Adolescent brain maturation and cortical folding: evidence for reductions in gyrification

Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development

Impact of FAAH Genotype and Marijuana Use on Brain Structure and Neuropsychological Performance in Emerging Adults

Introduction: Chronic MJ use may be associated with higher cognitive ability impairments (see Lisdahl et al., 2013). Regions undergoing later maturation (Gogtay 2004), may be at increased risk for MJ-induced alterations. Endogenous cannabinoid signaling (ECS) is modulated by the function the enzyme Fatty Acid Amide Hydrolase (see Ho & Hilard, 2005), thus the gene encoding for this enzyme (FAAH) impacts ECS (Sipe et al., 2002). Here, we examine the impact of MJ use and FAAH genotype on PFC complexity and underlying frontal white matter (WM) integrity in young adults. Methods: Participants included 37 MJ users and 37 non-using young adults (ages 18-25). Of those, 27 were FAAH A carriers and 47 were homozygous (C/C) carriers. Exclusion criteria included co-morbid psychiatric and neurologic disorders and excessive other drug use. Brain complexity and WM integrity was measured using local gyrification index and Tracula programs. The Letter Number Sequencing, PASAT and D-Kefs c/w interference measured complex attention and inhibition. Multiple regressions and Pearson r correlations were used to predict LGI, WM integrity and cognitive performance indices from MJ use status, FAAH status, and MJ*FAAH interactions controlling for demographic variables and comorbid drug use. Results: MJ users demonstrated decreased LGI in bilateral vmPFC (RH: [beta=-.54, p\u3c.001] and LH: [beta=-.55, p\u3c.001]); bilateral mPFC (RH: [beta=-.48, p=.001] and LH: [beta=-.51, p\u3c.001]); and bilateral frontal poles (RH: [beta=-.31, p=.02]; LH: [beta=-.43, p=.004]), with increased LGI in LH DLPFC [beta=.40, p=.004]. Controlling for the same variables, reduced WM integrity was found in bilateral UCF (RH: [beta=.32, p=.03] and LH: [beta=.31, p=.03]) and fMinor [beta=.27, p=.05] tracts of MJ users. Significant interactions between MJ*FAAH were seen predicting LGI in LH OFC [beta=-.24, p=.04] and WM integrity in fMinor [beta=.26, p=.04] and LH ATR [beta=.36, p=.003]. In MJ users, increased gyrification was associated with better LNS performance in RH mPFC [r=.51, p=.001], RH vmPFC [r=.41, p=.01], and RH frontal pole [r=.45, p=.005] and a negative correlation with gyrification and color-word completion time in LH vmPFC [r=-.32, p=.05]. In MJ users, decreased WM integrity was associated with greater PASAT performance in the RH UNC [r=.38, p=.02]. Discussion: MJ use was associated with reduced LGI in several PFC regions with one region showing an opposite relationship. These results are consistent with Mata and colleagues (2010). We also found reduced WM integrity in fronto-temporal tracts, which may have important emotion regulation implications. These brain characteristics were also moderated by FAAH genotype. Additional implications of ECS and brain health will be discussed

Shared pattern of impaired social communication and cognitive ability in the youth brain across diagnostic boundaries

Background Abnormalities in brain structure are shared across diagnostic categories. Given the high rate of comorbidity, the interplay of relevant behavioural factors may also cross these classic boundaries. Methods We aimed to detect brain-based dimensions of behavioural factors using canonical correlation and independent component analysis in a clinical youth sample (n = 1732, 64 % male, age: 5–21 years). Results We identified two correlated patterns of brain structure and behavioural factors. The first mode reflected physical and cognitive maturation (r = 0.92, p = .005). The second mode reflected lower cognitive ability, poorer social skills, and psychological difficulties (r = 0.92, p = .006). Elevated scores on the second mode were a common feature across all diagnostic boundaries and linked to the number of comorbid diagnoses independently of age. Critically, this brain pattern predicted normative cognitive deviations in an independent population-based sample (n = 1253, 54 % female, age: 8–21 years), supporting the generalisability and external validity of the reported brain-behaviour relationships. Conclusions These results reveal dimensions of brain-behaviour associations across diagnostic boundaries, highlighting potent disorder-general patterns as the most prominent. In addition to providing biologically informed patterns of relevant behavioural factors for mental illness, this contributes to a growing body of evidence in favour of transdiagnostic approaches to prevention and intervention.publishedVersio

Gyrification brain abnormalities as predictors of outcome in anorexia nervosa.

