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Background Studies have found that individuals with mild cognitive impairment (MCI) exhibit a range of deficits outside the realm of primary explicit memory, yet the role of response speed and implicit learning in older adults with MCI have not been established. Objective The current study aims to explore and document response speed and implicit learning in older adults with neuropsychologically defined MCI using a simple serial reaction (SRT) task. In addition, the study aims to explore the feasibility of a novel utilization of the simple cognitive task using machine learning procedures as a proof of concept. Method Participants were 22 cognitively healthy older adults and 20 older adults with MCI confirmed through comprehensive neuropsychological evaluation. Two-sample t-test, multivariate regression, and mixed-effect models were used to investigate group difference in response speed and implicit learning on the SRT task. We also explored the potential utility of SRT feature analysis through random forest classification. Results With demographic variables controlled, the MCI group showed overall slower reaction time and higher error rate compared to the cognitively healthy volunteers. Both groups showed significant simple motor learning and implicit learning. The learning patterns were not statistically different between the two groups. Random forest classification achieved overall accuracy of 80.9%. Conclusions Individuals with MCI demonstrated slower reaction time and higher error rate compared to cognitively healthy volunteers but demonstrated largely preserved motor learning and implicit sequence learning. Preliminary results from random forest classification using features from SRT performance supported further research in this area.

White matter lesions, quantified as ‘white matter signal abnormalities’ (WMSA) on neuroimaging, are common incidental findings on brain images of older adults. This tissue damage is linked to cerebrovascular dysfunction and is associated with cognitive decline. The regional distribution of WMSA throughout the cerebral white matter has been described at a gross scale; however, to date no prior study has described regional patterns relative to cortical gyral landmarks which may be important for understanding functional impact. Additionally, no prior study has described how regional WMSA volume scales with total global WMSA. Such information could be used in the creation of a pathologic ‘staging’ of WMSA through a detailed regional characterization at the individual level. Magnetic resonance imaging data from 97 cognitively-healthy older individuals (OC) aged 52–90 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were processed using a novel WMSA labeling procedure described in our prior work. WMSA were quantified regionally using a procedure that segments the cerebral white matter into 35 bilateral units based on proximity to landmarks in the cerebral cortex. An initial staging was performed by quantifying the regional WMSA volume in four groups based on quartiles of total WMSA volume (quartiles I–IV). A consistent spatial pattern of WMSA accumulation was observed with increasing quartile. A clustering procedure was then used to distinguish regions based on patterns of scaling of regional WMSA to global WMSA. Three patterns were extracted that showed high, medium, and non-scaling with global WMSA. Regions in the high-scaling cluster included periventricular, caudal and rostral middle frontal, inferior and superior parietal, supramarginal, and precuneus white matter. A data-driven staging procedure was then created based on patterns of WMSA scaling and specific regional cut-off values from the quartile analyses. Individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) were then additionally staged, and significant differences in the percent of each diagnostic group in Stages I and IV were observed, with more AD individuals residing in Stage IV and more OC and MCI individuals residing in Stage I. These data demonstrate a consistent regional scaling relationship between global and regional WMSA that can be used to classify individuals into one of four stages of white matter disease. White matter staging could play an important role in a better understanding and the treatment of cerebrovascular contributions to brain aging and dementia., Highlights • White signal abnormalities (WMSA) manifest in a stereotyped juxtacortical spatial pattern in cognitively healthy aging • We present a procedure for staging WMSA using cut-off values derived from statistical analyses • We present a method to assess how regional WMSA scales with global WMSA to identify vulnerable white matter regions • Regions at cerebral perfusion boundary zones scale higher with global WMSA load than regions with a dual blood supply • There are more individuals with Alzheimer's disease than cognitively heathy older controls in higher stages of WMSA

How the interactions between cortices through a specific white matter pathway change during cognitive processing in patients with epilepsy remains unclear. Here, we used surface-based structural connectivity analysis to examine the change in structural connectivity with Broca's area/the right Broca's homologue in the lateral temporal and inferior parietal cortices through the arcuate fasciculus (AF) in 17 patients with left temporal lobe epilepsy (TLE) compared with 17 healthy controls. Then, we investigated its functional relevance to the changes in task-related responses and task-modulated functional connectivity with Broca's area/the right Broca's homologue during a semantic classification task of a single word. The structural connectivity through the AF pathway and task-modulated functional connectivity with Broca's area decreased in the left midtemporal cortex. Furthermore, task-related response decreased in the left mid temporal cortex that overlapped with the region showing a decrease in the structural connectivity. In contrast, the region showing an increase in the structural connectivity through the AF overlapped with the regions showing an increase in task-modulated functional connectivity in the left inferior parietal cortex. These structural and functional changes in the overlapping regions were correlated. The results suggest that the change in the structural connectivity through the left frontal-temporal AF pathway underlies the altered functional networks between the frontal and temporal cortices during the language-related processing in patients with left TLE. The left frontal-parietal AF pathway might be employed to connect anterior and posterior brain regions during language processing and compensate for the compromised left frontal-temporal AF pathway. Hum Brain Mapp 37:4425-4438, 2016. © 2016 Wiley Periodicals, Inc.

The functional organization of the human brain consists of a high degree of connectivity between interhemispheric homologous regions. The degree of homotopic organization is known to vary across the cortex and homotopic connectivity is high in regions that share cross-hemisphere structural connections or are activated by common input streams (e.g., the visual system). Damage to one or both regions, as well as damage to the connections between homotopic regions, could disrupt this functional organization. Here were introduce and test a computationally efficient technique, surface-based homotopic interhermispheric connectivity (sHIC), that leverages surface-based registration and processing techniques in an attempt to improve the spatial specificity and accuracy of cortical interhemispheric connectivity estimated with resting state functional connectivity. This technique is shown to be reliable both within and across subjects. sHIC is also characterized in a dataset of nearly 1000 subjects. We confirm previous results showing increased interhemispheric connectivity in primary sensory regions, and reveal a novel rostro-caudal functionally defined network level pattern of sHIC across the brain. In addition, we demonstrate a structural-functional relationship between sHIC and atrophy of the corpus callosum in multiple sclerosis (r = 0.2979, p = 0.0461). sHIC presents as a sensitive and reliable measure of cortical homotopy that may prove useful as a biomarker in neurologic disease. Hum Brain Mapp 37:2849-2868, 2016. © 2016 Wiley Periodicals, Inc.

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100+years of age. HCP-D is enrolling 1300+healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200+healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200+participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain.

The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200+healthy adults aged 36 to 100+, with a subset of 600+participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville etal., 2018), and the image acquisition protocol common to both studies (Harms etal., 2018).

