Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers.

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems (n = 1742) and participants sleeping the recommended 7-8 h (n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings.SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

Stability of associations between neuroticism and microstructural asymmetry of the cingulum during late childhood and adolescence: Insights from a longitudinal study with up to 11 waves.

Adolescence is characterized by significant brain development and marks a period of the life span with an increased incidence of mood disorders, especially in females. The risk of developing mood disorders is also higher in individuals scoring high on neuroticism, a personality trait characterized by a tendency to experience negative and anxious emotions. We previously found in a cross-sectional study that neuroticism is associated with microstructural left-right asymmetry of the fronto-limbic white matter involved in emotional processing, with opposite effects in female and male adolescents. We now have extended this work collecting longitudinal data in 76 typically developing children and adolescents aged 7-18 years, including repeated MRI sampling up to 11 times. This enabled us, for the first time, to address the critical question, whether the association between neuroticism and frontal-limbic white matter asymmetry changes or remains stable across late childhood and adolescence. Neuroticism was assessed up to four times and showed good intraindividual stability and did not significantly change with age. Conforming our cross-sectional results, females scoring high on neuroticism displayed increased left-right cingulum fractional anisotropy (FA), while males showed decreased left-right cingulum FA asymmetry. Despite ongoing age-related increases in FA in cingulum, the association between neuroticism and cingulum FA asymmetry was already expressed in females in late childhood and remained stable across adolescence. In males, the association appeared to become more prominent during adolescence. Future longitudinal studies need to cover an earlier age span to elucidate the time point at which the relationship between neuroticism and cingulum FA asymmetry arises.

Education and Income Show Heterogeneous Relationships to Lifespan Brain and Cognitive Differences Across European and US Cohorts.

Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4-97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES-ICV associations rather are compatible with SES-brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

BACKGROUND: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle. METHODS: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls. RESULTS: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally. CONCLUSIONS: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure. IMPACT: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.

Right-left asymmetry in corticospinal tract microstructure and dexterity are uncoupled in late adulthood.

Ageing leads to a decline in white matter microstructure and dexterous function of the hand. In adolescents, it has previously been shown that the degree of right-left asymmetry in the corticospinal tract (CST) is linearly related with right-left asymmetry in dexterity. Here, we tested whether this association is also expressed in older adults. Participants completed a simple circle drawing task with their right and left hand as a measure of dexterity and underwent whole-brain diffusion weighted imaging at 3 Tesla (n = 199; aged 60-72 years). Fractional anisotropy and mean diffusivity of right and left CST were extracted from a manually defined region-of-interest. Linear regression analyses were computed to replicate the analyses in adolescents. Frequentist analyses were complemented with a Bayesian analytical framework. Outcome measures were compared with those previously reported in adolescents (aged 11-16 years). Asymmetries in white matter microstructure of the CST were evident and comparable to the degree of lateralisation observed in adolescence. Similarly, asymmetries in dexterity were evident, but to a lesser degree than in adolescents. Unlike in adolescents, we found no evidence of a linear relationship between asymmetries in CST microstructure and dexterity. Complementary Bayesian regression analysis provided moderate evidence in favour of the null hypothesis, pointing towards a lack of association between the structural and functional measures of right-left asymmetry. Our findings are compatible with the notion that, by late adulthood, a diverging impact of age on white matter structure and dexterous hand function dilutes the structure-function relationship between CST microstructure and manual proficiency that has been reported in adolescents.

Maturational trajectories of white matter microstructure underlying the right presupplementary motor area reflect individual improvements in motor response cancellation in children and adolescents.

