On the stability of canonical correlation analysis and partial least squares with application to brain-behavior associations.

Associations between datasets can be discovered through multivariate methods like Canonical Correlation Analysis (CCA) or Partial Least Squares (PLS). A requisite property for interpretability and generalizability of CCA/PLS associations is stability of their feature patterns. However, stability of CCA/PLS in high-dimensional datasets is questionable, as found in empirical characterizations. To study these issues systematically, we developed a generative modeling framework to simulate synthetic datasets. We found that when sample size is relatively small, but comparable to typical studies, CCA/PLS associations are highly unstable and inaccurate; both in their magnitude and importantly in the feature pattern underlying the association. We confirmed these trends across two neuroimaging modalities and in independent datasets with n ≈ 1000 and n = 20,000, and found that only the latter comprised sufficient observations for stable mappings between imaging-derived and behavioral features. We further developed a power calculator to provide sample sizes required for stability and reliability of multivariate analyses. Collectively, we characterize how to limit detrimental effects of overfitting on CCA/PLS stability, and provide recommendations for future studies.

The spatial extent of anatomical connections within the thalamus varies across the cortical hierarchy in humans and macaques.

Each cortical area has a distinct pattern of anatomical connections within the thalamus, a central subcortical structure composed of functionally and structurally distinct nuclei. Previous studies have suggested that certain cortical areas may have more extensive anatomical connections that target multiple thalamic nuclei, which potentially allows them to modulate distributed information flow. However, there is a lack of quantitative investigations into anatomical connectivity patterns within the thalamus. Consequently, it remains unknown if cortical areas exhibit systematic differences in the extent of their anatomical connections within the thalamus. To address this knowledge gap, we used diffusion magnetic resonance imaging (dMRI) to perform brain-wide probabilistic tractography for 828 healthy adults from the Human Connectome Project. We then developed a framework to quantify the spatial extent of each cortical area's anatomical connections within the thalamus. Additionally, we leveraged resting-state functional MRI, cortical myelin, and human neural gene expression data to test if the extent of anatomical connections within the thalamus varied along the cortical hierarchy. Our results revealed two distinct corticothalamic tractography motifs: 1) a sensorimotor cortical motif characterized by focal thalamic connections targeting posterolateral thalamus, associated with fast, feed-forward information flow; and 2) an associative cortical motif characterized by diffuse thalamic connections targeting anteromedial thalamus, associated with slow, feed-back information flow. These findings were consistent across human subjects and were also observed in macaques, indicating cross-species generalizability. Overall, our study demonstrates that sensorimotor and association cortical areas exhibit differences in the spatial extent of their anatomical connections within the thalamus, which may support functionally-distinct cortico-thalamic information flow.

Schizophrenia and bipolar disorder are associated with opposite brain reward anticipation-associated response.

Blunted and exaggerated neuronal response to rewards are hypothesized to be core features of schizophrenia spectrum disorders (SZ) and bipolar disorder (BD), respectively. Nonetheless, direct tests of this hypothesis, in which response between SZ and BD is compared in the same study, are lacking. Here we examined the functional correlates of reward processing during the Incentivized Control Engagement Task (ICE-T) using 3T fMRI. Reward-associated activation was examined in 49 healthy controls (HCs), 52 recent-onset individuals with SZ, and 22 recent-onset individuals with Type I BD using anterior cingulate (ACC), anterior insula, and ventral striatal regions of interest. Significant group X reward condition (neutral vs. reward) interactions were observed during reward anticipation in the dorsal ACC (F(2,120) = 4.21, P = 0.017) and right insula (F(2,120) = 4.77, P = 0.010). The ACC interaction was driven by relatively higher activation in the BD group vs. HCs (P = 0.007) and vs. individuals with SZ (P = 0.010). The insula interaction was driven by reduced activation in the SZ group relative to HCs (P = 0.018) and vs. people with BD (P = 0.008). A composite of reward anticipation-associated response across all associated ROIs also differed significantly by diagnosis (F(1,120) = 5.59, P = 0.02), BD > HC > SZ. No effects of group or group X reward interactions were observed during reward feedback. These results suggest that people with SZ and BD have opposite patterns of activation associated with reward anticipation but not reward receipt. Implications of these findings in regard to Research Domain Criteria-based classification of illness and the neurobiology of reward in psychosis are discussed.

Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = -.48 and -.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function-GSH-and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention.