Brain asymmetry is inherent to cognitive processing and seems to reflect processing efficiency. Lower frontal asymmetry is often observed in older adults during memory retrieval, yet it is unclear whether lower asymmetry implies an age-related increase in contralateral recruitment, whether less asymmetry reflects compensation, is limited to frontal regions, or predicts neurocognitive stability or decline. We assessed age-related differences in asymmetry across the entire cerebral cortex, using functional magnetic resonance imaging data from 89 young and 76 older adults during successful retrieval, and surface-based methods allowing direct homotopic comparison of activity between cortical hemispheres . An extensive left-asymmetric network facilitated retrieval in both young and older adults, whereas diverse frontal and parietal regions exhibited lower asymmetry in older adults. However, lower asymmetry was not associated with age-related increases in contralateral recruitment but primarily reflected either less deactivation in contralateral regions reliably signaling retrieval failure in the young or lower recruitment of the dominant hemisphere—suggesting that functional deficits may drive lower asymmetry in older brains, not compensatory activity. Lower asymmetry predicted neither current memory performance nor the extent of memory change across the preceding ~ 8 years in older adults. Together, these findings are inconsistent with a compensation account for lower asymmetry during retrieval and aging.

The objective of this study was to assess how longitudinal change in the quantity and quality of white matter signal abnormalities (WMSAs) contributes to the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). The Mahalanobis distance of WMSA from normal-appearing white matter using T1-, T2-, and PD-weighted MRI was defined as a quality measure for WMSA. Cross-sectional analysis of WMSA volume in 104 cognitively healthy older adults, 116 individuals with mild cognitive impairment who converted to AD within 3 years (MCI-C), 115 individuals with MCI that did not convert in that time (MCI-NC), and 124 individuals with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) revealed that WMSA volume was substantially greater in AD relative to the other groups, but did not differ between MCI-NC and MCI-C. Longitudinally, MCI-C exhibited faster WMSA quality progression but not volume compared to matched MCI-NC beginning eighteen months prior to MCI-C conversion to AD. The strongest difference in rate of change was seen in the time period starting 6 months before MCI-C conversion to AD and ending 6 months after conversion (p < 0.001). The relatively strong effect in this time period relative to AD conversion in the MCI-C was similar to the relative rate of change in hippocampal volume, a traditional imaging marker of AD pathology. These data demonstrate changes in white matter tissue properties that occur within WMSA in individuals with MCI that will subsequently obtain a clinical diagnosis of AD within 18 months. Individuals with AD have substantially greater WMSA volume than all MCI suggesting that there is a progressive accumulation of WMSA with progressive disease severity, and that quality change predates changes in this total volume. Given the timing of the changes in WMSA tissue quality relative to the clinical diagnosis of AD, these findings suggest that WMSAs are a critical component for this conversion and are a critical component of this clinical syndrome.

Introduction: Major depressive disorder (MDD) is often precipitated by life stress and growing evidence suggests that stress-induced alterations in reward processing may contribute to such risk. However, no human imaging studies have examined how recent life stress exposure modulates the neural systems that underlie reward processing in depressed and healthy individuals. Methods: In this proof-of-concept study, 12 MDD and 10 psychiatrically healthy individuals were interviewed using the Life Events and Difficulties Schedule (LEDS) to assess their perceived levels of recent acute and chronic life stress exposure. Additionally, each participant performed a monetary incentive delay task under baseline (no-stress) and stress (social-evaluative) conditions during functional MRI. Results: Across groups, medial prefrontal cortex (mPFC) activation to reward feedback was greater during acute stress versus no-stress conditions in individuals with greater perceived stressor severity. Under acute stress, depressed individuals showed a positive correlation between perceived stressor severity levels and reward-related mPFC activation (r¼0.79, p¼0.004), whereas no effect was found in healthy controls. Moreover, for depressed (but not healthy) individuals, the correlations between the stress (r¼0.79) and no-stress (r ¼� 0.48) conditions were significantly different. Finally, relative to controls, depressed participants showed significantly reduced mPFC gray matter, but functional findings remained robust while accounting for structural differences. Limitation: Small sample size, which warrants replication. Conclusion: Depressed individuals experiencing greater recent life stress recruited the mPFC more under stress when processing rewards. Our results represent an initial step toward elucidating mechanisms underlying stress sensitization and recurrence in depression. & 2015 Published by Elsevier B.V.

Clinical and cognitive symptoms domain-based subtyping in schizophrenia (Sz) has been critiqued due to the lack of neurobiological correlates and heterogeneity in symptom scores. We, therefore, present a novel data-driven framework using biclustered independent component analysis to detect subtypes from the reliable and stable gray matter concentration (GMC) of patients with Sz. The developed methodology consists of the following steps: source-based morphometry (SBM) decomposition, selection and sorting of two component loadings, subtype component reconstruction using group information-guided ICA (GIG-ICA). This framework was applied to the top two group discriminative components namely the insula/superior temporal gyrus/inferior frontal gyrus (I-STG-IFG component) and the superior frontal gyrus/middle frontal gyrus/medial frontal gyrus (SFG-MiFG-MFG component) from our previous SBM study, which showed diagnostic group difference and had the highest effect sizes. The aggregated multisite dataset consisted of 382 patients with Sz regressed of age, gender, and site voxelwise. We observed two subtypes (i.e., two different subsets of subjects) each heavily weighted on these two components, respectively. These subsets of subjects were characterized by significant differences in positive and negative syndrome scale (PANSS) positive clinical symptoms (p = 0.005). We also observed an overlapping subtype weighing heavily on both of these components. The PANSS general clinical symptom of this subtype was trend level correlated with the loading coefficients of the SFG-MiFG-MFG component (r = 0.25; p = 0.07). The reconstructed subtype-specific component using GIG-ICA showed variations in voxel regions, when compared to the group component. We observed deviations from mean GMC along with conjunction of features from two components characterizing each deciphered subtype. These inherent variations in GMC among patients with Sz could possibly indicate the need for personalized treatment and targeted drug development.

This paper presents a method for the statistical analysis of the associations between longitudinal neuroimaging measurements, e.g., of cortical thickness, and the timing of a clinical event of interest, e.g., disease onset. The proposed approach consists of two steps, the first of which employs a linear mixed effects (LME) model to capture temporal variation in serial imaging data. The second step utilizes the extended Cox regression model to examine the relationship between time-dependent imaging measurements and the timing of the event of interest. We demonstrate the proposed method both for the univariate analysis of image-derived biomarkers, e.g., the volume of a structure of interest, and the exploratory mass-univariate analysis of measurements contained in maps, such as cortical thickness and gray matter density. The mass-univariate method employs a recently developed spatial extension of the LME model. We applied our method to analyze structural measurements computed using FreeSurfer, a widely used brain Magnetic Resonance Image (MRI) analysis software package. We provide a quantitative and objective empirical evaluation of the statistical performance of the proposed method on longitudinal data from subjects suffering from Mild Cognitive Impairment (MCI) at baseline.

