Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function

Impaired cortical maturation is a postulated mechanism in the etiology of neurodevelopmental disorders, including schizophrenia. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. Whether thalamic activity also shapes prefrontal cortical maturation is unknown. Here, we show that inhibiting the midline thalamus during adolescence leads to a long-lasting decrease in thalamo-prefrontal projection density and cortical excitation. Adolescent thalamic inhibition also causes prefrontal-dependent cognitive deficits during adulthood that are associated with disrupted prefrontal cross-correlations and task outcome encoding. In contrast, thalamic inhibition during adulthood has no long-lasting consequences. Strikingly, exciting the thalamus in adulthood during a cognitive task rescues prefrontal cross-correlations, task outcome encoding, and cognitive deficits. These data point to adolescence as a sensitive window of thalamo-cortical circuit maturation. Furthermore, by supporting prefrontal network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders.

p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

Proper gene regulation is critical for both neuronal development and maintenance as the brain matures. We previously demonstrated that Akirin2, an essential nuclear protein that interacts with transcription factors and chromatin remodeling complexes, is required for the embryonic formation of the cerebral cortex. Here we show that Akirin2 plays a mechanistically distinct role in maintaining healthy neurons during cortical maturation. Restricting Akirin2 loss to excitatory cortical neurons resulted in progressive neurodegeneration via necroptosis and severe cortical atrophy with age. Comparing transcriptomes from Akirin2-null postnatal neurons and cortical progenitors revealed that targets of the tumor suppressor p53, a regulator of both proliferation and cell death encoded by Trp53, were consistently upregulated. Heterozygous deletion of Trp53 rescued neurodegeneration in Akirin2-null neurons. These data: 1) implicate Akirin2 as a critical neuronal maintenance protein; 2) identify p53 pathways as mediators of Akirin2 functions; and 3) suggest Akirin2 dysfunction may be relevant to neurodegenerative diseases.

Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited “absent” or “anomalous” P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

Preterm birth alters the development of cortical microstructure and morphology at term-equivalent age

Introduction: The dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. Methods: We sought to first map typical cortical micro and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth (n=270). Then we offer a comprehensive characterisation of the cortical consequences of preterm birth in 78 preterm infants scanned at term-equivalent age (37-44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. Results: In the term-born neonatal brain, we observed regionally specific age-associated changes in cortical morphology and microstructure, including rapid surface expansion, cortical thickness increase, reduction in cortical anisotropy and increase in neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. Conclusion: We showed that preterm birth alters cortical micro and macrostructural maturation near the time of full-term birth. Deviations from normative development were highly variable between individual preterm infants.

Central Auditory Nervous System Stimulation through the Cochlear Implant Use and Its Behavioral Impacts: A Longitudinal Study of Case Series

The purpose of this study was to investigate, over a period of five years, the cortical maturation of the central auditory pathways and its impacts on the auditory and oral language development of children with effective use and without effective use of a Cochlear Implant (CI). A case series study was conducted with seven children who were CI users and seven children with normal hearing, with age- and gender-matched to CI users. The assessment was performed by long-latency auditory evoked potentials and auditory and oral language behavioral protocols. The results pronounced P1 latency decrease in all CI users in the first nine months. Over five years, five children with effective CI use presented decrease or stabilization of P1 latency and a gradual development of auditory and oral language skills, although, for most of the children, the electrophysiological and behavior results remained poor than their hearing peers’ results. Two children who stopped the effective use of CI after the first year of activation had worsened auditory and oral language behavioral skills and presented increased P1 latency. A negative correlation was observed between behavioral measures and the P1 latency, the P1 component being considered an important clinical resource capable of measuring the cortical maturation and the behavioral evolution.

