Abstract
Schizophrenia is associated with frontostriatal network impairments underlying clinical and cognitive symptoms. We previously found disruptions in anatomical pathways, including the tract connecting the left nucleus accumbens and left dorsolateral prefrontal cortex (DLPFC). Similar deficits are observed in unaffected siblings of schizophrenia patients, indicating that these deficits are linked to a genetic vulnerability for the disorder. Frontostriatal tract disruptions may arise during adolescence, preceding the clinical manifestation of the disorder. However, to date, no studies have been performed to investigate frontostriatal tract connections in adolescents who are at increased familial risk for schizophrenia. In this study, we investigate the impact of familial risk on frontostriatal tract connections using diffusion tensor imaging in 27 adolescent offspring of schizophrenia patients and 32 matched control adolescents, aged 10–18 years. Mean fractional anisotropy (FA) was calculated for the tracts connecting the striatum (caudate nucleus, putamen, nucleus accumbens) and frontal cortex regions (DLPFC, medial orbital frontal cortex, inferior frontal gyrus). As expected, based on siblings data, we found an impact of familial risk on frontostriatal development: schizophrenia offspring showed increased FA in the tracts connecting nucleus accumbens and DLPFC as compared with control adolescents. Moreover, while FA increased across age in control adolescents, it did not in schizophrenia offspring. We did not find differences in FA in other frontostriatal tracts. These results indicate altered development of white matter in subjects who are at familial risk for schizophrenia and may precede frontostriatal white matter alterations in adult schizophrenia patients and siblings.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Andersson JLR, Skare S (2002). A model-based method for retrospective correction of geometric distortions in diffusion-weighted EPI. Neuroimage 16: 177–199.
Andersson JLR, Skare S, Ashburner J (2003). How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging. Neuroimage 20: 870–888.
Basser PJ, Pierpaoli C (1996). Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 111: 209–219.
Beaulieu C (2002). The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed 15: 435–455.
Bohlken MM, Brouwer RM, Mandl RCW, Heuvel MP, Van den, Hedman AM, De Hert M et al (2016). Structural brain connectivity as a genetic marker for schizophrenia. JAMA Psychiatry 73: 11–19.
Bracht T, Horn H, Strik W, Federspiel A, Razavi N, Stegmayer K et al (2014). White matter pathway organization of the reward system is related to positive and negative symptoms in schizophrenia. Schizophr Res 153: 136–142.
Casey BJ, Jones RM, Hare TA (2008). The adolescent brain. Ann NY Acad Sci 1124: 111–126.
Dougherty MK, Gu H, Bizzell J, Ramsey S, Gerig G, Perkins DO et al (2012). Differences in subcortical structures in young adolescents at familial risk for schizophrenia: a preliminary study. Psychiatry Res 204: 68–74.
Emsley R, Asmal L, Plessis S du, Chiliza B, Kidd M, Carr J et al (2015). Dorsal striatal volumes in never-treated patients with first-episode schizophrenia before and during acute treatment. Schizophr Res 169: 89–94.
First M (1997) User’s Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders—Clinical Version (CV). American Psychiatric Press: Washington, DC.
Fischl B, Salat DH, Kouwe AJW van der, Makris N, Ségonne F, Quinn BT et al (2004). Sequence-independent segmentation of magnetic resonance images. Neuroimage 23 (Suppl 1): S69–S84.
Giorgio A, Watkins KE, Douaud G, James AC, James S, De Stefano N et al (2008). Changes in white matter microstructure during adolescence. Neuroimage 39: 52–61.
Goghari VM, Sponheim SR, MacDonald AW (2010). The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neurosci Biobehav Rev 34: 468–486.
Grimm O, Heinz A, Walter H, Kirsch P, Erk S, Haddad L et al (2014). Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia. JAMA Psychiatry 71: 531–539.
Harms MP, Wang L, Campanella C, Aldridge K, Moffitt AJ, Kuelper J et al (2010). Structural abnormalities in gyri of the prefrontal cortex in individuals with schizophrenia and their unaffected siblings. Br J Psychiatry 196: 150–157.
