Research Article| Volume 441, 120381, October 15, 2022

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Structural and functional changes in the brains of patients with Rett syndrome: A multimodal MRI study

  • Ryo Takeguchi
    Corresponding author at: Department of Pediatrics, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido 078-8510, Japan.
    Department of Pediatrics, Asahikawa Medical University, Hokkaido 078-8510, Japan
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  • Mami Kuroda
    Department of Pediatrics, Asahikawa Medical University, Hokkaido 078-8510, Japan
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  • Ryosuke Tanaka
    Department of Pediatrics, Asahikawa Medical University, Hokkaido 078-8510, Japan
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  • Nao Suzuki
    Department of Pediatrics, Asahikawa Medical University, Hokkaido 078-8510, Japan
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  • Yuichi Akaba
    Department of Pediatrics, Asahikawa Medical University, Hokkaido 078-8510, Japan

    Group of Brain Function and Development, Nagoya University Neuroscience Institute of the Graduate School of Science, Nagoya, Aichi 464-8602, Japan

    Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya, Aichi 464-8602, Japan
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  • Keita Tsujimura
    Group of Brain Function and Development, Nagoya University Neuroscience Institute of the Graduate School of Science, Nagoya, Aichi 464-8602, Japan

    Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya, Aichi 464-8602, Japan
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  • Masayuki Itoh
    Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan
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  • Satoru Takahashi
    Department of Pediatrics, Asahikawa Medical University, Hokkaido 078-8510, Japan
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Published:August 18, 2022DOI:


      • 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.



      To clarify the relationship between structural and functional changes in the brains of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI).


      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.


      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.


      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



      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)
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