Lower resting state functional connectivity partially mediates adverse effects of prenatal alcohol exposure on arithmetic performance in children.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) include a range of neurocognitive and behavioral impairments resulting from prenatal alcohol exposure (PAE). Among the PAE-related cognitive deficits, number processing is particularly affected. This study examines alterations in number processing networks and whether changes in functional connectivity mediate the adverse effects of PAE on arithmetic performance. METHODS: Magnetic resonance imaging (MRI) was acquired in 57 children (mean (SD) age = 11.3 (+0.9) yr), 38 with FASD (19 fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 heavily exposed (HE)) and 19 controls. Whole-brain correlation analyses were performed from five seeds located in regions involved in number processing. RESULTS: Children with FAS/PFAS showed dose-dependent reductions in resting state functional connectivity between the seed in the right (R) posterior superior parietal lobule and a cluster in the left (L) inferior frontal gyrus, and between a seed in the R horizontal intraparietal sulcus and clusters in the R precentral gyrus and L cerebellar lobule VI. HE children showed lower resting state functional connectivity in a subset of these regions. Lower functional connectivity in the two fronto-parietal connections partially mediated the adverse effects of PAE on arithmetic performance. CONCLUSION: This study demonstrates PAE-related functional connectivity impairments in functional networks involved in number processing. The weaker connectivity between the R posterior superior parietal lobule and the L inferior frontal gyrus suggests that impaired verbal processing and visuospatial working memory may play a role in number processing deficits, while weaker connectivity between the R intraparietal sulcus and the R precentral gyrus points to poorer finger-based numerical representation, which has been linked to arithmetic computational skills.

A Set of FMRI Quality Control Tools in AFNI: Systematic, in-depth and interactive QC with afni_proc.py and more.

Quality control (QC) assessment is a vital part of FMRI processing and analysis, and a typically under discussed aspect of reproducibility. This includes checking datasets at their very earliest stages (acquisition and conversion) through their processing steps (e.g., alignment and motion correction) to regression modeling (correct stimuli, no collinearity, valid fits, enough degrees of freedom, etc.) for each subject. There are a wide variety of features to verify throughout any single subject processing pipeline, both quantitatively and qualitatively. We present several FMRI preprocessing QC features available in the AFNI toolbox, many of which are automatically generated by the pipeline-creation tool, afni_proc.py. These items include: a modular HTML document that covers full single subject processing from the raw data through statistical modeling; several review scripts in the results directory of processed data; and command line tools for identifying subjects with one or more quantitative properties across a group (such as triaging warnings, making exclusion criteria or creating informational tables). The HTML itself contains several buttons that efficiently facilitate interactive investigations into the data, when deeper checks are needed beyond the systematic images. The pages are linkable, so that users can evaluate individual items across group, for increased sensitivity to differences (e.g., in alignment or regression modeling images). Finally, the QC document contains rating buttons for each "QC block", as well as comment fields for each, to facilitate both saving and sharing the evaluations. This increases the specificity of QC, as well as its shareability, as these files can be shared with others and potentially uploaded into repositories, promoting transparency and open science. We describe the features and applications of these QC tools for FMRI.

Improving 3D edge detection for visual inspection of MRI coregistration and alignment.

BACKGROUND: Visualizing edges is critical for neuroimaging. For example, edge maps enable quality assurance for the automatic alignment of an image from one modality (or individual) to another. NEW METHOD: We suggest that using the second derivative (difference of Gaussian, or DoG) provides robust edge detection. This method is tuned by size (which is typically known in neuroimaging) rather than intensity (which is relative). RESULTS: We demonstrate that this method performs well across a broad range of imaging modalities. The edge contours produced consistently form closed surfaces, whereas alternative methods may generate disconnected lines, introducing potential ambiguity in contiguity. COMPARISON WITH EXISTING METHODS: Current methods for computing edges are based on either the first derivative of the image (FSL), or a variation of the Canny Edge detection method (AFNI). These methods suffer from two primary limitations. First, the crucial tuning parameter for each of these methods relates to the image intensity. Unfortunately, image intensity is relative for most neuroimaging modalities making the performance of these methods unreliable. Second, these existing approaches do not necessarily generate a closed edge/surface, which can reduce the ability to determine the correspondence between a represented edge and another image. CONCLUSION: The second derivative is well suited for neuroimaging edge detection. We include this method as part of both the AFNI and FSL software packages, standalone code and online.

