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Background: Medial temporal lobe atrophy has been linked to decline in neuropsychological measures of explicit memory function. While the hippocampus has long been identified as a critical structure in learning and memory processes, less is known about contributions of the amygdala to these functions. We sought to investigate the relationship between amygdala volume and memory functioning in a clinical sample of older adults with and without cognitive impairment., Methods: A serial clinical sample of older adults that underwent neuropsychological assessment at an outpatient neurology clinic was selected for retrospective chart review. Patients were included in the study if they completed a comprehensive neuropsychological assessment within six months of a structural magnetic resonance imaging scan. Regional brain volumes were quantified using Neuroreader® software. Associations between bilateral hippocampal and amygdala volumes and memory scores, derived from immediate and delayed recall conditions of a verbal story learning task and a visual design reconstruction task, were examined using mixed-effects general linear models, controlling for total intracranial volume, scanner model, age, sex and education. Partial correlation coefficients, adjusted for these covariates, were calculated to estimate the strength of the association between volumes and memory scores., Results: A total of 68 (39 F, 29 M) participants were included in the analyses, with a mean (SD) adjusted age of 80.1 (6.0) and educational level of 15.9 (2.5) years. Controlling for age, sex, education, and total intracranial volume, greater amygdala volumes were associated with better verbal and visual memory performance, with effect sizes comparable to hippocampal volume. No significant lateralized effects were observed. Partial correlation coefficients ranged from 0.47 to 0.33 (p<.001)., Conclusion: These findings contribute to a growing body of knowledge identifying the amygdala as a target for further research in memory functioning. This highlights the importance of considering the broader functioning of the limbic system in which multiple subcortical structures contribute to memory processes and decline in older adults., Competing Interests: Declaration of Competing Interest The authors involved with this work have no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings., Objectives: To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended., Design, Setting, and Participants: This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020., Main Outcomes and Measures: Percentage of children with IFs in each category and prevalence of specific IFs., Results: A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387)., Conclusions and Relevance: Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Sensory over-responsivity (SOR), extreme sensitivity to or avoidance of sensory stimuli (e.g., scratchy fabrics, loud sounds), is a highly prevalent and impairing feature of neurodevelopmental disorders such as autism spectrum disorders (ASD), anxiety, and ADHD. Previous studies have found overactive brain responses and reduced modulation of thalamocortical connectivity in response to mildly aversive sensory stimulation in ASD. These findings suggest altered thalamic sensory gating which could be associated with an excitatory/inhibitory neurochemical imbalance, but such thalamic neurochemistry has never been examined in relation to SOR. Here we utilized magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to examine the relationship between thalamic and somatosensory cortex inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate) neurochemicals with the intrinsic functional connectivity of those regions in 35 ASD and 35 typically developing pediatric subjects. Although there were no diagnostic group differences in neurochemical concentrations in either region, within the ASD group, SOR severity correlated negatively with thalamic GABA (r = -0.48, p < 0.05) and positively with somatosensory glutamate (r = 0.68, p < 0.01). Further, in the ASD group, thalamic GABA concentration predicted altered connectivity with regions previously implicated in SOR. These variations in GABA and associated network connectivity in the ASD group highlight the potential role of GABA as a mechanism underlying individual differences in SOR, a major source of phenotypic heterogeneity in ASD. In ASD, abnormalities of the thalamic neurochemical balance could interfere with the thalamic role in integrating, relaying, and inhibiting attention to sensory information. These results have implications for future research and GABA-modulating pharmacologic interventions.

Prior studies have demonstrated that infants and toddlers who later go on to develop autism spectrum disorder (ASD) show atypical functional connectivity as well as altered neural processing of language and other auditory stimuli, but the timeline underlying the emergence of these altered developmental trajectories is still unclear. Here we used resting-state fMRI (rsfMRI) during natural sleep to examine the longitudinal development of functional connectivity in language-related networks from 1.5 to 9 months of age. We found that functional connectivity of networks that underlie the integration of sensory and motor representations, which is crucial for language development, is disrupted in infants at high familial risk (HR) for developing ASD as early as 1.5 months of age. By 9 months of age, HR infants showed hyperconnectivity between auditory and somatosensory regions whereas low risk (LR) infants displayed greater intrahemispheric connectivity between auditory cortex and higher-order temporal regions as well as the hippocampus. Furthermore, while LR infants showed robust changes in functional connectivity during the first year of life with increasing long-range connectivity accompanied by decreasing short-range connectivity over time, HR infants displayed limited developmental changes. Our findings demonstrate that early disruptions in the development of language-related network connectivity may provide an early marker for the later emergence of ASD symptomatology., (Copyright © 2020. Published by Elsevier Ltd.)

