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[Display omitted] • The genetic underpinnings of ASD are not fully defined. • Immune genes controlling innate and adaptive immunity are likely to play a major role in ASD. • Autistic individuals show signs of immune dysfunction in blood, gut and brain. • Immune genes linked to ASD are also implicated in brain development and plasticity. • Immune genes may influence ASD by affecting immune and key neurodevelopmental processes. The aetiology of autism spectrum disorder (ASD) is complex and, partly, accounted by genetic factors. Nonetheless, the genetic underpinnings of ASD are poorly defined. The presence of immune dysregulations in autistic individuals, and their families, supports a role of the immune system and its genetic regulators. Albeit immune responses belong either to the innate or adaptive arms, the overall immune system genetics is broad, and encompasses a multitude of functionally heterogenous pathways which may have different influences on ASD. Hence, to gain insights on the immunogenetic underpinnings of ASD, we conducted a systematic literature review of previous immune genetic and transcription studies in ASD. We defined a list of immune genes relevant to ASD and explored their neuro-immune function. Our review confirms the presence of immunogenetic variability in ASD, accounted by inherited variations of innate and adaptive immune system genes and genetic expression changes in the blood and post-mortem brain of autistic individuals. Besides their immune function, the identified genes control neurodevelopment processes (neuronal and synaptic plasticity) and are highly expressed in pre/ peri -natal periods. Hence, our synthesis bolsters the hypothesis that perturbation in immune genes may contribute to ASD by derailing the typical trajectory of neurodevelopment. Our review also helped identifying some of the limitations of prior immunogenetic research in ASD. Thus, alongside clarifying the neurodevelopment role of immune genes, we outline key considerations for future work into the aetiology of ASD and possible novel intervention targets. [ABSTRACT FROM AUTHOR]

Abstract: This paper addresses the problem of the dynamic scheduling of data-intensive multiprocessor jobs. Each job requires some number of CPUs and some amount of data that needs to be downloaded into a local storage. The completion of each job brings some benefit (utility) to the system, and the goal is to find the optimal scheduling policy that maximizes the average utility per unit of time obtained from all completed jobs. A co-evolutionary solution methodology is proposed, where the utility-based policies for managing local storage and for scheduling jobs onto the available CPUs mutually affect each other’s environments, with both policies being adaptively tuned using the Reinforcement Learning (RL) methodology. The simulation results demonstrate that the performance of the scheduling policies increases significantly as a result of being tuned with RL, to the point that they significantly outperform the best scheduling algorithm suggested in the literature for jobs with soft-deadline utility functions. [ABSTRACT FROM AUTHOR]

Experimental data on monkeys and functional studies in humans support the existence of a complex fronto-parietal system activating for cognitive and motor tasks, which may be anatomically supported by the superior longitudinal fasciculus (SLF). Advanced tractography methods have recently allowed the separation of the three branches of the SLF but are not suitable for their functional investigation. In order to gather comprehensive information about the functional organisation of these fronto-parietal connections, we used an innovative method, which combined tractography of the SLF in the largest dataset so far (129 participants) with 14 meta-analyses of functional magnetic resonance imaging (fMRI) studies. We found that frontal and parietal functions can be clustered into a dorsal spatial/motor network associated with the SLF I, and a ventral non-spatial/motor network associated with the SLF III. Further, all the investigated functions activated a middle network mostly associated with the SLF II. Our findings suggest that dorsal and ventral fronto-parietal networks are segregated but also share regions of activation, which may support flexible response properties or conscious processing. In sum, our novel combined approach provided novel findings on the functional organisation of fronto-parietal networks, and may be successfully applied to other brain connections. [ABSTRACT FROM AUTHOR]

