Elsevier

Biological Psychiatry

Volume 57, Issue 1, 1 January 2005, Pages 83-90
Biological Psychiatry

Orignal articles
Direct and indirect effects of fetal irradiation on cortical gray and white matter volume in the macaque

https://doi.org/10.1016/j.biopsych.2004.10.014Get rights and content

Background

Schizophrenia is associated with reductions in thalamic neuronal number and cortical gray matter volume. Exposure of nonhuman primates to x-irradiation in early gestation has previously been shown to decrease thalamic volume and neuronal number. Here we examine whether early gestational irradiation also results in cortical volume reduction.

Methods

High-resolution, T1-weighted magnetic resonance scans were collected in adult monkeys 1) exposed to irradiation during the early gestational period (E33-E42) corresponding to thalamic neurogenesis, 2) irradiated in midgestation (E70-81) during neocortical neurogenesis, and 3) not exposed to irradiation. Cortical gray matter and white matter volumes were derived via manual segmentation; frontal and nonfrontal volumes were distinguished via sulcal landmarks.

Results

Monkeys irradiated in early gestation exhibited a trend reduction in nonfrontal gray matter volume (17%) and significant reductions in white matter volume in frontal (26%) and nonfrontal (36%) lobes. Monkeys irradiated in midgestation had smaller gray (frontal: 28%; nonfrontal: 22%) and white matter (frontal: 29%; nonfrontal: 38%) volumes.

Conclusions

The cortical deficits observed in midgestationally irradiated monkeys are consistent with a reduction in cortical neuronal number. Cortical volume reductions following early gestational irradiation may be secondary to reduced thalamic neuronal number and therefore model the thalamocortical pathology of schizophrenia.

Section snippets

Methods and materials

Thirteen adult macaque monkeys were analyzed in this study (Table 1). Three had been exposed to x-irradiation during the period of thalamogenesis (E33-42) in early gestation (eFIM); three had been irradiated in midgestation (mFIM) when neocortical neurons are generated (E70-E81), and seven were nonirradiated control animals (CON). The irradiation protocol has been described in detail previously (Algan and Rakic 1997). The exact time of exposure and dose of irradiation is shown in Table 1.

Frontal lobe gray matter

Frontal lobe GM volume in eFIMs was reduced by 13% compared with control subjects whereas that of mFIMs was 28% smaller than control animals (Figure 1, Table 2). There was a significant group effect (F2,10 = 5.57; p = .024) for GM (ranks). Post hoc comparison revealed that GM in mFIMs was significantly reduced compared with control animals; the difference in GM volume between eFIM and CON was not significant (Table 2).

Frontal lobe white matter

Frontal lobe WM was reduced by 26% in the eFIMs and by 29% in the mFIMs

Discussion

Monkeys that were exposed to irradiation in midgestation, when cortical neurons are undergoing final mitosis, exhibited pronounced deficits in cortical GM volume undoubtedly reflecting a substantial reduction in cortical neuronal number in these animals. Early gestational irradiation resulted in a more modest decreases in cortical GM volume in the posterior (nonfrontal) lobes and in the frontal lobe where the reduction did not reach significance although the magnitude (13%) of the reduction in

References (98)

  • P. Danos et al.

    Volumes of association thalamic nuclei in schizophreniaA postmortem study

    Schizophr Res

    (2003)
  • L.E. DeLisi et al.

    Schizophrenia as a chronic active brain processA study of progressive brain structural change subsequent to the onset of schizophrenia

    Pyschiatr Res

    (1997)
  • D. Eyles et al.

    Vitamin D3 and brain development

    Neuroscience

    (2003)
  • L.F. Jarskog et al.

    Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro

    Int J Develop Neurosci

    (1997)
  • L.C. Konick et al.

    Meta-analysis of thalamic size in schizophrenia

    Biol Psychiatry

    (2001)
  • S.M. Lawrie et al.

    Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia

    Biol Psychiatry

    (2001)
  • P. Levitt et al.

    The time of genesis, embryonic origin and differentiation of the brain stem monoamine neurons in the rhesus monkey

    Develop Brain Res

    (1982)
  • S.W. Lewis et al.

    Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia

    J Psychiatr Res

    (1987)
  • T.K. Loganovskaja et al.

    EEG, cognitive and psychopathological abnormalities in children irradiated in utero

    Int J Psychophysiol

    (1999)
  • C.E. Marx et al.

    Cytokine effects on cortical neuron MAP-2 immunoreactivityimplications for schizophrenia

    Biol Psychiatry

    (2001)
  • D.H. Mathalon et al.

    Correction for head size in brain-imaging measurements

    Psychiatry Res

    (1993)
  • R.W. McCarley et al.

    MRI anatomy of schizophrenia

    Biol Psychiatry

    (1999)
  • M.I. Miller et al.

    Bayesian construction of geometrically based cortical thickness metrics

    Neuroimage

    (2000)
  • B. Pakkenberg

    Total nerve cell number in neocortex in chronic schizophrenic and controls estimated using optical disectors

    Biol Psychiatry

    (1993)
  • C.M. Portas et al.

    Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging

    Biol Psychiatry

    (1998)
  • J.T. Ratnanather et al.

    Dynamic programming generation of boundaries of local coordinatized submanifolds in the neocortexApplication to the planum temporale

    Neuroimage

    (2003)
  • J.T. Ratnanather et al.

    Validating cortical surface analysis of medial prefrontal cortex

    Neuroimage

    (2001)
  • M. Schindler et al.