Autism spectrum disorder (ASD) is consistently associated with alterations in brain connectivity, but there are conflicting results as to where and when individuals with ASD display increased or reduced functional connectivity. Such inconsistent findings may be driven by atypical neurodevelopmental trajectories in ASD during adolescence, but no longitudinal studies to date have investigated this hypothesis. We thus examined the functional connectivity of three neurocognitive resting-state networks-the default mode network (DMN), salience network, and central executive network (CEN)-in a longitudinal sample of youth with ASD (n = 16) and without ASD (n = 22) studied during early/mid- and late adolescence. Functional connectivity between the CEN and the DMN displayed significantly altered developmental trajectories in ASD: typically developing (TD) controls-but not youth with ASD-exhibited an increase in negative functional connectivity between these two networks with age. This significant interaction was due to the ASD group displaying less negative functional connectivity than the TD group during late adolescence only, with no significant group differences in early/mid-adolescence. These preliminary findings suggest a localized age-dependency of functional connectivity alterations in ASD and underscore the importance of considering age when examining brain connectivity. Autism Research 2019, 12: 53-65. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Brain connectivity may develop differently during adolescence in youth with autism spectrum disorder (ASD). We looked at changes in brain connectivity over time within individuals and found that, for some brain regions, adolescents with ASD did not show the same changes in brain connectivity that typically developing adolescents did. This suggests it is important to consider age when studying brain connectivity in ASD., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Recent technological and analytical progress in brain imaging has enabled the examination of brain organization and connectivity at unprecedented levels of detail. The Human Connectome Project in Development (HCP-D) is exploiting these tools to chart developmental changes in brain connectivity. When complete, the HCP-D will comprise approximately ∼1750 open access datasets from 1300 + healthy human participants, ages 5-21 years, acquired at four sites across the USA. The participants are from diverse geographical, ethnic, and socioeconomic backgrounds. While most participants are tested once, others take part in a three-wave longitudinal component focused on the pubertal period (ages 9-17 years). Brain imaging sessions are acquired on a 3 T Siemens Prisma platform and include structural, functional (resting state and task-based), diffusion, and perfusion imaging, physiological monitoring, and a battery of cognitive tasks and self-reports. For minors, parents additionally complete a battery of instruments to characterize cognitive and emotional development, and environmental variables relevant to development. Participants provide biological samples of blood, saliva, and hair, enabling assays of pubertal hormones, health markers, and banked DNA samples. This paper outlines the overarching aims of the project, the approach taken to acquire maximally informative data while minimizing participant burden, preliminary analyses, and discussion of the intended uses and limitations of the dataset., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The cognitive and physiological processes underlying creativity remain unclear, and very few studies to date have attempted to identify the behavioral and brain characteristics that distinguish exceptional ("Big-C") from everyday ("little-c") creativity. The Big-C Project examined functional brain responses during tasks demanding divergent and convergent thinking in 35 Big-C Visual Artists (VIS), 41 Big-C Scientists (SCI), and 31 individuals in a "smart comparison group" (SCG) matched to the Big-C groups on parental educational attainment and estimated IQ. Functional MRI (fMRI) scans included two activation paradigms widely used in prior creativity research, the Alternate Uses Task (AUT) and Remote Associates Task (RAT), to assess brain function during divergent and convergent thinking, respectively. Task performance did not differ between groups. Functional MRI activation in Big-C and SCG groups differed during the divergent thinking task. No differences in activation were seen during the convergent thinking task. Big-C groups had less activation than SCG in frontal pole, right frontal operculum, left middle frontal gyrus, and bilaterally in occipital cortex. SCI displayed lower frontal and parietal activation relative to the SCG when generating alternate uses in the AUT, while VIS displayed lower frontal activation than SCI and SCG when generating typical qualities (the control condition in the AUT). VIS showed more activation in right inferior frontal gyrus and left supramarginal gyrus relative to SCI. All groups displayed considerable overlapping activation during the RAT. The results confirm substantial overlap in functional activation across groups, but suggest that exceptionally creative individuals may depend less on task-positive networks during tasks that demand divergent thinking., (Published by Elsevier Ltd.)

Observational neuroimaging studies with children and adolescents may identify neurological anomalies and other clinically relevant findings. Planning for the management of this information involves ethical considerations that may influence informed consent, confidentiality, and communication with participants about assessment results. Biomedical ethics principles include respect for autonomy, beneficence, non-maleficence, and justice. Each project presents unique challenges. The Adolescent Brain and Cognitive Development study (ABCD) collaborators have systematically developed recommendations with written guidelines for identifying and responding to potential risks that adhere to biomedical ethics principles. To illustrate, we will review the ABCD approach to three areas: (1) hazardous substance use; (2) neurological anomalies; and (3) imminent potential for self-harm or harm to others. Each ABCD site is responsible for implementing procedures consistent with these guidelines in accordance with their Institutional Review Board approved protocols, state regulations, and local resources. To assure that each site has related plans and resources in place, site emergency procedures manuals have been developed, documented and reviewed for adherence to ABCD guidelines. This article will describe the principles and process used to develop these ABCD bioethics and medical oversight guidelines, the concerns and options considered, and the resulting approaches advised to sites., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In neuroimaging, functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) signal in the brain. The degree of correlation of the BOLD signal in spatially independent regions of the brain defines the functional connectivity of those regions. During a cognitive fMRI task, a psychophysiological interaction (PPI) analysis can be used to examine changes in the functional connectivity during specific contexts defined by the cognitive task. An example of such a task is one that engages the memory system, asking participants to learn pairs of unrelated words (encoding) and recall the second word in a pair when presented with the first word (retrieval). In the present study, we used this type of associative memory task and a generalized PPI (gPPI) analysis to compare changes in hippocampal connectivity in older adults who are carriers of the Alzheimer's disease (AD) genetic risk factor apolipoprotein-E epsilon-4 (APOEε4). Specifically, we show that the functional connectivity of subregions of the hippocampus changes during encoding and retrieval, the two active phases of the associative memory task. Context-dependent changes in functional connectivity of the hippocampus were significantly different in carriers of APOEε4 compared to non-carriers. PPI analyses make it possible to examine changes in functional connectivity, distinct from univariate main effects, and to compare these changes across groups. Thus, a PPI analysis may reveal complex task effects in specific cohorts that traditional univariate methods do not capture. PPI analyses cannot, however, determine directionality or causality between functionally connected regions. Nevertheless, PPI analyses provide powerful means for generating specific hypotheses regarding functional relationships, which can be tested using causal models. As the brain is increasingly described in terms of connectivity and networks, PPI is an important method for analyzing fMRI task data that is in line with the current conception of the human brain.

