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Amygdala dysfunction has been proposed as a critical contributor to social impairment in autism spectrum disorders (ASD). The current study investigated biochemical abnormalities in the amygdala in 20 high functioning adults with autistic disorder or Asperger's disorder and 19 typically developing adults matched on age and IQ. Magnetic resonance spectroscopy was used to measure N-acetyl aspartate (NAA), creatine/phosphocreatine (Cre), choline/choline containing compounds (Cho), and Myoinositol (mI) in the right and left amygdala. There were no significant between-group differences in any of the metabolites. However, NAA and Cre levels were significantly correlated to clinical ratings on the Autism Diagnostic Interview-Revised. This suggests that altered metabolite levels in the amygdala may be associated with a more severe early developmental course in ASD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behaviors. A diagnosis of ASD is provided by a clinician following cognitive and behavioral evaluations, but there is currently no biomarker associating these metrics with neurological changes. Our lab has previously found that g-ratio, the proportion of axon width to myelin diameter, and axonal conduction velocity, which is associated with the capacity of an axon to carry information, are both decreased in ASD individuals. By associating these differences with performance on cognitive and behavioral tests, we can evaluate which tests most reveal changes in the brain. Analyzing 273 participants (148 with ASD) ages 8-to-17 (49% female) through an NIH-sponsored Autism Centers of Excellence (ACE) network (Grant#: MH100028), we observe widespread associations between behavioral and cognitive evaluations of autism and between behavioral and microstructural metrics. Analyzing data from all participants, conduction velocity but not g-ratio was significantly associated with many behavioral metrics. However, this pattern was reversed when looking solely at ASD participants. This reversal may suggest that the mechanism underlying differences between autistic and non-autistic individuals may be distinct from the mechanism underlying ASD behavioral severity. Two additional machine learning cluster analyses applied to neuroimaging data reinforce the association between neuroimaging and behavioral metrics and suggest that age-related maturation of brain metrics may drive changes in ASD behavior. By associating neuroimaging metrics with ASD, it may be possible to measure and identify individuals at high risk of ASD before behavioral tests can detect them.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a new approach to calculating axonal conduction velocity termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel formulation for calculating aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD., Competing Interests: Dr. James C. McPartland consults with Customer Value Partners, Bridgebio, Determined Health, and BlackThorn Therapeutics, has received research funding from Janssen Research and Development, serves on the Scientific Advisory Boards of Pastorus and Modern Clinics, and receives royalties from Guilford Press, Lambert, Oxford, and Springer. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors declare no conflicts of interest., (Copyright: © 2024 Newman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Theories of altered inhibitory/excitatory signaling in autism spectrum disorder (ASD) suggest that gamma amino butyric acid (GABA) and glutamate (Glu) abnormalities may underlie social and sensory challenges in ASD. Magnetic resonance spectroscopy was used to measure Glu and GABA+ levels in the amygdala-hippocampus region and cerebellum in autistic children (n = 30), a clinical control group with sensory abnormalities (SA) but not ASD (n = 30), and children with typical development (n = 37). All participants were clinically assessed using the Autism Diagnostic Interview-Revised, the Autism Diagnostic Observation Scale-2, and the Child Sensory Profile-2. The Social Responsiveness Scale-2, Sniffin Sticks Threshold Test, and the University of Pennsylvania Smell Identification Test were administered to assess social impairment and olfactory processing. Overall, autistic children showed increased cerebellar Glu levels compared to TYP children. Evidence for altered excitatory/inhibitory signaling in the cerebellum was more clear-cut when analyses were restricted to male participants. Further, lower cerebellar GABA+/Glu ratios were correlated to more severe social impairment in both autistic and SA males, suggesting that the cerebellum may play a transdiagnostic role in social impairment. Future studies of inhibitory/excitatory neural markers, powered to investigate the role of sex, may aid in parsing out disorder-specific neurochemical profiles., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: There is currently no format-independent method to determine delta-9-tetrahydrocannabinol (THC) in milligrams for self-report studies. Objectives: Validate self-report method for quantifying mg THC from commercially available cannabis products using product labeling, which includes both net weight and product potency. Methods: 53 adult cannabis users (24 M, 29F), 21-39 years of age ( M  = 28.38, SD = 4.15), were instructed to report daily use via a weekly survey for two consecutive weeks, provide product label photographs, abstain from use for 24 h, submit a urine sample and complete the Cannabis Use Disorder Identification Test - Revised (CUDIT-R) and the Marijuana Craving Questionnaire - Short Form (MCQ-SF). Milligrams of THC were determined by multiplying quantity of product used by its THC concentration. Urine was analyzed for the urine metabolite 11-nor-carboxy-THC (THC-COOH) via liquid chromatography mass spectroscopy. THC and THC-COOH values were log10 transformed prior to correlational analyses. Results: Median daily THC consumption was 102.53 mg ( M  = 203.68, SD = 268.13). Thirty-three (62%) of the 53 participants reported using two or more formats over the 2-week period. There was a significant positive correlation between log10 THC-COOH and log10 THC mg (r(41) = .59, p  < .001), log10 THC mg and MCQ-SF score (r(41) = .59, p  < .001), and log10 THC mg dose and CUDIT-R score, (r(41) = .39, p  = .010). Conclusion: Our label-based methodology provides consumption information across all modalities of cannabis use in standard units that can be combined across products for calculation of dose. It is a viable and valid method for quantifying mg of THC consumed and can be utilized in any region where cannabis is legal, and labeling is regulated.

