Convergent functional effects of antidepressants in major depressive disorder: a neuroimaging meta-analysis.

BACKGROUND: Neuroimaging studies have provided valuable insights into the macroscale impacts of antidepressants on brain functions in patients with major depressive disorder. However, the findings of individual studies are inconsistent. Here, we aimed to provide a quantitative synthesis of the literature to identify convergence of the reported findings at both regional and network levels and to examine their associations with neurotransmitter systems. METHODS: Through a comprehensive search in PubMed and Scopus databases, we reviewed 5258 abstracts and identified 36 eligible functional neuroimaging studies on antidepressant effects in major depressive disorder. Activation likelihood estimation was used to investigate regional convergence of the reported foci of antidepressant effects, followed by functional decoding and connectivity mapping of the convergent clusters. Additionally, utilizing group-averaged data from the Human Connectome Project, we assessed convergent resting-state functional connectivity patterns of the reported foci. Next, we compared the convergent circuit with the circuits targeted by transcranial magnetic stimulation therapy. Last, we studied the association of regional and network-level convergence maps with selected neurotransmitter receptors/transporters maps. RESULTS: No regional convergence was found across foci of treatment-associated alterations in functional imaging. Subgroup analysis in the Treated > Untreated contrast revealed a convergent cluster in the left dorsolateral prefrontal cortex, which was associated with working memory and attention behavioral domains. Moreover, we found network-level convergence of the treatment-associated alterations in a circuit more prominent in the frontoparietal areas. This circuit was co-aligned with circuits targeted by "anti-subgenual" and "Beam F3" transcranial magnetic stimulation therapy. We observed no significant correlations between our meta-analytic findings with the maps of neurotransmitter receptors/transporters. CONCLUSION: Our findings highlight the importance of the frontoparietal network and the left dorsolateral prefrontal cortex in the therapeutic effects of antidepressants, which may relate to their role in improving executive functions and emotional processing.

ALE meta-analyses of voxel-based morphometry studies: Parameter validation via large-scale simulations.

Activation likelihood estimation (ALE) meta-analysis has been applied to structural neuroimaging data since long, but up to now, any systematic assessment of the algorithm's behavior, power and sensitivity has been based on simulations using functional neuroimaging databases as their foundation. Here, we aimed to determine whether the guidelines offered by previous evaluations can be generalized to ALE meta-analyses of voxel-based morphometry (VBM) studies. We ran 365000 distinct ALE analyses filled with simulated experiments, randomly sampling parameters from BrainMap's VBM experiment database. We then examined the algorithm's sensitivity, its susceptibility to spurious convergence, and its susceptibility to excessive contributions by individual experiments. In general, the performance of the ALE algorithm was highly comparable between imaging modalities, with the algorithm's sensitivity and specificity reaching similar levels with structural data as previously observed with functional data. Because of the lower number of foci reported and the higher number of participants usually included in structural experiments, individual studies had, on average, a higher impact towards significant clusters. To prevent significant clusters from being driven by single experiments, we recommend that researchers include at least 23 experiments in a VBM ALE dataset, instead of the previously recommended minimum of n = 17. While these recommendations do not constitute hard borders, running ALE analyses on smaller datasets would require special diligence in assessing and reporting the contributions of experiments to individual clusters.

Deep neural network heatmaps capture Alzheimer's disease patterns reported in a large meta-analysis of neuroimaging studies.

Deep neural networks currently provide the most advanced and accurate machine learning models to distinguish between structural MRI scans of subjects with Alzheimer's disease and healthy controls. Unfortunately, the subtle brain alterations captured by these models are difficult to interpret because of the complexity of these multi-layer and non-linear models. Several heatmap methods have been proposed to address this issue and analyze the imaging patterns extracted from the deep neural networks, but no quantitative comparison between these methods has been carried out so far. In this work, we explore these questions by deriving heatmaps from Convolutional Neural Networks (CNN) trained using T1 MRI scans of the ADNI data set and by comparing these heatmaps with brain maps corresponding to Support Vector Machine (SVM) activation patterns. Three prominent heatmap methods are studied: Layer-wise Relevance Propagation (LRP), Integrated Gradients (IG), and Guided Grad-CAM (GGC). Contrary to prior studies where the quality of heatmaps was visually or qualitatively assessed, we obtained precise quantitative measures by computing overlap with a ground-truth map from a large meta-analysis that combined 77 voxel-based morphometry (VBM) studies independently from ADNI. Our results indicate that all three heatmap methods were able to capture brain regions covering the meta-analysis map and achieved better results than SVM activation patterns. Among them, IG produced the heatmaps with the best overlap with the independent meta-analysis.