Language mapping is a key goal in neurosurgical planning. fMRI mapping typically proceeds with a focus on Broca's and Wernicke's areas, although multiple other language-critical areas are now well-known. We evaluated whether clinicians could use a novel approach, including clinician-driven individualized thresholding, to reliably identify six language regions, including Broca's Area, Wernicke's Area (inferior, superior), Exner's Area, Supplementary Speech Area, Angular Gyrus, and Basal Temporal Language Area. We studied 22 epilepsy and tumor patients who received Wada and fMRI (age 36.4[12.5]; Wada language left/right/mixed in 18/3/1). fMRI tasks (two × three tasks) were analyzed by two clinical neuropsychologists who flexibly thresholded and combined these to identify the six regions. The resulting maps were compared to fixed threshold maps. Clinicians generated maps that overlapped significantly, and were highly consistent, when at least one task came from the same set. Cases diverged when clinicians prioritized different language regions or addressed noise differently. Language laterality closely mirrored Wada data (85% accuracy). Activation consistent with all six language regions was consistently identified. In blind review, three external, independent clinicians rated the individualized fMRI language maps as superior to fixed threshold maps; identified the majority of regions significantly more frequently; and judged language laterality to mirror Wada lateralization more often. These data provide initial validation of a novel, clinician-based approach to localizing language cortex. They also demonstrate clinical fMRI is superior when analyzed by an experienced clinician and that when fMRI data is of low quality judgments of laterality are unreliable and should be withheld. Hum Brain Mapp 38:4239-4255, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Research on bilinguals with brain lesions is complicated by high patient variability, making it difficult to find well-matched controls. We benefitted from a database of over 700 patients and conducted an analysis of pre-operative functional magnetic resonance imaging data to assess language dominance in 25 early, highly proficient Spanish-English bilinguals, and 25 carefully matched monolingual controls. Our results showed that early bilingualism is associated with greater bilateral hemispheric involvement, and monolingualism is associated with stronger left hemisphere lateralization (p=0.009). The bilinguals showed more pronounced right hemisphere activation (p=0.008). Although language dominance values were concordant in the bilingual group, there were a few (12%) atypical cases with different lateralization patterns in L1 and L2. Finally, we found distinct areas of activity in first and second language within the language network, in addition to regions of convergence. These data underscore the need to map all languages proficiently spoken by surgical candidates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Standard volumetric neuroimaging studies have demonstrated preferential atrophy of subcortical structures among individuals with HIV. However, to our knowledge, no study has investigated subcortical shape alterations secondary to HIV and whether advancing age impacts that relationship. This study employed 3D morphometry to examine the independent and interactive effects of HIV and age on shape differences in nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus in 81 participants ranging in age from 24 to 76 including 59 HIV+ individuals and 22 HIV-seronegative controls. T1-weighted MRI underwent a preprocessing pipeline followed by automated subcortical segmentation. Parametric statistical analyses were used to determine independent effects of HIV infection and age on volume and shape in each region of interest (ROI) and the interaction between age and HIV serostatus in predicting volume/shape in each ROI. Significant main effects for HIV were found in the shape of right caudate and nucleus accumbens, left pallidum, and hippocampus. Age was associated with differences in shape in left pallidum, right nucleus accumbens and putamen, and bilateral caudate, hippocampus, and thalamus. Of greatest interest, an age × HIV interaction effect was found in the shape of bilateral nucleus accumbens, amygdala, caudate, and thalamus as well as right pallidum and putamen such that increasing age in HIV participants was associated with greater shape alterations. Traditional volumemetric analyses revealed main effects for both HIV and age but no age × HIV interaction. These findings may suggest that age and HIV infection conferred additional deleterious effects on subcortical shape abnormalities beyond the independent effects of these factors. Hum Brain Mapp 38:1025-1037, 2017. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors report no conflicts of interest., (© 2016 Wiley Periodicals, Inc.)

The Wada test is an invasive procedure used to determine cerebral memory and language dominance as well as risk of cognitive deficits following neurosurgery. However, the potential risks of Wada testing have led some to consider foregoing Wada testing in candidates for resective epilepsy surgery with right hemispheric seizure onset. We present two atypical cases in which the Wada test showed unexpected memory and language lateralization. These cases underscore the importance of functional magnetic resonance in which imaging and Wada examination in right-handed individuals even when the lesion would not suggest atypical language representation.

Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: Although the amygdala and ventrolateral prefrontal cortex have been implicated in the pathophysiology of bipolar I disorder, the neural mechanisms underlying bipolar II disorder remain unknown. The authors examined neural activity in response to negative emotional faces during an emotion perception task that reliably activates emotion regulatory regions., Method: Twenty-one nonmedicated depressed bipolar II patients and 21 healthy comparison subjects underwent functional MRI (fMRI) while performing an emotional face-matching task. Within- and between-group whole-brain fMRI activation and seed-based connectivity analyses were conducted., Results: In depressed bipolar II patients, random-effects between-group fMRI analyses revealed a significant reduction in activation in several regions, including the left and right ventrolateral prefrontal cortices (Brodmann's area [BA] 47) and the right amygdala, a priori regions of interest. Additionally, bipolar patients exhibited significantly reduced negative functional connectivity between the right amygdala and the right orbitofrontal cortex (BA 10) as well as the right dorsolateral prefrontal cortex (BA 46) relative to healthy comparison subjects., Conclusions: These findings suggest that bipolar II depression is characterized by reduced regional orbitofrontal and limbic activation and altered connectivity in a fronto-temporal circuit implicated in working memory and emotional learning. While the amygdala hypoactivation observed in bipolar II depression is opposite to the direction seen in bipolar I mania and may therefore be state dependent, the observed orbitofrontal cortex hypoactivation is consistent with findings in bipolar I depression, mania, and euthymia, suggesting a physiologic trait marker of the disorder.

Although many Alzheimer's disease (AD) patients have a family history of the disease, it is rarely inherited in a predictable way. Functional magnetic resonance imaging (fMRI) studies of nondemented adults carrying familial AD mutations provide an opportunity to prospectively identify brain differences associated with early AD-related changes. We compared fMRI activity of 18 nondemented autosomal dominant AD mutation carriers with fMRI activity in eight of their noncarrier relatives as they performed a novelty encoding task in which they viewed novel and repeated images. Because age of disease onset is relatively consistent within families, we also correlated fMRI activity with subjects' distance from the median age of diagnosis for their family. Mutation carriers did not show significantly different voxelwise fMRI activity from noncarriers as a group. However, as they approached their family age of disease diagnosis, only mutation carriers showed increased fMRI activity in the fusiform and middle temporal gyri. This suggests that during novelty encoding, increased fMRI activity in the temporal lobe may relate to incipient AD processes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Patient studies have not provided consistent evidence for interictal neuronal hyperexcitability inside the seizure-onset zone (SOZ). We hypothesized that gray matter (GM) loss could have important effects on neuronal firing, and quantifying these effects would reveal significant differences in neuronal firing inside versus outside the SOZ., Methods: Magnetic resonance imaging (MRI) and computational unfolding of mesial temporal lobe (MTL) subregions was used to construct anatomic maps to compute GM loss in presurgical patients with medically intractable focal seizures in relation to controls. In patients, these same maps were used to locate the position of microelectrodes that recorded interictal neuronal activity. Single neuron firing and burst rates were evaluated in relation to GM loss and MTL subregions inside and outside the SOZ., Key Findings: MTL GM thickness was reduced inside and outside the SOZ in patients with respect to controls, yet GM loss was associated more strongly with firing and burst rates in several MTL subregions inside the SOZ. Adjusting single neuron firing and burst rates for the effects of GM loss revealed significantly higher firing rates in the subregion consisting of dentate gyrus and CA2 and CA3 (CA23DG), as well as CA1 and entorhinal cortex (EC) inside versus outside the SOZ where normalized MRI GM loss was ≥1.40 mm. Firing rates were higher in subicular cortex inside the SOZ at GM loss ≥1.97 mm, whereas burst rates were higher in CA23DG, CA1, and EC inside than outside the SOZ at similar levels of GM loss., Significance: The correlation between GM loss and increased firing and burst rates suggests GM structural alterations in MTL subregions are associated with interictal neuronal hyperexcitability inside the SOZ. Significant differences in firing rates and bursting in areas with GM loss inside compared to outside the SOZ indicate that synaptic reorganization following cell loss could be associated with varying degrees of epileptogenicity in patients with intractable focal seizures., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Peer rejection is particularly pervasive among adolescents with autism spectrum disorders (ASD). However, how adolescents with ASD differ from typically developing adolescents in their responses to peer rejection is poorly understood. The goal of the current investigation was to examine neural responses to peer exclusion among adolescents with ASD compared to typically developing adolescents. Nineteen adolescents with ASD and 17 typically developing controls underwent fMRI as they were ostensibly excluded by peers during an online game called Cyberball. Afterwards, participants reported their distress about the exclusion. Compared to typically developing adolescents, those with ASD displayed less activity in regions previously linked with the distressing aspect of peer exclusion, including the subgenual anterior cingulate and anterior insula, as well as less activity in regions previously linked with the regulation of distress responses during peer exclusion, including the ventrolateral prefrontal cortex and ventral striatum. Interestingly, however, both groups self-reported equivalent levels of distress. This suggests that adolescents with ASD may engage in differential processing of social experiences at the neural level, but be equally aware of, and concerned about, peer rejection. Overall, these findings contribute new insights about how this population may differentially experience negative social events in their daily lives.

