Loss of Twist1 and balanced retinoic acid signaling from the meninges causes cortical folding in mice.

Secondary lissencephaly evolved in mice due to effects on neurogenesis and the tangential distribution of neurons. Signaling pathways that help maintain lissencephaly are still poorly understood. We show that inactivating Twist1 in the primitive meninges causes cortical folding in mice. Cell proliferation in the meninges is reduced, causing loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Regionalized loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. The ventricular zone expands and the forebrain lengthens at this time due to expansion of apical radial glia. As the cortex expands, regionalized differences in the levels of neurogenesis are coupled with changes to the tangential distribution of neurons. Consequentially, cortical growth at and adjacent to the midline accelerates with respect to more dorsolateral regions, resulting in cortical buckling and folding. Maternal retinoic acid supplementation suppresses cortical folding by normalizing forebrain length, neurogenesis and the tangential distribution of neurons. These results suggest that Twist1 and balanced retinoic acid signaling from the meninges are required to maintain normal levels of neurogenesis and lissencephaly in mice.

Role of intracortical neuropil growth in the gyrification of the primate cerebral cortex.

The convolutions of the mammalian cerebral cortex allow the enlargement of its surface and addition of novel functional areas during evolution while minimizing expansion of the cranium. Cognitive neurodevelopmental disorders in humans, including microcephaly and lissencephaly, are often associated with impaired gyrification. In the classical model of gyrification, surface area is initially set by the number of radial units, and the forces driving cortical folding include neuronal growth, formation of neuropil, glial cell intercalation, and the patterned growth of subcortical white matter. An alternative model proposes that specified neurogenic hotspots in the outer subventricular zone (oSVZ) produce larger numbers of neurons that generate convexities in the cortex. This directly contradicts reports showing that cortical neurogenesis and settling of neurons into the cortical plate in primates, including humans, are completed well prior to the formation of secondary and tertiary gyri and indeed most primary gyri. In addition, during the main period of gyrification, the oSVZ produces mainly astrocytes and oligodendrocytes. Here we describe how rapid growth of intracortical neuropil, addition of glial cells, and enlargement of subcortical white matter in primates are the primary forces responsible for the post-neurogenic expansion of the cortical surface and formation of gyri during fetal development. Using immunohistochemistry for markers of proliferation and glial and neuronal progenitors combined with transcriptomic analysis, we show that neurogenesis in the ventricular zone and oSVZ is phased out and transitions to gliogenesis prior to gyral development. In summary, our data support the classical model of gyrification and provide insight into the pathogenesis of congenital cortical malformations.

Heterogeneous growth of the insula shapes the human brain.

The human cerebrum consists of a precise and stereotyped arrangement of lobes, primary gyri, and connectivity that underlies human cognition [P. Rakic, Nat. Rev. Neurosci. 10, 724-735 (2009)]. The development of this arrangement is less clear. Current models explain individual primary gyrification but largely do not account for the global configuration of the cerebral lobes [T. Tallinen, J. Y. Chung, J. S. Biggins, L. Mahadevan, Proc. Natl. Acad. Sci. U.S.A. 111, 12667-12672 (2014) and D. C. Van Essen, Nature 385, 313-318 (1997)]. The insula, buried in the depths of the Sylvian fissure, is unique in terms of gyral anatomy and size. Here, we quantitatively show that the insula has unique morphology and location in the cerebrum and that these key differences emerge during fetal development. Finally, we identify quantitative differences in developmental migration patterns to the insula that may underlie these differences. We calculated morphologic data in the insula and other lobes in adults (N = 107) and in an in utero fetal brain atlas (N = 81 healthy fetuses). In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Spherical projection analysis demonstrates that the lenticular nuclei obstruct 60 to 70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify radial glial fascicles that originate from the VZ and curve around the lenticular nuclei to form the insula. These results confirm existing models of radial migration to the cortex and illustrate findings that suggest differential insular and cerebral development, laying the groundwork to understand cerebral malformations and insular function and pathologies.

TMEM161B modulates radial glial scaffolding in neocortical development.

TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

Biomechanical models and mechanisms of cellular morphogenesis and cerebral cortical expansion and folding.