Anhedonia is one of the core symptoms of depression and has been linked to blunted responses to rewarding stimuli in striatal regions. Stress, a key vulnerability factor for depression, has been shown to induce anhedonic behavior, including reduced reward responsiveness in both animals and humans, but the brain processes associated with these effects remain largely unknown in humans. Emerging evidence suggests that stress has dissociable effects on distinct components of reward processing, as it has been found to potentiate motivation/‘wanting’ during the anticipatory phase but reduce reward responsiveness/‘liking’ during the consummatory phase. To examine the impact of stress on reward processing, we used a monetary incentive delay (MID) task and an acute stress manipulation (negative performance feedback) in conjunction with functional magnetic resonance imaging (fMRI). Fifteen healthy participants performed the MID task under no-stress and stress conditions. We hypothesized that stress would have dissociable effects on the anticipatory and consummatory phases in reward-related brain regions. Specifically, we expected reduced striatal responsiveness during reward consumption (mirroring patterns previously observed in clinical depression) and increased striatal activation during reward anticipation consistent with non-human findings. Supporting our hypotheses, significant Phase (Anticipation/Consumption) x Stress (Stress/No-stress) interactions emerged in the putamen, nucleus accumbens, caudate and amygdala. Post-hoc tests revealed that stress increased striatal and amygdalar activation during anticipation but decreased striatal activation during consumption. Importantly, stress-induced striatal blunting was similar to the profile observed in clinical depression under baseline (no-stress) conditions in prior studies. Given that stress is a pivotal vulnerability factor for depression, these results offer insight to better understand the etiology of this prevalent disorder.

Background miR-137 dysregulation has been implicated in the etiology of schizophrenia, but its functional role remains to be determined. Methods Functional magnetic resonance imaging scans were acquired on 48 schizophrenia patients and 63 healthy volunteers (total sample size N = 111 subjects), with similar mean age and sex distribution, while subjects performed a Sternberg Item Response Paradigm with memory loads of one, three, and five numbers. Dorsolateral prefrontal cortex (DLPFC) retrieval activation for the working memory load of three numbers, for which hyperactivation had been shown in schizophrenia patients compared with control subjects, was extracted. The genome-wide association study confirmed schizophrenia risk single nucleotide polymorphism rs1625579 (miR-137 locus) was genotyped (schizophrenia: GG n = 0, GT n = 9, TT n = 39; healthy volunteers: GG=2, GT n = 15, and TT n = 46). Fisher's exact test examined the effect of diagnosis on rs1625579 allele frequency distribution ( p = nonsignificant). Mixed model regression analyses examined the effects of diagnosis and genotype on working memory performance measures and DLPFC activation. Results Patients showed significantly higher left DLPFC retrieval activation on working memory load 3, lower working memory performance, and longer response times compared with controls. There was no effect of genotype on working memory performance or response times in either group. However, individuals with the rs1625579 TT genotype had significantly higher left DLPFC activation than those with the GG/GT genotypes. Conclusions Our study suggests that the rs1625579 TT (miR-137 locus) schizophrenia risk genotype is associated with the schizophrenia risk phenotype DLPFC hyperactivation commonly considered a measure of brain inefficiency.

Study objectiveTo assess the effect of armodafinil on task-related prefrontal cortex activation using functional magnetic resonance imaging (fMRI) in patients with obstructive sleep apnea (OSA) and excessive sleepiness despite continuous positive airway pressure (CPAP) therapy.MethodsThis 2-week, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study was conducted at five neuroimaging sites and four collaborating clinical study centers in the United States. Patients were 40 right-handed or ambidextrous men and women aged between 18 and 60 years, with OSA and persistent sleepiness, as determined by multiple sleep latency and Epworth Sleepiness Scale scores, despite effective, stable use of CPAP. Treatment was randomized (1:1) to once-daily armodafinil 200 mg or placebo. The primary efficacy outcome was a change from baseline at week 2 in the volume of activation meeting the predefined threshold in the dorsolateral prefrontal cortex during a 2-back working memory task. The key secondary measure was the change in task response latency.ResultsNo significant differences were observed between treatment groups in the primary or key secondary outcomes. Armodafinil was generally well tolerated. The most common adverse events (occurring in more than one patient [5%]) were headache (19%), nasopharyngitis (14%), and diarrhea (10%).ConclusionsArmodafinil did not improve fMRI-measured functional brain activation in CPAP-treated patients with OSA and excessive sleepiness.Study registrationDouble-Blind, Placebo-Controlled, Functional Neuroimaging Study of Armodafinil (200 mg/Day) on Prefrontal Cortical Activation in Patients With Residual Excessive Sleepiness Associated With Obstructive Sleep Apnea/Hypopnea.

Objective: To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. Methods: Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured. Results: Neurovascular coupling was associated with Trails B scores ( p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities ( p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs −2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. Conclusion: There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity.

Longitudinal neuroimaging (LNI) studies are rapidly becoming more prevalent and growing in size. Today, no standardized computational tools exist for the analysis of LNI data and widely used methods are sub-optimal for the types of data encountered in real-life studies. Linear Mixed Effects (LME) modeling, a mature approach well known in the statistics community, offers a powerful and versatile framework for analyzing real-life LNI data. This article presents the theory behind LME models, contrasts it with other popular approaches in the context of LNI, and is accompanied with an array of computational tools that will be made freely available through FreeSurfer - a popular Magnetic Resonance Image (MRI) analysis software package. Our core contribution is to provide a quantitative empirical evaluation of the performance of LME and competing alternatives popularly used in prior longitudinal structural MRI studies, namely repeated measures ANOVA and the analysis of annualized longitudinal change measures (e.g. atrophy rate). In our experiments, we analyzed MRI-derived longitudinal hippocampal volume and entorhinal cortex thickness measurements from a public dataset consisting of Alzheimer's patients, subjects with mild cognitive impairment and healthy controls. Our results suggest that the LME approach offers superior statistical power in detecting longitudinal group differences.

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala plays a central role in the processing of novelty and emotion in the brain. While there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory, and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioural assessment made in the laboratory at four months of age. This is the earliest known human behavioural phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high-levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or “endophenotypes”) indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically-defined disorder. Because the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory, and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the four-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.

Objective: Both amyloid-b (Ab) deposition and brain atrophy are associated with Alzheimer’s disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Ab deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD. Methods: A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to cortical thickness and hippocampal volume. Results: We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Ab deposition. Interpretation: We conclude that Ab deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment. ANN NEUROL 2010;000:000–000

Recent studies have demonstrated alterations in cortical gray to white matter tissue contrast with nondemented aging and in individuals with Alzheimer’s disease (AD). However, little information exists about the clinical relevance of such changes. It is possible that changes in MRI tissue contrast occur via independent mechanisms from those traditionally used in the assessment of AD associated degeneration such as hippocampal degeneration measured by more traditional volumetric magnetic resonance imaging (MRI). We created cortical surface models of 95 cognitively healthy individuals and 98 individuals with AD to characterize changes in regional gray and white matter T1-weighted signal intensities in dementia, and in normal aging and to evaluate how such measures related to classically described hippocampal and cortical atrophy. We found a reduction in gray matter to white matter tissue contrast throughout portions of medial and lateral temporal cortical regions as well as in anatomically associated regions including the posterior cingulate, precuneus, and medial frontal cortex. Decreases in tissue contrast were associated with hippocampal volume, however, the regional patterns of these associations differed for demented and nondemented individuals. In nondemented controls, lower hippocampal volume was associated with decreased gray/white matter tissue contrast globally across the cortical mantle. In contrast, in individuals with AD, selective associations were found between hippocampal volume and tissue contrast in temporal and limbic tissue. These results demonstrate that there are strong regional changes in neural tissue properties in AD which follow a spatial pattern including regions known to be affected from pathology studies. Such changes are associated with traditional imaging metrics of degeneration and may provide a unique biomarker of the tissue loss that occurs as a result of AD.