Development of syntactic processing was examined to evaluate maturational processes including left language lateralization functions and increased specialization of brain regions important for syntactic processing. We utilized multimodal methods, including indices of brain activity from fMRI during a syntactic processing task, cortical thickness measurements from structural MRI, and neuropsychological measures. To evaluate hypotheses about increasing lateralization and specialization with development, we examined relationships between cortical thickness and magnitude and spatial activation extent within the left inferior frontal gyrus (IFG) and its right hemisphere homologue. We predicted that increased activation in the left and decreased activation in the right IFG would be associated with increased syntactic proficiency. As predicted, a more mature pattern of increased thickness in the right pars triangularis was associated with decreased activation intensity and extent in the right IFG. These findings suggest a maturational shift towards decreased involvement of the right IFG for syntactic processing. Better syntactic skills were associated with increased activation in the left IFG independent from age, suggesting increased specialization of the left IFG with increased proficiency. Overall, our findings show relationships between structural and functional neurodevelopment that co-occur with improved syntactic processing in critical language regions of the IFG in typically developing children.

Objective: Structural brain changes appear years before the onset of Alzheimer's disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimer's disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment., Method: High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N=13; noncarriers: N=13) with at least one first-degree relative with Alzheimer's disease and 25 subjects (APOE-4 carriers: N=12; noncarriers: N=13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38-86 years) were cognitively healthy., Results: Family history of Alzheimer's disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimer's disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status., Conclusions: APOE-4 carrier status and family history of Alzheimer's disease are independently associated with and contribute additively to hippocampal cortical thinning.

Although amygdala and frontal lobe functional abnormalities have been reported in patients with mood disorders, the literature regarding major depressive disorder (MDD) is inconsistent. Likely confounds include heterogeneity of patient samples, medication status, and analytic approach. This study evaluated the amygdala and frontal lobe activation in unmedicated MDD patients. Fifteen MDD patients and 15 matched healthy controls were scanned using fMRI during the performance of an emotional face task known to robustly activate the amygdala and prefrontal cortex (PFC). Whole-brain and region of interest analyses were performed, and correlations between clinical features and activation were examined. Significant amygdala and lateral PFC activation were seen within patient and control groups. In a between-group comparison, patients showed significantly reduced activation in the insula, temporal and occipital cortices. In MDD, the presence of anxiety symptoms was associated with decreased orbitofrontal activation. We found robust activation in both the MDD and control groups in fronto-limbic regions with no significant between-group differences using either analytic approach. The current study replicates previous research on unmedicated subjects showing no significant differences in amygdala function in depressed vs. control subjects with respect to simple tasks involving emotion observation., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Vascular problems increase Alzheimer's disease (AD) risk, but the nature of this relationship remains unclear. Older adults having genetic risk for AD show regionally increased functional magnetic resonance imaging (fMRI) activity during memory, possibly representing compensation for a genetically induced neural deficit. We investigated whether vascular health risks, which similarly could lead to neuropsychological deficits, also showed increased fMRI activity during a memory task performed by 30 cognitively intact, primarily normotensive older adults (mean age=61). Vascular risk measures included systolic blood pressure (sBP), body mass index (BMI), and total cholesterol. Higher sBP and BMI (but not total cholesterol) were significantly correlated with increased activation in posterior cingulate cortex and frontal, temporal, and parietal regions. In posterior cingulate and parietal cortices, these relationships were evident even within sBP and BMI ranges considered normal, and were independent of hippocampal volume. Our results are similar to those in prior AD risk research, and suggest that fMRI reveals an abnormal response to cognitive processes in cognitively intact older adults with increased vascular risk., (Copyright 2008 Elsevier Inc. All rights reserved.)

Entorhinal cortex (ERC) volume in adults with mild cognitive impairment has been shown to predict prodromal Alzheimer's disease (AD). Likewise, neuronal loss in ERC has been associated with AD, but not with normal aging. Because ERC is part of a major pathway modulating input to the hippocampus, structural changes there may result in changes to cognitive performance and functional brain activity during memory tasks. In 32 cognitively intact older adults, we examined the relationship between left ERC thickness and functional magnetic resonance imaging (fMRI) activity during an associative verbal memory task. This task has been shown previously to activate regions that are sensitive to aging and AD risk. ERC was manually defined on native space, high resolution, oblique coronal MRI scans. Subjects having thicker left ERC showed greater activation in anterior cingulate and medial frontal regions during memory retrieval, but not encoding. This result was independent of hippocampal volume. Anterior cingulate cortex is directly connected to ERC, and is, along with medial frontal cortex, implicated in error detection, which is impaired in AD. Our results suggest that in healthy older adults, processes that engage frontal regions during memory retrieval are related to ERC structure., (2009 Wiley-Liss, Inc.)