Morphogenesis of the nervous system involves a highly complex spatio-temporal pattern of physical forces (mainly tension and pressure) acting on cells and tissues that are pliable but have an intricately organized cytoskeletal infrastructure. This review begins by covering basic principles of biomechanics and the core cytoskeletal toolkit used to regulate the shapes of cells and tissues during embryogenesis and neural development. It illustrates how the principle of 'tensegrity' provides a useful conceptual framework for understanding how cells dynamically respond to forces that are generated internally or applied externally. The latter part of the review builds on this foundation in considering the development of mammalian cerebral cortex. The main focus is on cortical expansion and folding - processes that take place over an extended period of prenatal and postnatal development. Cortical expansion and folding are likely to involve many complementary mechanisms, some related to regulating cell proliferation and migration and others related to specific types and patterns of mechanical tension and pressure. Three distinct multi-mechanism models are evaluated in relation to a set of 18 key experimental observations and findings. The Composite Tension Plus (CT+) model is introduced as an updated version of a previous multi-component Differential Expansion Sandwich Plus (DES+) model (Van Essen, 2020); the new CT+ model includes 10 distinct mechanisms and has the greatest explanatory power among published models to date. Much needs to be done in order to validate specific mechanistic components and to assess their relative importance in different species, and important directions for future research are suggested.

Anatomical and behavioural correlates of auditory perception in developmental dyslexia.

Developmental dyslexia is typically associated with difficulties in basic auditory processing and in manipulating speech sounds. However, the neuroanatomical correlates of auditory difficulties in developmental dyslexia (DD) and their contribution to individual clinical phenotypes are still unknown. Recent intracranial electrocorticography findings associated processing of sound amplitude rises and speech sounds with posterior and middle superior temporal gyrus (STG), respectively. We hypothesize that regional STG anatomy will relate to specific auditory abilities in DD, and that auditory processing abilities will relate to behavioral difficulties with speech and reading. One hundred and ten children (78 DD, 32 typically developing, age 7-15 years) completed amplitude rise time and speech in noise discrimination tasks. They also underwent a battery of cognitive tests. Anatomical MRI scans were used to identify regions in which local cortical gyrification complexity correlated with auditory behavior. Behaviorally, amplitude rise time but not speech in noise performance was impaired in DD. Neurally, amplitude rise time and speech in noise performance correlated with gyrification in posterior and middle STG, respectively. Furthermore, amplitude rise time significantly contributed to reading impairments in DD, while speech in noise only explained variance in phonological awareness. Finally, amplitude rise time and speech in noise performance were not correlated, and each task was correlated with distinct neuropsychological measures, emphasizing their unique contributions to DD. Overall, we provide a direct link between the neurodevelopment of the left STG and individual variability in auditory processing abilities in neurotypical and dyslexic populations.

Reduced gyrification in fetal growth restriction with prenatal magnetic resonance images.

Placental-related fetal growth restriction, resulting from placental dysfunction, impacts 3-5% of pregnancies and is linked to elevated risk of adverse neurodevelopmental outcomes. In response, the fetus employs a mechanism known as brain-sparing, redirecting blood flow to the cerebral circuit, for adequate supply to the brain. In this study we aimed to quantitatively evaluate disparities in gyrification and brain volumes among fetal growth restriction, small for gestational age and appropriate-for gestational-age fetuses. Additionally, we compared fetal growth restriction fetuses with and without brain-sparing. The study encompassed 106 fetuses: 35 fetal growth restriction (14 with and 21 without brain-sparing), 8 small for gestational age, and 63 appropriate for gestational age. Gyrification, supratentorial, and infratentorial brain volumes were automatically computed from T2-weighted magnetic resonance images, following semi-automatic brain segmentation. Fetal growth restriction fetuses exhibited significantly reduced gyrification and brain volumes compared to appropriate for gestational age (P < 0.001). Small for gestational age fetuses displayed significantly reduced gyrification (P = 0.038) and smaller supratentorial volume (P < 0.001) compared to appropriate for gestational age. Moreover, fetal growth restriction fetuses with BS demonstrated reduced gyrification compared to those without BS (P = 0.04), with no significant differences observed in brain volumes. These findings demonstrate that brain development is affected in fetuses with fetal growth restriction, more severely than in small for gestational age, and support the concept that vasodilatation of the fetal middle cerebral artery reflects more severe hypoxemia, affecting brain development.

Toward a better understanding of how a gyrified brain develops.