Lay Abstract: Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample. In a recent multisite study designed to identify biomarkers and behavioral endpoints for clinical trials (the Autism Biomarkers Consortium for Clinical Trials), school-age children with autism spectrum disorder were enrolled without excluding for medications, thus providing a unique opportunity to examine characteristics of psychotropic medication use in a research cohort and to guide future decisions on medication-related inclusion criteria. The aims of the current analysis were (1) to quantify the frequency and type of psychotropic medications reported in school-age children enrolled in the ABC-CT and (2) to examine behavioral features of children with autism spectrum disorder based on medication classes. Of the 280 children with autism spectrum disorder in the cohort, 42.5% were taking psychotropic medications, with polypharmacy in half of these children. The most commonly reported psychotropic medications included melatonin, stimulants, selective serotonin reuptake inhibitors, alpha agonists, and antipsychotics. Descriptive analysis showed that children taking antipsychotics displayed a trend toward greater overall impairment. Our findings suggest that exclusion of children taking concomitant psychotropic medications in trials could limit the clinical representativeness of the study population, perhaps even excluding children who may most benefit from new treatment options.

Comprehensive quantification of intracranial artery features may help to assess and understand regional variations of blood supply during early brain development and aging. We analyzed vasculature features of 27 healthy infants during natural sleep, 13 infants at 7-months (7.3 ± 1.0 month), and 14 infants at 12-months (11.7 ± 0.4 month), and 13 older healthy, awake adults (62.8 ± 8.7 years) to investigate age-related vascular differences as a preliminary study of vascular changes associated with brain development. 3D time-of-flight (TOF) magnetic resonance angiography (MRA) acquisitions were processed in iCafe, a technique to quantify arterial features (http://icafe.clatfd.cn), to characterize intracranial vasculature. Overall, adult subjects were found to have increased ACA length, tortuosity, and vasculature density compared to both 7-month-old and 12-month-old infants, as well as MCA length compared to 7-month-old infants. No brain laterality differences were observed for any vascular measures in either infant or adult age groups. Reduced skull and brain sharpness, indicative of increased head motion and brain/vascular pulsation, respectively, were observed in infants but not correlated with length, tortuosity, or vasculature density measures. Quantitative analysis of TOF MRA using iCafe may provide an objective approach for systematic study of infant brain vascular development and for clinical assessment of adult and pediatric brain vascular diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Shaw, Dager, Corrigan, Chu, Kleinhans, Kuhl, Hwang and Yuan.)

With legalization efforts across the United States, cannabis use is becoming increasingly mainstream. Various studies have documented the effects of acute and chronic cannabis use on brain structure and cognitive performance, including within the frontal executive control network, but little attention has been given to the effects on the cerebellum. Recent evidence increasingly points to the role of the cerebellum in various nonmotor networks, and the cerebellum's expression of cannabinoid receptors may pose particular vulnerabilities to the consequences of cannabis use. Using a combined approach of resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the present study aims to assess how cannabis use relates to the cerebellum's intrinsic functional connectivity and underlying white matter structure and whether these properties are associated with craving or severity of cannabis use. Resting-state fMRI and DTI data, as well as self-reports of substance use history, were analyzed from a sample of 26 adults at risk for cannabis use disorder (CUD) and an age- and sex-matched comparison group of 25 cannabis-naïve adults (control). Results demonstrated that individuals at risk for a CUD showed key differences in cerebellar functional connectivity, with specific impacts on the dorsal attention and default mode networks. In addition, group differences in white matter were localized to the middle cerebellar peduncle (MCP), with a relationship between lower MCP diffusivity and higher levels of self-reported craving. These findings lend further support to the cerebellum's role in key cognitive networks and potential consequences for substance use disorders., (© 2019 Society for the Study of Addiction.)

