition 91, 7178.
Essau, CA, Sasagawa, S and Frick, PJ (2006) Callous-unemotional traits in a community sample of adolescents. Assessment 13, 454469.
Fairchild, G, Hagan, CC, Walsh, ND, Passamonti, L, Calder, AJ and Goodyer, IM (2013) Brain structure abnormalities in adolescent girls with conduct disorder. Journal of Child Psychology and Psychiatry and Allied Disciplines 54, 8695.
Fairchild, G, Toschi, N, Hagan, CC, Goodyer, IM, Calder, AJ and Passamonti, L (2015) Cortical thickness, surface area, and folding alterations in male youths with conduct disorder and varying levels of callous-unemotional traits. NeuroImage: Clinical 8, 253260.
Finger, EC, Marsh, A, Blair, KS, Majestic, C, Evangelou, I, Gupta, K and Blair, RJ (2012) Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits. Psychiatry Research 202, 239244.
Haney-Caron, E, Caprihan, A and Stevens, MC (2014) DTI-measured white matter abnormalities in adolescents with conduct disorder. Journal of Psychiatric Research 48, 111120.
Harsan, LA, Poulet, P, Guignard, B, Steibel, J, Parizel, N, de Sousa, PL and Ghandour, MS (2006) Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging. Journal of Neuroscience Research 83, 392402.
Herpertz, SC, Huebner, T, Marx, I, Vloet, TD, Fink, GR, Stoecker, T and Herpertz-Dahlmann, B (2008) Emotional processing in male adolescents with childhood-onset conduct disorder. Journal of Child Psychology and Psychiatry 49, 781791.
Jones, DK, Christiansen, KF, Chapman, RJ and Aggleton, JP (2013) Distinct subdivisions of the cingulum bundle revealed by diffusion MRI fibre tracking: implications for neuropsychological investigations. Neuropsychologia 51, 6778.
Kaufman, J, Birmaher, B, Perel, J, Dahl, RE, Moreci, P, Nelson, B, … Ryan, ND (1997) The corticotropin-releasing hormone challenge in depressed abused, depressed nonabused, and normal control children. Biological Psychiatry 42, 669679.
Leech, R, Braga, R and Sharp, DJ (2012) Echoes of the brain within the posterior cingulate cortex. Journal of Neuroscience 32, 215222.
Menks, WM, Furger, R, Lenz, C, Fehlbaum, LV, Stadler, C and Raschle, NM (2017) Microstructural white matter alterations in the corpus callosum of girls with conduct disorder. Journal of the American Academy of Child & Adolescent Psychiatry 56, 258265. e1.
Passamonti, L, Fairchild, G, Fornito, A, Goodyer, IM, Nimmo-Smith, I, Hagan, CC and Calder, AJ (2012) Abnormal anatomical connectivity between the amygdala and orbitofrontal cortex in conduct disorder. PLoS ONE 7, e48789.
Puzzo, I, Seunarine, K, Sully, K, Darekar, A, Clark, C, Sonuga-Barke, EJS and Fairchild, G (2018) Altered white-matter microstructure in conduct disorder is specifically associated with elevated callous-unemotional traits. Journal of Abnormal Child Psychology 46, 14511466.
Raffelt, DA, Smith, RE, Ridgway, GR, Tournier, J-D, Vaughan, DN, Rose, S and Connelly, A (2015) Connectivity-based fixel enhancement: whole-brain statistical analysis of diffusion MRI measures in the presence of crossing fibres. NeuroImage 117, 4055.
Raschle, NM, Menks, WM, Fehlbaum, LV, Tshomba, E and Stadler, C (2015) Structural and functional alterations in right dorsomedial prefrontal and left insular cortex co-localize in adolescents with aggressive behaviour: an ALE meta-analysis. PLoS ONE 10, 124.
Rogers, JC and De Brito, SA (2016) Cortical and subcortical gray matter volume in youths with conduct problems. JAMA Psychiatry 73, 64.
Rolls, ET (2004) The functions of the orbitofrontal cortex. Brain and Cognition 55, 1129.
Rolls, ET (2015) Limbic systems for emotion and for memory, but no single limbic system. Cortex 62, 119157.
Rojkova, K, Volle, E, Urbanski, M, Humbert, F, Dell'Acqua, F, Thiebaut de Schotten, M (2016) Atlasing the frontal lobe connections and their variability due to age and education: a spherical deconvolution tractography study. Brain and Cognition 221, 17511766.