Greater loss in structural integrity of the ipsilesional corticospinal tract (CST) is associated with poorer motor outcome in patients with hemiparetic stroke. Animal models of stroke have demonstrated that structural remodeling of white matter in the ipsilesional and contralesional hemispheres is associated with improved motor recovery. Accordingly, motor recovery in patients with stroke may relate to the relative strength of CST degeneration and remodeling. This study examined the relationship between microstructural status of brain white matter tracts, indexed by the fractional anisotropy (FA) metric derived from diffusion tensor imaging (DTI) data, and motor skill of the stroke-affected hand in patients with chronic stroke. Voxelwise analysis revealed that motor skill significantly and positively correlated with FA of the ipsilesional and contralesional CST in the patients. Additional voxelwise analyses showed that patients with poorer motor skill had reduced FA of bilateral CST compared to normal control subjects, whereas patients with better motor skill had elevated FA of bilateral CST compared to controls. These findings were confirmed using a DTI-tractography method applied to the CST in both hemispheres. The results of this study suggest that the level of motor skill recovery achieved in patients with hemiparetic stroke relates to microstructural status of the CST in both the ipsilesional and contralesional hemispheres, which may reflect the net effect of degeneration and remodeling of bilateral CST.

MRI-based estimates of cerebral morphometric properties, e.g. cortical thickness, are pivotal to studies of normal and pathological brain changes. These measures are based on automated or manual segmentation procedures, which utilize the tissue contrast between gray and white matter on T(1)-weighted MR images. Tissue contrast is unlikely to remain a constant property across groups of different age and health. An important question is therefore how the sensitivity of cortical thickness estimates is influenced by variability in WM/GM contrast. The effect of adjusting for variability in WM/GM contrast on age sensitivity of cortical thickness was tested in 1189 healthy subjects from six different samples, enabling evaluation of consistency of effects within and between sites and scanners. Further, the influence of Alzheimer's disease (AD) diagnosis on cortical thickness with and without correction for contrast was tested in an additional sample of 96 patients. In healthy controls, regional increases in the sensitivity of the cortical thickness measure to age were found after correcting for contrast. Across samples, the strongest effects were observed in frontal, lateral temporal and parietal areas. Controlling for contrast variability also increased the cortical thickness estimates' sensitivity to AD, thus replicating the finding in an independent clinical sample. The results showed increased sensitivity of cortical estimates to AD in areas earlier reported to be compromised in AD, including medial temporal, inferior and superior parietal regions. In sum, the findings indicate that adjusting for contrast can increase the sensitivity of MR morphometry to variables of interest.

Objective. Patients with mesial temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) often show ictal and interictal propagation of epileptiform EEG activity to the ipsilateral temporal neocortex, the ipsilateral frontal lobe or the contralateral hippocampus, although structural MRI only shows unilateral involvement of the hippocampal formation. We used whole-head diffusion Tensor Imaging (DTI) to delineate a network that facilitates propagation of interictal epileptiform and seizure activity in this patient group. Methods. Isotropic 2 mm DTI was performed at 3 Tesla in 12 patients with medically intractable left TLE due to HS and compared to 12 controls. Whole-brain maps of fractional anisotropy (FA) were compared using a voxel based t-test to search for regions affected in patients with HS. This preliminary analysis was complementary to a set of anatomically guided region of interest (ROI) analyses that were manually defined on each individual’s FA map. Results. Left HS patients showed FA decreases in the temporal lobe white matter bilaterally, the ipsilateral frontal lobe white matter (WM) and in the genu and trunk of the corpus callosum. ROI analysis identified a significant FA decrease in left HS subjects in the affected hippocampus, WM of the ipsilateral parahippocampal gyrus and the genu and trunk of the corpus callosum. Conclusion. WM alterations occur bilaterally in the temporal lobe and in the ipsilateral superior frontal gyrus in left HS. The etiology and significance of these changes are unclear but the role of these regions in epileptogenesis and for pathways of epileptic spread should be further investigated.

Accumulating evidence suggests that altered cerebral white matter (WM) influences normal aging, and further that WM degeneration may modulate the clinical expression of Alzheimer’s disease (AD). Here we conducted a study of differences in WM volume across the adult age span and in AD employing a newly developed, automated method for regional parcellation of the subcortical WM that uses curvature landmarks and gray matter (GM)/WM surface boundary information. This procedure measures the volume of gyral WM, utilizing a distance constraint to limit the measurements from extending into the centrum semiovale. Regional estimates were first established to be reliable across two scan sessions in 20 young healthy individuals. Next, the method was applied to a large clinically-characterized sample of 299 individuals including 73 normal older adults and 91 age-matched participants with very mild to mild AD. The majority of measured regions showed a decline in volume with increasing age, with strong effects found in bilateral fusiform, lateral orbitofrontal, superior frontal, medial orbital frontal, inferior temporal, and middle temporal WM. The association between WM volume and age was quadratic in many regions suggesting that WM volume loss accelerates in advanced aging. A number of WM regions were further reduced in AD with parahippocampal, entorhinal, inferior parietal and rostral middle frontal WM showing the strongest AD-associated reductions. There were minimal sex effects after correction for intracranial volume, and there were associations between ventricular volume and regional WM volumes in the older adults and AD that were not apparent in the younger adults. Certain results, such as the loss of WM in the fusiform region with aging, were unexpected and provide novel insight into patterns of age associated neural and cognitive decline. Overall, these results demonstrate the utility of automated regional WM measures in revealing the distinct patterns of age and AD associated volume loss that may contribute to cognitive decline.

Introduction: Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. Methods: Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. Results: Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. Discussion: The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations.

Background: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. Methods: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. Results: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. Conclusions: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

There is still limited knowledge about the relationship between different structural brain parameters, despite huge progress in analysis of neuroimaging data. The aim of the present study was to test the relationship between fractional anisotropy (FA) from diffusion tensor imaging (DTI) and regional white matter (WM) volume. As WM volume has been shown to develop until middle age, the focus was on changes in WM properties in the age range of 40 to 60 years. 100 participants were scanned with magnetic resonance imaging (MRI). Each hemisphere was parcellated into 35 WM regions, and volume, FA, axial, and radial diffusion in each region were calculated. The relationships between age and the regional measures of FA and WM volume were tested, and then FA and WM volume were correlated, corrected for intracranial volume, age, and sex. WM volume was weakly related to age, while FA correlated negatively with age in 26 of 70 regions, caused by a mix of reduced axial and increased radial diffusion with age. 23 relationships between FA and WM volume were found, with seven being positive and sixteen negative. The positive correlations were mainly caused by increased radial diffusion. It is concluded that FA is more sensitive than volume to changes in WM integrity during middle age, and that FA-age correlations probably are related to reduced amount of myelin with increasing age. Further, FA and WM volume are moderately to weakly related and to a large extent sensitive to different characteristics of WM integrity.