Introduction: The smell of cannabis is a cue with universal relevance to cannabis users. However, most cue reactivity imaging studies have solely utilized visual images, auditory imagery scripts, or tactile cues in their experiments. This study introduces a multimodal cue reactivity paradigm that includes picture, odor, and bimodal picture + odor cues., Methods: Twenty-eight adults at risk for cannabis use disorder (CUD; defined as at least weekly use and Substance Involvement Score of ≥4 on the Cannabis sub-test of the Alcohol, Smoking and Substance Involvement Screening Test) and 26 cannabis-naive controls were exposed to cannabis and floral cues during event-related fMRI. Between-group differences in fMRI activation and correlations were tested using FMRIB's Local Analyses of Mixed Effects and corrected for multiple comparisons using a voxelwise threshold of z > 2.3 and a corrected cluster threshold of p < .05., Results: Both visual and olfactory modalities resulted in significant activation of craving and reward systems, with cannabis odor cues eliciting a significantly greater response in regions mediating anticipation and reward (nucleus accumbens, pallidum, putamen, and anterior insular cortex, supplementary motor area, angular gyrus and superior frontal gyrus) and cannabis picture cues eliciting a significantly greater response in the occipital cortex and amygdala. Furthermore, the CUD group showed significantly increased activation in the ventral tegmental area (VTA), the insula, and the pallidum compared to controls. Within the CUD group, activation in the insula, anterior cingulate, and occipital cortex to bimodal cannabis cues was significantly correlated with self-reported craving., Conclusion: Our multimodal cue reactivity paradigm is sensitive to neural adaptations associated with problematic cannabis use., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

A central tension in pediatric research ethics arises from our desire to protect children from harm while also allowing progress toward discoveries that could improve child health. A prime example of this tension is research on a controversial yet increasingly common practice: the use of cannabis by women to treat nausea and vomiting of pregnancy. Studies of cannabis use in pregnancy face a combination of ethical hurdles because of the inclusion of pregnant women and involvement of a schedule I controlled substance. Given the growing need for research on the safety and efficacy of cannabis for nausea and vomiting of pregnancy, we reflect on the multiple historical contexts that have contributed to the challenge of studying cannabis use during pregnancy and make a case for the ethical rationale for such research., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Comprehensive quantification of intracranial vascular characteristics by vascular tracing provides an objective clinical assessment of vascular structure. However, weak signal or low contrast in small distal arteries, artifacts due to volitional motion, and vascular pulsation are challenges for accurate vessel tracing from 3D time-of-flight (3D-TOF) magnetic resonance angiography (MRA) images., New Method: A vascular measurement refinement algorithm is developed and validated for robust quantification of intracranial vasculature from 3D-TOF MRA. After automated vascular tracing, centerline positions, lumen radii and centerline deviations are jointly optimized to restrict traces to within vascular regions in the straightened curved planar reformation (CPR) views. The algorithm is validated on simulated vascular images and on repeat 3D-TOF MRA acquired from infants and adults., Results: The refinement algorithm can reliably estimate vascular radius and correct deviated centerlines. For the simulated vascular image with noise level of 1 and deviation of centerline of 3, the mean radius difference is below 15.3 % for scan-rescan reliability. Vascular features from repeated clinical scans show significantly improved measurement agreement, with intra-class correlation coefficient (ICC) improvement from 0.55 to 0.7 for infants and from 0.59 to 0.92 for adults., Comparison With Existing Methods: The refinement algorithm is novel because it utilizes straightened CPR views that incorporate information from the entire artery. In addition, the optimization corrects centerline positions, lumen radii and centerline deviations simultaneously., Conclusions: Intracranial vasculature quantification using a novel refinement algorithm for vascular tracing improves the reliability of vascular feature measurements in both infants and adults., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Abnormalities in olfactory function have been identified in a number of neurological and psychiatric disorders, including Parkinson's disease and schizophrenia. However, little is known about olfactory function in autism spectrum disorder (ASD). The present study aims to assess the olfactory profiles of children with ASD, compared to an age- and sex-matched comparison group of typically developing children and a second clinical control group consisting of non-ASD children with sensory processing dysfunction (SPD). Participants completed a battery of sensory and behavioral assessments including olfactory tasks (Sniffin' Sticks Threshold Test and self-reported valence ratings for two target odorants (phenylethyl alcohol and vanillin) and the University of Pennsylvania Smell Identification Test), and an autism evaluation (Autism Diagnostic Observation Schedule-2). Children with ASD showed intact odor detection with reduced odor identification ability. Poor odor identification was significantly correlated with autism symptom severity. Children with SPD demonstrated reduced odor detection and identification ability. These findings provide evidence for differential patterns of smell processing among ASD and non-ASD neurodevelopmental disorders. Future studies are needed to determine whether the association of impaired olfaction and increased autism symptoms is due to shared etiology.