Gyrification brain abnormalities are considered a marker of early deviations from normal developmental trajectories and a putative predictor of poor outcome in psychiatric disorders. The aim of this study was to explore cortical folding morphology in patients with anorexia nervosa (AN). A MRI brain study was conducted on 38 patients with AN, 20 fully recovered patients, and 38 healthy women. Local gyrification was measured with procedures implemented in FreeSurfer. Vertex-wise comparisons were carried out to compare: (1) AN patients and healthy women; (2) patients with a full remission at a 3-year longitudinal follow-up assessment and patients who did not recover. AN patients exhibited significantly lower gyrification when compared with healthy controls. Patients with a poor 3-year outcome had significantly lower baseline gyrification when compared to both healthy women and patients with full recovery at follow-up, even after controlling for the effects of duration of illness and gray matter volume. No significant correlation has been found between gyrification, body mass index, amount of weight loss, onset age, and duration of illness. Brain gyrification significantly predicted outcome at follow-up even after controlling for the effects of duration of illness and other clinical prognostic factors. Although the role of starvation in determining our findings cannot be excluded, our study showed that brain gyrification might be a predictor of outcome in AN. Further studies are needed to understand if brain gyrification abnormalities are indices of early neurodevelopmental alterations, the consequence of starvation, or the interaction between both factors

Rethinking Phylogeny and Ontogeny in Hominin Brain Evolution

Theories of hominin and human cognitive evolution have traditionally focused on the phylogeny of the human brain, and on comparisons of human and primate brains in relation to social or ecological variables. Far less attention has been paid to ontogenetic processes, despite the recognition that experience has a profound influence on adult cognition. In this paper we discuss the interplay between phylogeny and ontogeny by examining relationships between human brain size, developmental scheduling and cognition. The correlates of large brains include not only altered subsistence and life-history strategies to meet associated energetic costs, but also on macro- and micro-scale structural adaptations required to meet increased processing costs. This means that larger brains are of necessity more highly interconnected brains, with higher degrees of folding of the neocortex (gyrification) and higher ratios of myelinated connections between neurons (white matter) to neurons themselves (grey matter). Here we argue that the combination of these evolutionary trends underpins the complexity of human behaviour, as the neural circuits involved in cognitive mechanisms such as the mirror neuron system (the system governing motor emulation and imitation) and theory of mind (fundamental in social cognition) mature only slowly, and require considerable socially-scaffolded experience to develop to their full potential. These abilities are likely to be fundamental in characteristically human behaviours such as the cultural transmission of complex forms of tool manufacture and use, attested to in the archaeological record. Their elaborated modern human forms, we argue, are possible only in the context of the evolution of relatively slower trajectories of brain growth and hence longer periods during which the growing brain can be influenced by experience among modern humans relative to other primates. Here we review some of the differences in ontogenetic brain development between humans and other primates, and compare the rates and trajectories of neural development between ourselves and our closest living relatives the chimpanzees to suggest that the human pattern of expanded periods of growth coupled with slower trajectories of neural development is likely to have been of huge significance during hominin evolution. In addition, we discuss fossil and archaeological proxies which might allow the reconstruction of evolutionary patterns of development, suggesting that it is only post-Homo erectus and specifically among Homo heidelbergensis and Homo neanderthalensis populations that developmental patterns approximate those of modern humans, arguing for a similar – but not identical – role for socially-scaffolded learning of complex technical skills as among modern groups in these species

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Altered Cortical Gyrification in Adults Who Were Born Very Preterm and Its Associations With Cognition and Mental Health

Background: The last trimester of pregnancy is a critical period for the establishment of cortical gyrification, and altered folding patterns have been reported following very preterm birth (\u3c 33 weeks of gestation) in childhood and adolescence. However, research is scant on the persistence of such alterations in adulthood and their associations with cognitive and psychiatric outcomes. Methods: We studied 79 very preterm and 81 age-matched full-term control adults. T1-weighted magnetic resonance images were used to measure a local gyrification index (LGI), indicating the degree of folding across multiple vertices of the reconstructed cortical surface. Group and group-by-sex LGI differences were assessed by means of per-vertex adjustment for cortical thickness and overall intracranial volume. Within-group correlations were also computed between LGI and functional outcomes, including general intelligence (IQ) and psychopathology. Results: Very preterm adults had significantly reduced LGI in extensive cortical regions encompassing the frontal, anterior temporal, and occipitoparietal lobes. Alterations in lateral fronto-temporal-parietal and medial occipitoparietal regions were present in both men and women, although men showed more extensive alterations. In both very preterm and control adults, higher LGI was associated with higher IQ and lower psychopathology scores, with the spatial distribution of these associations substantially differing between the two groups. Conclusions: Very preterm adults’ brains are characterized by significant and widespread local hypogyria, and these alterations might be implicated in cognitive and psychiatric outcomes. Gyrification reflects an early developmental process and provides a fingerprint for very preterm birth

Neurological soft signs in adolescents are associated with brain structure and postural control