The size and shape of the cerebral cortex have changed dramatically across evolution. For some species, the cortex remains smooth (lissencephalic) throughout their lifetime, while for other species, including humans and other primates, the cortex increases substantially in size and becomes folded (gyrencephalic). A folded cortex boasts substantially increased surface area, cortical thickness, and neuronal density, and it is therefore associated with higher-order cognitive abilities. The mechanisms that drive gyrification in some species, while others remain lissencephalic despite many shared neurodevelopmental features, have been a topic of investigation for many decades, giving rise to multiple perspectives of how the gyrified cerebral cortex acquires its unique shape. Recently, a structurally unique germinal layer, known as the outer subventricular zone, and the specialized cell type that populates it, called basal radial glial cells, were identified, and these have been shown to be indispensable for cortical expansion and folding. Transcriptional analyses and gene manipulation models have provided an invaluable insight into many of the key cellular and genetic drivers of gyrification. However, the degree to which certain biomechanical, genetic, and cellular processes drive gyrification remains under investigation. This review considers the key aspects of cerebral expansion and folding that have been identified to date and how theories of gyrification have evolved to incorporate this new knowledge.

Multimodal neuroimaging fusion unravel structural-functional-neurotransmitter change in Parkinson's disease with impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. METHODS: Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. RESULTS: Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of µ-opioid pathway (r = -0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. CONCLUSIONS: Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD.

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

Association between cortical gyrification and white matter integrity in spinocerebellar ataxia type 3.

Gray matter volume and thickness reductions have been reported in patients with spinocerebellar ataxia type 3 (SCA3), whereas cortical gyrification alterations of this disease remain largely unexplored. Using local gyrification index (LGI) and fractional anisotropy (FA) from structural and diffusion MRI data, this study investigated the cortical gyrification alterations as well as their relationship with white matter microstructural abnormalities in patients with SCA3 (n = 61) compared with healthy controls (n = 69). We found widespread reductions in cortical LGI and white matter FA in patients with SCA3 and that changes in these 2 features were also coupled. In the patient group, the LGI of the left middle frontal gyrus, bilateral insula, and superior temporal gyrus was negatively correlated with the severity of depressive symptoms, and the FA of a cluster in the left cerebellum was negatively correlated with the Scale for the Assessment and Rating of Ataxia scores. Our findings suggest that the gyrification abnormalities observed in this study may account for the clinical heterogeneity in SCA3 and are likely to be mediated by the underlying white matter microstructural abnormalities of this disease.

Neurological soft signs in adolescents are associated with brain structure.

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

Gyrification of the medial and lateral orbitofrontal cortex in first-degree relatives of patients with obsessive-compulsive disorder.

Gyrification patterns reflect early neurodevelopment and could be highly heritable. While some discrepant results have been reported, the most consistent finding was that patients with obsessive-compulsive disorder showed altered gyrification patterns in the orbitofrontal cortex. Nevertheless, no study has investigated the alterations in gyrification in unaffected first-degree relatives of patients with obsessive-compulsive disorder. We measured local gyrification by the FreeSurfer software in 23 unaffected first-degree relatives of patients with obsessive-compulsive disorder and 52 healthy control participants. We explored differences in the local gyrification index using vertex-wise whole-brain analysis and a region of interest-based approach in the medial and lateral orbitofrontal cortex. There was no significant difference in the local gyrification index between the 2 groups in the vertex-wise whole-brain analysis. Region of interest analyses showed that, compared with healthy controls, first-degree relatives showed significantly reduced local gyrification index in the left medial and lateral orbitofrontal cortex. A negative correlation was observed between the reduced local gyrification index in lateral orbitofrontal cortex and the subclinical anxiety scores of first-degree relatives. Our results showed that first-degree relatives of patients with obsessive-compulsive disorder had an altered local gyrification index in the orbitofrontal cortex. Especially, reduced local gyrification index in lateral orbitofrontal cortex associated with subclinical anxiety symptom could be a potential neurodevelopmental marker for the illness onset.

Intra-individual cortical networks in Anorexia Nervosa: Evidence from a longitudinal dataset.

OBJECTIVE: This work investigates cortical thickness (CT) and gyrification patterns in Anorexia Nervosa (AN) before and after short-term weight restoration using graph theory tools. METHODS: 38 female adolescents with AN underwent structural magnetic resonance imaging scans at baseline and after - on average - 3.5 months following short-term weight restoration while 53 age-matched healthy controls (HCs) were scanned once. Graph measures were compared between groups and longitudinally within the AN group. Associations with clinical measures such as age of onset, duration of illness, BMI standard deviation score (BMI-SDS), and longitudinal weight changes were tested via stepwise regression. RESULTS: Cortical thickness graphs of patients with acute AN displayed lower modularity and small-world index (SWI) than HCs. Modularity recovered after weight gain. Reduced global efficiency and SWI were observed in patients at baseline compared to HCs based on gyrification networks. Significant associations between local clustering of CT at admission and BMI-SDS, and clustering/global efficiency of gyrification and duration of illness emerged. CONCLUSIONS: Our results indicate a shift towards less organised CT networks in patients with acute AN. After weight recovery, the disarrangement seems to be partially reduced. However, longer-term follow-ups are needed to determine whether cortical organizational patterns fully return to normal.