Background: While religious faith remains one of the most significant features of human life, little is known about its relationship to ordinary belief at the level of the brain. Nor is it known whether religious believers and nonbelievers differ in how they evaluate statements of fact. Our lab previously has used functional neuroimaging to study belief as a general mode of cognition [1], and others have looked specifically at religious belief [2]. However, no research has compared these two states of mind directly., Methodology/principal Findings: We used functional magnetic resonance imaging (fMRI) to measure signal changes in the brains of thirty subjects-fifteen committed Christians and fifteen nonbelievers-as they evaluated the truth and falsity of religious and nonreligious propositions. For both groups, and in both categories of stimuli, belief (judgments of "true" vs judgments of "false") was associated with greater signal in the ventromedial prefrontal cortex, an area important for self-representation [3], [4], [5], [6], emotional associations [7], reward [8], [9], [10], and goal-driven behavior [11]. This region showed greater signal whether subjects believed statements about God, the Virgin Birth, etc. or statements about ordinary facts. A comparison of both stimulus categories suggests that religious thinking is more associated with brain regions that govern emotion, self-representation, and cognitive conflict, while thinking about ordinary facts is more reliant upon memory retrieval networks., Conclusions/significance: While religious and nonreligious thinking differentially engage broad regions of the frontal, parietal, and medial temporal lobes, the difference between belief and disbelief appears to be content-independent. Our study compares religious thinking with ordinary cognition and, as such, constitutes a step toward developing a neuropsychology of religion. However, these findings may also further our understanding of how the brain accepts statements of all kinds to be valid descriptions of the world.

The hippocampus is often a difficult structure to visualize with magnetic resonance imaging (MRI) and functional MRI (fMRI) due to its convoluted nature and susceptibility to signal dropout. Improving our ability to pinpoint changes in neural activity using fMRI in this structure remains an important challenge. Current fMRI/MRI methods typically do not permit visualization of the hippocampus and surrounding cortex at a resolution less than 1 mm. We present here improvements to our previous methods for obtaining structural MR images of the hippocampus, which provided an in-plane resolution of 0.4 mm(2) mm and two-dimensional "flat" maps of the hippocampus with an interpolated isotropic resolution of 0.4 mm(3) (Engel, S.A., Glover, G.H., and Wandell, B.A., (1997). Retinotopic organization in human visual cortex and the spatial precision of functional MRI. Cereb. Cortex 7, 181-192.; Zeineh, M.M., Engel, S.A., and Bookheimer, S.Y., (2000). Application of cortical unfolding techniques to functional MRI of the human hippocampal region. NeuroImage 11, 668-683.). We present changes to existing structural imaging sequences that now augment the resolution of previous scans, permitting visualization of the anterior portion of CA1, parts of the dentate gyrus, and CA23. These imaging improvements are of relevance generally to the field of imaging because they permit higher overall resolution imaging of the hippocampus than previously possible (at 3 T). We also introduce a novel application of a computational interpolation method that improves our ability to capture the convoluted three-dimensional shape of the hippocampus. Furthermore, we have developed a quantitative method for obtaining group activation patterns based on producing averaged flat maps using vector field warping techniques, allowing localization of activations to specific hippocampal subregions across groups of subjects. Together, these methods provide a means to improve imaging of neural activity in the human hippocampus and surrounding cortex during cognitive tasks.

The relation between the blood-oxygen-level-dependent (BOLD) signal, which forms the basis of functional magnetic resonance imaging (fMRI), and underlying neural activity is not well understood. We performed high-resolution fMRI in patients scheduled for implantation with depth electrodes for seizure monitoring while they navigated a virtual environment. We then recorded local field potentials (LFPs) and neural firing rate directly from the hippocampal area of the same subjects during the same task. Comparing BOLD signal changes with 396 LFP and 185 neuron recordings in the hippocampal area, we found that BOLD signal changes correlated positively with LFP power changes in the theta-band (4-8 Hz). This correlation, however, was largely present for parahippocampal BOLD signal changes; BOLD changes in the hippocampus correlated weakly or not at all with LFP power changes. We did not find a significant relationship between BOLD activity and neural firing rate in either region, which could not be accounted for by a lesser tendency for neurons to respond or a greater tendency for neurons to habituate to the task. Strengthening the idea of a dissociation between LFP power and neural firing rate in their relation to the BOLD signal, simultaneously recorded LFP power and neural firing rate changes were uncorrelated across electrodes. Together, our results suggest that the BOLD signal in the human hippocampal area has a more heterogenous relationship with underlying neural activity than has been described previously in other brain regions.

Objective: Previous research suggests that engaging in mentally stimulating tasks may improve brain health and cognitive abilities. Using computer search engines to find information on the Internet has become a frequent daily activity of people at any age, including middle-aged and older adults. As a preliminary means of exploring the possible influence of Internet experience on brain activation patterns, the authors performed functional magnetic resonance imaging (MRI) of the brain in older persons during search engine use and explored whether prior search engine experience was associated with the pattern of brain activation during Internet use., Design: Cross-sectional, exploratory observational study, Participants: The authors studied 24 subjects (age, 55-76 years) who were neurologically normal, of whom 12 had minimal Internet search engine experience (Net Naive group) and 12 had more extensive experience (Net Savvy group). The mean age and level of education were similar in the two groups., Measurements: Patterns of brain activation during functional MRI scanning were determined while subjects performed a novel Internet search task, or a control task of reading text on a computer screen formatted to simulate the prototypic layout of a printed book, where the content was matched in all respects, in comparison with a nontext control task., Results: The text reading task activated brain regions controlling language, reading, memory, and visual abilities, including left inferior frontal, temporal, posterior cingulate, parietal, and occipital regions, and both the magnitude and the extent of brain activation were similar in the Net Naive and Net Savvy groups. During the Internet search task, the Net Naive group showed an activation pattern similar to that of their text reading task, whereas the Net Savvy group demonstrated significant increases in signal intensity in additional regions controlling decision making, complex reasoning, and vision, including the frontal pole, anterior temporal region, anterior and posterior cingulate, and hippocampus. Internet searching was associated with a more than twofold increase in the extent of activation in the major regional clusters in the Net Savvy group compared with the Net Naive group (21,782 versus 8,646 total activated voxels)., Conclusion: Although the present findings must be interpreted cautiously in light of the exploratory design of this study, they suggest that Internet searching may engage a greater extent of neural circuitry not activated while reading text pages but only in people with prior computer and Internet search experience. These observations suggest that in middle-aged and older adults, prior experience with Internet searching may alter the brain's responsiveness in neural circuits controlling decision making and complex reasoning.

Functional neuroimaging studies of face processing deficits in autism have typically focused on visual processing regions, such as the fusiform face area (FFA), which have shown reduced activity in autism spectrum disorders (ASD), though inconsistently. We recently reported reduced activity in the inferior frontal region in ASD, implicating impaired mirror-neuron systems during face processing. In the present study, we used fMRI during a face processing task in which subjects had to match faces presented in the upright versus inverted position. Typically developing (TD) children showed a classic behavioral inversion effect, increased reaction time for inverted faces, while this effect was significantly reduced in ASD subjects. The fMRI data showed similar responses in the fusiform face area for ASD and TD children, with both groups demonstrating increased activation for inverted faces. However, the groups did differ in several brain regions implicated in social cognition, particularly prefrontal cortex and amygdala. These data suggest that the behavioral differences in processing upright versus inverted faces for TD children are related not to visual information processing but to the social significance of the stimuli. Our results are consistent with other recent studies implicating frontal and limbic dysfunction during face processing in autism.