Sarkar, S, Craig, MC, Catani, M, Dell ’Acqua, F, Fahy, T, Deeley, Q and Murphy, DGM (2013) Frontotemporal white-matter microstructural abnormalities in adolescents with conduct disorder: a diffusion tensor imaging study. Psychological Medicine 43, 401411.
Sethi, A, Gregory, S, Dell'Acqua, F, Periche Thomas, E, Simmons, A, Murphy, DGM and Craig, MC (2015) Emotional detachment in psychopathy: involvement of dorsal default-mode connections. Cortex 62, 1119.
Sethi, A, Sarkar, S, Dell'Acqua, F, Viding, E, Catani, M, Murphy, DGM and Craig, MC (2018) Anatomy of the dorsal default-mode network in conduct disorder: association with callous-unemotional traits. Developmental Cognitive Neuroscience 30, 8792.
Sidlauskaite, J, González-Madruga, K, Smaragdi, A, Riccelli, R, Puzzo, I, Batchelor, M and Fairchild, G (2018) Sex differences in risk-based decision making in adolescents with conduct disorder. European Child and Adolescent Psychiatry 27, 11331142.
Simmonds, DJ, Hallquist, MN, Asato, M and Luna, B (2014) Developmental stages and sex differences of white matter and behavioral development through adolescence: A longitudinal diffusion tensor imaging (DTI) study. NeuroImage 92, 356368.
Smaragdi, A, Cornwell, H, Toschi, N, Riccelli, R, Gonzalez-Madruga, K, Wells, A and Fairchild, G (2017) Sex differences in the relationship between conduct disorder and cortical structure in adolescents. Journal of the American Academy of Child and Adolescent Psychiatry 56, 703712.
Stieltjes, B, Brunner, RM, Fritzsche, KH and Laun, FB (2013) Diffusion Tensor Imaging. Berlin, Heidelberg: Springer Berlin Heidelberg.
Van Casteren, M and Davis, MH (2007) Match: a program to assist in matching the conditions of factorial experiments. Behavior Research Methods 39, 973978.
Vanderauwera, J, Vandermosten, M, Dell'Acqua, F, Wouters, J and Ghesquière, P (2015) Disentangling the relation between left temporoparietal white matter and reading: a spherical deconvolution tractography study. Human Brain Mapping 36, 32733287.
Wang, Y, Horst, KK, Kronenberger, WG, Hummer, TA, Mosier, KM, Kalnin, AJ and Mathews, VP (2012) White matter abnormalities associated with disruptive behavior disorder in adolescents with and without attention-deficit/hyperactivity disorder. Psychiatry Research – Neuroimaging 202, 245251.
Wechsler, D (1999) Wechsler Abbreviated Scale of Intelligence (WASI). Psychological Corporation, 1.
Wechsler, D (2003) Wechsler Intelligence Scale for Children–Fourth Edition (WISC-IV). NCS Pearson, 4.
White, SF, Clanton, R, Brislin, SJ, Meffert, H, Hwang, S, Sinclair, S and Blair, RJ (2014) Reward: empirical contribution. Temporal discounting and conduct disorder in adolescents. Journal of Personality Disorders 28, 518.
Zhang, J, Gao, J, Shi, H, Huang, B, Wang, X, Situ, W and Yao, S (2014) Sex differences of uncinate fasciculus structural connectivity in individuals with conduct disorder. BioMed Research International 14, 9.
Zhou, J, Yao, N, Fairchild, G, Cao, X, Zhang, Y, Xiang, Y-T and Wang, X (2016) Disrupted default mode network connectivity in male adolescents with conduct disorder. Brain Imaging and Behavior 10, 9951003.


Related content

Powered by UNSILO
Type Description Title
Supplementary materials

González-Madruga et al. supplementary material
González-Madruga et al. supplementary material

 Word (232 KB)
232 KB

White matter microstructure of the extended limbic system in male and female youth with conduct disorder

  • Karen González-Madruga (a1), Jack Rogers (a2), Nicola Toschi (a3), Roberta Riccelli (a1), Areti Smaragdi (a4), Ignazio Puzzo (a5), Roberta Clanton (a2), Jesper Andersson (a6), Sarah Baumann (a7), Gregor Kohls (a7), Nora Raschle (a8), Lynn Fehlbaum (a8), Willeke Menks (a8), Christina Stadler (a8), Kerstin Konrad (a7), Christine M. Freitag (a9), Stephane A. De Brito (a2), Edmund Sonuga-Barke (a10) and Graeme Fairchild (a11)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.