Trends in the sample size, statistics, and contributions to the BrainMap database of activation likelihood estimation meta-analyses: An empirical study of 10-year data.

The literature of neuroimaging meta-analysis has been thriving for over a decade. A majority of them were coordinate-based meta-analyses, particularly the activation likelihood estimation (ALE) approach. A meta-evaluation of these meta-analyses was performed to qualitatively evaluate their design and reporting standards. The publications listed from the BrainMap website were screened. Six hundred and three ALE papers published during 2010-2019 were included and analysed. For reporting standards, most of the ALE papers reported their total number of Papers involved and mentioned the inclusion/exclusion criteria on Paper selection. However, most papers did not describe how data redundancy was avoided when multiple related Experiments were reported within one paper. The most prevalent repeated-measures correction methods were voxel-level FDR (54.4%) and cluster-level FWE (33.8%), with the latter quickly replacing the former since 2016. For study characteristics, sample size in terms of number of Papers included per ALE paper and number of Experiments per analysis seemed to be stable over the decade. One-fifth of the surveyed ALE papers failed to meet the recommendation of having >17 Experiments per analysis. For data sharing, most of them did not provide input and output data. In conclusion, the field has matured well in terms of rising dominance of cluster-level FWE correction, and slightly improved reporting on elimination of data redundancy and providing input data. The provision of Data and Code availability statements and flow chart of literature screening process, as well as data submission to BrainMap, should be more encouraged.

Imaging local genetic influences on cortical folding.

Recent progress in deciphering mechanisms of human brain cortical folding leave unexplained whether spatially patterned genetic influences contribute to this folding. High-resolution in vivo brain MRI can be used to estimate genetic correlations (covariability due to shared genetic factors) in interregional cortical thickness, and biomechanical studies predict an influence of cortical thickness on folding patterns. However, progress has been hampered because shared genetic influences related to folding patterns likely operate at a scale that is much more local (<1 cm) than that addressed in prior imaging studies. Here, we develop methodological approaches to examine local genetic influences on cortical thickness and apply these methods to two large, independent samples. We find that such influences are markedly heterogeneous in strength, and in some cortical areas are notably stronger in specific orientations relative to gyri or sulci. The overall, phenotypic local correlation has a significant basis in shared genetic factors and is highly symmetric between left and right cortical hemispheres. Furthermore, the degree of local cortical folding relates systematically with the strength of local correlations, which tends to be higher in gyral crests and lower in sulcal fundi. The relationship between folding and local correlations is stronger in primary sensorimotor areas and weaker in association areas such as prefrontal cortex, consistent with reduced genetic constraints on the structural topology of association cortex. Collectively, our results suggest that patterned genetic influences on cortical thickness, measurable at the scale of in vivo MRI, may be a causal factor in the development of cortical folding.

Hemodynamic and metabolic correspondence of resting-state voxel-based physiological metrics in healthy adults.

Voxel-based physiological (VBP) variables derived from blood oxygen level dependent (BOLD) fMRI time-course variations include: amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity (ReHo). Although these BOLD-derived variables can detect between-group (e.g. disease vs control) spatial pattern differences, physiological interpretations are not well established. The primary objective of this study was to quantify spatial correspondences between BOLD VBP variables and PET measurements of cerebral metabolic rate and hemodynamics, being well-validated physiological standards. To this end, quantitative, whole-brain PET images of metabolic rate of glucose (MRGlu; 18FDG) and oxygen (MRO2; 15OO), blood flow (BF; H215O) and blood volume (BV; C15O) were obtained in 16 healthy controls. In the same subjects, BOLD time-courses were obtained for computation of ALFF, fALFF and ReHo images. PET variables were compared pair-wise with BOLD variables. In group-averaged, across-region analyses, ALFF corresponded significantly only with BV (R = 0.64; p < 0.0001). fALFF corresponded most strongly with MRGlu (R = 0.79; p < 0.0001), but also significantly (p < 0.0001) with MRO2 (R = 0.68), BF (R = 0.68) and BV (R=0.68). ReHo performed similarly to fALFF, with significant strong correspondence (p < 0.0001) with MRGlu (R = 0.78), MRO2 (R = 0.54), and, but less strongly with BF (R = 0.50) and BV (R=0.50). Mutual information analyses further clarified these physiological interpretations. When conditioned by BV, ALFF retained no significant MRGlu, MRO2 or BF information. When conditioned by MRGlu, fALFF and ReHo retained no significant MRO2, BF or BV information. Of concern, however, the strength of PET-BOLD correspondences varied markedly by brain region, which calls for future investigation on physiological interpretations at a regional and per-subject basis.