BOLD Response is more than just magnitude: Improving detection sensitivity through capturing hemodynamic profiles.

Typical fMRI analyses often assume a canonical hemodynamic response function (HRF) that primarily focuses on the peak height of the overshoot, neglecting other morphological aspects. Consequently, reported analyses often reduce the overall response curve to a single scalar value. In this study, we take a data-driven approach to HRF estimation at the whole-brain voxel level, without assuming a response profile at the individual level. We then employ a roughness penalty at the population level to estimate the response curve, aiming to enhance predictive accuracy, inferential efficiency, and cross-study reproducibility. By examining a fast event-related FMRI dataset, we demonstrate the shortcomings and information loss associated with adopting the canonical approach. Furthermore, we address the following key questions: 1) To what extent does the HRF shape vary across different regions, conditions, and participant groups? 2) Does the data-driven approach improve detection sensitivity compared to the canonical approach? 3) Can analyzing the HRF shape help validate the presence of an effect in conjunction with statistical evidence? 4) Does analyzing the HRF shape offer evidence for whole-brain response during a simple task?

Highlight results, don't hide them: Enhance interpretation, reduce biases and improve reproducibility.

Most neuroimaging studies display results that represent only a tiny fraction of the collected data. While it is conventional to present "only the significant results" to the reader, here we suggest that this practice has several negative consequences for both reproducibility and understanding. This practice hides away most of the results of the dataset and leads to problems of selection bias and irreproducibility, both of which have been recognized as major issues in neuroimaging studies recently. Opaque, all-or-nothing thresholding, even if well-intentioned, places undue influence on arbitrary filter values, hinders clear communication of scientific results, wastes data, is antithetical to good scientific practice, and leads to conceptual inconsistencies. It is also inconsistent with the properties of the acquired data and the underlying biology being studied. Instead of presenting only a few statistically significant locations and hiding away the remaining results, studies should "highlight" the former while also showing as much as possible of the rest. This is distinct from but complementary to utilizing data sharing repositories: the initial presentation of results has an enormous impact on the interpretation of a study. We present practical examples and extensions of this approach for voxelwise, regionwise and cross-study analyses using publicly available data that was analyzed previously by 70 teams (NARPS; Botvinik-Nezer, et al., 2020), showing that it is possible to balance the goals of displaying a full set of results with providing the reader reasonably concise and "digestible" findings. In particular, the highlighting approach sheds useful light on the kind of variability present among the NARPS teams' results, which is primarily a varied strength of agreement rather than disagreement. Using a meta-analysis built on the informative "highlighting" approach shows this relative agreement, while one using the standard "hiding" approach does not. We describe how this simple but powerful change in practice-focusing on highlighting results, rather than hiding all but the strongest ones-can help address many large concerns within the field, or at least to provide more complete information about them. We include a list of practical suggestions for results reporting to improve reproducibility, cross-study comparisons and meta-analyses.

Quality control practices in FMRI analysis: Philosophy, methods and examples using AFNI.