Objective: To investigate neural activity in prefrontal cortex and amygdala during bipolar depression., Methods: Eleven bipolar I depressed and 17 normal subjects underwent functional magnetic resonance imaging (fMRI) while performing a task known to activate prefrontal cortex and amygdala. Whole brain activation patterns were determined using statistical parametric mapping (SPM) when subjects matched faces displaying neutral or negative affect (match condition) or matched a geometric form (control condition). Contrasts for each group for the match versus control conditions were used in a second-level random effects analysis., Results: Random effects between-group analysis revealed significant attenuation in right and left orbitofrontal cortex (BA47) and right dorsolateral prefrontal cortex (DLPFC) (BA9) in bipolar depressed subjects. Additionally, random effects analysis showed a significantly increased activation in left lateral orbitofrontal cortex (BA10) in the bipolar depressed versus control subjects. Within-group contrasts demonstrated significant amygdala activation in the controls and no significant amygdala activation in the bipolar depressed subjects. The amygdala between-group difference, however, was not significant., Conclusions: Bipolar depression is associated with attenuated bilateral orbitofrontal (BA47) activation, attenuated right DLPFC (BA9) activation and heightened left orbitofrontal (BA10) activation. BA47 attenuation has also been reported in mania and may thus represent a trait feature of the disorder. Increased left prefrontal (BA10) activation may be a state marker to bipolar depression. Our findings suggest dissociation between mood-dependent and disease-dependent functional brain abnormalities in bipolar disorder.

Localization and targeting of depth electrodes in specific regions of the human brain is critical for accurate clinical diagnoses and treatment as well as for neuroscientific electrophysiological research. By using high-resolution magnetic resonance imaging combined with 2D computational unfolding, the authors present a method that improves electrode localization in the medial temporal lobe. This method permits visualization of electrode placements in subregions of the hippocampus and parahippocampal gyrus, allowing for greater specificity in relating electrophysiological and anatomical features in the human medial temporal lobe. Such methods may be extended to therapeutic procedures targeting specific neuronal circuitry in subfields of structures deep in the human brain.

Background: 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., Methodology/principal Findings: 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., Conclusions/significance: 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.

Purpose: This study examined whether locomotor training, which included body weight-supported treadmill therapy, improved walking and induced cortical representational adaptations using functional magnetic resonance imaging in the remaining sensorimotor network after cerebral hemispherectomy., Methods: Hemispherectomy patients (n = 12) underwent 2 weeks of gait training for at least 30 hours each. They were tested pre- and posttraining with the Fugl-Meyer Motor Assessment, unassisted single-limb stance time, and usual and fastest walking speeds. Three patients performed voluntary ankle movements as the functional magnetic resonance imaging activation task pre- and posttraining. Control subjects included 5 healthy children tested 2 weeks apart, 2 of whom trained on the treadmill, and 2 hemispherectomy patients who received upper extremity rehabilitation and no gait therapy., Results: Although patients reported improvements with gait training, behavioral outcomes did not significantly change. Training was associated with increased volume and intensity of cortical activation in the primary sensorimotor (S1M1), supplementary motor, motor cingulate, and secondary somatosensory cortex for the paretic foot, along with greater overlap in the representation for each moving foot in S1M1 and the supplementary motor area of the remaining hemisphere. Control subjects showed a decrease in activation in these cortical regions after training., Conclusions: Locomotor training of hemispherectomy patients improved mobility subjectively in association with functional magnetic resonance imaging evidence of cortical remodeling with ankle dorsiflexion. These findings support the notion that hemispherectomy patients may respond to rehabilitation interventions through mechanisms of activity-dependent cortical plasticity. The authors hypothesize that developmentally persistent descending ipsilateral and contralateral corticospinal tracts may allow the remaining hemisphere to maintain bilateral lower extremity motor control after surgery.

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.

Objective: Executive dysfunction in ADHD is well supported. However, recent studies suggest that more fundamental impairments may be contributing. We assessed brain function in adults with ADHD during simple and complex forms of processing., Method: We used functional magnetic resonance imaging with forward and backward digit spans to investigate number repetitions and complex working memory function. If pathology is limited to higher cognitive operations, group differences should be confined to the backward condition., Results: During the forward digit span, ADHD participants exhibited greater activation of LH linguistic processing areas and increased activation of right frontal and parietal cortices. During the backward digit span, they exhibited greater activation of LH linguistic processing areas and failed to activate bilateral parietal regions important for the complex executive operations., Conclusion: Abnormal brain function among adult ADHD participants was not limited to complex executive functions. Abnormal processing of numeric stimuli was indicated during both simple and complex cognitive operations.

Both working memory (WM) and controlled (attention-mediated) semantic processing functions have been thought to operate as limited capacity systems, but the possible link between these processes has not been investigated. We found that increased WM load attenuated semantic priming (i.e., reduced the response time advantage for semantically primed relative to unprimed items) and changed fMRI signal intensities in brain regions usually associated with both WM (dorsolateral prefrontal cortex) and controlled semantic retrieval (inferior frontal gyrus [IFG], pars orbitalis). fMRI signal changes in dorsolateral prefrontal cortex were negatively correlated with signal changes in pars orbitalis. The findings suggest that controlled semantic processing and working memory share neural system resources.

Patients with lesions in or near eloquent cortex typically undergo one of several invasive techniques to prevent loss of function following surgery. One of the most promising potential clinical applications of functional magnetic resonance imaging (fMRI) is to map these functions as part of the pre-surgical work-up to identify patients at-risk, guide the surgical entry, or tailor the surgical procedure to prevent deficits. While motor and sensory mapping are relatively straightforward, language mapping is far more complex. The language system is variable in location across individuals and in many cases may reorganize partially or completely to the contralateral hemisphere. In addition, multiple regions of the brain contribute to language functioning including essential regions that must not be removed in surgery, and contributory regions that may result in transient or insignificant impairments post-surgery. Despite these challenges, an increasing number of studies have supported the use of fMRI for pre-surgical language mapping in a variety of disorders. This article reviews the literature from three disorders for which patients benefit from preoperative language mapping: epilepsy, brain tumors, and arteriovenous malformations. Each disorder presents unique challenges to language mapping. Specific case studies are presented highlighting the both the potential benefits of preclinical fMRI for language mapping as well as the potential risks and pitfalls.

