Multimodal MRI Neuroimaging Biomarkers for Cognitive Normal Adults, Amnestic Mild Cognitive Impairment, and Alzheimer's Disease

Multimodal magnetic resonance imaging (MRI) techniques have been developed to noninvasively measure structural, metabolic, hemodynamic and functional changes of the brain. These advantages have made MRI an important tool to investigate neurodegenerative disorders, including diagnosis, disease progression monitoring, and treatment efficacy evaluation. This paper discusses recent findings of the multimodal MRI in the context of surrogate biomarkers for identifying the risk for AD in normal cognitive (NC) adults, brain anatomical and functional alterations in amnestic mild cognitive impairment (aMCI), and Alzheimer's disease (AD) patients. Further developments of these techniques and the establishment of promising neuroimaging biomarkers will enhance our ability to diagnose aMCI and AD in their early stages and improve the assessment of therapeutic efficacy in these diseases in future clinical trials

Estimating the prevalence of missing experiments in a neuroimaging meta-analysis.

Coordinate-based meta-analyses (CBMA) allow researchers to combine the results from multiple functional magnetic resonance imaging experiments with the goal of obtaining results that are more likely to generalize. However, the interpretation of CBMA findings can be impaired by the file drawer problem, a type of publication bias that refers to experiments that are carried out but are not published. Using foci per contrast count data from the BrainMap database, we propose a zero-truncated modeling approach that allows us to estimate the prevalence of nonsignificant experiments. We validate our method with simulations and real coordinate data generated from the Human Connectome Project. Application of our method to the data from BrainMap provides evidence for the existence of a file drawer effect, with the rate of missing experiments estimated as at least 6 per 100 reported. The R code that we used is available at https://osf.io/ayhfv/

Progressive Bidirectional Age-Related Changes in Default Mode Network Effective Connectivity across Six Decades

The default mode network (DMN) is a set of regions that is tonically engaged during the resting state and exhibits task-related deactivation that is readily reproducible across a wide range of paradigms and modalities. The DMN has been implicated in numerous disorders of cognition and, in particular, in disorders exhibiting age-related cognitive decline. Despite these observations, investigations of the DMN in normal aging are scant. Here, we used blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) acquired during rest to investigate age-related changes in functional connectivity of the DMN in 120 healthy normal volunteers comprising six, 20-subject, decade cohorts (from 20–29 to 70–79). Structural equation modeling (SEM) was used to assess age-related changes in inter-regional connectivity within the DMN. SEM was applied both using a previously published, meta-analytically derived, node-and-edge model, and using exploratory modeling searching for connections that optimized model fit improvement. Although the two models were highly similar (only 3 of 13 paths differed), the sample demonstrated significantly better fit with the exploratory model. For this reason, the exploratory model was used to assess age-related changes across the decade cohorts. Progressive, highly significant changes in path weights were found in 8 (of 13) paths: four rising, and four falling (most changes were significant by the third or fourth decade). In all cases, rising paths and falling paths projected in pairs onto the same nodes, suggesting compensatory increases associated with age-related decreases. This study demonstrates that age-related changes in DMN physiology (inter-regional connectivity) are bidirectional, progressive, of early onset and part of normal aging

Progressive Bidirectional Age-Related Changes in Default Mode Network Effective Connectivity across Six Decades

The default mode network (DMN) is a set of regions that is tonically engaged during the resting state and exhibits task-related deactivation that is readily reproducible across a wide range of paradigms and modalities. The DMN has been implicated in numerous disorders of cognition and, in particular, in disorders exhibiting age-related cognitive decline. Despite these observations, investigations of the DMN in normal aging are scant. Here, we used blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) acquired during rest to investigate age-related changes in functional connectivity of the DMN in 120 healthy normal volunteers comprising six, 20-subject, decade cohorts (from 20–29 to 70–79). Structural equation modeling (SEM) was used to assess age-related changes in inter-regional connectivity within the DMN. SEM was applied both using a previously published, meta-analytically derived, node-and-edge model, and using exploratory modeling searching for connections that optimized model fit improvement. Although the two models were highly similar (only 3 of 13 paths differed), the sample demonstrated significantly better fit with the exploratory model. For this reason, the exploratory model was used to assess age-related changes across the decade cohorts. Progressive, highly significant changes in path weights were found in 8 (of 13) paths: four rising, and four falling (most changes were significant by the third or fourth decade). In all cases, rising paths and falling paths projected in pairs onto the same nodes, suggesting compensatory increases associated with age-related decreases. This study demonstrates that age-related changes in DMN physiology (inter-regional connectivity) are bidirectional, progressive, of early onset and part of normal aging