Data-driven multivariate identification of gyrification patterns in a transdiagnostic patient cohort: A cluster analysis approach.

BACKGROUND: Multivariate data-driven statistical approaches offer the opportunity to study multi-dimensional interdependences between a large set of biological parameters, such as high-dimensional brain imaging data. For gyrification, a putative marker of early neurodevelopment, direct comparisons of patterns among multiple psychiatric disorders and investigations of potential heterogeneity of gyrification within one disorder and a transdiagnostic characterization of neuroanatomical features are lacking. METHODS: In this study we used a data-driven, multivariate statistical approach to analyze cortical gyrification in a large cohort of N = 1028 patients with major psychiatric disorders (Major depressive disorder: n = 783, bipolar disorder: n = 129, schizoaffective disorder: n = 44, schizophrenia: n = 72) to identify cluster patterns of gyrification beyond diagnostic categories. RESULTS: Cluster analysis applied on gyrification data of 68 brain regions (DK-40 atlas) identified three clusters showing difference in overall (global) gyrification and minor regional variation (regions). Newly, data-driven subgroups are further discriminative in cognition and transdiagnostic disease risk factors. CONCLUSIONS: Results indicate that gyrification is associated with transdiagnostic risk factors rather than diagnostic categories and further imply a more global role of gyrification related to mental health than a disorder specific one. Our findings support previous studies highlighting the importance of association cortices involved in psychopathology. Explorative, data-driven approaches like ours can help to elucidate if the brain imaging data on hand and its a priori applied grouping actually has the potential to find meaningful effects or if previous hypotheses about the phenotype as well as its grouping have to be revisited.

Multivariate Concavity Amplitude Index (MCAI) for characterizing Heschl's gyrus shape.

Heschl's gyrus (HG), which includes primary auditory cortex, is highly variable in its shape (i.e. gyrification patterns), between hemispheres and across individuals. Differences in HG shape have been observed in the context of phonetic learning skill and expertise, and of professional musicianship, among others. Two of the most common configurations of HG include single HG, where a single transverse temporal gyrus is present, and common stem duplications (CSD), where a sulcus intermedius (SI) arises from the lateral aspect of HG. Here we describe a new toolbox, called 'Multivariate Concavity Amplitude Index' (MCAI), which automatically assesses the shape of HG. MCAI works on the output of TASH, our first toolbox which automatically segments HG, and computes continuous indices of concavity, which arise when sulci are present, along the outer perimeter of an inflated representation of HG, in a directional manner. Thus, MCAI provides a multivariate measure of shape, which is reproducible and sensitive to small variations in shape. We applied MCAI to structural magnetic resonance imaging (MRI) data of N=181 participants, including professional and amateur musicians and from non-musicians. Former studies have shown large variations in HG shape in the former groups. We validated MCAI by showing high correlations between the dominant (i.e. highest) lateral concavity values and continuous visual assessments of the degree of lateral gyrification of the first gyrus. As an application of MCAI, we also replicated previous visually obtained findings showing a higher likelihood of bilateral CSDs in musicians. MCAI opens a wide range of applications in evaluating HG shape in the context of individual differences, expertise, disorder and genetics.

The longitudinal impact of type 2 diabetes on brain gyrification.

Type 2 diabetes has an effect on brain structure, including cortical gyrification. The significance of these changes is better understood if assessed over time. However, there is a lack of studies assessing longitudinally the effect of this disease with complex aethology in gyrification. While changes in this feature have been associated mainly with genetic legacy, our study allowed to shed light on the effect of the variation of glycaemic profile over time in gyrification in this metabolic disease. In this longitudinal study, we analysed brain anatomical magnetic resonance images of 15 participants with type 2 diabetes and 13 healthy control participants to investigate the impact of this metabolic disease on the gyrification index over a 7-year period. We observed a significant interaction between time and group in six regions, four of which (left precentral gyrus, left gyrus rectus, left subcentral gyrus and sulci and right inferior temporal gyrus) showed an increase in gyrification in type 2 diabetes and a decrease in the control group and the two others (left pericallosal sulcus and right inferior frontal sulcus) the opposite pattern. The variation of the gyrification was correlated with the variation of the glycaemic profile. Following the interaction, the simple main effect of time in each group separately has shown that in the group with diabetes, there were more regions susceptible to alterations of gyrification. In sum, our results raise credit for the possibility that glycaemic control also might influence gyrification in type 2 diabetes.