Neurological soft signs (NSS) are minor deviations from the norm in sensory and motor performance. NSS exist in the general population but are more frequently found in cohorts with neurodevelopmental disorders. NSS are considered a diffuse and unspecific marker of altered neurodevelopment but receive increasing attention since the presence of NSS in children has been found to be predictive of psychiatric disorders in late adolescence. To date, only little is known about potential neurodevelopmental alterations that may underlay the presence of NSS. The prevalence of NSS has been shown to decrease during adolescence as part of continued neural development and brain re-wiring processes. Therefore, adolescence has been proposed as an important phase for the manifestation or outgrowing of NSS. The underlying mechanisms that may underly this process, however, are largely unknown. As NSS are subtle signs and commonly identified by subjective observer-based neurological examinations, quantitative tools may help to objectively investigate functional and structural correlates associated with NSS. For the work included in this dissertation, healthy adolescent athletes from three European countries were investigated. All participants underwent a neurological examination, resulting in a categorization of participants into groups with and without NSS (NSS+/NSS-). A total NSS score was calculated to provide a continuous measure spanning the whole spectrum of NSS. Two quantitative tools were used to investigate functional and structural correlates of NSS in healthy adolescents: Study I) Instrumented force plate measures to investigate postural control (Bonke et al., 2023), and Study II) Structural magnetic resonance imaging to investigate brain morphology and white matter microstructure (Bonke et al., 2022). Study I aimed to investigate the incremental value of instrumented force plate measures in addition to observer-based neurological examinations. Such associations have not been assessed before but are important for capturing subtle alterations in postural control. This will help to acquire a more comprehensive assessment of motor development. We found no statistically significant differences in postural control between NSS+ and NSS- group. However, participants performing non-optimal in the diadochokinesis sub-test measuring pronation/supination of forearms showed significantly reduced postural control in the medial-lateral (ML) direction. Moreover, the total NSS score correlated significantly with postural control performance in the ML direction. Findings from this study reveal that adolescents with NSS, and in particular adolescents that perform non-optimal in pronation/supination movements of the forearms also perform worse in ML postural control assessed by force plate assessments. As pronation/supination movements of forearms and ML postural control continue to mature until adolescence, it can be assumed that these functions are related and may indicate altered motor development. Study II aimed to identify and characterize NSS-related brain structure alterations using structural magnetic resonance imaging. NSS-related brain structure alterations have not yet been investigated in healthy adolescents. However, this investigation is of high relevance to better understand potential alterations in adolescent brain-rewiring processes related to NSS. Using T1-weighted imaging, we found significantly higher gyrification in the left superior frontal and parietal lobe in the group of adolescents with NSS, likely reflecting alterations in synaptic pruning. We did not find differences in cortical volume or thickness. Using diffusion tensor imaging, we found lower tissue fractional anisotropy (FAt) and higher tissue radial diffusivity (RDt) in widespread white matter clusters in the group of adolescents with NSS, likely indicating alterations in myelination. Findings from this study reveal that NSS in healthy adolescents are associated with brain structure alterations that can be objectively quantified using magnetic resonance imaging. As of now, the relevance of NSS-related brain structure alterations in otherwise healthy adolescents is not fully understood. Future studies should assess whether these alterations may explain the described association between NSS and psychiatric disorders. In summary, the work presented in this doctoral dissertation uses two different quantitative measures to objectively investigate functional and structural differences between adolescents with and without NSS. Insights derived from this work show the beneficial use of instrumented tools to complement neurological examinations for a better understanding of functional and structural correlates of NSS. This work will help to generate a more complete picture of NSS-related developmental alterations and potentially related psychiatric vulnerabilities. Future research should make use of larger and more representative datasets to replicate, as well as extend our findings. Specific attention should be drawn on the investigation of factors that contribute to the development of NSS, longitudinal studies that allow to capture NSS-related alterations in developmental trajectories, as well as on investigating the underlying neural mechanisms of NSS

An analysis of MRI derived cortical complexity in premature-born adults : regional patterns, risk factors, and potential significance

Premature birth bears an increased risk for aberrant brain development concerning its structure and function. Cortical complexity (CC) expresses the fractal dimension of the brain surface and changes during neurodevelopment. We hypothesized that CC is altered after premature birth and associated with long-term cognitive development. One-hundred-and-one very premature-born adults (gestational age <32 weeks and/or birth weight <1500 ​g) and 111 term-born adults were assessed by structural MRI and cognitive testing at 26 years of age. CC was measured based on MRI by vertex-wise estimation of fractal dimension. Cognitive performance was measured based on Griffiths-Mental-Development-Scale (at 20 months) and Wechsler-Adult-Intelligence-Scales (at 26 years). In premature-born adults, CC was decreased bilaterally in large lateral temporal and medial parietal clusters. Decreased CC was associated with lower gestational age and birth weight. Furthermore, decreased CC in the medial parietal cortices was linked with reduced full-scale IQ of premature-born adults and mediated the association between cognitive development at 20 months and IQ in adulthood. Results demonstrate that CC is reduced in very premature-born adults in temporoparietal cortices, mediating the impact of prematurity on impaired cognitive development. These data indicate functionally relevant long-term alterations in the brain’s basic geometry of cortical organization in prematurity