Human olfactory processing is understudied relative to other sensory modalities, despite its links to neurodevelopmental and neurodegenerative disorders. To address this limitation, we developed a fast, robust fMRI odor paradigm that is appropriate for all ages and levels of cognitive functioning. To test this approach, thirty-four typically developing children aged 7-12 underwent fMRI during brief, repeated exposure to phenylethyl alcohol, a flower-scented odor. Prior to fMRI scanning, olfactory testing (odor detection and identification) was conducted. During fMRI stimulus presentation, odorant release was synchronized to each participant's inspiratory phase to ensure participants were inhaling during the odorant exposure. Between group differences and correlations between activation and odor detection threshold scores were tested using the FMRIB Software Library. Results demonstrated that our 2-min paradigm significantly activated primary and secondary olfactory regions. In addition, a significant relationship between odor detection threshold and higher activation in the right amygdala and lower activation in the left frontal, insular, occipital, and cerebellar regions was observed, suggesting that this approach is sensitive to individual differences in olfactory processing. These findings demonstrate the feasibility of studying olfactory function in children using brain imaging techniques., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Atypical inhibitory function is often present in individuals with autism spectrum disorder (ASD), who may have difficulty suppressing context-inappropriate behaviors. We investigated the neural correlates of inhibition in ASD in response to both emotional and non-emotional stimuli using an fMRI Go/NoGo inhibition task with human faces and letters. We also related neural activation to behavioral dysfunction in ASD. Our sample consisted of 19 individuals with ASD (mean age=25.84) and 22 typically developing (TD) control participants (mean age=29.03). As expected, no group differences in task performance (inhibition accuracy and response time) were found. However, adults with ASD exhibited greater angular gyrus activation in face response inhibition blocks, as well as greater fusiform gyrus activation than controls, in a condition comparing face inhibition to letter inhibition. In contrast, control participants yielded significantly greater anterior cingulate cortex (ACC) activation in letter inhibition blocks. A positive relationship between communication and language impairment and angular gyrus activation during face inhibition was also found. Group activation differences during inhibition tasks in the context of comparable task performance and the relationship between activation and dysfunction highlight brain regions that may be related to ASD-specific dysfunction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Research on the biological basis of autism spectrum disorder has yielded a list of brain abnormalities that are arguably as diverse as the set of behavioral symptoms that characterize the disorder. Among these are patterns of abnormal cortical connectivity and abnormal basal ganglia development. In attempts to integrate the existing literature, the current paper tests the hypothesis that impairments in the basal ganglia's function to flexibly select and route task-relevant neural signals to the prefrontal cortex underpins patterns of abnormal synchronization between the prefrontal cortex and other cortical processing centers observed in individuals with autism spectrum disorder (ASD). We tested this hypothesis using a Dynamic Causal Modeling analysis of neuroimaging data collected from 16 individuals with ASD (mean age=25.3 years; 6 female) and 17 age- and IQ-matched neurotypical controls (mean age=25.6, 6 female), who performed a Go/No-Go test of executive functioning. Consistent with the hypothesis tested, a random-effects Bayesian model selection procedure determined that a model of network connectivity in which basal ganglia activation modulated connectivity between the prefrontal cortex and other key cortical processing centers best fit the data of both neurotypicals and individuals with ASD. Follow-up analyses suggested that the largest group differences were observed for modulation of connectivity between prefrontal cortex and the sensory input region in the occipital lobe [t(31)=2.03, p=0.025]. Specifically, basal ganglia activation was associated with a small decrease in synchronization between the occipital region and prefrontal cortical regions in controls; however, in individuals with ASD, basal ganglia activation resulted in increased synchronization between the occipital region and the prefrontal cortex. We propose that this increased synchronization may reflect a failure in basal ganglia signal gating mechanisms, resulting in a non-selective copying of signals to prefrontal cortex. Such a failure to prioritize and filter signals to the prefrontal cortex could result in the pervasive impairments in cognitive flexibility and executive functioning that characterize autism spectrum disorder, and may offer a mechanistic explanation of some of the observed abnormalities in patterns of cortical synchronization in ASD., (Published by Elsevier Ltd.)