Asymmetric cortical development and prognosis in fetuses with isolated mild fetal ventriculomegaly: an observational prospective study

Background Assessments of cortical development and identifying factors that may result in a poor prognosis for fetuses with isolated mild ventriculomegaly (IMVM) is a hot research topic. We aimed to perform a constant, detailed assessment of cortical development in IMVM fetuses using ultrasound and determine whether asymmetric cortical development occurred. Moreover, we aimed to estimate the prognosis of IMVM fetuses and compare the difference in the prognosis of IMVM fetuses presenting symmetric and asymmetric cortical maturation. Methods IMVM was diagnosed by regular ultrasound, neurosonography and fetal MRI. Genetic and TORCH examinations were conducted to exclude common genetic abnormalities and TORCH infection of fetuses. Ultrasound examinations were conducted at an interval of 2–3 weeks to record sulcus development in IMVM fetuses using a scoring system. The neonatal behavioral neurological assessment (NBNA), the Ages and Stages Questionnaire, Third Edition (ASQ-3) and the Bayley Scales of Infant Development, First Edition (BSID-I) were performed after birth. Results Forty fetuses with IMVM were included: twenty showed asymmetric cortical maturation and twenty showed symmetric cortical maturation. For IMVM fetuses presenting asymmetric cortical maturation, the mean gestational age (GA) at the first diagnosis of relatively delayed development was 24.23 weeks for the parieto-occipital sulcus, 24.71 weeks for the calcarine sulcus, and 26.43 weeks for the cingulate sulcus. All the sulci with delayed development underwent ‘catch-up growth’ and developed to the same grade as the sulci of the other hemisphere. The mean GA at which the two sides developed to the same grade was 29.40 weeks for the parieto-occipital sulcus, 29.30 weeks for the calcarine sulcus and 31.27 weeks for the cingulate sulcus. The NBNA, ASQ-3 and BSID-I scores of all patients were in the normal range. Conclusions IMVM fetuses may show mild asymmetric cortical maturation in the second trimester, but the relatively delayed sulci undergo ‘catch-up growth’. The neurodevelopment of IMVM fetuses presenting asymmetric cortical maturation and ‘catch-up growth’ is not statistically significantly different from IMVM fetuses presenting symmetric cortical maturation.

Characterization of late structural maturation with a neuroanatomical marker that considers both cortical thickness and intracortical myelination

ABSTRACTThe cortical ribbon changes throughout a person’s lifespan, with the most significant changes occurring during crucial development and aging periods. Changes during adulthood are rarely investigated due to the scarcity of neuroimaging data during this period. After childhood, the brain loses gray matter, which is evidenced by an apparent reduction in cortical thickness (CT); one factor of this thinning process is intense ongoing intracortical myelination (MYEL). Here, we report age-related changes in CT, MYEL, and their ratio in 447 participants aged 18 to 57 years (BIL&GIN cohort). We propose the CT/MYEL ratio to be a multimodal cortical maturation index (MATUR) capable of reflecting 1) stages during which CT and MYEL patterns diverge and 2) the regional differences in cortical maturation that occur in adulthood. Age mainly decreased CT in all cortical regions, with larger reductions occurring in the bilateral insular lobes, temporal and frontal poles, and cingulate cortices. Age led to a linear increase in MYEL in the entire cortex and larger increases in the primary motor, auditory, and visual cortices. The effects of age on the MATUR index were characterized by both linear and quadratic components. The linear component mimicked the pattern found in CT, with 1) a robust amplification of the global and regional effects of age on CT and 2) evidence of new bilateral linear decreases in the frontal and cortical cortices. Most importantly, age exhibited additional large quadratic effects on the MATUR index in the bilateral frontal (more prominent in the right hemisphere), parietal, temporal, and cingulate regions that were not highlighted by the CT metric. Thus, the MATUR index was more sensitive to age-related cortical structural changes during adulthood than was either CT or MYEL alone. As evidenced by the large quadratic component of the effect of age, the newly proposed maturation index dramatically improved the characterization of the regional cortical territories, uncovering the latest brain maturation steps that occur before stabilization and deterioration occur in mid- and late adulthood.