Elsevier

Neuroscience

Volume 178, 31 March 2011, Pages 261-269
Neuroscience

Regeneration, Repair, and Developmental Neuroscience
Research Paper
Selectively diminished corpus callosum fibers in congenital central hypoventilation syndrome

https://doi.org/10.1016/j.neuroscience.2011.01.021Get rights and content

Abstract

Congenital central hypoventilation syndrome (CCHS), a condition associated with mutations in the PHOX2B gene, is characterized by loss of breathing drive during sleep, insensitivity to CO2 and O2, and multiple somatomotor, autonomic, neuropsychological, and ophthalmologic deficits, including impaired intrinsic and extrinsic eye muscle control. Brain structural studies show injury in peri-callosal regions and the corpus callosum (CC), which has the potential to affect functions disturbed in the syndrome; however, the extent of CC injury in CCHS is unclear. Diffusion tensor imaging (DTI)-based fiber tractography procedures display fiber directional information and allow quantification of fiber integrity. We performed DTI in 13 CCHS children (age, 18.2±4.7 years; eight male) and 31 control (17.4±4.9 years; 18 male) subjects using a 3.0-Tesla magnetic resonance imaging scanner; CC fibers were assessed globally and regionally with tractography procedures, and fiber counts and densities compared between groups using analysis-of-covariance (covariates; age and sex). Global CC evaluation showed reduced fiber counts and densities in CCHS over control subjects (CCHS vs. controls; fiber-counts, 4490±854 vs. 5232±777, P<0.001; fiber-density, 10.0±1.5 vs. 10.8±0.9 fibers/mm2, P<0.020), and regional examination revealed that these changes are localized to callosal axons projecting to prefrontal (217±47 vs. 248±32, P<0.005), premotor (201±51 vs. 241±47, P<0.012), parietal (179±64 vs. 238±54, P<0.002), and occipital regions (363±46 vs. 431±82, P<0.004). Corpus callosum fibers in CCHS are compromised in motor, cognitive, speech, and ophthalmologic regulatory areas. The mechanisms of fiber injury are unclear, but may result from hypoxia or perfusion deficits accompanying the syndrome, or from consequences of PHOX2B action.

Research highlights

▶We assessed corpus callosum (CC) fibers in CCHS, using DTI-based fiber tracking. ▶CC fiber injury appeared in specific, but not all areas projecting to cortices. ▶CC injury may underlie selected clinical deficits, especially ophthalmologic issues. ▶Injury may result from hypoxia or consequences of PHOX2B action in the syndrome.

Section snippets

Subjects

We studied 13 CCHS (mean age±SD: 18.2±4.7 years; age range: 7–23 years; body-mass-index±SD: 22.8±6.1 kg/m2; eight male) and 31 control (17.4±4.9 years; 7–24 years; 21.8±4.7 kg/m2; 18 male) subjects. These CCHS and control subjects were used in one previously-published manuscript (Kumar et al., 2010), dealing with other issues; that earlier manuscript described different types of tissue injury (axonal vs. myelin injury) in wide-spread brain areas in CCHS over control subjects. The CCHS diagnosis

Demographics

No significant differences in age (P=0.60), or body-mass-index (P=0.58) appeared between the CCHS and control groups. Significant sex difference did not emerge between the groups (P=0.83).

Corpus callosum fiber evaluation

The global CC fiber characteristics of CCHS and control subjects are summarized in Table 1, and individual fiber counts and density values are displayed in scatter plots (Fig. 2A, B). A substantial reduction in global CC fibers is visually evident in sample images of a CCHS and age- and sex-matched control

Overview

Global CC fiber counts and densities in CCHS were significantly reduced over control subjects, controlling for age and sex. These diminished fibers were localized within the CC in areas that project to prefrontal, premotor, parietal, and occipital regions. This study focused on using tractography procedures to outline interhemispheric characteristics of CC fibers. Other structural studies, including voxel-based T2-relaxometry and radial and axial diffusivity DTI procedures in CCHS subjects,

Conclusion

Global CC fibers are reduced in CCHS compared to control subjects. Regional reductions of fibers appeared in areas of the CC that serve interhemispheric communication for prefrontal, premotor, parietal, and occipital cortex, which are implicated in motor, speech, cognition, and ophthalmologic regulation; aspects of visuomotor and intrinsic eye control, as well as planning are especially affected in CCHS. The primary motor and temporal CC fibers are relatively spared in the condition. The

Acknowledgments

Authors thank Ms. Rebecca Harper and Mr. Edwin M. Valladares for assistance with data collection, Drs. Jennifer Ogren and Heidi Richardson for scientific editing, and Ms. Alexa Chavez for assistance with data analyses. We thank CCHS subjects and their parents/guardians for their participation in this study. This research was supported by the National Institute of Child Health and Human Development R01 HD-22695.