The ability to effectively suppress motor response tendencies is essential for focused and goal-directed behavior. Here, we tested the hypothesis that developmental improvement in the ability to cancel a motor response is reflected by maturational changes in the white matter underlying the right presupplementary motor area (preSMA) and posterior inferior frontal gyrus (IFG), two cortical key areas of the fronto-basal ganglia "stopping" network. Eighty-eight typically-developing children and adolescents, aged 7-19 years, were longitudinally assessed with the stop-signal task (SST) and diffusion tensor imaging (DTI) of the brain over a period of six years. Participants were examined from two to nine times with an average of 6.6 times, resulting in 576 SST-DTI datasets. We applied tract-based spatial statistics to extract mean fractional anisotropy (FA) from regions-of-interest in the white matter underlying the right IFG (IFGFA) and right preSMA (preSMAFA) at each time point. Motor response cancelation performance, estimated with the stop-signal reaction time (SSRT), improved with age. Initially well performing children plateaued around the age of 11 years, while initially poor performers caught up at the age of 13-14 years. White matter microstructure continued to mature across the investigated age range. Males generally displayed linear maturational trajectories, while females displayed more curvilinear trajectories that leveled off around 12-14 years of age. Maturational increases in right preSMAFA but not right IFGFA were associated with developmental improvements in SSRT. This association differed depending on the mean right preSMAFA across the individual maturational trajectory. Children with lower mean right preSMAFA exhibited poorer SSRT performance at younger ages but steeper developmental trajectories of SSRT improvement. Children with higher mean right preSMAFA exhibited flatter trajectories of SSRT improvement along with faster SSRT already at the first assessments. The results suggest that no further improvement in motor response cancellation is achieved once a certain level of maturity in the white matter underlying the right preSMA is reached. Similar dynamics may apply to other behavioral read-outs and brain structures and, thus, need to be considered in longitudinal MRI studies designed to map brain structural correlates of behavioral changes during development.

The Center for Integrated Molecular Brain Imaging (Cimbi) database.

We here describe a multimodality neuroimaging containing data from healthy volunteers and patients, acquired within the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) in Copenhagen, Denmark. The data is of particular relevance for neurobiological research questions related to the serotonergic transmitter system with its normative data on the serotonergic subtype receptors 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 and the 5-HT transporter (5-HTT), but can easily serve other purposes. The Cimbi database and Cimbi biobank were formally established in 2008 with the purpose to store the wealth of Cimbi-acquired data in a highly structured and standardized manner in accordance with the regulations issued by the Danish Data Protection Agency as well as to provide a quality-controlled resource for future hypothesis-generating and hypothesis-driven studies. The Cimbi database currently comprises a total of 1100 PET and 1000 structural and functional MRI scans and it holds a multitude of additional data, such as genetic and biochemical data, and scores from 17 self-reported questionnaires and from 11 neuropsychological paper/computer tests. The database associated Cimbi biobank currently contains blood and in some instances saliva samples from about 500 healthy volunteers and 300 patients with e.g., major depression, dementia, substance abuse, obesity, and impulsive aggression. Data continue to be added to the Cimbi database and biobank.

Children and adolescents previously treated with glucocorticoids display lower verbal intellectual abilities.

AIM: Perinatal exposure to glucocorticoids has been associated with adverse cerebral effects, but little is known about their effect on cognitive development and exposure later in childhood. This study examined intellectual abilities, memory and behavioural problems in children previously treated with glucocorticoids. METHODS: We evaluated 38 children aged from seven to 16 years, who had been treated with glucocorticoids for rheumatic disease or nephrotic syndrome, together with 42 healthy controls matched for age, gender and parental education. The median cumulative dose of prednisolone equivalents was 158 mg/kg (range 21-723) and the mean time that had elapsed since treatment was three-and-a-half (standard deviation 2.2) years. Intellectual abilities were assessed with the Wechsler Intelligence Scale for Children and memory performance and behavioural problems with a pattern recognition memory task and the Child Behaviour Check List. RESULTS: There were no significant differences between the groups in pattern recognition memory, perceptual organisation index or behavioural problems, but patients had a significantly lower verbal comprehension index and this difference was present in both disease groups. There were no significant dose-response relationships regarding verbal intellectual abilities. CONCLUSION: Children and adolescents previously treated with glucocorticoids seemed to have lower intellectual verbal abilities than healthy controls.

Automated longitudinal intra-subject analysis (ALISA) for diffusion MRI tractography.