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases., National Institute on Aging (K23-AG22509), National Institute on Aging (P50-AG05134), National Institute on Aging (P50-AG05681), National Institute on Aging (P01-AG03991), National Institute on Aging (R01-AG29411), National Institute on Aging (R21-AG29840), National Institute of Neurological Disorders and Stroke (U.S.) (grant R01-NS042861), National Center for Research Resources (U.S.) (P41RR14075), National Center for Research Resources (U.S.) (U24-RR021382), Alzheimer's Association, Howard Hughes Medical Institute, Mental Illness and Neuroscience Discovery (MIND) Institute

To perform well on any challenging task, it is necessary to evaluate your performance so that you can learn from errors. Recent theoretical and experimental work suggests that the neural sequellae of error commission in a dorsal anterior cingulate circuit index a type of contingency- or reinforcement-based learning, while activation in a rostral anterior cingulate circuit reflects appraisal of the affective or motivational significance of errors. Patients with schizophrenia show rigid, perseverative behaviour that is not optimally responsive to outcome. Findings of reduced anterior cingulate cortex (ACC) activity during error commission in schizophrenia suggest that difficulties in evaluating and modifying behaviour in response to errors may contribute to behavioural rigidity. Using event-related functional MRI and an antisaccade paradigm with concurrent monitoring of eye position, the present study examined error-related activation and its relation to task performance in the anatomic components of two ACC circuits that are theorized to make distinct contributions to error processing. Eighteen chronic-medicated schizophrenia patients and 15 healthy controls participated. Compared to controls, patients showed increased antisaccade error rates and decreased error-related activation in the reinforcement learning network--dorsal ACC, striatum and brainstem (possibly substantia nigra)--and also in the affective appraisal network--rostral ACC, insula and amygdala. These reductions remained when the effects of antipsychotic medication dose and error rate were statistically controlled. Activation in these networks was inversely related to error rate in both patient and control groups, but the slope of this relation was shallower in patients (i.e. across participants with schizophrenia, decrements in error rate were associated with smaller decrements in activation). This indicates that the blunted neural response to errors in schizophrenia was not simply a reflection of more frequent errors. Our findings demonstrate a blunted response to error commission that is associated with worse performance in two ACC circuits in schizophrenia. In the dACC circuit, the blunted response may reflect deficient modification of prepotent stimulus-response mappings in response to errors, and in the rACC network it may reflect diminished concern regarding behavioural outcomes. However, despite these deficits and in the absence of external feedback regarding errors, patients corrected their errors as frequently as controls suggesting intact error recognition and ability to institute corrective action. Impairments in evaluating and learning from errors in schizophrenia may contribute to behaviour that is rigid and perseverative rather than optimally guided by outcomes, and may compromise performance across a wide range of tasks.

This study examined how task (implicit vs. explicit) and semantic relationship (direct vs. indirect) modulated hemodynamic activity during lexico-semantic processing. Participants viewed directly related, indirectly related, and unrelated prime-target word-pairs as they performed (a) an implicit lexical decision (LD) task in which they decided whether each target was a real word or a nonword, and (b) an explicit relatedness judgment (RJ) task in which they determined whether each word-pair was related or unrelated in meaning. Task influenced both the polarity and neuroanatomical localization of hemodynamic modulation. Semantic relationship influenced the neuroanatomical localization of hemodynamic modulation. The implicit LD task was primarily associated with inferior prefrontal and ventral inferior temporal/fusiform hemodynamic response suppression to directly related (relative to unrelated) word-pairs, and with more widespread temporal-occipital response suppression to indirectly related (relative to unrelated) word-pairs. In contrast, the explicit RJ task was primarily associated with left inferior parietal hemodynamic response enhancement to both directly and indirectly related (relative to unrelated) word-pairs, as well as with additional left inferior prefrontal hemodynamic response enhancement to indirectly related (relative to unrelated) word-pairs. These findings are discussed in relation to the specific neurocognitive processes thought to underlie implicit and explicit semantic processes. Hum Brain Mapp, 2008. (c) 2007 Wiley-Liss, Inc.

In the present report, estimates of test–retest and between‐site reliability of fMRI assessments were produced in the context of a multicenter fMRI reliability study (FBIRN Phase 1, http://www.nbirn.net). Five subjects were scanned on 10 MRI scanners on two occasions. The fMRI task was a simple block design sensorimotor task. The impulse response functions to the stimulation block were derived using an FIR‐deconvolution analysis with FMRISTAT. Six functionally‐derived ROIs covering the visual, auditory and motor cortices, created from a prior analysis, were used. Two dependent variables were compared: percent signal change and contrast‐to‐noise‐ratio. Reliability was assessed with intraclass correlation coefficients derived from a variance components analysis. Test–retest reliability was high, but initially, between‐site reliability was low, indicating a strong contribution from site and site‐by‐subject variance. However, a number of factors that can markedly improve between‐site reliability were uncovered, including increasing the size of the ROIs, adjusting for smoothness differences, and inclusion of additional runs. By employing multiple steps, between‐site reliability for 3T scanners was increased by 123%. Dropping one site at a time and assessing reliability can be a useful method of assessing the sensitivity of the results to particular sites. These findings should provide guidance toothers on the best practices for future multicenter studies. Hum Brain Mapp, 2008. © 2007 Wiley‐Liss, Inc.

Serotonin (5-HT) is a neurotransmitter critically involved in a broad range of brain functions and implicated in the pathophysiology of neuropsychiatric illnesses including major depression, anxiety and sleep disorders. Despite being widely distributed throughout the brain, there is limited knowledge on the contribution of 5-HT to intrinsic brain activity. The dorsal raphe (DR) and median raphe (MR) nuclei are the source of most serotonergic neurons projecting throughout the brain and thus provide a compelling target for a seed-based probe of resting-state activity related to 5-HT. Here we implemented a novel multimodal neuroimaging approach for investigating resting-state functional connectivity (FC) between DR and MR and cortical, subcortical and cerebellar target areas. Using [(11)C]DASB positron emission tomography (PET) images of the brain serotonin transporter (5-HTT) combined with structural MRI from 49 healthy volunteers, we delineated DR and MR and performed a seed-based resting-state FC analysis. The DR and MR seeds produced largely similar FC maps: significant positive FC with brain regions involved in cognitive and emotion processing including anterior cingulate, amygdala, insula, hippocampus, thalamus, basal ganglia and cerebellum. Significant negative FC was observed within pre- and postcentral gyri for the DR but not for the MR seed. We observed a significant association between DR and MR FC and regional 5-HTT binding. Our results provide evidence for a resting-state network related to DR and MR and comprising regions receiving serotonergic innervation and centrally involved in 5-HT related behaviors including emotion, cognition and reward processing. These findings provide a novel advance in estimating resting-state FC related to 5-HT signaling, which can benefit our understanding of its role in behavior and neuropsychiatric illnesses.

