J Korean Med Sci.  2010 Dec;25(12):1700-1709. 10.3346/jkms.2010.25.12.1700.

Structural Brain Alterations in Individuals at Ultra-high Risk for Psychosis: A Review of Magnetic Resonance Imaging Studies and Future Directions

• Jung WH
• Jang JH
• Byun MS
• An SK
• Kwon JS

• KMID: 1792891
• DOI: http://doi.org/10.3346/jkms.2010.25.12.1700

Abstract

Individuals at ultra-high-risk (UHR) for psychosis have become a major focus for research designed to explore markers for early detection of and clinical intervention in schizophrenia. In particular, structural magnetic resonance imaging studies in UHR individuals have provided important insight into the neurobiological basis of psychosis and have shown the brain changes associated with clinical risk factors. In this review, we describe the structural brain abnormalities in magnetic resonance images in UHR individuals. The current accumulated data demonstrate that abnormalities in the prefrontal and temporal cortex and anterior cingulate cortex occur before illness onset. These regions are compatible with the regions of structural deficits found in schizophrenia and first-episode patients. In addition, the burgeoning evidence suggests that such structural abnormalities are potential markers for the transition to psychosis. However, most findings to date are limited because they are from cross-sectional rather than longitudinal studies. Recently, researchers have emphasized neurodevelopmental considerations with respect to brain structural alterations in UHR individuals. Future studies should be conducted to characterize the differences in the brain developmental trajectory between UHR individuals and healthy controls using a longitudinal design. These new studies should contribute to early detection and management as well as provide more predictive markers of later psychosis.

Keyword

Schizophrenia; Ultra-high-risk; Magnetic Resonance Imaging; Psychotic Disorders; Neurodevelopment; Predictive Marker

MeSH Terms

Brain/abnormalities/*pathology
Gyrus Cinguli/pathology
Humans
Longitudinal Studies
*Magnetic Resonance Imaging
Predictive Value of Tests
Psychotic Disorders/diagnosis/*pathology
Risk Factors
Temporal Lobe/pathology

Reference

1. Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res. 2001. 49:1–52.

2. Fornito A, Yucel M, Patti J, Wood SJ, Pantelis C. Mapping grey matter reductions in schizophrenia: an anatomical likelihood estimation analysis of voxel-based morphometry studies. Schizophr Res. 2009. 108:104–113.

3. Cannon TD. Clinical and genetic high-risk strategies in understanding vulnerability to psychosis. Schizophr Res. 2005. 79:35–44.

4. Wood SJ, Pantelis C, Velakoulis D, Yucel M, Fornito A, McGorry PD. Progressive changes in the development toward schizophrenia: studies in subjects at increased symptomatic risk. Schizophr Bull. 2008. 34:322–329.

5. Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue EW, McGuire PK, Riecher-Rössler A, Borgwardt SJ. Neuroimaging predictors of transition to psychosis-A systematic review and metaanalysis. Neurosci Biobehav Rev. 2010. 34:1207–1222.

6. Pantelis C, Yucel M, Bora E, Fornito A, Testa R, Brewer WJ, Velakoulis D, Wood SJ. Neurobiological markers of illness onset in psychosis and schizophrenia: the search for a moving target. Neuropsychol Rev. 2009. 19:385–398.

7. Buehlmann E, Berger GE, Aston J, Gschwandtner U, Pflueger MO, Borgwardt SJ, Radue EW, Riecher-Rössler A. Hippocampus abnormalities in at risk mental states for psychosis? A cross-sectional high resolution region of interest magnetic resonance imaging study. J Psychiatr Res. 2010. 44:447–453.

8. Wood SJ, Kennedy D, Phillips LJ, Seal ML, Yucel M, Nelson B, Yung AR, Jackson G, McGorry PD, Velakoulis D, Pantelis C. Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study. Neuroimage. 2010. 52:62–68.