Meta-analysis in human neuroimaging: computational modeling of large-scale databases.

Spatial normalization--applying standardized coordinates as anatomical addresses within a reference space--was introduced to human neuroimaging research nearly 30 years ago. Over these three decades, an impressive series of methodological advances have adopted, extended, and popularized this standard. Collectively, this work has generated a methodologically coherent literature of unprecedented rigor, size, and scope. Large-scale online databases have compiled these observations and their associated meta-data, stimulating the development of meta-analytic methods to exploit this expanding corpus. Coordinate-based meta-analytic methods have emerged and evolved in rigor and utility. Early methods computed cross-study consensus, in a manner roughly comparable to traditional (nonimaging) meta-analysis. Recent advances now compute coactivation-based connectivity, connectivity-based functional parcellation, and complex network models powered from data sets representing tens of thousands of subjects. Meta-analyses of human neuroimaging data in large-scale databases now stand at the forefront of computational neurobiology.

Evaluation of thresholding methods for activation likelihood estimation meta-analysis via large-scale simulations.

In recent neuroimaging studies, threshold-free cluster enhancement (TFCE) gained popularity as a sophisticated thresholding method for statistical inference. It was shown to feature higher sensitivity than the frequently used approach of controlling the cluster-level family-wise error (cFWE) and it does not require setting a cluster-forming threshold at voxel level. Here, we examined the applicability of TFCE to a widely used method for coordinate-based neuroimaging meta-analysis, Activation Likelihood Estimation (ALE), by means of large-scale simulations. We created over 200,000 artificial meta-analysis datasets by independently varying the total number of experiments included and the amount of spatial convergence across experiments. Next, we applied ALE to all datasets and compared the performance of TFCE to both voxel-level and cluster-level FWE correction approaches. All three multiple-comparison correction methods yielded valid results, with only about 5% of the significant clusters being based on spurious convergence, which corresponds to the nominal level the methods were controlling for. On average, TFCE's sensitivity was comparable to that of cFWE correction, but it was slightly worse for a subset of parameter combinations, even after TFCE parameter optimization. cFWE yielded the largest significant clusters, closely followed by TFCE, while voxel-level FWE correction yielded substantially smaller clusters, showcasing its high spatial specificity. Given that TFCE does not outperform the standard cFWE correction but is computationally much more expensive, we conclude that employing TFCE for ALE cannot be recommended to the general user.

Immediate and long-term effects of speech treatment targets and intensive dosage on Parkinson's disease dysphonia and the speech motor network: Randomized controlled trial.

This study compared acoustic and neural changes accompanying two treatments matched for intensive dosage but having two different treatment targets (voice or articulation) to dissociate the effects of treatment target and intensive dosage in speech therapies. Nineteen participants with Parkinsonian dysphonia (11 F) were randomized to three groups: intensive treatment targeting voice (voice group, n = 6), targeting articulation (articulation group, n = 7), or an untreated group (no treatment, n = 6). The severity of dysphonia was assessed by the smoothed cepstral peak prominence (CPPS) and neuronal changes were evaluated by cerebral blood flow (CBF) recorded at baseline, posttreatment, and 7-month follow-up. Only the voice treatment resulted in significant posttreatment improvement in CPPS, which was maintained at 7 months. Following voice treatment, increased activity in left premotor and bilateral auditory cortices was observed at posttreatment, and in the left motor and auditory cortices at 7-month follow-up. Articulation treatment resulted in increased activity in bilateral premotor and left insular cortices that were sustained at a 7-month follow-up. Activation in the auditory cortices and a significant correlation between the CPPS and CBF in motor and auditory cortices was observed only in the voice group. The intensive dosage resulted in long-lasting behavioral and neural effects as the no-treatment group showed a progressive decrease in activity in areas of the speech motor network out to a 7-month follow-up. These results indicate that dysphonia and the speech motor network can be differentially modified by treatment targets, while intensive dosage contributes to long-lasting effects of speech treatments.