The amygdala is a complex structure with distinct subregions and dissociable functional networks. The laterobasal subregion of the amygdala is hypothesized to mediate the presentation and severity of autism symptoms, although very little data are available regarding amygdala dysfunction at the subregional level. In this study, we investigated the relationship between abnormal amygdalar intrinsic connectivity, autism symptom severity, and anxiety and depressive symptoms. We collected resting state fMRI data on 31 high functioning adolescents and adults with autism spectrum disorder and 38 typically developing (TD) controls aged 14-45. Twenty-five participants with ASD and 28 TD participants were included in the final analyses. ASD participants were administered the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule. Adult participants were administered the Beck Depression Inventory II and the Beck Anxiety Inventory. Functional connectivity analyses were conducted from three amygdalar subregions: centromedial (CM), laterobasal (LB) and superficial (SF). In addition, correlations with the behavioral measures were tested in the adult participants. In general, the ASD group showed significantly decreased connectivity from the LB subregion and increased connectivity from the CM and SF subregions compared to the TD group. We found evidence that social symptoms are primarily associated with under-connectivity from the LB subregion whereas over-connectivity and under-connectivity from the CM, SF and LB subregions are related to co-morbid depression and anxiety in ASD, in brain regions that were distinct from those associated with social dysfunction, and in different patterns than were observed in mildly symptomatic TD participants. Our findings provide new evidence for functional subregional differences in amygdala pathophysiology in ASD. Autism Res 2016, 9: 760-772. © 2015 International Society for Autism Research, Wiley Periodicals, Inc., (© 2015 International Society for Autism Research, Wiley Periodicals, Inc.)

Purpose: Urological chronic pelvic pain syndromes have refractory bladder or pelvic pain as the dominant symptom. This has been attributed to changes in the central nervous system caused by a chronic barrage of noxious stimuli. We developed what is to our knowledge a novel challenge protocol that induced bladder distention in study participants to reproduce pain and urinary symptoms. We tested to see whether it could discriminate between persons with urological chronic pelvic pain syndrome-like symptoms and asymptomatic controls., Materials and Methods: We recruited 10 female twin pairs who were discordant for urological chronic pelvic pain syndrome-like symptoms. Before scanning each twin urinated to completion and then consumed 500 cc water. Each twin was scanned with our resting state functional magnetic resonance imaging protocol immediately and approximately 50 minutes after consumption. Time series were extracted from the right and left periaqueductal gray, and the right and left amygdala subregions. We performed the repeated measures 2-sample t-test to assess differences in connectivity between symptomatic and asymptomatic twins before and after bladder distention., Results: Group by condition interaction effects were found from the periaqueductal gray to the right cerebellum VIIIa, the amygdala, the right premotor cortex/supplementary motor area and the insular cortex, and between the amygdala and the frontal pole/medial orbital frontal cortex, the hypothalamus, the insular cortex, the thalamus and the anterior cingulate cortex., Conclusions: These findings demonstrate that our noninvasive bladder distention protocol can detect differences in the processing of urinary sensation between twins discordant for lower urinary tract pain., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Abnormal fMRI habituation in autism spectrum disorders (ASDs) has been proposed as a critical component in social impairment. This study investigated habituation to fearful faces and houses in ASD and whether fMRI measures of brain activity discriminate between ASD and typically developing (TD) controls. Two identical fMRI runs presenting masked fearful faces, houses, and scrambled images were collected. We found significantly slower fMRI responses to fearful faces but not houses in ASD. In addition, the pattern of slow to emerge amygdala activation to faces had robust discriminability [ASD vs. TD; area under the curve (AUC) = .852, p < .001]. In contrast, habituation to houses had no predictive value (AUC = .573, p = .365). Amygdala habituation to emotional faces may be useful for quantifying risk in ASD.

Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer's disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism.

Abnormalities in structural and functional connectivity have been reported in autism spectrum disorders (ASD) across a wide age range. However, developmental changes in white matter microstructure are poorly understood. We used a cross-sectional design to determine whether white matter abnormalities measured using diffusion tensor imaging (DTI) were present in adolescents and adults with ASD and whether age-related changes in white matter microstructure differed between ASD and typically developing (TD) individuals. Participants included 28 individuals with ASD and 33 TD controls matched on age and IQ and assessed at one time point. Widespread decreased fractional anisotropy (FA), and increased radial diffusivity (RaD) and mean diffusivity (MD) were observed in the ASD group compared to the TD group. In addition, significant group-by-age interactions were observed in FA, RaD, and MD in all major tracts except the brain stem, indicating that age-related changes in white matter microstructure differed between the groups. We propose that white matter microstructural changes in ASD may reflect myelination and/or other structural differences including differences in axonal density/arborization. In addition, we suggest that white matter microstuctural impairments may be normalizing during young adulthood in ASD. Future longitudinal studies that include a wider range of ages and more extensive clinical characterization will be critical for further uncovering the neurodevelopmental processes unfolding during this dynamic time in development., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We studied whether self-reported intent to exert cognitive control over eating was associated with differences in brain response to food cues, independent of genetic background. Subjects were ten pairs of identical twins in which one twin was a restrained eater and the co-twin was unrestrained, as classified by the Herman and Polivy Restraint Scale. Before and after ingestion of a milkshake, we used functional magnetic resonance imaging to measure brain response to photographs of objects, "fattening" food, and "non-fattening" food. At baseline, restrained eaters had greater activation in the left amygdala and the right thalamus in response to fattening food cues than did their unrestrained co-twins. When restrained eaters drank a milkshake, activation in response to fattening food photographs decreased across multiple brain areas, whereas activation induced by non-fattening food photographs increased. As compared to their unrestrained co-twins, restrained eaters who drank a milkshake had greater decreases in activation by fattening food images in the left amygdala and occipital lobe, and greater increases in activation by non-fattening food images in the medial orbitofrontal cortex. Because of the discordant monozygotic twin study design, the findings provide a rigorous level of support for the hypothesis that adopting an intention to restrain eating alters brain response to food cues., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To use functional magnetic resonance imaging (fMRI) in craniopharyngioma (CP) patients to examine the hypothesis that hypothalamic damage due to CP and its treatment results in enhanced perception of food reward and/or impaired central satiety processing., Methods: Pre- and post-meal responses to visual food cues in brain regions of interest (ROI; bilateral nucleus accumbens, bilateral insula, and medial orbitofrontal cortex) were assessed in 4 CP patients versus 4 age- and weight-matched controls. Stimuli consisted of images of high- ('fattening') and low-calorie ('non-fattening') foods in blocks, alternating with non-food object blocks. After the first fMRI scan, subjects drank a high-calorie test meal to suppress appetite, then completed a second fMRI scan. Within each ROI, we calculated mean z-scores for activation by fattening as compared to non-fattening food images., Results: Following the test meal, controls showed suppression of activation by food cues while CP patients showed trends towards higher activation., Conclusion: These data, albeit in a small group of patients, support our hypothesis that perception of food cues may be altered in hypothalamic obesity (HO), especially after eating, i.e. in the satiated state. The fMRI approach is encouraging for performing future mechanistic studies of the brain response to food cues and satiety in patients with hypothalamic or other forms of childhood obesity., (Copyright © 2012 S. Karger GmbH, Freiburg.)