Behavior, sensitivity, and power of activation likelihood estimation characterized by massive empirical simulation

Given the increasing number of neuroimaging publications, the automated knowledge extraction on brain-behavior associations by quantitative meta-analyses has become a highly important and rapidly growing field of research. Among several methods to perform coordinate-based neuroimaging meta-analyses, Activation Likelihood Estimation (ALE) has been widely adopted. In this paper, we addressed two pressing questions related to ALE meta-analysis: i) Which thresholding method is most appropriate to perform statistical inference? ii) Which sample size, i.e., number of experiments, is needed to perform robust meta-analyses? We provided quantitative answers to these questions by simulating more than 120,000 meta-analysis datasets using empirical parameters (i.e., number of subjects, number of reported foci, distribution of activation foci) derived from the BrainMap database. This allowed to characterize the behavior of ALE analyses, to derive first power estimates for neuroimaging meta-analyses, and to thus formulate recommendations for future ALE studies. We could show as a first consequence that cluster-level family-wise error (FWE) correction represents the most appropriate method for statistical inference, while voxel-level FWE correction is valid but more conservative. In contrast, uncorrected inference and false-discovery rate correction should be avoided. As a second consequence, researchers should aim to include at least 20 experiments into an ALE meta-analysis to achieve sufficient power for moderate effects. We would like to note, though, that these calculations and recommendations are specific to ALE and may not be extrapolated to other approaches for (neuroimaging) meta-analysis

Chronic cigarette smoking is linked with structural alterations in brain regions showing acute nicotinic drug-induced functional modulations

Background Whereas acute nicotine administration alters brain function which may, in turn, contribute to enhanced attention and performance, chronic cigarette smoking is linked with regional brain atrophy and poorer cognition. However, results from structural magnetic resonance imaging (MRI) studies comparing smokers versus nonsmokers have been inconsistent and measures of gray matter possess limited ability to inform functional relations or behavioral implications. The purpose of this study was to address these interpretational challenges through meta-analytic techniques in the service of clarifying the impact of chronic smoking on gray matter integrity and more fully contextualizing such structural alterations. Methods We first conducted a coordinate-based meta-analysis of structural MRI studies to identify consistent structural alterations associated with chronic smoking. Subsequently, we conducted two additional meta-analytic assessments to enhance insight into potential functional and behavioral relations. Specifically, we performed a multimodal meta-analytic assessment to test the structural?functional hypothesis that smoking-related structural alterations overlapped those same regions showing acute nicotinic drug-induced functional modulations. Finally, we employed database driven tools to identify pairs of structurally impacted regions that were also functionally related via meta-analytic connectivity modeling, and then delineated behavioral phenomena associated with such functional interactions via behavioral decoding. Results Across studies, smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structural?functional relation, we observed that smoking-related gray matter decreases overlapped with the acute functional effects of nicotinic agonist administration in the left insula, ventromedial PFC, and mediodorsal thalamus. Suggesting structural-behavioral implications, we observed that the left insula?s task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellum?s interactions with other regions were associated with overt body movements, interactions between the parahippocampus and thalamus were linked with memory processes, and interactions between medial PFC regions were associated with face processing. Conclusions Collectively, these findings emphasize brain regions (e.g., ventromedial PFC, insula, thalamus) critically linked with cigarette smoking, suggest neuroimaging paradigms warranting additional consideration among smokers (e.g., pain processing), and highlight regions in need of further elucidation in addiction (e.g., cerebellum). Electronic supplementary material The online version of this article (doi:10.1186/s12993-016-0100-5) contains supplementary material, which is available to authorized users

Functional Activation and Effective Connectivity Differences in Adolescent Marijuana Users Performing a Simulated Gambling Task