Hoogendam JM, Kahn RS, Hillegers MHJ, Buuren M, van, Vink M (2013). Different developmental trajectories for anticipation and receipt of reward during adolescence. Dev Cogn Neurosci 6: 113–124.
Howes OD, Kapur S (2009). The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35: 549–562.
Jeurissen B, Leemans A, Tournier J-D, Jones DK, Sijbers J (2013). Investigating the prevalence of complex fiber configurations in white matter tissue with diffusion magnetic resonance imaging. Hum Brain Mapp 34: 2747–2766.
Kaufman J, Birmaher B, Brent DA, Ryan ND, Rao U (2000). K-SADS-PL. J Am Acad Child Adolesc Psychiatry 39: 1208.
Kikinis Z, Fallon JH, Niznikiewicz M, Nestor P, Davidson C, Bobrow L et al (2010). Gray matter volume reduction in rostral middle frontal gyrus in patients with chronic schizophrenia. Schizophr Res 123: 153–159.
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.
de Leeuw M, Bohlken MM, Mandl RCW, Kahn RS, Vink M (2015a). Reduced fronto-striatal white matter integrity in schizophrenia patients and unaffected siblings: a DTI study. NPJ Schizophr 1: 15001.
de Leeuw M, Kahn RS, Vink M (2015b). Fronto-striatal dysfunction during reward processing in unaffected siblings of schizophrenia patients. Schizophr Bull 41: 94–103.
de Leeuw M, Kahn RS, Zandbelt BB, Widschwendter CG, Vink M (2013). Working memory and default mode network abnormalities in unaffected siblings of schizophrenia patients. Schizophr Res 150: 555–562.
Mandl RCW, Schnack HG, Luigjes J, Heuvel MP van den, Cahn W, Kahn RS et al (2010). Tract-based analysis of magnetization transfer ratio and diffusion tensor imaging of the frontal and frontotemporal connections in schizophrenia. Schizophr Bull 36: 778–787.
McClure SM, Laibson DI, Loewenstein G, Cohen JD (2004). Separate neural systems value immediate and delayed monetary rewards. Science 306: 503–507.
Morris RW, Vercammen A, Lenroot R, Moore L, Langton JM, Short B et al (2012). Disambiguating ventral striatum fMRI-related BOLD signal during reward prediction in schizophrenia. Mol Psychiatry 17: 280–289.
Nielsen MØ, Rostrup E, Wulff S, Bak N, Lublin H, Kapur S et al (2012). Alterations of the brain reward system in antipsychotic naïve schizophrenia patients. Biol Psychiatry 71: 898–905.
Nienhuis FJ, Van De Willige G, Rijnders CAT, De Jonge P, Wiersma D (2010). Validity of a short clinical interview for psychiatric diagnosis: the mini-SCAN. Br J Psychiatry 196: 64–68.
O’Hanlon E, Leemans A, Kelleher I, Clarke MC, Roddy S, Coughlan H et al (2015). White matter differences among adolescents reporting psychotic experiences: a population-based diffusion magnetic resonance imaging study. JAMA Psychiatry 72: 668–677.
Paus T, Keshavan M, Giedd JN (2008). Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci 9: 947–957.
Peper JS, Mandl RCW, Braams BR, De Water E, Heijboer AC, PCMP Koolschijn et al (2013). Delay discounting and frontostriatal fiber tracts: a combined DTI and MTR study on impulsive choices in healthy young adults. Cereb Cortex 23: 1695–1702.
Peters BD, Szeszko PR, Radua J, Ikuta T, Gruner P, Derosse P et al (2012). White matter development in adolescence: diffusion tensor imaging and meta-analytic results. Schizophr Bull 38: 1308–1317.
Prata DP, Mechelli A, Picchioni MM, Fu CHY, Toulopoulou T, Bramon E et al (2009). Altered effect of dopamine transporter 3′UTR VNTR genotype on prefrontal and striatal function in schizophrenia. Arch Gen Psychiatry 66: 1162–1172.