Association between childhood maltreatment and cortical folding in women with eating disorders.

Childhood maltreatment (CM) is associated with distinct clinical and biological characteristics in people with eating disorders (EDs). The measurement of local gyrification index (lGI) may help to better characterize the impact of CM on cortical structure. Thus, the present study investigated the association of CM with lGI in women with EDs. Twenty-six women with anorexia nervosa (AN) and 24 with bulimia nervosa (BN) underwent a 3T MRI scan. All participants filled in the Childhood Trauma Questionnaire. All neuroimaging data were processed by FreeSurfer. LGI maps underwent a general linear model to evaluate differences between groups with or without CM. People with AN and BN were merged together. Based on the Childhood Trauma Questionnaire cutoff scores, 24 participants were identified as maltreated and 26 as non-maltreated. Maltreated people with EDs showed a significantly lower lGI in the left middle temporal gyrus compared with non-maltreated people, whereas no differences emerged in the right hemisphere between groups. The present study showed that in people with EDs, CM is associated with reduced cortical folding in the left middle temporal gyrus, an area that could be involved in ED psychopathology. This finding corroborates the hypothesis of a 'maltreated ecophenotype', which argues that CM may allow to biologically, other than clinically, distinguish individuals with the same psychiatric disorder.

Cortical folding: when, where, how, and why?

Why the cerebral cortex folds in some mammals but not in others has long fascinated and mystified neurobiologists. Over the past century-especially the past decade-researchers have used theory and experiment to support different folding mechanisms such as tissue buckling from mechanical stress, axon tethering, localized proliferation, and external constraints. In this review, we synthesize these mechanisms into a unifying framework and introduce a hitherto unappreciated mechanism, the radial intercalation of new neurons at the top of the cortical plate, as a likely proximate force for tangential expansion that then leads to cortical folding. The interplay between radial intercalation and various biasing factors, such as local variations in proliferation rate and connectivity, can explain the formation of both random and stereotypically positioned folds.

Similar cortical morphometry trajectories from 5 to 9 years in children with perinatal HIV who started treatment before age 2 years and uninfected controls.

BACKGROUND: Life-long early ART (started before age 2 years), often with periods of treatment interruption, is now the standard of care in pediatric HIV infection. Although cross-sectional studies have investigated HIV-related differences in cortical morphology in the setting of early ART and ART interruption, the long-term impact on cortical developmental trajectories is unclear. This study compares the longitudinal trajectories of cortical thickness and folding (gyrification) from age 5 to 9 years in a subset of children perinatally infected with HIV (CPHIV) from the Children with HIV Early antiRetroviral therapy (CHER) trial to age-matched children without HIV infection. METHODS: 75 CHER participants in follow-up care at FAMCRU (Family Centre for Research with Ubuntu), as well as 66 age-matched controls, received magnetic resonance imaging (MRI) on a 3 T Siemens Allegra at ages 5, 7 and/or 9 years. MR images were processed, and cortical surfaces reconstructed using the FreeSurfer longitudinal processing stream. Vertex-wise linear mixed effects (LME) analyses were performed across the whole brain to compare the means and linear rates of change of cortical thickness and gyrification from 5 to 9 years between CPHIV and controls, as well as to examine effects of ART interruption. RESULTS: Children without HIV demonstrated generalized cortical thinning from 5 to 9 years, with the rate of thinning varying by region, as well as regional age-related gyrification increases. Overall, the means and developmental trajectories of cortical thickness and gyrification were similar in CPHIV. However, at an uncorrected p < 0.005, 6 regions were identified where the cortex of CPHIV was thicker than in uninfected children, namely bilateral insula, left supramarginal, lateral orbitofrontal and superior temporal, and right medial superior frontal regions. Planned ART interruption did not affect development of cortical morphometry. CONCLUSIONS: Although our results suggest that normal development of cortical morphometry between the ages of 5 and 9 years is preserved in CPHIV who started ART early, these findings require further confirmation with longitudinal follow-up through the vulnerable adolescent period.