Abstract: Individual differences in cognitive style can be characterized along two dimensions: ‘systemizing’ (S, the drive to analyze or build ‘rule-based’ systems) and ‘empathizing’ (E, the drive to identify another''s mental state and respond to this with an appropriate emotion). Discrepancies between these two dimensions in one direction (S>E) or the other (E>S) are associated with sex differences in cognition: on average more males show an S>E cognitive style, while on average more females show an E>S profile. The neurobiological basis of these different profiles remains unknown. Since individuals may be typical or atypical for their sex, it is important to move away from the study of sex differences and towards the study of differences in cognitive style. Using structural magnetic resonance imaging we examined how neuroanatomy varies as a function of the discrepancy between E and S in 88 adult males from the general population. Selecting just males allows us to study discrepant E-S profiles in a pure way, unconfounded by other factors related to sex and gender. An increasing S>E profile was associated with increased gray matter volume in cingulate and dorsal medial prefrontal areas which have been implicated in processes related to cognitive control, monitoring, error detection, and probabilistic inference. An increasing E>S profile was associated with larger hypothalamic and ventral basal ganglia regions which have been implicated in neuroendocrine control, motivation and reward. These results suggest an underlying neuroanatomical basis linked to the discrepancy between these two important dimensions of individual differences in cognitive style. [Copyright &y& Elsevier]

Abstract: It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer''s disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS−) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS−, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy ( 1 H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS− (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS− and healthy controls. In contrast neither DS+ nor DS− differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS−). Our secondary aim of comparing brain metabolites in DS+ and DS− to Alzheimer''s disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS−. [mI] may modify risk for dementia in this vulnerable population. [Copyright &y& Elsevier]

Abstract: The purpose of this study is to create a white matter atlas of the human brain using diffusion tensor imaging (DTI) tractography and to describe the constant and variable features of the major pathways. DTI was acquired from 40 healthy right-handed adults and reconstructed tracts mapped within a common reference space (MNI). Group effect maps of each tract defined constant anatomical features while overlap maps were generated to study inter-subject variability and to compare DTI derived anatomy with a histological atlas. Two patients were studied to assess the localizing validity of the atlas. The DTI-derived maps are overall consistent with a previously published histological atlas. A statistically significant leftward asymmetry was found for the volume and number of streamlines of the cortico-spinal tract and the direct connections between Broca''s and Wernicke''s territories (long segment). A statistically significant rightward asymmetry was found for the inferior fronto-occipital fasciculus and the fronto-parietal connections (anterior segment) of the arcuate fasciculus. Furthermore, males showed a left lateralization of the fronto-temporal segment of the arcuate fasciculus (long segment), while females had a more bilateral distribution. In two patients with brain lesions, DTI was acquired and tractography used to show that the tracts affected by the lesions were correctly identified by the atlas. This study suggests that DTI-derived maps can be used together with a previous histological atlas to establish the relationship of focal lesions with nearby tracts and improve clinico-anatomical correlation. [Copyright &y& Elsevier]

Abstract: Fragile X Syndrome (FraX) is caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and is a leading cause of learning disability (mental retardation) worldwide. Relatively few studies, however, have examined the neuroanatomical abnormalities associated with FraX. Of those that are available many included mixed gender populations, combined FraX children and adults into one sample, and employed manual tracing techniques which measures bulk volume of particular regions. Hence, there is relatively little information on differences in grey and white matter content across whole brain. We employed magnetic resonance imaging to investigate brain anatomy in 17 adult males with FraX and 18 healthy controls that did not differ significantly in age. Data were analysed using stereology and VBM to compare (respectively) regional brain bulk volume, and localised grey/white matter content. Using stereology we found that FraX males had a significant increase in bulk volume bilaterally of the caudate nucleus and parietal lobes and of the right brainstem, but a significant decrease in volume of the left frontal lobe. Our complimentary VBM analysis revealed an increased volume of grey matter in fronto-striatal regions (including bilaterally in the caudate nucleus), and increased white matter in regions extending from the brainstem to the parahippocampal gyrus, and from the left cingulate cortex extending into the corpus callosum. People with FraX have regionally specific differences in brain anatomy from healthy controls with enlargement of the caudate nuclei that persists into adulthood. [ABSTRACT FROM AUTHOR]