9. Wood SJ, Yucel M, Velakoulis D, Phillips LJ, Yung AR, Brewer W, McGorry PD, Pantelis C. Hippocampal and anterior cingulate morphology in subjects at ultra-high-risk for psychosis: the role of family history of psychotic illness. Schizophr Res. 2005. 75:295–301.

10. Velakoulis D, Wood SJ, Wong MT, McGorry PD, Yung A, Phillips L, Smith D, Brewer W, Proffitt T, Desmond P, Pantelis C. Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry. 2006. 63:139–149.

11. Meisenzahl EM, Koutsouleris N, Bottlender R, Scheuerecker J, Jager M, Teipel SJ, Holzinger S, Frodl T, Preuss U, Schmitt G, Burgermeister B, Reiser M, Born C, Moller HJ. Structural brain alterations at different stages of schizophrenia: a voxel-based morphometric study. Schizophr Res. 2008. 104:44–60.

12. Borgwardt SJ, Riecher-Rössler A, Dazzan P, Chitnis X, Aston J, Drewe M, Gschwandtner U, Haller S, Pfluger M, Rechsteiner E, D'Souza M, Stieglitz RD, Radü EW, McGuire PK. Regional gray matter volume abnormalities in the at risk mental state. Biol Psychiatry. 2007. 61:1148–1156.

13. Meisenzahl EM, Koutsouleris N, Gaser C, Bottlender R, Schmitt GJ, McGuire P, Decker P, Burgermeister B, Born C, Reiser M, Möller HJ. Structural brain alterations in subjects at high-risk of psychosis: a voxel-based morphometric study. Schizophr Res. 2008. 102:150–162.

14. Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biol Psychiatry. 2006. 59:863–871.

15. Brewer WJ, Francey SM, Wood SJ, Jackson HJ, Pantelis C, Phillips LJ, Yung AR, Anderson VA, McGorry PD. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am J Psychiatry. 2005. 162:71–78.

16. Pukrop R, Ruhrmann S, Schultze-Lutter F, Bechdolf A, Brockhaus-Dumke A, Klosterkötter J. Neurocognitive indicators for a conversion to psychosis: comparison of patients in a potentially initial prodromal state who did or did not convert to a psychosis. Schizophr Res. 2007. 92:116–125.

17. Hurlemann R, Jessen F, Wagner M, Frommann I, Ruhrmann S, Brockhaus A, Picker H, Scheef L, Block W, Schild HH, Moller-Hartmann W, Krug B, Falkai P, Klosterkotter J, Maier W. Interrelated neuropsychological and anatomical evidence of hippocampal pathology in the at-risk mental state. Psychol Med. 2008. 38:843–851.

18. Phillips LJ, Velakoulis D, Pantelis C, Wood S, Yuen HP, Yung AR, Desmond P, Brewer W, McGorry PD. Non-reduction in hippocampal volume is associated with higher risk of psychosis. Schizophr Res. 2002. 58:145–158.

19. Witthaus H, Mendes U, Brüne M, Ozgürdal S, Bohner G, Gudlowski Y, Kalus P, Andreasen N, Heinz A, Klingebiel R, Juckel G. Hippocampal subdivision and amygdalar volumes in patients in an at-risk mental state for schizophrenia. J Psychiatry Neurosci. 2010. 35:33–40.

20. Stone JM, Day F, Tsagaraki H, Valli I, McLean MA, Lythgoe DJ, O'Gorman RL, Barker GJ, McGuire PK. OASIS. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry. 2009. 66:533–539.

21. Wood SJ, Berger G, Velakoulis D, Phillips LJ, McGorry PD, Yung AR, Desmond P, Pantelis C. Proton magnetic resonance spectroscopy in first episode psychosis and ultra high-risk individuals. Schizophr Bull. 2003. 29:831–843.

22. Kwon JS, McCarley RW, Hirayasu Y, Anderson JE, Fischer IA, Kikinis R, Jolesz FA, Shenton ME. Left planum temporale volume reduction in schizophrenia. Arch Gen Psychiatry. 1999. 56:142–148.