A meta-analysis on neural changes of cognitive training for mental disorders in executive function tasks: increase or decrease brain activation?

BACKGROUND: Cognitive impairment is often found in patients with psychiatric disorders, and cognitive training (CT) has been shown to help these patients. To better understand the mechanisms of CT, many neuroimaging studies have investigated the neural changes associated with it. However, the results of those studies have been inconsistent, making it difficult to draw conclusions from the literature. Therefore, the objective of this meta-analysis was to identify consistent patterns in the literature of neural changes associated with CT for psychiatric disorders. METHODS: We searched for cognitive training imaging studies in PubMed, Cochrane library, Scopus, and ProQuest electronic databases. We conducted an activation likelihood estimation (ALE) for coordinate-based meta-analysis of neuroimaging studies, conduct behavioral analysis of brain regions identified by ALE analysis, conduct behavioral analysis of brain regions identified by ALE analysis, and then created a functional meta-analytic connectivity model (fMACM) of the resulting regions. RESULTS: Results showed that CT studies consistently reported increased activation in the left inferior frontal gyrus (IFG) and decreased activation in the left precuneus and cuneus from pre- to post- CT. CONCLUSION: CT improves cognitive function by supporting language and memory function, and reducing neuronal resources associated with basic visual processing.

BACON: A tool for reverse inference in brain activation and alteration.

Over the past decades, powerful MRI-based methods have been developed, which yield both voxel-based maps of the brain activity and anatomical variation related to different conditions. With regard to functional or structural MRI data, forward inferences try to determine which areas are involved given a mental function or a brain disorder. A major drawback of forward inference is its lack of specificity, as it suggests the involvement of brain areas that are not specific for the process/condition under investigation. Therefore, a different approach is needed to determine to what extent a given pattern of cerebral activation or alteration is specifically associated with a mental function or brain pathology. In this study, we present a new tool called BACON (Bayes fACtor mOdeliNg) for performing reverse inference both with functional and structural neuroimaging data. BACON implements the Bayes' factor and uses the activation likelihood estimation derived-maps to obtain posterior probability distributions on the evidence of specificity with regard to a particular mental function or brain pathology.

Disruption of the Atrophy-based Functional Network in Multiple Sclerosis Is Associated with Clinical Disability: Validation of a Meta-Analytic Model in Resting-State Functional MRI.

Background In multiple sclerosis (MS), gray matter (GM) atrophy exhibits a specific pattern, which correlates strongly with clinical disability. However, the mechanism of regional specificity in GM atrophy remains largely unknown. Recently, the network degeneration hypothesis (NDH) was quantitatively defined (using coordinate-based meta-analysis) as the atrophy-based functional network (AFN) model, which posits that localized GM atrophy in MS is mediated by functional networks. Purpose To test the NDH in MS in a data-driven manner using the AFN model to direct analyses in an independent test sample. Materials and Methods Model fit testing was conducted with structural equation modeling, which is based on the computation of semipartial correlations. Model verification was performed in coordinate-based data of healthy control participants from the BrainMap database (https://www.brainmap.org). Model validation was conducted in prospectively acquired resting-state functional MRI in participants with relapsing-remitting MS who were recruited between September 2018 and January 2019. Correlation analyses of model fit indices and volumetric measures with Expanded Disability Status Scale (EDSS) scores and disease duration were performed. Results Model verification of healthy control participants included 80 194 coordinates from 9035 experiments. Model verification in healthy control data resulted in excellent model fit (root mean square error of approximation, 0.037; 90% CI: 0.036, 0.039). Twenty participants (mean age, 36 years ± 9 [standard deviation]; 12 women) with relapsing-remitting MS were evaluated. Model validation in resting-state functional MRI in participants with MS resulted in deviation from optimal model fit (root mean square error of approximation, 0.071; 90% CI: 0.070, 0.072), which correlated with EDSS scores (r = 0.68; P = .002). Conclusion The atrophy-based functional network model predicts functional network disruption in multiple sclerosis (MS), thereby supporting the network degeneration hypothesis. On resting-state functional MRI scans, reduced functional network integrity in participants with MS had a strong positive correlation with clinical disability. © RSNA, 2021 Online supplemental material is available for this article.