Quality control (QC) is a necessary, but often an under-appreciated, part of FMRI processing. Here we describe procedures for performing QC on acquired or publicly available FMRI datasets using the widely used AFNI software package. This work is part of the Research Topic, "Demonstrating Quality Control (QC) Procedures in fMRI." We used a sequential, hierarchical approach that contained the following major stages: (1) GTKYD (getting to know your data, esp. its basic acquisition properties), (2) APQUANT (examining quantifiable measures, with thresholds), (3) APQUAL (viewing qualitative images, graphs, and other information in systematic HTML reports) and (4) GUI (checking features interactively with a graphical user interface); and for task data, and (5) STIM (checking stimulus event timing statistics). We describe how these are complementary and reinforce each other to help researchers stay close to their data. We processed and evaluated the provided, publicly available resting state data collections (7 groups, 139 total subjects) and task-based data collection (1 group, 30 subjects). As specified within the Topic guidelines, each subject's dataset was placed into one of three categories: Include, exclude or uncertain. The main focus of this paper, however, is the detailed description of QC procedures: How to understand the contents of an FMRI dataset, to check its contents for appropriateness, to verify processing steps, and to examine potential quality issues. Scripts for the processing and analysis are freely available.

Hyperbolic trade-off: The importance of balancing trial and subject sample sizes in neuroimaging.

Here we investigate the crucial role of trials in task-based neuroimaging from the perspectives of statistical efficiency and condition-level generalizability. Big data initiatives have gained popularity for leveraging a large sample of subjects to study a wide range of effect magnitudes in the brain. On the other hand, most task-based FMRI designs feature a relatively small number of subjects, so that resulting parameter estimates may be associated with compromised precision. Nevertheless, little attention has been given to another important dimension of experimental design, which can equally boost a study's statistical efficiency: the trial sample size. The common practice of condition-level modeling implicitly assumes no cross-trial variability. Here, we systematically explore the different factors that impact effect uncertainty, drawing on evidence from hierarchical modeling, simulations and an FMRI dataset of 42 subjects who completed a large number of trials of cognitive control task. We find that, due to an approximately symmetric hyperbola-relationship between trial and subject sample sizes in the presence of relatively large cross-trial variability, 1) trial sample size has nearly the same impact as subject sample size on statistical efficiency; 2) increasing both the number of trials and subjects improves statistical efficiency more effectively than focusing on subjects alone; 3) trial sample size can be leveraged alongside subject sample size to improve the cost-effectiveness of an experimental design; 4) for small trial sample sizes, trial-level modeling, rather than condition-level modeling through summary statistics, may be necessary to accurately assess the standard error of an effect estimate. We close by making practical suggestions for improving experimental designs across neuroimaging and behavioral studies.

Multiple parietal pathways are associated with rTMS-induced hippocampal network enhancement and episodic memory changes.

Repetitive transcranial magnetic stimulation (rTMS) of the inferior parietal cortex (IPC) increases resting-state functional connectivity (rsFC) of the hippocampus with the precuneus and other posterior cortical areas and causes proportional improvement of episodic memory. The anatomical pathway(s) responsible for the propagation of these effects from the IPC is unknown and may not be direct. In order to assess the relative contributions of candidate pathways from the IPC to the MTL via the parahippocampal cortex and precuneus, to the effects of rTMS on rsFC and memory improvement, we used diffusion tensor imaging to measure the extent to which individual differences in fractional anisotropy (FA) in these pathways accounted for individual differences in response. FA in the IPC-parahippocampal pathway and several MTL pathways predicted changes in rsFC. FA in both parahippocampal and hippocampal pathways was related to changes in episodic, but not procedural, memory. These results implicate pathways to the MTL in the enhancing effect of parietal rTMS on hippocampal rsFC and memory.

A comprehensive macaque fMRI pipeline and hierarchical atlas.

Functional neuroimaging research in the non-human primate (NHP) has been advancing at a remarkable rate. The increase in available data establishes a need for robust analysis pipelines designed for NHP neuroimaging and accompanying template spaces to standardize the localization of neuroimaging results. Our group recently developed the NIMH Macaque Template (NMT), a high-resolution population average anatomical template and associated neuroimaging resources, providing researchers with a standard space for macaque neuroimaging . Here, we release NMT v2, which includes both symmetric and asymmetric templates in stereotaxic orientation, with improvements in spatial contrast, processing efficiency, and segmentation. We also introduce the Cortical Hierarchy Atlas of the Rhesus Macaque (CHARM), a hierarchical parcellation of the macaque cerebral cortex with varying degrees of detail. These tools have been integrated into the neuroimaging analysis software AFNI to provide a comprehensive and robust pipeline for fMRI processing, visualization and analysis of NHP data. AFNI's new @animal_warper program can be used to efficiently align anatomical scans to the NMT v2 space, and afni_proc.py integrates these results with full fMRI processing using macaque-specific parameters: from motion correction through regression modeling. Taken together, the NMT v2 and AFNI represent an all-in-one package for macaque functional neuroimaging analysis, as demonstrated with available demos for both task and resting state fMRI.

