Increased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear ...the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9-12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms.
While C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9-10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia.
Our results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.
A small molecule (FDDNP) that binds amyloid senile plaques and tau neurofibrillary tangles (the neuropathological findings in Alzheimer's disease) was injected into subjects before PET scanning. ...FDDNP binding was highest in subjects with Alzheimer's disease, intermediate in those with mild cognitive impairment, and lowest in normal controls. Whether there will be clinical applications for this noninvasive method of detecting cerebral plaques and tangles is not known.
A small molecule (FDDNP) that binds amyloid senile plaques and tau neurofibrillary tangles was injected into subjects before PET scanning. FDDNP binding was highest in subjects with Alzheimer's disease.
Mild cognitive impairment is a transitional stage between normal aging and Alzheimer's disease. A recent study suggests that the prevalence of mild cognitive impairment, characterized by a cognitive decline without impairment of the ability to carry out activities of daily living, is 19% among persons younger than 75 years of age and 29% among those 85 years of age or older.
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Among persons with mild cognitive impairment, about 30% have amnestic mild cognitive impairment, characterized by abnormal memory for age but normal general cognitive functioning.
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Approximately 12% of patients with amnestic mild cognitive impairment have progression to Alzheimer's disease . . .
Imaging, electrophysiological studies, and lesion work have shown that the medial temporal lobe (MTL) is important for episodic memory; however, it is unclear whether different MTL regions support ...the spatial, temporal, and item elements of episodic memory. In this study we used fMRI to examine retrieval performance emphasizing different aspects of episodic memory in the context of a spatial navigation paradigm. Subjects played a taxi-driver game ("yellowcab"), in which they freely searched for passengers and delivered them to specific landmark stores. Subjects then underwent fMRI scanning as they retrieved landmarks, spatial, and temporal associations from their navigational experience in three separate runs. Consistent with previous findings on item memory, perirhinal cortex activated most strongly during landmark retrieval compared with spatial or temporal source information retrieval. Both hippocampus and parahippocampal cortex activated significantly during retrieval of landmarks, spatial associations, and temporal order. We found, however, a significant dissociation between hippocampal and parahippocampal cortex activations, with spatial retrieval leading to greater parahippocampal activation compared with hippocampus and temporal order retrieval leading to greater hippocampal activation compared with parahippocampal cortex. Our results, coupled with previous findings, demonstrate that the hippocampus and parahippocampal cortex are preferentially recruited during temporal order and spatial association retrieval--key components of episodic "source" memory. (Contains 3 figures and 2 tables.)
Adaptive functioning, or the suite of skills essential for real-world, day-to-day functioning, includes daily living, communication, and socialization abilities. Even in the absence of co-occurring ...intellectual disability (IQ < 70), difficulties in adaptive functioning are prominent in autism spectrum disorder (ASD). Further, ASD individuals without co-occurring intellectual disability (ID) demonstrate a gap between IQ and adaptive functioning, which widens with age. Existing studies of IQ-adaptive functioning discrepancies have characterized predominantly male ASD samples; thus, whether the gap is demonstrated in ASD females is unknown. To probe sex- versus diagnosis-specific differences in adaptive functioning in ASD, we characterized adaptive functioning using the Vineland Adaptive Behavior Scales, Second Edition in 177 non-ID (IQ > 70) ASD (females = 75, males = 102), and 178 typically developing (TD) (females = 87, males = 91) youth, aged 8–17 years. We examined whether each group evidenced a gap between full-scale IQ and adaptive skills and its associations with age. ASD youth evinced significantly lower adaptive skills and a significantly greater IQ-adaptive functioning gap than their same-sex TD peers. In this cross-sectional sample, the increase in the IQ-adaptive functioning gap with age was of similar magnitude for ASD males and females, but only reached statistical significance in males. We discuss unique implications the profound IQ-socialization skills gap in particular may have for ASD females.
Lay abstract
Adaptive functioning refers to skills that are vital to success in day-to-day life, including daily living (e.g. grocery shopping, food preparation, transportation use), communication (e.g. verbal expression of needs), and socialization skills (e.g. interpersonal skills, including expressing and recognizing emotions, and understanding turn-taking in conversation). Among autistic individuals without intellectual disability, adaptive functioning is not commensurate with intellectual ability (IQ), and instead a gap exists between these individuals’ intellectual ability and their adaptive skills. Further, these autistic individuals show a widening of this gap with increasing age. Existing studies of the gap between IQ and adaptive functioning have studied predominantly male samples. Thus, we do not know if the gap also exists in autistic females. We therefore looked at adaptive functioning and the gap between IQ and adaptive functioning in a large sample of autistic girls and boys without intellectual disability. To disentangle effects of group (autistic vs typically developing) from effects of sex (girls vs boys), we compared autistic girls and boys to one another as well as to their same-sex typically developing peers. Analyses took into consideration differences in IQ between autistic and typically developing youth. We found autistic girls, like autistic boys, show lower adaptive functioning than their same-sex typically developing peers. Results underscore the need to evaluate adaptive functioning in autistic individuals without intellectual disability and to provide necessary supports. The large gap between intellectual ability and socialization skills, in particular, may be of critical importance in improving our understanding of outcomes and mental health difficulties among autistic females.
Sensory over-responsivity (SOR) is an impairing sensory processing challenge in autism spectrum disorder (ASD) which shows heterogenous developmental trajectories and appears to improve into ...adulthood in some but not all autistic individuals. However, the neural mechanisms underlying interindividual differences in these trajectories are currently unknown.