Recent evidence suggests that a rapid, automatic face detection system is supported by subcortical structures including the amygdala, pulvinar, and superior colliculus. Early-emerging abnormalities in these structures may be related to reduced social orienting in children with autism, and subsequently, to aberrant development of cortical circuits involved in face processing. Our objective was to determine whether functional abnormalities in the subcortical face processing system are present in adults with autism spectrum disorders (ASD) during supraliminal fearful face processing. Participants included twenty-eight individuals with ASD and 25 controls group-matched on age, IQ, and behavioral performance. The ASD group met diagnostic criteria on the ADI-R, ADOS-G, and DSM-IV. Both the ASD and control groups showed significant activation in bilateral fusiform gyri. The control group exhibited additional significant responses in the right amygdala, right pulvinar, and bilateral superior colliculi. In the direct group comparison, the controls showed significantly greater activation in the left amygdala, bilateral fusiform gyrus, right pulvinar, and bilateral superior colliculi. No brain region showed significantly greater activation in the ASD group compared to the controls. Thus, basic rapid face identification mechanisms appear to be functional in ASD. However, individuals with ASD failed to engage the subcortical brain regions involved in face detection and automatic emotional face processing, suggesting a core mechanism for impaired socioemotional processing in ASD. Neural abnormalities in this system may contribute to early-emerging deficits in social orienting and attention, the putative precursors to abnormalities in social cognition and cortical face processing specialization., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape-matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Brain activity patterns during face processing have been extensively explored with functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs). ERP source localization adds a spatial dimension to the ERP time series recordings, which allows for a more direct comparison and integration with fMRI findings. The goals for this study were (1) to compare the spatial descriptions of neuronal activity during face processing obtained with fMRI and ERP source localization using low-resolution electromagnetic tomography (LORETA), and (2) to use the combined information from source localization and fMRI to explore how the temporal sequence of brain activity during face processing is summarized in fMRI activation maps. fMRI and high-density ERP data were acquired in separate sessions for 17 healthy adult males for a face and object processing task. LORETA statistical maps for the comparison of viewing faces and viewing houses were coregistered and compared to fMRI statistical maps for the same conditions. The spatial locations of face processing-sensitive activity measured by fMRI and LORETA were found to overlap in a number of areas including the bilateral fusiform gyri, the right superior, middle and inferior temporal gyri, and the bilateral precuneus. Both the fMRI and LORETA solutions additionally demonstrated activity in regions that did not overlap. fMRI and LORETA statistical maps of face processing-sensitive brain activity were found to converge spatially primarily at LORETA solution latencies that were within 18 ms of the N170 latency. The combination of data from these techniques suggested that electrical brain activity at the latency of the N170 is highly represented in fMRI statistical maps.

Objective: To develop a non-invasive method of studying brain mechanisms involved in energy homeostasis and appetite regulation in humans by using visual food cues that are relevant to individuals attempting weight loss., Design: Functional magnetic resonance imaging (fMRI) was used to compare brain activation in regions of interest between groups of food photographs., Participants: Ten healthy, non-obese women who were not dieting for weight loss., Measurements: Independent raters viewed food photographs and evaluated whether the foods depicted should be eaten by individuals attempting a calorically-restricted diet. Based on their responses, we categorized photographs into 'non-fattening' and 'fattening' food groups, the latter characterized by high-caloric content and usually also high-fat or high-sugar content. Blood oxygen level-dependent (BOLD) response was measured by fMRI while participants viewed photographs of 'fattening' food, 'non-fattening' food, and non-food objects., Results: Viewing photographs of fattening food compared with non-food objects resulted in significantly greater activation in the brainstem; hypothalamus; left amygdala; left dorsolateral prefrontal cortex; left orbitofrontal cortex; right insular cortex; bilateral striatum, including the nucleus accumbens, caudate nucleus, and putamen; bilateral thalamus; and occipital lobe. By comparison, only the occipital region had greater activation by non-fattening food than by object photographs. Combining responses to all food types resulted in attenuation of activation in the brainstem, hypothalamus, and striatum., Conclusion: These findings suggest that, in non-obese women, neural circuits engaged in energy homeostasis and reward processing are selectively attuned to representations of high-calorie foods that are perceived as fattening. Studies to investigate hormonal action or manipulation of energy balance may benefit from fMRI protocols that contrast energy-rich food stimuli with non-food or low-calorie food stimuli.

Objective: Amygdala dysfunction has been proposed as a critical component in social impairment in autism spectrum disorders. This study was designed to investigate whether abnormal habituation characterizes amygdala dysfunction in autism spectrum disorders and whether the rate of amygdala habituation is related to social impairment., Method: Using functional MRI, the authors measured change over time in activation of the amygdala and fusiform gyrus to neutral facial stimuli in adults with autism spectrum disorders and healthy comparison adults., Results: The comparison group evidenced significantly greater amygdala habituation bilaterally than the autism spectrum group. There were no group differences in overall fusiform habituation. For the autism spectrum group, lower levels of habituation of the amygdala to the face stimuli were associated with more severe social impairment., Conclusions: These results suggest amygdala hyperarousal in autism spectrum disorders in response to socially relevant stimuli. Further, sustained amygdala arousal may contribute to the social deficits observed in autism spectrum disorders.

