Multimodal image analysis of clinical influences on preterm brain development.

OBJECTIVE: Premature birth is associated with numerous complex abnormalities of white and gray matter and a high incidence of long-term neurocognitive impairment. An integrated understanding of these abnormalities and their association with clinical events is lacking. The aim of this study was to identify specific patterns of abnormal cerebral development and their antenatal and postnatal antecedents. METHODS: In a prospective cohort of 449 infants (226 male), we performed a multivariate and data-driven analysis combining multiple imaging modalities. Using canonical correlation analysis, we sought separable multimodal imaging markers associated with specific clinical and environmental factors and correlated to neurodevelopmental outcome at 2 years. RESULTS: We found five independent patterns of neuroanatomical variation that related to clinical factors including age, prematurity, sex, intrauterine complications, and postnatal adversity. We also confirmed the association between imaging markers of neuroanatomical abnormality and poor cognitive and motor outcomes at 2 years. INTERPRETATION: This data-driven approach defined novel and clinically relevant imaging markers of cerebral maldevelopment, which offer new insights into the nature of preterm brain injury. Ann Neurol 2017;82:233-246.

Specialization and integration of functional thalamocortical connectivity in the human infant.

Connections between the thalamus and cortex develop rapidly before birth, and aberrant cerebral maturation during this period may underlie a number of neurodevelopmental disorders. To define functional thalamocortical connectivity at the normal time of birth, we used functional MRI (fMRI) to measure blood oxygen level-dependent (BOLD) signals in 66 infants, 47 of whom were at high risk of neurocognitive impairment because of birth before 33 wk of gestation and 19 of whom were term infants. We segmented the thalamus based on correlation with functionally defined cortical components using independent component analysis (ICA) and seed-based correlations. After parcellating the cortex using ICA and segmenting the thalamus based on dominant connections with cortical parcellations, we observed a near-facsimile of the adult functional parcellation. Additional analysis revealed that BOLD signal in heteromodal association cortex typically had more widespread and overlapping thalamic representations than primary sensory cortex. Notably, more extreme prematurity was associated with increased functional connectivity between thalamus and lateral primary sensory cortex but reduced connectivity between thalamus and cortex in the prefrontal, insular and anterior cingulate regions. This work suggests that, in early infancy, functional integration through thalamocortical connections depends on significant functional overlap in the topographic organization of the thalamus and that the experience of premature extrauterine life modulates network development, altering the maturation of networks thought to support salience, executive, integrative, and cognitive functions.

Parents' experiences of information and communication in the neonatal unit about brain imaging and neurological prognosis: a qualitative study.

AIM: To explore parental information and communication needs during their baby's care in the neonatal unit with a focus on brain imaging and neurological prognosis. METHODS: Eighteen parents recruited from one neonatal unit in the United Kingdom participated in semi-structured qualitative interviews using a grounded theory approach. The topic guide focused on information received about neonatal brain imaging, diagnosis and prognosis, emotional impact and support. RESULTS: Parents expressed different information needs influenced by their history, expectations, coping strategies and experiences. Most felt they initially were passive recipients of information and attempted to gain control of the information flow. Nurses were the main providers of information; doctors and other parents were also valuable. Attending ward rounds was important. Some parents felt accessing specific information such as the results of brain imaging could be difficult. Concerns about long-term developmental outcomes and the need for information did not diminish over time. The emotional impact of having a preterm baby had a negative effect on parents' ability to retain information, and all had an ongoing need for reassurance. CONCLUSION: The findings provide insights about the needs and experiences of parents who have a continuing requirement for information about their infant's care, development and prognosis.

Punctate White Matter Lesions Associated With Altered Brain Development And Adverse Motor Outcome In Preterm Infants.

Preterm infants who develop neurodevelopmental impairment do not always have recognized abnormalities on cerebral ultrasound, a modality routinely used to assess prognosis. In a high proportion of infants, MRI detects punctate white matter lesions that are not seen on ultrasonography. To determine the relation of punctate lesions to brain development and early neurodevelopmental outcome we used multimodal brain MRI to study a large cohort of preterm infants. Punctate lesions without other focal cerebral or cerebellar lesions were detected at term equivalent age in 123 (24.3%) (59 male) of the 506 infants, predominantly in the centrum semiovale and corona radiata. Infants with lesions had higher gestational age, birth weight, and less chronic lung disease. Punctate lesions showed a dose dependent relation to abnormalities in white matter microstructure, assessed with tract-based spatial statistics, and reduced thalamic volume (p < 0.0001), and predicted unfavourable motor outcome at a median (range) corrected age of 20.2 (18.4-26.3) months with sensitivity (95% confidence intervals) 71 (43-88) and specificity 72 (69-77). Punctate white matter lesions without associated cerebral lesions are common in preterm infants currently not regarded as at highest risk for cerebral injury, and are associated with widespread neuroanatomical abnormalities and adverse early neurodevelopmental outcome.

The toxicity of high molecular weight glutenin subunits of wheat to patients with coeliac disease.