Background: White matter changes in aging and neuropsychiatric disorders may produce disconnection of neural circuits. Temporal correlations in regional blood oxygen level dependent (BOLD) signals may be used to assess effective functional connectivity in specific circuits, such as prefrontal cortex (PFC) circuits supporting working memory (WM) tasks. We hypothesized healthy older subjects would show lower connectivity than younger subjects., Methods: Healthy younger (n = 9, 25.9 (SD 6.0) years) and older adults (n = 11, 68.3 (4.9) years) performed WM tasks during functional MRI. Subjects viewed images and were instructed to label them, either simultaneously or after a delay; BOLD responses with and without delay were contrasted to assess differential WM activation and connectivity. Two tasks were used: a semantic task, with line drawings categorized as 'alive' or 'not living', and an emotional task, with emotive faces as stimuli and subjects selecting the better emotional description., Results: In both tasks, older subjects activated larger regions and had greater inter-individual variability in extent of activation. In the semantic task, connectivity was lower in the older subjects for the amygdala/orbital PFC circuit (p = 0.04). Contrary to our predictions, older subjects exhibited higher connectivity than younger subjects in the circuit linking orbital and dorsolateral PFC in both semantic (p = 0.04) and emotional (p = 0.02) tasks., Conclusions: Healthy subjects exhibited age-dependent differences in connectivity in working memory circuits, but this may reflect effects of aging on white matter, compensatory mechanisms, and other factors. Volumetric determination of white matter hyperintensities in future studies may clarify the functional importance of structural damage.

Background: Patients with bipolar disorder have been reported to have abnormal cortical function during mania. In this study, we sought to investigate neural activity in the frontal lobe during mania, using functional magnetic resonance imaging (fMRI). Specifically, we sought to evaluate activation in the lateral orbitofrontal cortex, a brain region that is normally activated during activities that require response inhibition., Methods: Eleven manic subjects and 13 control subjects underwent fMRI while performing the Go-NoGo task, a neuropsychological paradigm known to activate the orbitofrontal cortex in normal subjects. Patterns of whole-brain activation during fMRI scanning were determined with statistical parametric mapping. Contrasts were made for each subject for the NoGo minus Go conditions. Contrasts were used in a second-level analysis with subject as a random factor., Results: Functional MRI data revealed robust activation of the right orbitofrontal cortex (Brodmann's area [BA] 47) in control subjects but not in manic subjects. Random-effects analyses demonstrated significantly less magnitude in signal intensity in the right lateral orbitofrontal cortex (BA 47), right hippocampus, and left cingulate (BA 24) in manic compared with control subjects., Conclusions: Mania is associated with a significant attenuation of task-related activation of right lateral orbitofrontal function. This lack of activation of a brain region that is usually involved in suppression of responses might account for some of the disinhibition seen in mania. In addition, hippocampal and cingulate activation seem to be decreased. The relationship between this reduced function and the symptoms of mania remain to be further explored.

Objective: This study sought to investigate neural activity in the amygdala during episodes of mania., Method: Nine manic subjects and nine healthy comparison subjects underwent functional magnetic resonance imaging (fMRI) while performing a neuropsychological paradigm known to activate the amygdala. Subjects viewed faces displaying affect (experimental task) and geometric forms (control task) and matched them to one of two simultaneously presented similar images., Results: Manic subjects had significantly increased activation in the left amygdala and reduced bilateral activation in the lateral orbitofrontal cortex relative to the comparison subjects., Conclusions: Increased activation in the amygdala and decreased activation in the orbitofrontal cortex may represent disruption of a specific neuroanatomic circuit involved in mania. These brain regions may be implicated in disorders involving regulation of affect.

Objective: In this study, we developed an a priori system to stratify surgical intervention of perisylvian arteriovenous malformations (AVMs) in 20 patients. We stratified the patients into three categories based on preoperative functional magnetic resonance imaging (fMRI) language activation pattern and relative location of the AVM., Methods: In Group I (minimal risk), the AVM was at least one gyrus removed from language activation, and patients subsequently underwent asleep resection. In Group II (high risk), the AVM and language activation were intimately associated. Because the risk of postoperative language deficit was high, these patients were then referred to radiosurgery. In Group III (indeterminate risk), the AVM and language were adjacent to each other. The risk of language deficit could not be predicted on the basis of the fMRI alone. These patients underwent awake craniotomy with electrocortical stimulation mapping and optical imaging of intrinsic signals for language mapping., Results: All patients from Group I (minimal risk) underwent asleep resection without deficit. All Group II (high-risk) patients tolerated radiosurgery without complication. In Group III (indeterminate risk), three patients underwent successful resection, whereas two underwent aborted resection after intracranial mapping., Conclusion: We advocate the use of fMRI to assist in the preoperative determination of operability by asleep versus awake craniotomy versus radiosurgery referral. In addition, we advocate the use of all three functional mapping (fMRI, electrocortical stimulation mapping, and optical imaging of intrinsic signals) techniques to clarify the eloquence score of the Spetzler-Martin system before definitive treatment (anesthetized resection versus radiosurgery versus intraoperative resection versus intraoperative closure and radiosurgery referral).

Perfusion-dependent brain mapping modalities, such as functional magnetic resonance imaging, positron emission tomography, and optical imaging of intrinsic signals, have become increasingly popular for neurosurgical guidance because they offer a relatively rapid and noninvasive means of mapping brain function. These modalities are unique because they rely on perfusion-related signals that are coupled with neuronal activity to map the brain instead of measuring electrophysiological responses. They consequently present unique challenges to the clinician in terms of understanding the significance and limitations of the maps they produce. In particular, one must be aware of limitations of the modalities with respect to spatial specificity, sensitivity, and reliability of these maps and how the presence of intracranial lesions may further complicate these issues. The authors review the evolution, interpretation, and limitations of perfusion-based brain mapping techniques, with special attention to clinical implications of the brain maps.

Category-specific naming deficits and differential brain activation patterns have been reported in patients naming living as opposed to nonliving objects. The authors report on a case in which they used preoperative functional magnetic resonance (fMR) imaging, intraoperative electrocortical stimulation mapping (ESM), and postoperative neuropsychological testing to map language function. Using the latter two modalities, the authors identified a specific locus for category-specific naming in the posterior inferior temporal lobe, presumably a part of the basal temporal language area. Preoperative fMR imaging findings revealed the presence of a language area in the inferior temporal lobe; intraoperative ESM results indicated that this cortical area may be category specific for living objects; and after resection of the area, the results of postoperative neuropsychological testing confirmed that the patient made significantly more errors while naming living objects compared with nonliving ones (p < 0.001), independent of the effects of word frequency and with an intact system of object recognition and comprehension. These authors are the first to identify a specific and well-localized area of category-specific naming in the inferior temporal lobe and to demonstrate congruence of intraoperative and postoperative category-specific naming deficits. They also emphasize the roles of preoperative and intraoperative testing in predicting clinical outcomes.