© 2015 American College of Neuropsychopharmacology The amplitude of low-frequency fluctuations (ALFF) in the blood oxygenation level-dependent (BOLD) signal during resting-state fMRI reflects the magnitude of local low-frequency BOLD oscillations, rather than interregional connectivity. ALFF is of interest to studies of cognition because fluctuations in spontaneous intrinsic brain activity relate to, and possibly even constrain, task-evoked brain responses in healthy people. Lower ALFF has been reported in schizophrenia, but the cognitive correlates of these reductions remain unknown. Here, we assess relationships between ALFF and attention and working memory in order to establish the functional relevance of intrinsic BOLD oscillatory power alterations with respect to specific cognitive impairments in schizophrenia. As part of the multisite FBIRN study, resting-state fMRI data were collected from schizophrenia subjects (SZ; n=168) and healthy controls (HC; n=166). Voxelwise fractional ALFF (fALFF), a normalized ALFF measure, was regressed on neuropsychological measures of sustained attention and working memory in SZ and HC to identify regions showing either common slopes across groups or slope differences between groups (all findings p

© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both sourcebased morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.

Previous research indicates that long-term meditation practice is associated with altered resting electroencephalogram patterns, suggestive of long lasting changes in brain activity. We hypothesized that meditation practice might also be associated with changes in the brain’s physical structure. Magnetic resonance imaging was used to assess cortical thickness in 20 participants with extensive Insight meditation experience, which involves focused attention to internal experiences. Brain regions associated with attention, interoception and sensory processing were thicker in meditation participants than matched controls, including the prefrontal cortex and right anterior insula. Between-group diierences in prefrontal cortical thickness were most pronounced in older participants, suggesting that meditation might oiset age-related cortical thinning. Finally, the thickness of two regions correlated with meditation experience. These data provide the ¢rst structural evidence for experience-dependent cortical plasticity associated with meditation practice. NeuroReport 16:1893^1897 � c 2005 Lippincott Williams & Wilkins.

Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognition of stimuli afterward. MTL regions of interest were identified from each individual's structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline.

This study describes the neural circuitry underlying temporally separated components of working memory (WM) performance-stimulus encoding, maintenance of information during a delay, and the response to a probe. While other studies have applied event-related fMRI to separate epochs of WM tasks, this study differs in that it employs a methodology that does not make any a priori assumptions about the shape of the hemodynamic response (HDR). This is important because no one model of the HDR is valid across the range of activated brain regions and stimulus types. Systematic modeling inaccuracies may lead to the misattribution of activity to adjacent events. Twelve healthy subjects performed a numerical version of the Sternberg Item Recognition Paradigm adapted for rapid presentation event-related fMRI. This paradigm emphasized maintenance rather than manipulative WM processes and used a subcapacity WM load. WM trials with different delay lengths were compared to fixation. The HDR of the entire WM trial for each trial type was estimated using a finite impulse response (FIR). Regional activity associated with the Encode, Delay, and Probe epochs was identified using contrasts that were based on the FIR estimates and by examining the HDRs. Each epoch was associated with a distinct but overlapping pattern of regional activity. Activation of the dorsolateral prefrontal cortex, thalamus, and basal ganglia was exclusively associated with the probe. This suggests that frontostriatal neural circuitry participates in selecting an appropriate response based on the contents of WM.

Background Previous studies have shown that the activity of the amygdala is elevated in people experiencing clinical and subclinical levels of anxiety and depression (negative affect). It has been proposed that a reduction in inhibitory input to the amygdala from the prefrontal cortex and resultant over-activity of the amygdala underlies this association. Prior studies have found relationships between negative affect and 1) amygdala over-activity and 2) reduced amygdala-prefrontal connectivity. However, it is not known whether elevated amygdala activity is associated with decreased amygdala-prefrontal connectivity during negative affect states. Methods Here we used resting-state arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in combination to test this model, measuring the activity (regional cerebral blood flow, rCBF) and functional connectivity (correlated fluctuations in the BOLD signal) of one subregion of the amygdala with strong connections with the prefrontal cortex, the basolateral nucleus (BLA), and subsyndromal anxiety levels in 38 healthy subjects. Results BLA rCBF was strongly correlated with anxiety levels. Moreover, both BLA rCBF and anxiety were inversely correlated with the strength of the functional coupling of the BLA with the caudal ventromedial prefrontal cortex. Lastly, BLA perfusion was found to be a mediator of the relationship between BLA-prefrontal connectivity and anxiety. Conclusions These results show that both perfusion of the BLA and a measure of its functional coupling with the prefrontal cortex directly index anxiety levels in healthy subjects, and that low BLA-prefrontal connectivity may lead to increased BLA activity and resulting anxiety. Thus, these data provide key evidence for an often-cited circuitry model of negative affect, using a novel, multi-modal imaging approach.

Exploratory (i.e., voxelwise) spatial methods are commonly used in neuroimaging to identify areas that show an effect when a region-of-interest (ROI) analysis cannot be performed because no strong a priori anatomical hypothesis exists. However, noise at a single voxel is much higher than noise in a ROI making noise management critical to successful exploratory analysis. This work explores how preprocessing choices affect the bias and variability of voxelwise kinetic modeling analysis of brain positron emission tomography (PET) data. These choices include the use of volume- or cortical surface-based smoothing, level of smoothing, use of voxelwise partial volume correction (PVC), and PVC masking threshold. PVC was implemented using the Muller-Gartner method with the masking out of voxels with low gray matter (GM) partial volume fraction. Dynamic PET scans of an antagonist serotonin-4 receptor radioligand ([11C]SB207145) were collected on sixteen healthy subjects using a Siemens HRRT PET scanner. Kinetic modeling was used to compute maps of non-displaceable binding potential (BPND) after preprocessing. The results showed a complicated interaction between smoothing, PVC, and masking on BPND estimates. Volume-based smoothing resulted in large bias and intersubject variance because it smears signal across tissue types. In some cases, PVC with volume smoothing paradoxically caused the estimated BPND to be less than when no PVC was used at all. When applied in the absence of PVC, cortical surface-based smoothing resulted in dramatically less bias and the least variance of the methods tested for smoothing levels 5 mm and higher. When used in combination with PVC, surface-based smoothing minimized the bias without significantly increasing the variance. Surface-based smoothing resulted in 2–4 times less intersubject variance than when volume smoothing was used. This translates into more than 4 times fewer subjects needed in a group analysis to achieve similarly powered statistical tests. Surface-based smoothing has less bias and variance because it respects cortical geometry by smoothing the PET data only along the cortical ribbon and so does not contaminate the GM signal with that of white matter and cerebrospinal fluid. The use of surface-based analysis in PET should result in substantial improvements in the reliability and detectability of effects in exploratory PET analysis, with or without PVC.