Different activation signatures in the primary sensorimotor and higher-level regions for haptic three-dimensional curved surface exploration.

Haptic object perception begins with continuous exploratory contact, and the human brain needs to accumulate sensory information continuously over time. However, it is still unclear how the primary sensorimotor cortex (PSC) interacts with these higher-level regions during haptic exploration over time. This functional magnetic resonance imaging (fMRI) study investigates time-dependent haptic object processing by examining brain activity during haptic 3D curve and roughness estimations. For this experiment, we designed sixteen haptic stimuli (4 kinds of curves × 4 varieties of roughness) for the haptic curve and roughness estimation tasks. Twenty participants were asked to move their right index and middle fingers along the surface twice and to estimate one of the two features-roughness or curvature-depending on the task instruction. We found that the brain activity in several higher-level regions (e.g., the bilateral posterior parietal cortex) linearly increased as the number of curves increased during the haptic exploration phase. Surprisingly, we found that the contralateral PSC was parametrically modulated by the number of curves only during the late exploration phase but not during the early exploration phase. In contrast, we found no similar parametric modulation activity patterns during the haptic roughness estimation task in either the contralateral PSC or in higher-level regions. Thus, our findings suggest that haptic 3D object perception is processed across the cortical hierarchy, whereas the contralateral PSC interacts with other higher-level regions across time in a manner that is dependent upon the features of the object.

To pool or not to pool: Can we ignore cross-trial variability in FMRI?

In this work, we investigate the importance of explicitly accounting for cross-trial variability in neuroimaging data analysis. To attempt to obtain reliable estimates in a task-based experiment, each condition is usually repeated across many trials. The investigator may be interested in (a) condition-level effects, (b) trial-level effects, or (c) the association of trial-level effects with the corresponding behavior data. The typical strategy for condition-level modeling is to create one regressor per condition at the subject level with the underlying assumption that responses do not change across trials. In this methodology of complete pooling, all cross-trial variability is ignored and dismissed as random noise that is swept under the rug of model residuals. Unfortunately, this framework invalidates the generalizability from the confine of specific trials (e.g., particular faces) to the associated stimulus category ("face"), and may inflate the statistical evidence when the trial sample size is not large enough. Here we propose an adaptive and computationally tractable framework that meshes well with the current two-level pipeline and explicitly accounts for trial-by-trial variability. The trial-level effects are first estimated per subject through no pooling. To allow generalizing beyond the particular stimulus set employed, the cross-trial variability is modeled at the population level through partial pooling in a multilevel model, which permits accurate effect estimation and characterization. Alternatively, trial-level estimates can be used to investigate, for example, brain-behavior associations or correlations between brain regions. Furthermore, our approach allows appropriate accounting for serial correlation, handling outliers, adapting to data skew, and capturing nonlinear brain-behavior relationships. By applying a Bayesian multilevel model framework at the level of regions of interest to an experimental dataset, we show how multiple testing can be addressed and full results reported without arbitrary dichotomization. Our approach revealed important differences compared to the conventional method at the condition level, including how the latter can distort effect magnitude and precision. Notably, in some cases our approach led to increased statistical sensitivity. In summary, our proposed framework provides an effective strategy to capture trial-by-trial responses that should be of interest to a wide community of experimentalists.

Executive function network's white matter alterations relate to Parkinson's disease motor phenotype.