References (71)

  • V.J. Wedeen et al.

    Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers

    Neuroimage

    (2008)
  • M.Y. Yazgan et al.

    Functional significance of individual variations in callosal area

    Neuropsychologia

    (1995)
  • Idiopathic congenital central hypoventilation syndrome: diagnosis and management

    Am J Respir Crit Care Med

    (1999)
  • D.H. Badaruddin et al.

    Social and behavioral problems of children with agenesis of the corpus callosum

    Child Psychiatry Hum Dev

    (2007)
  • S. Bakola et al.

    Cortical connections of parietal field PEc in the macaque: linking vision and somatic sensation for the control of limb action

    Cereb Cortex

    (2010)
  • A.K. Barbey et al.

    Structured event complexes in the medial prefrontal cortex support counterfactual representations for future planning

    Philos Trans R Soc Lond B Biol Sci

    (2009)
  • A. Battaglia-Mayer et al.

    Eye-hand coordination during reaching. IIAn analysis of the relationships between visuomanual signals in parietal cortex and parieto-frontal association projections

    Cereb Cortex

    (2001)
  • R. Breveglieri et al.

    Somatosensory cells in area PEc of macaque posterior parietal cortex

    J Neurosci

    (2006)
  • S. Caille et al.

    Sensory and motor interhemispheric integration after section of different portions of the anterior corpus callosum in nonepileptic patients

    Neurosurgery

    (2005)
  • T.E. Conturo et al.

    Tracking neuronal fiber pathways in the living human brain

    Proc Natl Acad Sci U S A

    (1999)
  • I. Darian-Smith et al.

    Posterior parietal cortex: relations of unit activity to sensorimotor function

    Annu Rev Physiol

    (1979)
  • S. Dauger et al.

    Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways

    Development

    (2003)
  • C. Davatzikos et al.

    Correlation of corpus callosal morphometry with cognitive and motor function in periventricular leukomalacia

    Neuropediatrics

    (2003)
  • M.C. de Lacoste et al.

    Topography of the human corpus callosum

    J Neuropathol Exp Neurol

    (1985)
  • V. Dubreuil et al.

    A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

    Proc Natl Acad Sci U S A

    (2008)
  • T.J. Eluvathingal et al.

    Quantitative diffusion tensor tractography of association and projection fibers in normally developing children and adolescents

    Cereb Cortex

    (2007)
  • P.C. Fang et al.

    Ipsilateral cortical connections of motor, premotor, frontal eye, and posterior parietal fields in a prosimian primate, Otolemur garnetti

    J Comp Neurol

    (2005)
  • T. Flannery et al.

    Isolated conjugate gaze palsy after frontal lobe tumour surgery

    Br J Neurosurg

    (2004)
  • S. Funahashi et al.

    Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex

    J Neurophysiol

    (1989)
  • M.S. Gazzaniga et al.

    Dissociation of language and cognitionA psychological profile of two disconnected right hemispheres

    Brain

    (1984)
  • D.S. Goldberg et al.

    Congenital central hypoventilation syndrome: ocular findings in 37 children

    J Pediatr Ophthalmol Strabismus

    (1996)
  • J.O. Gronli et al.

    Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death

    Pediatr Pulmonol

    (2008)
  • G.G. Haddad et al.

    Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate

    Medicine

    (1978)
  • U. Halsband et al.

    The role of premotor cortex and the supplementary motor area in the temporal control of movement in man

    Brain

    (1993)
  • C.P. Hess et al.

    Q-ball reconstruction of multimodal fiber orientations using the spherical harmonic basis

    Magn Reson Med

    (2006)
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