Fiber tractography (FT), which aims to reconstruct the three-dimensional trajectories of white matter (WM) fibers non-invasively, is one of the most popular approaches for analyzing diffusion tensor imaging (DTI) data given its high inter- and intra-rater reliability and scan-rescan reproducibility. The major disadvantage of manual FT segmentations, unfortunately, is that placing regions-of-interest for tract selection can be very labor-intensive and time-consuming. Although there are several methods that can identify specific WM fiber bundles in an automated way, manual FT segmentations across multiple subjects performed by a trained rater with neuroanatomical expertise are generally assumed to be more accurate. However, for longitudinal DTI analyses it may still be beneficial to automate the FT segmentation across multiple time points, but then for each individual subject separately. Both the inter-subject and intra-subject automation in this situation are intended for subjects without gross pathology. In this work, we propose such an automated longitudinal intra-subject analysis (dubbed ALISA) approach, and assessed whether ALISA could preserve the same level of reliability as obtained with manual FT segmentations. In addition, we compared ALISA with an automated inter-subject analysis. Based on DTI data sets from (i) ten healthy subjects that were scanned five times (six-month intervals, aged 7.6-8.6years at the first scan) and (ii) one control subject that was scanned ten times (weekly intervals, 12.2years at the first scan), we demonstrate that the increased efficiency provided by ALISA does not compromise the high degrees of precision and accuracy that can be achieved with manual FT segmentations. Further automation for inter-subject analyses, however, did not provide similarly accurate FT segmentations.

In abstinent MDMA users the cortisol awakening response is off-set but associated with prefrontal serotonin transporter binding as in non-users.

Serotonergic signaling is considered critical for an appropriate adaptation to stress. We have previously observed that in healthy volunteers, prefrontal serotonin transporter (SERT) binding is positively associated with hypothalamic-pituitary-adrenal (HPA)-axis output in terms of the cortisol awakening response (CAR). Here, we tested (1) if such a correlation persists in a human model of chronic serotonin depletion, namely in 3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') users, and (2) if CAR differed between MDMA users (N = 18) and non-using healthy volunteers (N = 32). Participants underwent SERT brain imaging with [11C]DASB-PET, and performed home-sampling of CAR, defined as the area under curve with respect to cortisol increase from awakening level. When adjusting for age and group, CAR was positively coupled to prefrontal SERT binding (p = 0.006) and MDMA users showed significantly higher CAR than the control group (p = 0.0003). In conclusion, our data confirm the recently described positive association between prefrontal SERT binding and CAR, this time in a human model of serotonin deficiency. Also, we find that CAR was higher in MDMA users relative to non-users. We suggest that the inhibitory control on HPA-axis output is less efficient in the off-balance state established by recent MDMA use, most likely through mechanisms other than those that can be compensated by lowering SERT levels.

Children at Familial High risk of Schizophrenia and Bipolar Disorder Exhibit Altered Connectivity Patterns During Pre-attentive Processing of an Auditory Prediction Error.

BACKGROUND AND HYPOTHESIS: Individuals with schizophrenia or bipolar disorder have attenuated auditory mismatch negativity (MMN) responses, indicating impaired sensory information processing. Computational models of effective connectivity between brain areas underlying MMN responses show reduced connectivity between fronto-temporal areas in individuals with schizophrenia. Here we ask whether children at familial high risk (FHR) of developing a serious mental disorder show similar alterations. STUDY DESIGN: We recruited 67 children at FHR for schizophrenia, 47 children at FHR for bipolar disorder as well as 59 matched population-based controls from the Danish High Risk and Resilience study. The 11-12-year-old participants engaged in a classical auditory MMN paradigm with deviations in frequency, duration, or frequency and duration, while we recorded their EEG. We used dynamic causal modeling (DCM) to infer on the effective connectivity between brain areas underlying MMN. STUDY RESULTS: DCM yielded strong evidence for differences in effective connectivity among groups in connections from right inferior frontal gyrus (IFG) to right superior temporal gyrus (STG), along with differences in intrinsic connectivity within primary auditory cortex (A1). Critically, the 2 high-risk groups differed in intrinsic connectivity in left STG and IFG as well as effective connectivity from right A1 to right STG. Results persisted even when controlling for past or present psychiatric diagnoses. CONCLUSIONS: We provide novel evidence that connectivity underlying MMN responses in children at FHR for schizophrenia and bipolar disorder is altered at the age of 11-12, echoing findings that have been found in individuals with manifest schizophrenia.

Hippocampal anterior- posterior shift in childhood and adolescence.