Parkinson's disease (PD) patients with postural instability and gait disorder phenotype (PIGD) are at high risk of cognitive deficits compared to those with tremor dominant phenotype (TD). Alterations of white matter (WM) integrity can occur in patients with normal cognitive functions (PD-N). However, the alterations of WM integrity related to cognitive functions in PD-N, especially in these two motor phenotypes, remain unclear. Diffusion tensor imaging (DTI) is a non-invasive neuroimaging method to evaluate WM properties and by applying DTI tractography, one can identify WM tracts connecting functional regions. Here, we 1) compared the executive function (EF) in PIGD phenotype with normal cognitive functions (PIGD-N) and TD phenotype with normal cognitive functions (TD-N) phenotypes; 2) used DTI tractography to evaluated differences in WM alterations between these two phenotypes within a task-based functional network; and 3) examined the WM integrity alterations related to EF in a whole brain network for PD-N patients regardless of phenotypes. Thirty-four idiopathic PD-N patients were classified into two groups based on phenotypes: TD-N and PIGD-N, using an algorithm based on UPDRS part III. Neuropsychological tests were used to evaluate patients' EF, including the Trail making test part A and B, the Stroop color naming, the Stroop word naming, the Stroop color-word interference task, as well as the FAS verbal fluency task and the animal category fluency tasks. DTI measures were calculated among WM regions associated with the verbal fluency network defined from previous task fMRI studies and compared between PIGD-N and TD-N groups. In addition, the relationship of DTI measures and verbal fluency scores were evaluated for our full cohort of PD-N patients within the whole brain network. These values were also correlated with the scores of the FAS verbal fluency task. Only the FAS verbal fluency test showed significant group differences, having lower scores in PIGD-N when compared to TD-N phenotype (p < 0.05). Compared to the TD-N, PIGD-N group exhibited significantly higher MD and RD in the tracts connecting the left superior temporal gyrus and left insula, and those connecting the right pars opercularis and right insula. Moreover, compared to TD-N, PIGD-N group had significantly higher RD in the tracts connecting right pars opercularis and right pars triangularis, and the tracts connecting right inferior temporal gyrus and right middle temporal gyrus. For the entire PD-N cohort, FAS verbal fluency scores positively correlated with MD in the superior longitudinal fasciculus (SLF). This study confirmed that PIGD-N phenotype has more deficits in verbal fluency task than TD-N phenotype. Additionally, our findings suggest: (1) PIGD-N shows more microstructural changes related to FAS verbal fluency task when compared to TD-N phenotype; (2) SLF plays an important role in FAS verbal fluency task in PD-N patients regardless of motor phenotypes.

Reduced fractional anisotropy in projection, association, and commissural fiber networks in neonates with prenatal methamphetamine exposure.

Prenatal exposure to methamphetamine is associated with neurostructural changes, including alterations in white matter microstructure. This study investigated the effects of methamphetamine exposure on microstructure of global white matter networks in neonates. Pregnant women were interviewed beginning in mid-pregnancy regarding their methamphetamine use. Diffusion weighted imaging sets were acquired for 23 non-sedated neonates. White matter bundles associated with pairs of target regions within five networks (commissural fibers, left and right projection fibers, and left and right association fibers) were estimated using probabilistic tractography, and fractional anisotropy (FA) and diffusion measures determined within each connection. Multiple regression analyses showed that increasing methamphetamine exposure was significantly associated with reduced FA in all five networks, after control for potential confounders. Increased exposure was associated with lower axial diffusivity in the right association fiber network and with increased radial diffusivity in the right projection and left and right association fiber networks. Within the projection and association networks a subset of individual connections showed a negative correlation between FA and methamphetamine exposure. These findings are consistent with previous reports in older children and demonstrate that microstructural changes associated with methamphetamine exposure are already detectable in neonates.

A series of five population-specific Indian brain templates and atlases spanning ages 6-60 years.