Here, we used functional magnetic resonance imaging (fMRI) to investigate the association between age and neural activity linearly and nonlinearly in response to mildly aversive sensory stimulation as well as how SOR severity moderates this association. Participants included 52 ASD (14F) and 41 (13F) typically developing (TD) youth, aged 8.6-18.0 years.
We found that in pre-teens, ASD children showed widespread activation differences in sensorimotor, frontal and cerebellar regions compared to TD children, while there were fewer differences between ASD and TD teens. In TD youth, older age was associated with less activation in the prefrontal cortex. In contrast, in ASD youth, older age was associated with more engagement of sensory integration and emotion regulation regions. In particular, orbitofrontal and medial prefrontal cortices showed a nonlinear relationship with age in ASD, with an especially steep increase in sensory-evoked neural activity during the mid-to-late teen years. There was also an interaction between age and SOR severity in ASD youth such that these age-related trends were more apparent in youth with higher SOR.
The cross-sectional design limits causal interpretations of the data. Future longitudinal studies will be instrumental in determining how prefrontal engagement and SOR co-develop across adolescence.
Our results suggest that enhanced recruitment of prefrontal regions may underlie age-related decreases in SOR for a subgroup of ASD youth.
•fMRI was used to examine the brain mechanisms through which tactile stimuli disrupt processing of social cues in youth with ASD.•Tactile stimuli caused up-regulation of auditory language areas in TD ...youth but decreases in these areas in ASD youth.•Directing attention to social cues mitigated the effect of the sensory distracter so that activation was sustained in auditory-language areas.•Attentional direction to social cues was associated with increases in medial prefrontal cortex for ASD youth.•Severity of sensory over-responsivity modulated the effect of the distracter and attentional direction on brain processing of social cues.
Sensory over-responsivity (SOR) is a common condition in autism spectrum disorders (ASD) that is associated with greater social impairment. However, the mechanisms through which sensory stimuli may affect social functioning are not well understood. This study used fMRI to examine brain activity while interpreting communicative intent in 15 high-functioning youth with ASD and 16 age- and IQ-matched typically-developing (TD) controls. Participants completed the task with and without a tactile sensory distracter, and with and without instructions directing their attention to relevant social cues. When completing the task in the presence of the sensory distracter, TD youth showed increased activity in auditory language and frontal regions whereas ASD youth showed decreased activation in these areas. Instructions mitigated this effect such that ASD youth did not decrease activation during tactile stimulation; instead, the ASD group showed increased medial prefrontal activity. SOR severity modulated the effect of the tactile stimulus on social processing. Results demonstrate for the first time a neural mechanism through which sensory stimuli cause disruption of social cognition, and that attentional modulation can restore neural processing of social cues through prefrontal regulation. Findings have implications for novel, integrative interventions that incorporate attentional directives to target both sensory and social symptoms.
Examining the function of individual human hippocampal subfields remains challenging because of their small sizes and convoluted structures. Previous human fMRI studies at 3 T have successfully ...detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, CA3, and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study, we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution fMRI scanning at 7 T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acquisition of a new skill is generally associated with a decrease in the need for effortful control over performance, leading to the development of automaticity. Automaticity by definition has been ...achieved when performance of a primary task is minimally affected by other ongoing tasks. The neural basis of automaticity was examined by testing subjects in a serial reaction time (SRT) task under both single-task and dual-task conditions. The diminishing cost of dual-task performance was used as an index for automaticity. Subjects performed the SRT task during two functional magnetic imaging sessions separated by 3 h of behavioral training over multiple days. Behavioral data showed that, by the end of testing, subjects had automated performance of the SRT task. Before behavioral training, performance of the SRT task concurrently with the secondary task elicited activation in a wide network of frontal and striatal regions, as well as parietal lobe. After extensive behavioral training, dual-task performance showed comparatively less activity in bilateral ventral premotor regions, right middle frontal gyrus, and right caudate body; activity in other prefrontal and striatal regions decreased equally for single-task and dual-task conditions. These data suggest that lateral and dorsolateral prefrontal regions, and their corresponding striatal targets, subserve the executive processes involved in novice dual-task performance. The results also showed that supplementary motor area and putamen/globus pallidus regions showed training-related decreases for sequence conditions but not for random conditions, confirming the role of these regions in the representation of learned motor sequences.
Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and ...tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding.
We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects.
Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group.
We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli.
Autism is a developmental disorder characterized by decreased interest and engagement in social interactions and by enhanced self-focus. While previous theoretical approaches to understanding autism ...have emphasized social impairments and altered interpersonal interactions, there is a recent shift towards understanding the nature of the representation of the self in individuals with autism spectrum disorders (ASD). Still, the neural mechanisms subserving self-representations in ASD are relatively unexplored.
We used event-related fMRI to investigate brain responsiveness to images of the subjects' own face and to faces of others. Children with ASD and typically developing (TD) children viewed randomly presented digital morphs between their own face and a gender-matched other face, and made "self/other" judgments. Both groups of children activated a right premotor/prefrontal system when identifying images containing a greater percentage of the self face. However, while TD children showed activation of this system during both self- and other-processing, children with ASD only recruited this system while viewing images containing mostly their own face.
This functional dissociation between the representation of self versus others points to a potential neural substrate for the characteristic self-focus and decreased social understanding exhibited by these individuals, and suggests that individuals with ASD lack the shared neural representations for self and others that TD children and adults possess and may use to understand others.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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