Object: The goal of this study was to evaluate the utility of preoperative functional magnetic resonance (fMR) imaging in the prediction of whether a given cortical area would be deemed essential for language processing by electrocortical stimulation mapping (ESM)., Methods: The authors studied patients with vascular malformations, specifically arteriovenous malformations (AVMs) and cavernous angiomas, in whom blood-flow patterns are not normal and in whom a perfusion-dependent mapping signal may be questionable. Ten patients were studied (seven harboring AVMs and three with cavernous angiomas). The authors used a battery of linguistic tasks, including visual object naming, word generation, auditory responsive naming, visual responsive naming, and sentence comprehension, to identify brain regions that were consistently activated across expression and comprehension linguistic tasks. In a comparison of ESM and fMR imaging activations, the authors varied the matching criteria (overlapping activations, adjacent activations, and deep activations) and the radii of influence of ESM (2.5, 5, and 10 mm) to determine the effects of these factors on the sensitivity and specificity of fMR imaging. The sensitivity and specificity of fMR imaging were dependent on the task, lobe, and matching criterion. For the population studied, the sensitivity and specificity of fMR imaging activations during expressive linguistic tasks were found to be up to 100 and 66.7%, respectively, in the frontal lobe, and during comprehension linguistic tasks up to 96.2 and 69.8%, respectively, in the temporal and parietal lobes. The sensitivity and specificity of each disease population (patients with AVMs and those with cavernous angiomas) and of individuals were consistent with those values reported for the entire population studied., Conclusions: The authors conclude that preoperative fMR imaging is a highly sensitive preoperative planning tool for the identification of which cortical areas are essential for language and that this imaging modality may play a future role in presurgical planning for patients with vascular malformations.

Objective: The objective of this study is to demonstrate the assessment of hippocampal atrophy within a standard brain atlas for persons with age-associated memory impairment (AAMI) compared with cognitively intact elderly., Methods: High-resolution three-dimensional (3D) brain magnetic resonance imaging (MRI) was performed on 20 nondemented persons: 10 had AAMI and 10 were normal elderly. Scans were aligned to a common atlas template to control for errors due to variable brain size and orientation as well as facilitating communication of results across centers. Manual outlining every 1 mm with volumes determined for both the hippocampal head and body was accomplished after coronal resampling perpendicular to the long axis of the hippocampus., Results: Subject groups were similar in age, sex ratios, and educational achievement. The AAMI group had significantly lower volumes for the right hippocampus and hippocampal head (p =.02) compared with controls., Conclusion: A growing body of work suggests the right hippocampal head as an early site of atrophy in early memory impairment. Subtle atrophic changes are detectable within a common atlas template allowing imaging assessment across centers.

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network - an early-emerging neural network involved in orienting attention to the most salient aspects of ones internal and external environment - may predict the development of ASD symptoms such as reduced social attention and atypical sensory processing. Six-week-old infants at high likelihood of developing ASD based on family history exhibited stronger Salience Network connectivity with sensorimotor regions; infants at typical likelihood of developing ASD demonstrated stronger Salience Network connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in Salience Network connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with vulnerability to ASD.

Sensory over-responsivity (SOR) is a prevalent cross-diagnostic condition that is often associated with anxiety. The biological mechanisms underlying the co-occurrence of SOR and anxiety symptoms are not well understood, despite having important implications for targeted intervention. We therefore investigated the unique associations of SOR and anxiety symptoms with physiological and neural responses to sensory stimulation for youth with anxiety disorders (ANX), autism spectrum disorder (ASD), or typical development (TD). Age/IQ-matched youth aged 8-18 years (22 ANX; 30 ASD; 22 TD) experienced mildly aversive tactile and auditory stimuli during functional magnetic resonance imaging and then during skin conductance response (SCR) and heart rate (HR) measurements. Caregivers reported on participants' SOR and anxiety symptoms. ASD/ANX youth had elevated SOR and anxiety symptoms compared to TD. ASD/ANX youth showed similar, heightened brain responses to sensory stimulation compared to TD youth, but brain responses were more highly related to SOR symptoms in ASD youth and to anxiety symptoms in ANX youth. Across ASD/ANX youth, anxiety symptoms uniquely related to greater SCR whereas SOR uniquely related to greater HR responses to sensory stimulation. Behavioral and neurobiological over-responsivity to sensory stimulation was shared across diagnostic groups. However, findings support SOR and anxiety as distinct symptoms with unique biological mechanisms, and with different relationships to neural over-reactivity dependent on diagnostic group. Results indicate a need for targeted treatment approaches.

Despite growing evidence implicating thalamic functional connectivity atypicalities in autism spectrum disorder (ASD), it remains unclear how such alterations emerge early in human development. Because the thalamus plays a critical role in sensory processing and neocortical organization early in life, its connectivity with other cortical regions could be key for studying the early onset of core ASD symptoms. Here, we investigated emerging thalamocortical functional connectivity in infants at high (HL) and typical (TL) familial likelihood for ASD in early and late infancy. We report significant thalamo-limbic hyperconnectivity in 1.5-month-old HL infants, and thalamo-cortical hypoconnectivity in prefrontal and motor regions in 9-month-old HL infants. Importantly, early sensory over-responsivity (SOR) symptoms in HL infants predicted a direct trade-off in thalamic connectivity whereby stronger thalamic connectivity with primary sensory regions and basal ganglia was inversely related to connectivity with higher order cortices. This trade-off suggests that ASD may be characterized by early differences in thalamic gating. The patterns reported here could directly underlie atypical sensory processing and attention to social vs. nonsocial stimuli observed in ASD. These findings lend support to a theoretical framework of ASD whereby early disruptions in sensorimotor processing and attentional biases early in life may cascade into core ASD symptomatology.

BACKGROUND: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimers disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. OBJECTIVE: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. METHODS: A total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t-test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. RESULTS: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. CONCLUSIONS: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels.

BackgroundSensory 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.MethodsHere, 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.ResultsWe 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.LimitationsThe 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.ConclusionsOur results suggest that enhanced recruitment of prefrontal regions may underlie age-related decreases in SOR for a subgroup of ASD youth.