23. Sun J, Maller JJ, Guo L, Fitzgerald PB. Superior temporal gyrus volume change in schizophrenia: a review on region of interest volumetric studies. Brain Res Rev. 2009. 61:14–32.

24. Takahashi T, Wood SJ, Yung AR, Soulsby B, McGorry PD, Suzuki M, Kawasaki Y, Phillips LJ, Velakoulis D, Pantelis C. Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis. Arch Gen Psychiatry. 2009. 66:366–376.

25. Takahashi T, Wood SJ, Yung AR, Walterfang M, Phillips LJ, Soulsby B, Kawasaki Y, McGorry PD, Suzuki M, Velakoulis D, Pantelis C. Superior temporal gyrus volume in antipsychotic-naive people at risk of psychosis. Br J Psychiatry. 2010. 196:206–211.

26. Hirayasu Y, Shenton ME, Salisbury DF, Dickey CC, Fischer IA, Mazzoni P, Kisler T, Arakaki H, Kwon JS, Anderson JE, Yurgelun-Todd D, Tohen M, McCarley RW. Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry. 1998. 155:1384–1391.

27. Kasai K, Shenton ME, Salisbury DF, Hirayasu Y, Onitsuka T, Spencer MH, Yurgelun-Todd DA, Kikinis R, Jolesz FA, McCarley RW. Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry. 2003. 60:766–775.

28. Barta PE, Pearlson GD, Powers RE, Richards SS, Tune LE. Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia. Am J Psychiatry. 1990. 147:1457–1462.

29. Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, Wible CG, Hokama H, Martin J, Metcalf D, Coleman M, McCarley RW. Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N Engl J Med. 1992. 327:604–612.

30. Salisbury DF, Kuroki N, Kasai K, Shenton ME, McCarley RW. Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry. 2007. 64:521–529.

31. Shin KS, Kim JS, Kang DH, Koh Y, Choi JS, O'Donnell BF, Chung CK, Kwon JS. Pre-attentive auditory processing in ultra-high-risk for schizophrenia with magnetoencephalography. Biol Psychiatry. 2009. 65:1071–1078.

32. Koutsouleris N, Schmitt GJ, Gaser C, Bottlender R, Scheuerecker J, McGuire P, Burgermeister B, Born C, Reiser M, Moller HJ, Meisenzahl EM. Neuroanatomical correlates of different vulnerability states for psychosis and their clinical outcomes. Br J Psychiatry. 2009. 195:218–226.

33. Witthaus H, Kaufmann C, Bohner G, Ozgurdal S, Gudlowski Y, Gallinat J, Ruhrmann S, Brune M, Heinz A, Klingebiel R, Juckel G. Gray matter abnormalities in subjects at ultra-high risk for schizophrenia and first-episode schizophrenic patients compared to healthy controls. Psychiatry Res. 2009. 173:163–169.

34. Jung WH, Kim JS, Jang JH, Choi JS, Jung MH, Park JY, Han JY, Choi CH, Kang DH, Chung CK, Kwon JS. Cortical thickness reduction in individuals at ultra-high-risk for psychosis. Schizophr Bull. 2009. doi: 10.1093/schbul/sbp151.

35. LaBar KS, Crupain MJ, Voyvodic JT, McCarthy G. Dynamic perception of facial affect and identity in the human brain. Cereb Cortex. 2003. 13:1023–1033.

36. Shin YW, Na MH, Ha TH, Kang DH, Yoo SY, Kwon JS. Dysfunction in configural face processing in patients with schizophrenia. Schizophr Bull. 2008. 34:538–543.

37. Kim HS, Shin NY, Choi JS, Jung MH, Jang JH, Kang DH, Kwon JS. Processing of facial configuration in individuals at ultra-high risk for schizophrenia. Schizophr Res. 2010. 118:81–87.

38. Shim G, Kang DH, Chung YS, Yoo SY, Shin NY, Kwon JS. Social functioning deficits in young people at risk for schizophrenia. Aust N Z J Psychiatry. 2008. 42:678–685.