Abstract: Turner syndrome (TS) is a model for X chromosome influences on neurodevelopment because it is most commonly caused by absence of one X chromosome and associated with altered brain structure and function. However, all prior in vivo magnetic resonance imaging studies of the brain in TS have either used manual approaches or voxel-based morphometry (VBM) to measure cortical volume (CV). These methods, unlike surface-based morphometry (SBM), cannot measure the two neurobiologically distinct determinants of CV– cortical thickness (CT) and surface area (SA) – which have differing genetic determinants and may be independently altered. Therefore, in 24 adults with X monosomy and 19 healthy female controls, we used SBM to compare (i) lobar CV, CT and SA; (ii) an index of hemispheric gyrification; (iii) CT throughout the cortical sheet; and (iv) CT correlation between cortical regions. Compared to controls, females with TS had (i) significantly increased CT and decreased SA in parietal and occipital lobes (resulting in no significant difference in lobar CV); (ii) reduced hemispheric gyrification bilaterally; (iii) foci of significantly increased CT involving inferior temporal, lateral occipital, intraparietal sulcus (IPS), cingulate and orbitofrontal cortices; and (iv) significantly reduced CT correlation between the left IPS and cortical regions including supramarginal and lateral occipital gyri. Our findings suggest that females with TS have complex, sometimes “opposing”, abnormalities in SA/gyrification (decreased) and CT (increased), which can result in no overall detectable differences in CV. Thus, haploinsufficiency of X chromosome genes, may differentially impact the distinct mechanisms shaping SA (e.g. cortical folding) and CT (e.g. dendritic arborization/pruning). CT disruptions are maximal within and between cortical regions previously implicated in the TS cognitive phenotype. [Copyright &y& Elsevier]

Abstract: Autistic spectrum disorder (ASD) is accompanied by subtle and spatially distributed differences in brain anatomy that are difficult to detect using conventional mass-univariate methods (e.g., VBM). These require correction for multiple comparisons and hence need relatively large samples to attain sufficient statistical power. Reports of neuroanatomical differences from relatively small studies are thus highly variable. Also, VBM does not provide predictive value, limiting its diagnostic value. Here, we examined neuroanatomical networks implicated in ASD using a whole-brain classification approach employing a support vector machine (SVM) and investigated the predictive value of structural MRI scans in adults with ASD. Subsequently, results were compared between SVM and VBM. We included 44 male adults; 22 diagnosed with ASD using “gold-standard” research interviews and 22 healthy matched controls. SVM identified spatially distributed networks discriminating between ASD and controls. These included the limbic, frontal-striatal, fronto-temporal, fronto-parietal and cerebellar systems. SVM applied to gray matter scans correctly classified ASD individuals at a specificity of 86.0% and a sensitivity of 88.0%. Cases (68.0%) were correctly classified using white matter anatomy. The distance from the separating hyperplane (i.e., the test margin) was significantly related to current symptom severity. In contrast, VBM revealed few significant between-group differences at conventional levels of statistical stringency. We therefore suggest that SVM can detect subtle and spatially distributed differences in brain networks between adults with ASD and controls. Also, these differences provide significant predictive power for group membership, which is related to symptom severity. [Copyright &y& Elsevier]

Abstract: It has been suggested that people with autistic spectrum disorder (ASD) have altered development (and connectivity) of limbic circuits. However, direct evidence of anatomical differences specific to white matter pathways underlying social behaviour and emotions in ASD is lacking. We used Diffusion Tensor Imaging Tractography to compare, in vivo, the microstructural integrity and age-related differences in the extended limbic pathways between subjects with Asperger syndrome and healthy controls. Twenty-four males with Asperger syndrome (mean age 23±12 years, age range: 9–54 years) and 42 age-matched male controls (mean age 25±10 years, age range: 9–54 years) were studied. We quantified tract-specific diffusivity measurements as indirect indexes of microstructural integrity (e.g. fractional anisotropy, FA; mean diffusivity, MD) and tract volume (e.g. number of streamlines) of the main limbic tracts. The dissected limbic pathways included the inferior longitudinal fasciculus, inferior frontal occipital fasciculus, uncinate, cingulum and fornix. There were no significant between-group differences in FA and MD. However, compared to healthy controls, individuals with Asperger syndrome had a significantly higher number of streamlines in the right (p =.003) and left (p =.03) cingulum, and in the right (p =.03) and left (p =.04) inferior longitudinal fasciculus. In contrast, people with Asperger syndrome had a significantly lower number of streamlines in the right uncinate (p =.02). Within each group there were significant age-related differences in MD and number of streamlines, but not FA. However, the only significant age-related between-group difference was in mean diffusivity of the left uncinate fasciculus (Z obs =2.05) (p =.02). Our preliminary findings suggest that people with Asperger syndrome have significant differences in the anatomy, and maturation, of some (but not all) limbic tracts. [Copyright &y& Elsevier]