Impaired language is a prominent behavioral marker of autism spectrum disorders (ASD), but its neurobiological underpinnings are incompletely understood. We studied letter and category fluency in 14 high functioning ASD individuals and 14 age-matched controls. Each fluency condition was compared to self-paced repetition of the word "nothing." Responses were recorded to monitor performance. In letter fluency, the ASD group had significantly greater activation than controls in the right frontal and right superior temporal lobes. Between-group differences were not observed in left prefrontal cortex. By examining functional asymmetry in frontal cortex, we found that the ASD group had significantly reduced lateralization of activation patterns in letter fluency compared to the controls. In category fluency, no between-group differences in lateralization were found, in light of greater bilateral activation in controls. These findings indicate reduced hemispheric differentiation for certain verbal fluency tasks in ASD, consistent with some previous evidence of atypical functional and structural asymmetries in autism. Abnormal functional organization may contribute to the language impairment seen in ASD.

Abnormalities in the interactions between functionally linked brain regions have been suggested to be associated with the clinical impairments observed in autism spectrum disorders (ASD). We investigated functional connectivity within the limbic system during face identification; a primary component of social cognition, in 19 high-functioning adults with ASD and 21 age-and IQ-matched control adults. Activation during identification of previously viewed faces and houses using a one-back paradigm was compared. The fusiform face area (FFA) was individually localized in each participant and used as the seed point for functional connectivity analyses. The degree of correlation between FFA and the extended neural circuitry involved in face identification was tested. A whole brain analysis was also conducted in order to determine whether connectivity from the FFA to aberrant brain locations was present in the ASD group. Measures of clinical severity (ADOS social score and ADI-R social score) were included as independent variables into the functional connectivity analyses. Significant FFA-amygdala and FFA-superior temporal sulcus functional connectivity was found in both the ASD and control participants. However, the control group had significantly increased connectivity to the left amygdala and the posterior cingulate compared to ASD. Post hoc analyses additionally found increased connectivity to the thalamus in the controls. A significant relationship between abnormal functional connectivity and clinical severity in the ASD group was observed. Specifically, greater social impairment was associated with reduced FFA-amygdala connectivity and increased FFA-right inferior frontal connectivity. These results suggest that abnormal neural connections within the limbic system may contribute to the social impairments observed in ASD.

Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 age-matched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD.

Recent evidence suggests that the role of the amygdala may extend beyond threat detection to include processing socially relevant stimuli in general. Thus, we investigated perception and memory for neutral faces; a stimulus-type that lacks emotional valence yet contains relevant social information. Participants viewed neutral faces or houses when undergoing functional MRI. Neutral face memory testing was conducted outside the scanner. In the functional MRI of faces vs. houses contrast, significant bilateral activation in the amygdala and lateral fusiform gyrus was observed. Increased bilateral amygdala activation was associated with better delayed-memory performance. These findings indicate that the role of the amygdala may include processing neutral yet socially relevant stimuli. Further, amygdala activation, independent of emotional valence, appears to be associated with memory enhancement.

Language delay and impairment are salient features of autism. More specifically, there is evidence of atypical semantic organization in autism, but the functional brain correlates are not well understood. The current study used functional MRI to examine activation associated with semantic category decision. Ten high-functioning men with autism spectrum disorder and 10 healthy control subjects matched for gender, handedness, age, and nonverbal IQ were studied. Participants indicated via button press response whether visually presented words belonged to a target category (tools, colors, feelings). The control condition required target letter detection in unpronounceable letter strings. Significant activation for semantic decision in the left inferior frontal gyrus (Brodmann areas 44 and 45) was found in the control group. Corresponding activation in the autism group was more limited, with smaller clusters in left inferior frontal areas 45 and 47. Autistic participants, however, showed significantly greater activation compared to controls in extrastriate visual cortex bilaterally (areas 18 and 19), which correlated with greater number of errors on the semantic task. Our findings suggest an important role of perceptual components (possibly visual imagery) during semantic decision, consistent with previous evidence of atypical lexicosemantic performance in autism. In the context of similar findings from younger typically developing children, our results suggest an immature pattern associated with inefficient processing, presumably due to atypical experiential embedding of word acquisition in autism.