39. Sun D, Phillips L, Velakoulis D, Yung A, McGorry PD, Wood SJ, van Erp TG, Thompson PM, Toga AW, Cannon TD, Pantelis C. Progressive brain structural changes mapped as psychosis develops in 'at risk' individuals. Schizophr Res. 2009. 108:85–92.

40. Jessen F, Scherk H, Traber F, Theyson S, Berning J, Tepest R, Falkai P, Schild HH, Maier W, Wagner M, Block W. Proton magnetic resonance spectroscopy in subjects at risk for schizophrenia. Schizophr Res. 2006. 87:81–88.

41. Byun MS, Choi JS, Yoo SY, Kang DH, Choi CH, Jang DP, Jung WH, Jung MH, Jang JH, Lee JM, Kwon JS. Depressive symptoms and brain metabolite alterations in subjects at ultra-high risk for psychosis: a Preliminary Study. Psychiatry Investig. 2009. 6:264–271.

42. Wood SJ, Pantelis C, Proffitt T, Phillips LJ, Stuart GW, Buchanan JA, Mahony K, Brewer W, Smith DJ, McGorry PD. Spatial working memory ability is a marker of risk-for-psychosis. Psychol Med. 2003. 33:1239–1247.

43. Chung YS, Kang DH, Shin NY, Yoo SY, Kwon JS. Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia. Schizophr Res. 2008. 99:111–118.

44. Nelson B, Fornito A, Harrison BJ, Yucel M, Sass LA, Yung AR, Thompson A, Wood SJ, Pantelis C, McGorry PD. A disturbed sense of self in the psychosis prodrome: linking phenomenology and neurobiology. Neurosci Biobehav Rev. 2009. 33:807–817.

45. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008. 1124:1–38.

46. Shim G, Oh JS, Jung WH, Jang JH, Choi CH, Kim E, Park HY, Choi JS, Jung MH, Kwon JS. Altered resting-state connectivity in subjects at ultra-high risk for psychosis: an fMRI study. Behav Brain Funct. 2010. 6:58.

47. Benes FM. Neurobiological investigations in cingulate cortex of schizophrenic brain. Schizophr Bull. 1993. 19:537–549.

48. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS. Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry. 1992. 160:179–186.

49. Yücel M, Wood SJ, Phillips LJ, Stuart GW, Smith DJ, Yung A, Velakoulis D, McGorry PD, Pantelis C. Morphology of the anterior cingulate cortex in young men at ultra-high risk of developing a psychotic illness. Br J Psychiatry. 2003. 182:518–524.

50. Fornito A, Yung AR, Wood SJ, Phillips LJ, Nelson B, Cotton S, Velakoulis D, McGorry PD, Pantelis C, Yucel M. Anatomic abnormalities of the anterior cingulate cortex before psychosis onset: an MRI study of ultra-high-risk individuals. Biol Psychiatry. 2008. 64:758–765.

51. Ryan MC, Sharifi N, Condren R, Thakore JH. Evidence of basal pituitary-adrenal overactivity in first episode, drug naive patients with schizophrenia. Psychoneuroendocrinology. 2004. 29:1065–1070.

52. MacMaster FP, Kusumakar V. MRI study of the pituitary gland in adolescent depression. J Psychiatr Res. 2004. 38:231–236.

53. Garner B, Pariante CM, Wood SJ, Velakoulis D, Phillips L, Soulsby B, Brewer WJ, Smith DJ, Dazzan P, Berger GE, Yung AR, van den Buuse M, Murray R, McGorry PD, Pantelis C. Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis. Biol Psychiatry. 2005. 58:417–423.

54. Thompson KN, Phillips LJ, Komesaroff P, Yuen HP, Wood SJ, Pantelis C, Velakoulis D, Yung AR, McGorry PD. Stress and HPA-axis functioning in young people at ultra high risk for psychosis. J Psychiatr Res. 2007. 41:561–569.