Abstract: Recent evidence suggests that loss of ovarian function following ovariectomy is a risk factor for Alzheimer''s disease (AD); however, the biological basis of this risk remains poorly understood. We carried out an fMRI study into the interaction between loss of ovarian function (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD). Behaviorally, cholinergic depletion produced a deficit in verbal recognition performance in both GnRHa-treated women and wait list controls, but only GnRHa-treated women made more false positive errors with cholinergic depletion. Similarly, cholinergic depletion produced a decrease in activation in the left inferior frontal gyrus (LIFG; Brodmann area 45) – a brain region implicated in retrieving word meaning – in both groups, and activation in this area was further reduced following GnRHa treatment. These findings suggest biological mechanisms through which ovarian hormone suppression may interact with the cholinergic system and the LIFG. Furthermore, this interaction may provide a useful model to help explain reports of increased risk for cognitive decline and AD in women following ovariectomy. [Copyright &y& Elsevier]

Abstract: It has been proposed that the biological basis of autism spectrum disorder includes cerebellar ‘disconnection’. However, direct in vivo evidence in support of this is lacking. Here, the microstructural integrity of cerebellar white matter in adults with Asperger syndrome was studied using diffusion tensor magnetic resonance tractography. Fifteen adults with Asperger syndrome and 16 age–IQ–gender-matched healthy controls underwent diffusion tensor magnetic resonance imaging. For each subject, tract-specific measurements of mean diffusivity and fractional anisotropy were made within the inferior, middle, superior cerebellar peduncles and short intracerebellar fibres. No group differences were observed in mean diffusivity. However, people with Asperger syndrome had significantly lower fractional anisotropy in the short intracerebellar fibres (p <0.001) and right superior cerebellar (output) peduncle (p <0.001) compared to controls; but no difference in the input tracts. Severity of social impairment, as measured by the Autistic Diagnostic Interview, was negatively correlated with diffusion anisotropy in the fibres of the left superior cerebellar peduncle. These findings suggest a vulnerability of specific cerebellar neural pathways in people with Asperger syndrome. The localised abnormalities in the main cerebellar outflow pathway may prevent the cerebral cortex from receiving those cerebellar feedback inputs necessary for a successful adaptive social behaviour. [Copyright &y& Elsevier]

Abstract: Gonadotropin Hormone Releasing Hormone agonists (GnRHa) produce an acute decline in ovarian hormone production leading to a ‘pseudo’ menopause. This is therapeutically useful in the management of a variety of gynaecological conditions but also serves as a powerful model to study the effects of ovarian hormones on cognition. Animal and human behavioral studies report that memory is particularly sensitive to the effects ovarian hormone suppression (e.g. post GnRHa). Further, it has recently been reported that ovariectomy in young women increases the risk of cognitive impairment in later life. However, the underlying brain networks and/or stages of memory processing that might be modulated by acute ovarian hormone suppression remain poorly understood. We used event-related fMRI to examine the effect of GnRHa on visual working memory (VWM). Neuroimaging outcomes from 17 pre-menopausal healthy women were assessed at baseline and 8 weeks after GnRHa treatment. Seventeen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. We report GnRHa was associated with attenuation of left parahippocampal (BA 35) and middle temporal gyri (BA 21 ,22, 39) activation, with a significant group-by-time interaction at left precuneus (BA 7) and posterior cingulate cortex (PCC) (BA 31) at encoding, and with cerebellar activation at recognition in the context of unimpaired behavioral responses. Our study suggests that acute ovarian hormone withdrawal following GnRHa, and perhaps at other times, (e.g. following surgical menopause and postpartum) alters the neural circuitry underlying performance of VWM. [Copyright &y& Elsevier]