OBJECTIVES: The ability of the gliadin fraction of wheat gluten to exacerbate coeliac disease is well documented. We investigated the possible toxicity of high molecular weight glutenin subunits (HMW-GS) in coeliac disease in vitro using gluten-sensitive T cells, and in vivo with challenge studies in patient volunteers. METHODS: A mixture of four HMW-GS was chemically separated from wheat flour and checked for purity by HPLC, SDS-PAGE and ELISA. T-cell lines, grown up from small intestinal biopsies from coeliac patients (n=17), were tested for their reactivity to HMW-GS. Adults with coeliac disease and who were on a gluten-free diet (n=3) underwent in-vivo challenges with HMW-GS. Duodenal biopsies, taken prior to the challenge and at intervals up to 6 h afterwards, were assessed for morphology, intra-epithelial lymphocyte count, and interleukin 15 (IL-15) expression, by immunohistochemistry. RESULTS: T-cell lines from 11 of 17 patients were stimulated by HMW-GS. There was a significant change in small intestinal morphology 4 h after commencing infusions with HMW-GS in all three subjects. For example villus height to crypt depth ratios were reduced in the three patients from 3.0+/-0.5 to 1.29+/-0.2, 2.53+/-0.7 to 0.81+/-0.6 and 3.0+/-0.7 to 1.85+/-0.3, P<0.0001 in all cases. There was increased expression of IL-15 in the small intestine from 2 h after the HMW-GS challenges. CONCLUSION: Mixed HMW-GS stimulate T-cell lines from some coeliac patients and exacerbate coeliac disease in vivo, inducing expression, within 2 h, of IL-15. This suggests an innate immune response to these proteins.

Effects of hypoxia and thyroid hormone on mRNA levels and activity of phosphoglycerate mutase in rabbit tissues.

AIM: In the present work, we studied the effects of hypoxia and triiodothyronine (T(3)) on phosphoglycerate mutase (PGAM) activity and expression in rabbit liver, brain, and skeletal muscle under in vivo conditions. METHODS: Hypoxia was induced in a methacrylate cage with a mixture of 90% nitrogen and 10% oxygen. Hyperthyroidism was induced daily by T(3) injection (250 microg/kg). RESULTS: Hypoxia increases the PGAM activity in liver and brain, tissues which possess type PGAM-BB isozyme, but does not affect the PGAM activity in muscle which possesses type PGAM-MM isozyme. T(3) administration increases the PGAM activity in muscle and liver, but does not affect the enzyme activity in the brain. In all cases, the activity changes in parallel with those of PGAM mRNA levels. CONCLUSION: The tissue-specific effects of hypoxia and T(3) could be explained by the tissue-specific distribution of both PGAM isozyme and T(3) receptors.

Effects of thyroid hormone on mRNAs of phosphoglycerate mutase subunits in rat muscle during development.

BACKGROUND: We previously showed that triiodothyronine (T3) stimulates muscle phosphoglycerate mutase (PGAM) activity and isozyme transition in rat skeletal and cardiac muscles. METHODS: The effects of T3 on PGAM types B and M subunit expression in rat muscle during development are reported. RESULTS: T3 administration during the first 21 days of rat life more than doubles type M PGAM mRNA levels, but produces minor effects on type B PGAM mRNA levels. The antihormone propylthiouracil (PTU) slightly decreases both type B and M mRNA levels, but this decrease is not statistically significant. CONCLUSION: Thyroid hormone influences PGAM mRNA isozyme levels differently and increases type M mRNA.

Effects of thyroid hormone and hypoxia on 2,3-bisphosphoglycerate, bisphosphoglycerate synthase and phosphoglycerate mutase in rabbit erythroblasts and reticulocytes in vivo.

OBJECTIVES: The effects of triiodothyronine (T(3)) and hypoxia on 2,3-bisphosphoglycerate (2,3-BPG) studied in vitro are unclear. To clarify these effects we selected a more physiologic approach: the in vivo study in rabbits. We also present the changes produced by T(3) and hypoxia on phosphoglycerate mutase (PGAM), which requires 2,3-BPG as a cofactor, and 2,3-BPG synthase (BPGS), the enzyme responsible for 2,3-BPG synthesis in erythroblasts and reticulocytes. METHODS: Hyperthyroidism was induced by daily T(3) injection (250 microg/kg), hypoxia by a mixture of 90% nitrogen and 10% oxygen and hypothyroidism by propylthiouracil (PTU) added to drinking water. RESULTS: Both T(3) administration and hypoxic conditions increased 2,3-BPG levels and BPGS mRNA levels and activity in erythroblasts but not in reticulocytes. Unlike BPGS, both PGAM mRNA levels and activity were increased in erythroblasts and reticulocytes under hyperthyrodism and hypoxia. The antihormone PTU produced opposite effects to T(3). CONCLUSION: The results presented here suggest that both hyperthyroidism and hypoxia modulate in vivo red cell 2,3-BPG content by changes in the expression of BPGS. Similarly, the changes in PGAM activity are also explained by changes in its expression.