Quan M, Lee S-H, Kubicki M, Kikinis Z, Rathi Y, Seidman LJ et al (2013). White matter tract abnormalities between rostral middle frontal gyrus, inferior frontal gyrus and striatum in first-episode schizophrenia. Schizophr Res 145: 1–10.
Raemaekers M, Ramsey NF, Vink M, van den Heuvel MP, Kahn RS (2006). Brain activation during antisaccades in unaffected relatives of schizophrenic patients. Biol Psychiatry 59: 530–535.
Rapoport JL, Giedd JN, Gogtay N (2012). Neurodevelopmental model of schizophrenia: update 2012. Mol Psychiatry 2012: 1–11.
Rasic D, Hajek T, Alda M, Uher R (2014). Risk of mental illness in offspring of parents with schizophrenia, bipolar disorder, and major depressive disorder: a meta-analysis of family high-risk studies. Schizophr Bull 40: 28–38.
Sesack SR, Grace AA (2010). Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35: 27–47.
Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al (2006). Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31: 1487–1505.
Veelen NMJ, van Vink M, Ramsey NF, Buuren M van, Hoogendam JM, Kahn RS (2011). Prefrontal lobe dysfunction predicts treatment response in medication-naive first-episode schizophrenia. Schizophr Res 129: 156–162.
Veelen NMJ, van Vink M, Ramsey NF, Kahn RS (2010). Left dorsolateral prefrontal cortex dysfunction in medication-naive schizophrenia. Schizophr Res 123: 22–29.
Vink M, Derks JM, Hoogendam JM, Hillegers M, Kahn RS (2014a). Functional differences in emotion processing during adolescence and early adulthood. Neuroimage 91: 70–76.
Vink M, de Leeuw M, Luykx JJ, van Eijk KR, van den Munkhof HE, van Buuren M et al (2016a). DRD2 schizophrenia-risk allele is associated with impaired striatal functioning in unaffected siblings of schizophrenia patients. Schizophr Bull 42: 843–850.
Vink M, de Leeuw M, Pouwels R, van den Munkhof HE, Kahn RS, Hillegers M (2016b). Diminishing striatal activation across adolescent development during reward anticipation in offspring of schizophrenia patients. Schizophr Res 170: 73–79.
Vink M, Ramsey NF, Raemaekers M, Kahn RS (2006). Striatal dysfunction in schizophrenia and unaffected relatives. Biol Psychiatry 60: 32–39.
Vink M, Zandbelt BB, Gladwin T, Hillegers M, Hoogendam JM, Wildenberg WPM van den et al (2014b). Frontostriatal activity and connectivity increase during proactive inhibition across adolescence and early adulthood. Hum Brain Mapp 35: 4415–4427.
Yung AR, Phillips LJ, McGorry PD, McFarlane CA, Francey S, Harrigan S et al (1998). Prediction of psychosis. A step towards indicated prevention of schizophrenia. Br J Psychiatry Suppl 172: 14–20.
Zandbelt BB, Buuren M, van, Kahn RS, Vink M (2011). Reduced proactive inhibition in schizophrenia is related to corticostriatal dysfunction and poor working memory. Biol Psychiatry 70: 1151–1158.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Supplementary information
Rights and permissions
About this article
Cite this article
de Leeuw, M., Bohlken, M., Mandl, R. et al. Changes in White Matter Organization in Adolescent Offspring of Schizophrenia Patients. Neuropsychopharmacol 42, 495–501 (2017). https://doi.org/10.1038/npp.2016.130
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2016.130
This article is cited by
-
Polygenic risk for schizophrenia is associated with white matter microstructure, cognitive and mental health
Schizophrenia (2025)
-
Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia
Translational Psychiatry (2025)
-
Long-term neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics: a systematic review and meta-analysis
European Child & Adolescent Psychiatry (2018)