    Abnormalities of thalamic volume and shape detected in fetally-irradiated rhesus monkeys with high dimensional brain mapping

    Biol Psychiatry

    (2002)
  • L.D. Selemon et al.

    The reduced neuropil hypothesisA circuit based model of schizophrenia

    Biol Psychiatry

    (1999)
  • D.W. Shattuck et al.

    Magnetic resonance image tissue classification using a partial volume model

    Neuroimage

    (2001)
  • M.E. Shenton et al.

    A review of MRI findings in schizophrenia

    Schizopr Res

    (2001)
  • J.J. Thune et al.

    Total number of neurons in the prefrontal cortex in schizophrenics and controls

    J Psychiatr Res

    (2001)
  • B.T. Woods et al.

    MRI brain abnormalities in chronic schizophreniaOne process or more?

    Biol Psychiatry

    (1996)
  • K.A. Young et al.

    Reduced number of mediodoral and anterior thalamic neurons in schizophrenia

    Biol Psychiatry

    (2000)
  • M. Akil et al.

    Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects

    Am J Psychiatry

    (1999)
  • O. Algan et al.

    Radiation-induced, lamina-specific deletions of neurons in the primate visual cortex

    J Comp Neurol

    (1997)
  • N.C. Andreasen et al.

    Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging

    JAMA

    (1994)
  • N.C. Andreasen et al.

    Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging

    Science

    (1994)
  • W.F.C. Baare et al.

    Volumes of brain structures in twins discordant for schizophrenia

    Arch Gen Psychiatry

    (2001)
  • A. Breier et al.

    Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures

    Arch Gen Psychiatry

    (1992)
  • A.S. Brown et al.

    Maternal exposure to respiratory infections and adult schizophrenia spectrum disordersA prospective birth cohort study

    Schizophr Bull

    (2000)
  • M.S. Buchsbaum et al.

    PET and MRI of the thalamus in never-medicated patients with schizophrenia

    Am J Psychiatry

    (1996)
  • W. Byne et al.

    Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder

    Arch Gen Psychiatry

    (2001)
  • W. Byne et al.

    Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia

    Am J Psychiatry

    (2002)
  • T.D. Cannon et al.

    Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia

    Proc Natl Acad Sci U S A

    (2002)
  • S.A. Castner et al.

    Two nonhuman primate models of psychosisFetal irradiation and amphetamine sensitization

    Soc Neurosci Abst

    (1996)
  • J.G. Csernansky et al.

    Hippocampal morphometry in schizophrenia by high dimensional brain mapping

    Proc Natl Acad Sci U S A

    (1998)
  • J.G. Csernansky et al.

    Abnormalities of thalamic volume and shape in schizophrenia

    Am J Psychiatry

    (2004)
  • J.G. Csernansky et al.

    Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping

    Am J Psychiatry

    (2002)
  • Cited by (34)

    • Nonhuman primate models in the study of spaceflight stressors: Past contributions and future directions

      2021, Life Sciences in Space Research
      Citation Excerpt :

      In the only study cited, rhesus monkeys were exposed to X-ray irradiation during early- and mid-gestation and cortical gray and white matter volumes were recorded. Results from this work showed that early-gestation exposure reduced nonfrontal gray matter volume (17%) and white matter volume in frontal (26%) and nonfrontal (36%) lobes, whereas mid-gestation irradiation resulted in smaller gray (frontal: 28%; nonfrontal: 22%) and white matter (frontal: 29%; nonfrontal: 38%) volumes (Selemon et al., 2005). Such observations suggest that changes in NHP brain structure and function may be highly sensitive to radiation exposure.

    • Reduced Midbrain Dopamine Neuron Number in the Adult Non-human Primate Brain after Fetal Radiation Exposure

      2020, Neuroscience
      Citation Excerpt :

      It is particularly noteworthy that the timing of radiation exposure is a critical determinant of the resulting behavioral deficits, as for instance radiation exposure at embryonic day 11 (E11) in the mouse results in both spatial and reference memory deficits whereas following E10 exposure spatial memory is spared (Verreet et al., 2016). Previous studies of fetal irradiation in the non-human primate have also established that the pathology associated with x-irradiation is dependent on the timing of exposure (Algan and Rakic, 1997; Schindler et al., 2002; Selemon et al., 2005, 2009, 2013). Indeed, the prolonged gestational period of neurogenesis in the non-human primate brain allows for targeting of subcortical versus cortical populations of neurons.

    • Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation

      2013, Neuroscience
      Citation Excerpt :

      Our previous studies have uncovered a remarkable degree of similarity between the neuropathology following early gestational exposure to radiation in the macaque and the neuropathology of schizophrenia. Widespread, but non-uniform, volume deficits have been observed most prominently in the thalamus, cortical gray matter and putamen (Schindler et al., 2002; Selemon et al., 2005, 2009; Aldridge et al., 2012). A similar global neuropathologic profile has been described in schizophrenia (Harrison, 1999; Selemon, 2001; Shenton et al., 2001, 2010).

    • Primate models of schizophrenia: Future possibilities

      2009, Progress in Brain Research
      Citation Excerpt :

      Thus, we should always be cautious about negative results in rodent models, and encourage further research in more elaborate models when warranted. NHP models using irradiation (Selemon et al., 2005) or chronic amphetamine exposure (Selemon et al., 2007) have already provided insights regarding circuit changes, and AAV technology promises to further our understanding of genetic insults on PFC structure and function. As schizophrenia is a disorder of the association cortices, primate models will be important for understanding the impact of genetic insults on the elaborate neuronal architecture and cortical circuitry distinct to the primate brain.

    View all citing articles on Scopus
    View full text