Hippocampal-cortical networks play an important role in neurocognitive development. Applying the method of Connectivity-Based Parcellation (CBP) on hippocampal-cortical structural covariance (SC) networks computed from T1-weighted magnetic resonance images, we examined how the hippocampus differentiates into subregions during childhood and adolescence (N = 1105, 6-18 years). In late childhood, the hippocampus mainly differentiated along the anterior-posterior axis similar to previous reported functional differentiation patterns of the hippocampus. In contrast, in adolescence a differentiation along the medial-lateral axis was evident, reminiscent of the cytoarchitectonic division into cornu ammonis and subiculum. Further meta-analytical characterization of hippocampal subregions in terms of related structural co-maturation networks, behavioural and gene profiling suggested that the hippocampal head is related to higher order functions (e.g. language, theory of mind, autobiographical memory) in late childhood morphologically co-varying with almost the whole brain. In early adolescence but not in childhood, posterior subicular SC networks were associated with action-oriented and reward systems. The findings point to late childhood as an important developmental period for hippocampal head morphology and to early adolescence as a crucial period for hippocampal integration into action- and reward-oriented cognition. The latter may constitute a developmental feature that conveys increased propensity for addictive disorders.

Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan: A pooled analysis in the European Lifebrain consortium.

BACKGROUND: Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. METHODS: We included 3838 participants aged 18-90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. RESULTS: High alcohol use was associated with lower hippocampal volume (r = -0.10, p = 0.021), and overweight/obesity with lower total GMV (r = -0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = -0.08, p = 0.001), but not hippocampal volume (r = -0.01, p = 0.625). CONCLUSIONS: This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.

No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy.

Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration-which is shorter than current recommendations.

Executive Control and Associated Brain Activity in Children With Familial High-Risk of Schizophrenia or Bipolar Disorder: A Danish Register-based Study.

BACKGROUND AND HYPOTHESES: Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. STUDY DESIGN: Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. STUDY RESULTS: We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. CONCLUSION: FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

Hypothalamic-pituitary-adrenal axis tonus is associated with hippocampal microstructural asymmetry.

It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since there is growing evidence for hemispheric lateralization in brain systems regulating arousal and emotion. Here we tested the hypotheses that individual variations in basal morning and afternoon/evening cortisol levels would be associated with the degree of hemispheric asymmetry in hippocampal microstructure. Fifty healthy adults aged 19 to 86 years were included in the analyses. Diffusion-weighted imaging was acquired from all subjects. Hippocampal mean diffusivity (MD) and volume was extracted. Cortisol measures were based on 5 morning and 3 afternoon/evening saliva samples. Higher left relative to right hippocampus MD was associated with higher basal cortisol levels. Associations were anatomically specific and not attributable to hippocampal volume asymmetry. No correlation between hippocampal volume and MD was observed, suggesting that MD and volume index distinct biological properties of the hippocampus. Observed associations raise a number of possibilities, among them an asymmetric role of the hippocampus on HPA-axis regulation, or conversely, that individual variations in secreted cortisol, perhaps associated with stress, may have lateralized effects on hippocampal microstructure. Our results point to an important relationship between the limbic system and neuroendocrine function in terms of left-right asymmetries, raising additional questions about how the limbic system is related to neuroendocrine functions.

Cortisol awakening response and negative emotionality linked to asymmetry in major limbic fibre bundle architecture.

The limbic system plays an important role in regulating the hypothalamic-pituitary-adrenal (HPA) axis as well as aspects of emotion, and both neuroendocrine disturbance and increased negative emotionality are associated with risk for developing affective disorders. However, the extent to which the architecture of connections between limbic structures may be linked to individual differences in basal HPA-axis reactivity and negative emotionality is unknown. Here we tested the hypotheses that microstructural asymmetry of the major limbic fibre bundles would be associated with cortisol awakening response (CAR) and neuroticism, a personality trait associated with the tendency to experience negative emotions. Sixty-nine healthy adults were studied with diffusion-weighted imaging, and fractional anisotropy (FA) was extracted from the cingulum and uncinate fasciculus. Higher neuroticism scores, which were associated with higher CAR, were also correlated with higher right relative to left cingulum FA. Elevated CAR was associated with the degree of FA asymmetry within both the cingulum and the uncinate fasciculus, but in opposing directions. These results suggest that the balance between left- and right-sided limbic circuits may bear an important relationship to hypothalamic-pituitary-adrenal axis reactivity, and to the tendency to experience negative emotions, and they raise important questions about the significance of limbic system architecture.