A neural model is described of how the brain may autonomously learn a body-centered representation of a three-dimensional (3-D) target position by combining information about retinal target position, eye position, and head position in real time. Such a body-centered spatial representation enables accurate movement commands to the limbs to be generated despite changes in the spatial relationships between the eyes, head, body, and limbs through time. The model learns a vector representation—otherwise known as a parcellated distributed representation—of target vergence with respect to the two eyes, and of the horizontal and vertical spherical angles of the target with respect to a cyclopean egocenter. Such a vergence-spherical representation has been reported in the caudal midbrain and medulla of the frog, as well as in psychophysical movement studies in humans. A head-centered vergence-spherical representation of foveated target position can be generated by two stages of opponent processing that combine corollary discharges of outflow movement signals to the two eyes. Sums and differences of opponent signals define angular and vergence coordinates, respectively. The head-centered representation interacts with a binocular visual representation of nonfoveated target position to learn a visuomotor representation of both foveated and nonfoveated target position that is capable of commanding yoked eye movements. This head-centered vector representation also interacts with representations of neck movement commands to learn a body-centered estimate of target position that is capable of Commanding coordinated arm movements. Learning occurs during head movements made while gaze remains fixed on a foveated target. An initial estimate is stored and a VOR-mediated gating signal prevents the stored estimate from being reset during a gaze-maintaining head movement. As the head moves, new estimates are compared with the stored estimate to compute difference vectors which act as error signals that drive the learning process, as well as control the on-line merging of multimodal information.

Schizophrenia patients show significant subcortical brain abnormalities. We examined these abnormalities using automated image analysis software and provide effect size estimates for prospective multi-scanner schizophrenia studies. Subcortical and intracranial volumes were obtained using FreeSurfer 5.0.0 from high-resolution structural imaging scans from 186 schizophrenia patients (mean age±S.D.=38.9±11.6, 78% males) and 176 demographically similar controls (mean age±S.D.=37.5±11.2, 72% males). Scans were acquired from seven 3-Tesla scanners. Univariate mixed model regression analyses compared between-group volume differences. Weighted mean effect sizes (and number of subjects needed for 80% power at α=0.05) were computed based on the individual single site studies as well as on the overall multi-site study. Schizophrenia patients have significantly smaller intracranial, amygdala, and hippocampus volumes and larger lateral ventricle, putamen and pallidum volumes compared with healthy volunteers. Weighted mean effect sizes based on single site studies were generally larger than effect sizes computed based on analysis of the overall multi-site sample. Prospectively collected structural imaging data can be combined across sites to increase statistical power for meaningful group comparisons. Even when using similar scan protocols at each scanner, some between-site variance remains. The multi-scanner effect sizes provided by this study should help in the design of future multi-scanner schizophrenia imaging studies.

Among brain functions, language is one of the most lateralized. Cortical language areas are also some of the most asymmetrical in the brain. An open question is whether the asymmetry in function is linked to the asymmetry in anatomy. To address this question, we measured anatomical asymmetry in 34 participants shown with fMRI to have language dominance of the left hemisphere (LLD) and 21 participants shown to have atypical right hemisphere dominance (RLD). All participants were healthy and left-handed, and most (80%) were female. Gray matter (GM) volume asymmetry was measured using an automated surface-based technique in both ROIs and exploratory analyses. In the ROI analysis, a significant difference between LLD and RLD was found in the insula. No differences were found in planum temporale (PT), pars opercularis (POp), pars triangularis (PTr), or Heschl's gyrus (HG). The PT, POp, insula, and HG were all significantly left lateralized in both LLD and RLD participants. Both the positive and negative ROI findings replicate a previous study using manually labeled ROIs in a different cohort [Keller, S. S., Roberts, N., Garcia-Finana, M., Mohammadi, S., Ringelstein, E. B., Knecht, S., et al. Can the language-dominant hemisphere be predicted by brain anatomy? Journal of Cognitive Neuroscience, 23, 2013–2029, 2011]. The exploratory analysis was accomplished using a new surface-based registration that aligns cortical folding patterns across both subject and hemisphere. A small but significant cluster was found in the superior temporal gyrus that overlapped with the PT. A cluster was also found in the ventral occipitotemporal cortex corresponding to the visual word recognition area. The surface-based analysis also makes it possible to disentangle the effects of GM volume, thickness, and surface area while removing the effects of curvature. For both the ROI and exploratory analyses, the difference between LLD and RLD volume laterality was most strongly driven by differences in surface area and not cortical thickness. Overall, there were surprisingly few differences in GM volume asymmetry between LLD and RLD indicating that gross morphometric asymmetry is only subtly related to functional language laterality.

Objective: In Alzheimer’s FDG PET research, the choice of reference region for normalization and use of partial volume correction are inconsistent and have not been studied in a large multi-center study. Herein, we identified which normalization region provided the highest degree of discrimination between subjects who were classified as normal aging, mild cognitive impairment, or Alzheimer’s disease. The effects of partial volume correction using either a gray matter mask or cortical thickness and subcortical volume residuals were also examined. Methods: Stepwise logistic regression models were used to identify the optimal normalization region and partial volume correction method to discriminate between disease stages in over 400 subjects from research sites across North America. Normalization region candidates were the brainstem, precentral gyrus, postcentral gyrus, cerebellum, and thalamus. Partial volume correction methods tested were anatomically or statistically based. Results: Pre- and post- central gyri, and the thalamus showed AD-related changes in FDG PET and did not qualify for further testing. Normalizing to the cerebellum while using the gray matter mask for partial volume correction provided the highest indicator of discrimination. Conclusions: Normalization region and partial volume correction are critical to FDG PET analysis and candidate normalization regions should be tested for disease effects in the study sample prior to use. Cerebellar normalization and gray matter mask partial volume correction are recommended for use with the ADNI dataset.

This study examined the cortical representation of vibrotactile detection in humans using event-related fMRI paired with psychophysics. Suprathreshold vibrotactile stimulation activated several areas, including primary (SI) and second somatosensory cortices (SII/PV). For threshold-level stimuli, poststimulus activity in contralateral and ipsilateral SII/PV was the best correlate of detection success. In these areas, evoked signals on hit trials were significantly greater than on missed trials in all participants, and the relative activity level across stimulation amplitudes matched perceptual performance. Activity in the anterior insula and superior temporal gyrus also correlated with hits and misses, suggesting that a “ventral stream” of somatosensory representations may play a crucial role in detection. In contrast, poststimulus activity in Area SI was not well correlated with perception and showed an overall negative response profile for threshold-level stimulation. A different correlate of detection success was, however, observed in SI. Activity in this representation immediately before stimulus onset predicted performance, a finding that was unique to SI. These findings emphasize the potential role of SII/PV in detection, the importance of state dynamics in SI for perception, and the possibility that changes in the temporal and spatial pattern of SI activity may be essential to the optimal representation of threshold-level stimuli for detection.