Background. Adolescent marijuana use is associated with structural and functional differences in forebrain regions while performing memory and attention tasks. In the present study, we investigated neural processing in adolescent marijuana users experiencing rewards and losses. Fourteen adolescents with frequent marijuana use (\u3e5 uses per week) and 14 nonuser controls performed a computer task where they were required to guess the outcome of a simulated coin flip while undergoing magnetic resonance imaging. Results. Across all participants, ?Wins? and ?Losses? were associated with activations including cingulate, middle frontal, superior frontal, and inferior frontal gyri and declive activations. Relative to controls, users had greater activity in the middle and inferior frontal gyri, caudate, and claustrum during ?Wins? and greater activity in the anterior and posterior cingulate, middle frontal gyrus, insula, claustrum, and declive during ?Losses.? Effective connectivity analyses revealed similar overall network interactions among these regions for users and controls during both ?Wins? and ?Losses.? However, users and controls had significantly different causal interactions for 10 out of 28 individual paths during the ?Losses? condition. Conclusions. Collectively, these results indicate adolescent marijuana users have enhanced neural responses to simulated monetary rewards and losses and relatively subtle differences in effective connectivity

ALE Meta-Analysis Workflows Via the Brainmap Database: Progress Towards A Probabilistic Functional Brain Atlas

With the ever-increasing number of studies in human functional brain mapping, an abundance of data has been generated that is ready to be synthesized and modeled on a large scale. The BrainMap database archives peak coordinates from published neuroimaging studies, along with the corresponding metadata that summarize the experimental design. BrainMap was designed to facilitate quantitative meta-analysis of neuroimaging results reported in the literature and supports the use of the activation likelihood estimation (ALE) method. In this paper, we present a discussion of the potential analyses that are possible using the BrainMap database and coordinate-based ALE meta-analyses, along with some examples of how these tools can be applied to create a probabilistic atlas and ontological system of describing function–structure correspondences

Multi-region hemispheric specialization differentiates human from nonhuman primate brain function

The human behavioral repertoire greatly exceeds that of nonhuman primates. Anatomical specializations of the human brain include an enlarged neocortex and prefrontal cortex (Semendeferi et al. in Am J Phys Anthropol 114:224?241, 2001), but regional enlargements alone cannot account for these vast functional differences. Hemispheric specialization has long believed to be a major contributing factor to such distinctive human characteristics as motor dominance, attentional control and language. Yet structural cerebral asymmetries, documented in both humans and some nonhuman primate species, are relatively minor compared to behavioral lateralization. Identifying the mechanisms that underlie these functional differences remains a goal of considerable interest. Here, we investigate the intrinsic connectivity networks in four primate species (humans, chimpanzees, baboons, and capuchin monkeys) using resting-state fMRI to evaluate the intra- and inter- hemispheric coherences of spontaneous BOLD fluctuation. All three nonhuman primate species displayed lateralized functional networks that were strikingly similar to those observed in humans. However, only humans had multi-region lateralized networks, which provide fronto-parietal connectivity. Our results indicate that this pattern of within-hemisphere connectivity distinguishes humans from nonhuman primates

Neural response to monetary loss among youth with disruptive behavior disorders and callous-unemotional traits in the ABCD study

Etiological models highlight reduced punishment sensitivity as a core risk factor for disruptive behavior disorders (DBD) and callous-unemotional (CU) traits. The current study examined neural sensitivity to the anticipation and receipt of loss, one key aspect of punishment sensitivity, among youth with DBD, comparing those with and without CU traits. Data were obtained from the Adolescent Brain and Cognitive Development (ABCD)SM Study (N = 11,874; Mage = 9.51; 48% female). Loss-related fMRI activity during the monetary incentive delay task was examined across 16 empirically-derived a priori brain regions (e.g., striatum, amygdala, insula, anterior cingulate cortex, medial prefrontal cortex) and compared across the following groups: (1) typically developing (n = 693); (2) DBD (n = 995), subdivided into those (3) with CU traits (DBD + CU, n = 198), and (4) without CU traits (DBD-only, n = 276). Latent variable modeling was also employed to examine network-level activity. There were no significant between-group differences in brain activity to loss anticipation or receipt. Null findings were confirmed with and without covariates, using alternative grouping approaches, and in dimensional models. Network-level analyses also demonstrated comparable activity across groups during loss anticipation and receipt. Findings suggest that differences in punishment sensitivity among youth with DBD are unrelated to loss anticipation or receipt. More precise characterizations of other aspects punishment sensitivity are needed to understand risk for DBD and CU traits