Abstract: The ability to acquire MRI data with consistent tissue contrast at multiple time points, and/or across different imaging centres has become increasingly important as the number of large longitudinal and multicentre studies has grown. Here, the use of quantitative magnetic resonance relaxation times measurement, or, voxel-wise determination of the intrinsic longitudinal and transverse relaxation times, T 1 and T 2 respectively, for standardizing the structural imaging component of such studies is reported. To demonstrate the ability to standardize across multiple time-points and imaging centres, T 1 and T 2 maps of seven healthy volunteers were acquired using the rapid DESPOT1 and DESPOT2 (driven equilibrium single pulse observation of T 1 and T 2) mapping techniques at three centres across the United Kingdom (each centre utilizing scanners from competing manufacturers and/or with varying gradient performance). An average coefficient of variation of the estimates of T 1 and T 2 was found to be approximately 6.5% and 8%, respectively, across the three centres and comparable to that achieved between repeated imaging sessions performed at the same centre. With a total combined imaging time of less than 12 min for whole-brain ∼1.2 mm isotropic voxel T 1 and T 2 maps, quantitative voxel-wise T 1 and T 2 mapping represents an attractive and easy-to-implement approach for signal intensity standardization and normalization. Further, as T 1 and T 2 are related to tissue microstructure and biochemistry, quantitative images provide additional diagnostic information that can be compared between patient and control populations, for example through voxel-based analysis techniques. [Copyright &y& Elsevier]

Abstract: Women frequently complain of memory problems at times in their reproductive lives that are associated with changes in estrogen concentration (e.g. around menopause and childbirth). Further, behavioural studies suggest that memory performance may fluctuate across the menstrual cycle. For example, performance on verbal tasks has been reported to be greatest during phases associated with high estrogen concentrations whereas the opposite has been reported with visuo-spatial tasks. The biological basis of these reported effects remains poorly understood. However, brain imaging studies into the effects of estrogen therapy in postmenopausal women suggest that estrogen modulates the metabolism and function of brain regions sub-serving memory. Furthermore, we have recently reported that acute suppression of ovarian function in young women (with a Gonadotropin Hormone Releasing Hormone agonist) is associated with decreased activation in left prefrontal cortex, particularly the left inferior frontal gyrus (LIFG), during successful verbal memory encoding. We therefore investigated whether physiological variation in plasma estradiol concentration is associated with differences in activity of the LIFG during successful verbal encoding. We hypothesised that higher plasma concentrations of estradiol would be associated with increased brain activity at the LIFG and improved recall performance. Although we did not find a significant relationship between plasma estradiol concentration and verbal recall performance, we report a positive correlation between brain function and estradiol concentration at the LIFG. [Copyright &y& Elsevier]

Abstract: Facial emotion perception is fundamental to human social behaviour, and changes with age. Nevertheless, age-related differences in the relative activation of components of emotion processing networks are poorly understood. Thus we measured brain activity with event-related fMRI in 40 right handed healthy male controls, age range 8–50 years, during implicit processing of fearful, disgusted, and a control condition of neutral facial expressions. There was a significant negative correlation between increasing age and neural response to fearful and disgusted expressions in dorsomedial prefrontal cortex (BA 10), and middle frontal gyri (BA 6). Hence, in healthy subjects, the functional anatomy of facial emotion processing is not ‘hard-wired’, but undergoes progressive change into adulthood. Possible explanations for the age-related changes in dorsomedial and middle frontal cortical activity may include a reduction in the attentional demands of appraising facial expressions as perceptual skill increases, or changes in processing the self-relevance of facial expressions during social and cognitive development. [Copyright &y& Elsevier]

Abstract: Estrogen Therapy (ET) may protect against age-related cognitive decline and neuropsychiatric disorders (e.g. Alzheimer''s disease). The biological basis for this putative neuroprotective effect is not fully understood, but may include modulation of cholinergic systems. Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer''s disease. However, to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging, and related this to cognitive function. We used Single Photon Emission Tomography (SPET) and (R,R)[123I]-I-QNB, a novel ligand with high affinity for m1/m4 muscarinic receptors, to examine the effect of long-term ET and age on brain m1/m4 receptors in healthy females. We included 10 younger premenopausal subjects and 22 postmenopausal women; 11 long-term ET users (all treated following surgical menopause) and 11 ET never-users (surgical menopause, n =2). Also, verbal memory and executive function was assessed in all postmenopausal subjects. Compared to young women, postmenopausal women (ET users and never-users combined) had significantly lower muscarinic receptor density in all brain regions examined. ET users also had higher muscarinic receptor density than ET never-users in all the brain regions, and this reached statistical significance in left striatum and hippocampus, lateral frontal cortex and thalamus. Moreover, in ET users, (R,R)[123I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels. We also found evidence for improved executive function in ET users as compared to ET never-users. However, there was no significant relationship between receptor binding and cognitive function within any of the groups. In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding, and this may be related to serum estradiol levels. [Copyright &y& Elsevier]