Near-infrared spectroscopy (NIRS) signals have been shown to correlate with resting-state BOLD-fMRI data across the whole brain volume, particularly at frequencies below 0.1 Hz. While the physiological origins of this correlation remain unclear, its existence may have a practical application in minimizing the background physiological noise present in BOLD-fMRI recordings. We performed simultaneous, resting-state fMRI and 28-channel NIRS in seven adult subjects in order to assess the utility of NIRS signals in the regression of physiological noise from fMRI data. We calculated the variance of the residual error in a general linear model of the baseline fMRI signal, and the reduction of this variance achieved by including NIRS signals in the model. In addition, we introduced a sequence of simulated hemodynamic response functions (HRFs) into the resting-state fMRI data of each subject in order to quantify the effectiveness of NIRS signals in optimizing the recovery of that HRF. For comparison, these calculations were also performed using a pulse and respiration RETROICOR model. Our results show that the use of 10 or more NIRS channels can reduce variance in the residual error by as much as 36% on average across the whole cortex. However the same number of low-pass filtered white noise regressors is shown to produce a reduction of 19%. The RETROICOR model obtained a variance reduction of 6.4%. Our HRF simulation showed that the mean-squared error (MSE) between the recovered and true HRFs is reduced by 21% on average when 10 NIRS channels are applied and by introducing an optimized time lag between the NIRS and fMRI time series, a single NIRS channel can provide an average MSE reduction of 14%. The RETROICOR model did not provide a significant change in MSE. By each of the metrics calculated, NIRS recording is shown to be of significant benefit to the regression of low-frequency physiological noise from fMRI data.

An increasing number of studies use functional MRI (fMRI) and blood oxygen level-dependent (BOLD) signal to investigate the neurofunctional basis of acute alcohol effects on the brain. However, the BOLD signal reflects neural activity only indirectly as it depends on regional hemodynamic changes and is therefore sensitive to vasoactive substances, such as alcohol. We used MRI-based pulsed arterial spin labeling (ASL) method to quantify effects of acute intoxication on resting cerebral perfusion. Gender effects have not been previously examined and yet they are of particular interest given the differences in hormonal dynamics, alcohol metabolism, and hemodynamic regulation. Nineteen young, healthy individuals (nine women) with no personal or familial alcohol- or drug-related problems served as their own controls by participating in both alcohol (0.6g/kg ethanol for men, 0.55g/kg for women) and placebo scanning sessions in a counterbalanced manner. Regionally specific effects of the moderate alcohol dose on gray matter perfusion were examined with voxel-wise and region-of-interest analyses suggesting an interaction between gender and alcohol beverage. Acute intoxication increased perfusion in bilateral frontal regions in men but not in women. Under placebo, stronger cortical perfusion was observed in women compared with men primarily in the left hemisphere in frontal, parietal, and temporal areas. These results emphasize gender differences and regional specificity of alcohol's effects of cerebral perfusion possibly because of interactive influences on hormonal, metabolic, and hemodynamic autoregulatory systems. Alcohol-induced perfusion increase correlated positively with impulsivity/antisocial tendencies, consistent with dopaminergic mediation of reward, and its effects on cortical perfusion. Additional ASL studies are needed to investigate dose- and time-dependent effects of alcohol intoxication and gender on the hemodynamic factors that conjointly influence BOLD signal to disambiguate the vascular/metabolic mechanisms from the neurally based changes.

This article describes how corollary discharges from outflow eye movement commands can be transformed by two stages of opponent neural processing into a head-centered representation of 3-D target position. This representation implicitly defines a cyclopean coordinate system whose variables approximate the binocular vergence and spherical horizontal and vertical angles with respect to the observer's head. Various psychophysical data concerning binocular distance perception and reaching behavior are clarified by this representation. The representation provides a foundation for learning head-centered and body-centered invariant representations of both foveated and non-foveated 3-D target positions. It also enables a solution to be developed of the classical motor equivalence problem, whereby many different joint configurations of a redundant manipulator can all be used to realize a desired trajectory in 3-D space.

Cortical subpial demyelination is frequent in multiple sclerosis (MS) and is closely associated with disease progression and poor neurological outcome. Although cortical lesions have been difficult to detect using conventional MRI, preliminary data using T2*-weighted imaging at ultra-high field 7T MRI showed improved sensitivity for detecting and categorizing different histological types of cortical MS lesions. In this study we combined high-resolution 7T MRI with a surface-based analysis technique to quantify and map subpial T2*-weighted signal changes in seventeen patients with MS. We applied a robust method to register 7T data with the reconstructed cortical surface of each individual and used a general linear model to assess in vivo an increase in subpial T2*-weighted signal in patients versus age-matched controls, and to investigate the spatial distribution of cortical subpial changes across the cortical ribbon. We also assessed the relationship between subpial T2* signal changes at 7T, Expanded Disability Status Scale (EDSS) score and white matter lesion load (WMLL). Patients with MS showed significant T2*-weighted signal increase in the frontal lobes (parsopercularis, precentral gyrus, middle and superior frontal gyrus, orbitofrontal cortex), anterior cingulate, temporal (superior, middle and inferior temporal gyri), and parietal cortices (superior and inferior parietal cortex, precuneus), but also in occipital regions of the left hemisphere. We found significant correlations between subpial T2*-weighted signal and EDSS score in the precentral gyrus (R=0.56, P=0.02) and between T2*-weighted signal and WMLL in the lateral orbitofrontal, superior parietal, cuneus, precentral and superior frontal regions. Our data support the presence of disseminated subpial increases in T2* signal in subjects with MS, which may reflect the diffuse subpial pathology described in neuropathology.

Investigators perform multi-site functional magnetic resonance imaging studies to increase statistical power, to enhance generalizability, and to improve the likelihood of sampling relevant subgroups. Yet undesired site variation in imaging methods could off-set these potential advantages. We used variance components analysis to investigate sources of variation in the blood oxygen level-dependent (BOLD) signal across four 3-T magnets in voxelwise and region-of-interest (ROI) analyses. Eighteen participants traveled to four magnet sites to complete eight runs of a working memory task involving emotional or neutral distraction. Person variance was more than 10 times larger than site variance for five of six ROIs studied. Person-by-site interactions, however, contributed sizable unwanted variance to the total. Averaging over runs increased between-site reliability, with many voxels showing good to excellent between-site reliability when eight runs were averaged and regions of interest showing fair to good reliability. Between-site reliability depended on the specific functional contrast analyzed in addition to the number of runs averaged. Although median effect size was correlated with between-site reliability, dissociations were observed for many voxels. Brain regions where the pooled effect size was large but between-site reliability was poor were associated with reduced individual differences. Brain regions where the pooled effect size was small but between-site reliability was excellent were associated with a balance of participants who displayed consistently positive or consistently negative BOLD responses. Although between-site reliability of BOLD data can be good to excellent, acquiring highly reliable data requires robust activation paradigms, ongoing quality assurance, and careful experimental control.

Prior work has demonstrated that the memory dysfunction of Alzheimer’s disease (AD) is accompanied by marked cortical pathology in medial temporal lobe (MTL) gray matter. In contrast, changes in white matter (WM) of pathways associated with the MTL have rarely been studied. We used diffusion tensor imaging (DTI) to examine regional patterns of WM tissue changes in individuals with AD. Alterations of diffusion properties with AD were found in several regions including parahippocampal WM, and in regions with direct and secondary connections to the MTL. A portion of the changes measured, including effects in the parahippocampal WM, were independent of gray matter degeneration as measured by hippocampal volume. Examination of regional changes in unique diffusion parameters including anisotropy and axial and radial diffusivity demonstrated distinct zones of alterations, potentially stemming from differences in underlying pathology, with a potential myelin specific pathology in the parahippocampal WM. These results demonstrate that deterioration of neocortical connections to the hippocampal formation results in part from the degeneration of critical MTL and associated fiber pathways.