Anatomical brain templates are commonly used as references in neurological MRI studies, for bringing data into a common space for group-level statistics and coordinate reporting. Given the inherent variability in brain morphology across age and geography, it is important to have templates that are as representative as possible for both age and population. A representative-template increases the accuracy of alignment, decreases distortions as well as potential biases in final coordinate reports. In this study, we developed and validated a new set of T1w Indian brain templates (IBT) from a large number of brain scans (total n = 466) acquired across different locations and multiple 3T MRI scanners in India. A new tool in AFNI, make_template_dask.py, was created to efficiently make five age-specific IBTs (ages 6-60 years) as well as maximum probability map (MPM) atlases for each template; for each age-group's template-atlas pair, there is both a "population-average" and a "typical" version. Validation experiments on an independent Indian structural and functional-MRI dataset show the appropriateness of IBTs for spatial normalization of Indian brains. The results indicate significant structural differences when comparing the IBTs and MNI template, with these differences being maximal along the Anterior-Posterior and Inferior-Superior axes, but minimal Left-Right. For each age-group, the MPM brain atlases provide reasonably good representation of the native-space volumes in the IBT space, except in a few regions with high intersubject variability. These findings provide evidence to support the use of age and population-specific templates in human brain mapping studies.

Beware (Surprisingly Common) Left-Right Flips in Your MRI Data: An Efficient and Robust Method to Check MRI Dataset Consistency Using AFNI.

Knowing the difference between left and right is generally assumed throughout the brain MRI research community. However, we note widespread occurrences of left-right orientation errors in MRI open database repositories where volumes have contained systematic left-right flips between subject EPIs and anatomicals, due to having incorrect or missing file header information. Here we present a simple method in AFNI for determining the consistency of left and right within a pair of acquired volumes for a particular subject; the presence of EPI-anatomical inconsistency, for example, is a sign that dataset header information likely requires correction. The method contains both a quantitative evaluation as well as a visualizable verification. We test the functionality using publicly available datasets. Left-right flipping is not immediately obvious in most cases, so we also present visualization methods for looking at this problem (and other potential problems), using examples from both FMRI and DTI datasets.

Untangling the relatedness among correlations, part III: Inter-subject correlation analysis through Bayesian multilevel modeling for naturalistic scanning.

While inter-subject correlation (ISC) analysis is a powerful tool for naturalistic scanning data, drawing appropriate statistical inferences is difficult due to the daunting task of accounting for the intricate relatedness in data structure as well as handling the multiple testing issue. Although the linear mixed-effects (LME) modeling approach (Chen et al., 2017a) is capable of capturing the relatedness in the data and incorporating explanatory variables, there are a few challenging issues: 1) it is difficult to assign accurate degrees of freedom for each testing statistic, 2) multiple testing correction is potentially over-penalizing due to model inefficiency, and 3) thresholding necessitates arbitrary dichotomous decisions. Here we propose a Bayesian multilevel (BML) framework for ISC data analysis that integrates all regions of interest into one model. By loosely constraining the regions through a weakly informative prior, BML dissolves multiplicity through conservatively pooling the effect of each region toward the center and improves collective fitting and overall model performance. In addition to potentially achieving a higher inference efficiency, BML improves spatial specificity and easily allows the investigator to adopt a philosophy of full results reporting. A dataset of naturalistic scanning is utilized to illustrate the modeling approach with 268 parcels and to showcase the modeling capability, flexibility and advantages in results reporting. The associated program will be available as part of the AFNI suite for general use.

Fighting or embracing multiplicity in neuroimaging? neighborhood leverage versus global calibration.