55. Takahashi T, Wood SJ, Yung AR, Phillips LJ, Soulsby B, McGorry PD, Tanino R, Zhou SY, Suzuki M, Velakoulis D, Pantelis C. Insular cortex gray matter changes in individuals at ultra-high-risk of developing psychosis. Schizophr Res. 2009. 111:94–102.

56. Borgwardt SJ, Radue EW, Gotz K, Aston J, Drewe M, Gschwandtner U, Haller S, Pfluger M, Stieglitz RD, McGuire PK, Riecher-Rössler A. Radiological findings in individuals at high risk of psychosis. J Neurol Neurosurg Psychiatry. 2006. 77:229–233.

57. Choi JS, Kang DH, Park JY, Jung WH, Choi CH, Chon MW, Jung MH, Lee JM, Kwon JS. Cavum septum pellucidum in subjects at ultra-high risk for psychosis: compared with first-degree relatives of patients with schizophrenia and healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry. 2008. 32:1326–1330.

58. Kwon JS, Shenton ME, Hirayasu Y, Salisbury DF, Fischer IA, Dickey CC, Yurgelun-Todd D, Tohen M, Kikinis R, Jolesz FA, McCarley RW. MRI study of cavum septi pellucidi in schizophrenia, affective disorder, and schizotypal personality disorder. Am J Psychiatry. 1998. 155:509–515.

59. Takahashi T, Yung AR, Yucel M, Wood SJ, Phillips LJ, Harding IH, Soulsby B, McGorry PD, Suzuki M, Velakoulis D, Pantelis C. Prevalence of large cavum septi pellucidi in ultra high-risk individuals and patients with psychotic disorders. Schizophr Res. 2008. 105:236–244.

60. Takahashi T, Suzuki M, Zhou SY, Nakamura K, Tanino R, Kawasaki Y, Seal ML, Seto H, Kurachi M. Prevalence and length of the adhesio interthalamica in schizophrenia spectrum disorders. Psychiatry Res. 2008. 164:90–94.

61. Winkler AM, Kochunov P, Blangero J, Almasy L, Zilles K, Fox PT, Duggirala R, Glahn DC. Cortical thickness or grey matter volume? The importance of selecting the phenotype for imaging genetics studies. Neuroimage. 2010. 53:1135–1146.

62. Koutsouleris N, Meisenzahl EM, Davatzikos C, Bottlender R, Frodl T, Scheuerecker J, Schmitt G, Zetzsche T, Decker P, Reiser M, Möller HJ, Gaser C. Use of neuroanatomical pattern classification to identify subjects in at-risk mental states of psychosis and predict disease transition. Arch Gen Psychiatry. 2009. 66:700–712.

63. Haller S, Borgwardt SJ, Schindler C, Aston J, Radue EW, Riecher-Rössler A. Can cortical thickness asymmetry analysis contribute to detection of at-risk mental state and first-episode psychosis? A pilot study. Radiology. 2009. 250:212–221.

64. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW. Longitudinal mapping of cortical thickness and brain growth in normal children. J Neurosci. 2004. 24:8223–8231.

65. Sowell ER, Thompson PM, Toga AW. Mapping changes in the human cortex throughout the span of life. Neuroscientist. 2004. 10:372–392.

66. Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ, Yung AR, Bullmore ET, Brewer W, Soulsby B, Desmond P, McGuire PK. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003. 361:281–288.

67. Borgwardt SJ, McGuire PK, Aston J, Gschwandtner U, Pfluger MO, Stieglitz RD, Radue EW, Riecher-Rössler A. Reductions in frontal, temporal and parietal volume associated with the onset of psychosis. Schizophr Res. 2008. 106:108–114.

68. Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R, Toga AW, Rapoport JL. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001. 98:11650–11655.

69. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry. 2006. 188:510–518.

70. Haug H. Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: a stereological investigation of man and his variability and a comparison with some mammals (primates, whales, marsupials, insectivores, and one elephant). Am J Anat. 1987. 180:126–142.