Validation of T2 -based oxygen extraction fraction measurement with 15 O positron emission tomography.

PURPOSE: To evaluate the accuracy of T2 -based whole-brain oxygen extraction fraction (OEF) estimation by comparing it with gold standard 15 O-PET measurements. METHODS: Sixteen healthy adult subjects underwent MRI and 15 O-PET OEF measurements on the same day. On MRI, whole-brain OEF was quantified by T2 -relaxation-under-spin-tagging (TRUST) MRI, based on subject-specific hematocrit. The TRUST OEF was compared to the whole-brain averaged OEF produced by 15 O-PET. Agreement between TRUST and 15 O-PET whole-brain OEF measurements was examined in terms of intraclass correlation coefficient (ICC) and in absolute OEF values. In a subset of 10 subjects, test-retest reproducibility of whole-brain OEF was also evaluated and compared between the two modalities. RESULTS: Across the 16 subjects, the mean whole-brain OEF of TRUST and 15 O-PET were 36.44 ± 4.07% and 36.45 ± 3.65%, respectively, showing no difference between the two modalities (P = .99). TRUST whole-brain OEF strongly correlated with that of 15 O-PET (N = 16, ICC = 0.90, P = 4 × 10-7 ). The coefficient-of-variation of TRUST and 15 O-PET whole-brain OEF measurements were 1.79 ± 0.67% and 2.06 ± 1.55%, respectively, showing no difference between the two modalities (N = 10, P = .64). Further analyses on the effect of hematocrit revealed that correlation between PET OEF and TRUST OEF with assumed hematocrit remained significant (ICC = 0.8, P < 2 × 10-5 ). CONCLUSION: Whole-brain OEF measured by TRUST was in excellent agreement with gold standard 15 O-PET, with highly comparable accuracy and reproducibility. These findings suggest that TRUST MRI can provide accurate quantification of whole-brain OEF noninvasively.

Restriction Spectrum Imaging-Magnetic Resonance Imaging to Improve Prostate Cancer Imaging in Men on Active Surveillance.

PURPOSE: Restriction spectrum imaging-magnetic resonance imaging is a short duration enhanced diffusion-weighted technique that seeks to standardize sequences and predict upgrading. We test this technology for active surveillance biopsies. Our objective is to investigate the utility of restriction spectrum imaging-magnetic resonance imaging to improve upgrading detection in a prostate cancer active surveillance cohort. MATERIALS AND METHODS: We prospectively enrolled men on active surveillance undergoing repeat biopsy from January 2016 to June 2019. Subjects underwent prostate multiparametric magnetic resonance imaging and restriction spectrum imaging-magnetic resonance imaging reviewed by a urological radiologist for PI-RADS® scored lesions, followed by magnetic resonance imaging-guided prostate biopsy by a urologist. Restriction spectrum imaging-magnetic resonance imaging analysis with proprietary research software (CorTechs Labs, San Diego, California) generated a restricted signal map. We compared the restricted signal map and apparent diffusion coefficient values using T-test, ANOVA, and logistic regression analyses for prediction of upgrading. RESULTS: Of 123 enrolled men we identified 74 restriction spectrum imaging-magnetic resonance imaging regions of interest (targeted lesions) in 110 subjects, with 105 subjects completing biopsy. The restricted signal map was significant per PI-RADS score for true-positive lesion detection (mean difference 28, SD 0.7, p=0.001), and better than apparent diffusion coefficient (mean difference -15, SD 55, p=0.6). Restriction spectrum imaging generated restricted signal map values >50 improved sensitivity, specificity, positive predictive value and negative predictive value (81.0%, 81.8%, 54.2% and 94.2%) over PI-RADS ≥3 (71.4%, 38.9%, 23.7% and 83.7%, respectively) for Gleason upgrading. Overall restriction spectrum imaging is able to improve the AUC of 0.70 (95% CI 0.49-0.92, p=0.03) to 0.90 (95% CI 0.82-0.98, p <0.001). CONCLUSIONS: Restriction spectrum imaging-magnetic resonance imaging enhances the standard PI-RADS system by providing a noninvasive radiological biomarker to predict upgrading in active surveillance.

