Highlights
- •Rett syndrome (RTT) brains were examined using multimodal MRI techniques.
- •Reduced interhemispheric and cerebro-cerebellar connections were noted.
- •Clinical severity of RTT patients correlated with the altered connections.
- •These alterations may underlie the functional changes in RTT brains.
Abstract
Objective
To clarify the relationship between structural and functional changes in the brains
of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI).
Methods
Nine subjects with typical RTT (RTTs) and an equal number of healthy controls (HCs)
underwent structural MRI, diffusion tensor imaging (DTI), and resting-state functional
MRI (rs-fMRI). The measurements obtained from each modality were statistically compared
between RTTs and HCs and examined for their correlation with the clinical severity
of RTTs.
Results
Structural MRI imaging revealed volume reductions in most cortical and subcortical
regions of the brain. Remarkable volume reductions were observed in the frontal and
parietal lobes, cerebellum, and subcortical regions including the putamen, hippocampus,
and corpus callosum. DTI analysis revealed decreased white matter integrity in broad
regions of the brain. Fractional anisotropy values were greatly decreased in the superior
longitudinal fasciculus, corpus callosum, and middle cerebellar peduncle. Rs-fMRI
analysis showed decreased functional connectivity in the interhemispheric dorsal attention
network, and between the visual and cerebellar networks. The clinical severity of
RTTs correlated with the volume reduction of the frontal lobe and cerebellum, and
with changes in DTI indices in the fronto-occipital fasciculus, corpus callosum, and
cerebellar peduncles.
Conclusion
Regional volume and white matter integrity of RTT brains were reduced in broad areas,
while most functional connections remained intact. Notably, two functional connectivities,
between cerebral hemispheres and between the cerebrum and cerebellum, were decreased
in RTT brains, which may reflect the structural changes in these brain regions.
Graphical abstract
Graphical Abstract
Keywords
Abbreviations:
AD (axial diffusivity), BCC (body of corpus callosum), CC (corpus callosum.), CGC (cingulum (cingulate gyrus part)), CGH (perihippocampal cingulum tract), CP (cerebral peduncle), CSS (clinical severity score), CSS-C (sum of CSS scores related to communication skills), CSS-M (sum of CSS scores related to motor functions), DAN (dorsal attention network), DTI (diffusion tensor imaging), EC (external capsule), FA (fractional anisotropy), FDR (false discovery rate), FEF (frontal eye field), FX (fornix), FXST (fornix/stria terminalis), GCC (genu of corpus callosum), GM (gray matter), HCs (healthy controls), ICP (inferior cerebellar peduncle), IPS (intraparietal sulcus), MCP (middle cerebellar peduncle), MD (mean diffusivity), MeCP2 (methyl-CpG-binding protein 2), PCR (posterior corona radiata), PLIC (posterior limb of internal capsule), PTR (posterior thalamic radiation), RD (radial diffusivity), ROI (region of interest), rs-fMRI (resting-state functional MRI), RTT (Rett syndrome), SCC (splenium of corpus callosum), SCP (superior cerebellar peduncle), SCR (superior corona radiata), SFOF (superior fronto-occipital fasciculus), SLF (superior longitudinal fasciculus), SS (sagittal stratum), WM (white matter)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.Nat. Genet. 1999; 23: 185-188
- On a unusual brain atrophy syndrome in hyperammonemia in childhood.Wien. Med. Wochenschr. 1966; 116: 723-726
- A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases.Ann. Neurol. 1983; 14: 471-479
- Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.Nature. 1998; 393: 386-389
- Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.Nat. Genet. 1998; 19: 187-191
- MeCP2, a key contributor to neurological disease, activates and represses transcription.Science. 2008; 320: 1224-1229
- Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus.Hum. Mol. Genet. 2009; 18: 2431-2442
- A high-resolution imaging approach to investigate chromatin architecture in complex tissues.Cell. 2015; 163: 246-255
- MeCP2 levels regulate the 3D structure of heterochromatic foci in mouse neurons.J. Neurosci. 2020; 40: 8746-8766
- MeCP2 links heterochromatin condensates and neurodevelopmental disease.Nature. 2020; 586: 440-444
- Pervasive neuroanatomic abnormalities of the brain in three cases of Rett’s syndrome.Neurology. 1995; 45: 1581-1586
- Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.Nat. Genet. 2001; 27: 327-331
- Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation.Neurobiol. Dis. 2013; 58: 3-12
- Neuropathology of Rett syndrome.J. Child Neurol. 2005; 20: 747-753
- Selective cerebral volume reduction in Rett syndrome: a multiple-approach MR imaging study.AJNR Am. J. Neuroradiol. 2008; 29: 436-441
- Quantitative magnetic resonance imaging in Rett syndrome.J. Neuropsychiatr. Clin. Neurosci. 1991; 3: 66-72
- Cerebellar and cerebral abnormalities in Rett syndrome: a quantitative MR analysis.AJR Am. J. Roentgenol. 1992; 159: 177-183
- Neuroanatomy of Rett syndrome: a volumetric imaging study.Ann. Neurol. 1993; 34: 227-234
- Neuroanatomy in Rett syndrome: cerebral cortex and posterior fossa.Neurology. 1997; 48: 399-407
- Surface- and voxel-based brain morphologic study in Rett and Rett-like syndrome with MECP2 mutation.Int. J. Dev. Neurosci. 2019; 73: 83-88
- White matter impairment in Rett syndrome: diffusion tensor imaging study with clinical correlations.AJNR Am. J. Neuroradiol. 2010; 31: 295-299
- Assessment of system dysfunction in the brain through MRI-based connectomics.Lancet Neurol. 2013; 12: 1189-1199
- Rett syndrome: revised diagnostic criteria and nomenclature.Ann. Neurol. 2010; 68: 944-950
- Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome.Neurology. 2008; 70: 1313-1321
- An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.Neuroimage. 2006; 31: 968-980
- Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.Neuron. 2002; 33: 341-355
- Characterization and propagation of uncertainty in diffusion-weighted MR imaging.Magn. Reson. Med. 2003; 50: 1077-1088
- MRtrix3: a fast, flexible and open software framework for medical image processing and visualisation.Neuroimage. 2019; 202116137
- Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template.Neuroimage. 2008; 40: 570-582
- Tract probability maps in stereotaxic spaces: analyses of white matter anatomy and tract-specific quantification.Neuroimage. 2008; 39: 336-347
- Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks.Brain Connect. 2012; 2: 125-141
- Handbook of Functional Connectivity Magnetic Resonance Imaging Methods in CONN.Hilbert Press, Boston, MA2020
- On the role of the corpus callosum in interhemispheric functional connectivity in humans.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 13278-13283
- Role of the dorsal attention network in distracter suppression based on features.Cogn. Neurosci. 2020; 11: 37-46
- Functional connectivity of the dorsal attention network predicts selective attention in 4-7 year-old girls.Cereb. Cortex. 2017; 27: 4350-4360
- Dissociated functional connectivity profiles for motor and attention deficits in acute right-hemisphere stroke.Brain. 2016; 139: 2024-2038
- Resting-state functional connectivity in the dorsal attention network relates to behavioral performance in spatial attention tasks and may show task-related adaptation.Front. Hum. Neurosci. 2021; 15757128
- Impaired visual search in children with Rett syndrome.Pediatr. Neurol. 2019; 92: 26-31
- Rett syndrome: an eye-tracking study of attention and recognition memory.Dev. Med. Child Neurol. 2013; 55: 364-371
- Decreased interhemispheric functional connectivity rather than corpus callosum volume as a potential biomarker for autism spectrum disorder.Cortex. 2019; 119: 258-266
- Functional alterations associated with structural abnormalities in adults with high-functioning autism Spectrum disorder.Brain Connect. 2020; 10: 368-376
- Disrupted functional brain connectivity during verbal working memory in children and adolescents with schizophrenia.Cereb. Cortex. 2011; 21: 510-518
- The cerebellum: its role in language and related cognitive and affective functions.Brain Lang. 2013; 127: 334-342
- Resting state networks and consciousness.Front. Psychol. 2012; 3
- Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during Propofol-induced loss of consciousness.Anesthesiology. 2010; 113: 1038-1053
- Neural correlates of sevoflurane-induced unconsciousness identified by simultaneous functional magnetic resonance imaging and electroencephalography.Anesthesiology. 2016; 125: 861-872
- Default mode network abnormalities in children with autism spectrum disorder detected by resting-state functional magnetic resonance imaging.J. Med. Investig. JMI. 2016; 63: 204-208
Article info
Publication history
Published online: August 18, 2022
Accepted:
August 14,
2022
Received in revised form:
August 5,
2022
Received:
April 26,
2022
Identification
Copyright
© 2022 Elsevier B.V. All rights reserved.