Neuroimaging faces the daunting challenge of multiple testing - an instance of multiplicity - that is associated with two other issues to some extent: low inference efficiency and poor reproducibility. Typically, the same statistical model is applied to each spatial unit independently in the approach of massively univariate modeling. In dealing with multiplicity, the general strategy employed in the field is the same regardless of the specifics: trust the local "unbiased" effect estimates while adjusting the extent of statistical evidence at the global level. However, in this approach, modeling efficiency is compromised because each spatial unit (e.g., voxel, region, matrix element) is treated as an isolated and independent entity during massively univariate modeling. In addition, the required step of multiple testing "correction" by taking into consideration spatial relatedness, or neighborhood leverage, can only partly recoup statistical efficiency, resulting in potentially excessive penalization as well as arbitrariness due to thresholding procedures. Moreover, the assigned statistical evidence at the global level heavily relies on the data space (whole brain or a small volume). The present paper reviews how Stein's paradox (1956) motivates a Bayesian multilevel (BML) approach that, rather than fighting multiplicity, embraces it to our advantage through a global calibration process among spatial units. Global calibration is accomplished via a Gaussian distribution for the cross-region effects whose properties are not a priori specified, but a posteriori determined by the data at hand through the BML model. Our framework therefore incorporates multiplicity as integral to the modeling structure, not a separate correction step. By turning multiplicity into a strength, we aim to achieve five goals: 1) improve the model efficiency with a higher predictive accuracy, 2) control the errors of incorrect magnitude and incorrect sign, 3) validate each model relative to competing candidates, 4) reduce the reliance and sensitivity on the choice of data space, and 5) encourage full results reporting. Our modeling proposal reverberates with recent proposals to eliminate the dichotomization of statistical evidence ("significant" vs. "non-significant"), to improve the interpretability of study findings, as well as to promote reporting the full gamut of results (not only "significant" ones), thereby enhancing research transparency and reproducibility.

An integrative Bayesian approach to matrix-based analysis in neuroimaging.

Understanding the correlation structure associated with brain regions is a central goal in neuroscience, as it informs about interregional relationships and network organization. Correlation structure can be conveniently captured in a matrix that indicates the relationships among brain regions, which could involve electroencephalogram sensors, electrophysiology recordings, calcium imaging data, or functional magnetic resonance imaging (FMRI) data-We call this type of analysis matrix-based analysis, or MBA. Although different methods have been developed to summarize such matrices across subjects, including univariate general linear models (GLMs), the available modeling strategies tend to disregard the interrelationships among the regions, leading to "inefficient" statistical inference. Here, we develop a Bayesian multilevel (BML) modeling framework that simultaneously integrates the analyses of all regions, region pairs (RPs), and subjects. In this approach, the intricate relationships across regions as well as across RPs are quantitatively characterized. The adoption of the Bayesian framework allows us to achieve three goals: (a) dissolve the multiple testing issue typically associated with seeking evidence for the effect of each RP under the conventional univariate GLM; (b) make inferences on effects that would be treated as "random" under the conventional linear mixed-effects framework; and (c) estimate the effect of each brain region in a manner that indexes their relative "importance". We demonstrate the BML methodology with an FMRI dataset involving a cognitive-emotional task and compare it to the conventional GLM approach in terms of model efficiency, performance, and inferences. The associated program MBA is available as part of the AFNI suite for general use.

Handling Multiplicity in Neuroimaging Through Bayesian Lenses with Multilevel Modeling.

Here we address the current issues of inefficiency and over-penalization in the massively univariate approach followed by the correction for multiple testing, and propose a more efficient model that pools and shares information among brain regions. Using Bayesian multilevel (BML) modeling, we control two types of error that are more relevant than the conventional false positive rate (FPR): incorrect sign (type S) and incorrect magnitude (type M). BML also aims to achieve two goals: 1) improving modeling efficiency by having one integrative model and thereby dissolving the multiple testing issue, and 2) turning the focus of conventional null hypothesis significant testing (NHST) on FPR into quality control by calibrating type S errors while maintaining a reasonable level of inference efficiency. The performance and validity of this approach are demonstrated through an application at the region of interest (ROI) level, with all the regions on an equal footing: unlike the current approaches under NHST, small regions are not disadvantaged simply because of their physical size. In addition, compared to the massively univariate approach, BML may simultaneously achieve increased spatial specificity and inference efficiency, and promote results reporting in totality and transparency. The benefits of BML are illustrated in performance and quality checking using an experimental dataset. The methodology also avoids the current practice of sharp and arbitrary thresholding in the p-value funnel to which the multidimensional data are reduced. The BML approach with its auxiliary tools is available as part of the AFNI suite for general use.