Using the Schmahmann Syndrome Scale to Assess Cognitive Impairment in Young Adults with Metabolic Syndrome: a Hypothesis-Generating Report.

The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Hum Brain Mapp 40(12):3575-3588, 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post hoc analyses using T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) in the form of voxel-wise tract-based spatial statistics (TBSS), biometric, and psychometric data from young participants with (n = 52, aged 18-35 years) and without MetS (n = 52, aged 18-35 years). To test the predictive value of components of the Schmahmann syndrome scale (SSS), also known as the cerebellar cognitive affective syndrome scale, we used structural equation modeling to adapt available psychometric scores in our participant sample to the SSS and compare them to the composite score of all psychometric data available. Our key findings point to a statistically significant correlation between TBSS fractional anisotropy (FA) values from DTI and adapted SSS psychometric scores in individuals with MetS (r2 = .139, 95% CI = 0.009, .345). This suggests that the SSS could be applied to assess cognitive and likely neuroanatomical effects associated with MetS. We strongly suggest that future work aimed at investigating the neurocognitive effects of MetS and related comorbidities (i.e., dyslipidemia, diabetes, obesity) would benefit from implementing and further exploring the validity of the SSS in this patient population.

Minimal Relationship between Local Gyrification and General Cognitive Ability in Humans.

Previous studies suggest that gyrification is associated with superior cognitive abilities in humans, but the strength of this relationship remains unclear. Here, in two samples of related individuals (total N = 2882), we calculated an index of local gyrification (LGI) at thousands of cortical surface points using structural brain images and an index of general cognitive ability (g) using performance on cognitive tests. Replicating previous studies, we found that phenotypic and genetic LGI-g correlations were positive and statistically significant in many cortical regions. However, all LGI-g correlations in both samples were extremely weak, regardless of whether they were significant or nonsignificant. For example, the median phenotypic LGI-g correlation was 0.05 in one sample and 0.10 in the other. These correlations were even weaker after adjusting for confounding neuroanatomical variables (intracranial volume and local cortical surface area). Furthermore, when all LGIs were considered together, at least 89% of the phenotypic variance of g remained unaccounted for. We conclude that the association between LGI and g is too weak to have profound implications for our understanding of the neurobiology of intelligence. This study highlights potential issues when focusing heavily on statistical significance rather than effect sizes in large-scale observational neuroimaging studies.

Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with cognitive impairments, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognition. METHODS: Using data from 1892 Mexican-American individuals from extended pedigrees, including 402 with type 2 diabetes, we examined possible pleiotropy between type 2 diabetes and cognitive functioning, as measured by a comprehensive neuropsychological test battery. RESULTS: Negative phenotypic correlations (ρp) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d']: ρp = -0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: ρp = -0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: ρp = -0.127, p = 0.002; PFMT Delayed: ρp = -0.148, p = 2 × 10-4), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (ρg) were also observed between type 2 diabetes and measures of attention (CPT d': ρg = -0.401, p = 0.001), working memory (digit span backward test: ρg = -0.380, p = 0.005), and face memory (PFMT: ρg = -0.476, p = 2 × 10-4; PFMT Delayed: ρg = -0.376, p = 0.005), suggesting that the same genetic factors underlying risk for type 2 diabetes also influence poor cognitive performance in these domains. Performance in these domains was also associated with type 2 diabetes risk using an endophenotype ranking value approach. Specifically, on measures of attention (CPT d': ß = -0.219, p = 0.005), working memory (digit span backward: ß = -0.326, p = 0.035), and face memory (PFMT: ß = -0.171, p = 0.023; PFMT Delayed: ß = -0.215, p = 0.005), individuals with type 2 diabetes showed the lowest performance, while unaffected/unrelated individuals showed the highest performance, and those related to an individual with type 2 diabetes performed at an intermediate level. CONCLUSIONS/INTERPRETATION: These findings suggest that cognitive impairment may be a useful endophenotype of type 2 diabetes and, therefore, help to elucidate the pathophysiological underpinnings of this chronic disease. DATA AVAILABILITY: The data analysed in this study is available in dbGaP: www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001215.v2.p2.

Functional differentiation in the human ventromedial frontal lobe: A data-driven parcellation.

Ventromedial regions of the frontal lobe (vmFL) are thought to play a key role in decision-making and emotional regulation. However, aspects of this area's functional organization, including the presence of a multiple subregions, their functional and anatomical connectivity, and the cross-species homologies of these subregions with those of other species, remain poorly understood. To address this uncertainty, we employed a two-stage parcellation of the region to identify six distinct structures within the region on the basis of data-driven classification of functional connectivity patterns obtained using the meta-analytic connectivity modeling (MACM) approach. From anterior to posterior, the derived subregions included two lateralized posterior regions, an intermediate posterior region, a dorsal and ventral central region, and a single anterior region. The regions were characterized further by functional connectivity derived using resting-state fMRI and functional decoding using the Brain Map database. In general, the regions could be differentiated on the basis of different patterns of functional connectivity with canonical "default mode network" regions and/or subcortical regions such as the striatum. Together, the findings suggest the presence of functionally distinct neural structures within vmFL, consistent with data from experimental animals as well prior demonstrations of anatomical differences within the region. Detailed correspondence with the anterior cingulate, medial orbitofrontal cortex, and rostroventral prefrontal cortex, as well as specific animal homologs are discussed. The findings may suggest future directions for resolving potential functional and structural correspondence of subregions within the frontal lobe across behavioral contexts, and across mammalian species.

Finding specificity in structural brain alterations through Bayesian reverse inference.

In the field of neuroimaging reverse inferences can lead us to suppose the involvement of cognitive processes from certain patterns of brain activity. However, the same reasoning holds if we substitute "brain activity" with "brain alteration" and "cognitive process" with "brain disorder." The fact that different brain disorders exhibit a high degree of overlap in their patterns of structural alterations makes forward inference-based analyses less suitable for identifying brain areas whose alteration is specific to a certain pathology. In the forward inference-based analyses, in fact, it is impossible to distinguish between areas that are altered by the majority of brain disorders and areas that are specifically affected by certain diseases. To address this issue and allow the identification of highly pathology-specific altered areas we used the Bayes' factor technique, which was employed, as a proof of concept, on voxel-based morphometry data of schizophrenia and Alzheimer's disease. This technique allows to calculate the ratio between the likelihoods of two alternative hypotheses (in our case, that the alteration of the voxel is specific for the brain disorder under scrutiny or that the alteration is not specific). We then performed temporal simulations of the alterations' spread associated with different pathologies. The Bayes' factor values calculated on these simulated data were able to reveal that the areas, which are more specific to a certain disease, are also the ones to be early altered. This study puts forward a new analytical instrument capable of innovating the methodological approach to the investigation of brain pathology.

A view behind the mask of sanity: meta-analysis of aberrant brain activity in psychopaths.

Psychopathy is a disorder of high public concern because it predicts violence and offense recidivism. Recent brain imaging studies suggest abnormal brain activity underlying psychopathic behavior. No reliable pattern of altered neural activity has been disclosed so far. This study sought to identify consistent changes of brain activity in psychopaths and to investigate whether these could explain known psychopathology. First, we used activation likelihood estimation (p < 0.05, corrected) to meta-analyze brain activation changes associated with psychopathy across 28 functional magnetic resonance imaging studies reporting 753 foci from 155 experiments. Second, we characterized the ensuing regions functionally by employing metadata of a large-scale neuroimaging database (p < 0.05, corrected). Psychopathy was consistently associated with decreased brain activity in the right laterobasal amygdala, the dorsomedial prefrontal cortex, and bilaterally in the lateral prefrontal cortex. A robust increase of activity was observed in the fronto-insular cortex on both hemispheres. Data-driven functional characterization revealed associations with semantic language processing (left lateral prefrontal and fronto-insular cortex), action execution and pain processing (right lateral prefrontal and left fronto-insular), social cognition (dorsomedial prefrontal cortex), and emotional as well as cognitive reward processing (right amygdala and fronto-insular cortex). Aberrant brain activity related to psychopathy is located in prefrontal, insular, and limbic regions. Physiological mental functions fulfilled by these brain regions correspond to disturbed behavioral patterns pathognomonic for psychopathy. Hence, aberrant brain activity may not just be an epiphenomenon of psychopathy but directly related to the psychopathology of this disorder.