Finding the neural correlates of collaboration using a three-person fMRI hyperscanning paradigm.

Humans have an extraordinary ability to interact and cooperate with others. Despite the social and evolutionary significance of collaboration, research on finding its neural correlates has been limited partly due to restrictions on the simultaneous neuroimaging of more than one participant (also known as hyperscanning). Several studies have used dyadic fMRI hyperscanning to examine the interaction between two participants. However, to our knowledge, no study to date has aimed at revealing the neural correlates of social interactions using a three-person (or triadic) fMRI hyperscanning paradigm. Here, we simultaneously measured the blood-oxygenation level-dependent signal from 12 triads (n = 36 participants), while they engaged in a collaborative drawing task based on the social game of Pictionary General linear model analysis revealed increased activation in the brain regions previously linked with the theory of mind during the collaborative phase compared to the independent phase of the task. Furthermore, using intersubject correlation analysis, we revealed increased synchronization of the right temporo-parietal junction (R TPJ) during the collaborative phase. The increased synchrony in the R TPJ was observed to be positively associated with the overall team performance on the task. In sum, our paradigm revealed a vital role of the R TPJ among other theory-of-mind regions during a triadic collaborative drawing task.

Accuracy, precision, and error in age estimation of Florida manatees using growth layer groups in earbones.

Ages of Florida manatees (Trichechus manatus latirostris) can be estimated by counting annual growth layer groups (GLGs) in the periotic dome portion of the tympanoperiotic complex of their earbones. The Florida Fish and Wildlife Conservation Commission manages an archive of more than 8,700 Florida manatee earbones collected from salvaged carcasses from 1989 to 2017. Our goal was to comprehensively evaluate techniques used to estimate age, given this large sample size and changes to processing protocols and earbone readers over time. We developed new standards for estimating ages from earbones, involving two independent readers to obtain measurements of within- and between-reader precision. To quantify accuracy, precision, and error, 111 earbones from manatees with approximately known ages (first known as calves: "KAC") and 69 earbones from manatees with minimum known ages ("MKA," based on photo-identification sighting histories) were processed, and their ages were estimated. There was greater precision within readers (coefficient of variation, CV: 2.4-8.5%) than between readers (CV: 13.1-13.3%). The median of age estimates fell within the true age range for 63.1% of KAC cases and was at least the sighting duration for 75.0% of MKA cases. Age estimates were generally unbiased, as indicated by an average raw error ± SD of -0.05 ± 3.05 years for the KAC group. The absolute error (i.e., absolute value of raw error) of the KAC data set averaged 1.75 ± 2.50 years. Accuracy decreased and error increased with increasing known age, especially for animals over 15 years old, whose ages were mostly underestimated due to increasing levels of resorption (the process of bone turnover that obscures GLGs). Understanding the degree of uncertainty in age estimates will help us assess the utility of age data in manatee population models. We emphasize the importance of standardizing and routinely reviewing age estimation and processing protocols to ensure that age data remain consistent and reliable.

Functional network changes and cognitive control in schizophrenia.

Cognitive control is a cognitive and neural mechanism that contributes to managing the complex demands of day-to-day life. Studies have suggested that functional impairments in cognitive control associated brain circuitry contribute to a broad range of higher cognitive deficits in schizophrenia. To examine this issue, we assessed functional connectivity networks in healthy adults and individuals with schizophrenia performing tasks from two distinct cognitive domains that varied in demands for cognitive control, the RiSE episodic memory task and DPX goal maintenance task. We characterized general and cognitive control-specific effects of schizophrenia on functional connectivity within an expanded frontal parietal network (FPN) and quantified network topology properties using graph analysis. Using the network based statistic (NBS), we observed greater network functional connectivity in cognitive control demanding conditions during both tasks in both groups in the FPN, and demonstrated cognitive control FPN specificity against a task independent auditory network. NBS analyses also revealed widespread connectivity deficits in schizophrenia patients across all tasks. Furthermore, quantitative changes in network topology associated with diagnostic status and task demand were observed. The present findings, in an analysis that was limited to correct trials only, ensuring that subjects are on task, provide critical insights into network connections crucial for cognitive control and the manner in which brain networks reorganize to support such control. Impairments in this mechanism are present in schizophrenia and these results highlight how cognitive control deficits contribute to the pathophysiology of this illness.

Teaching "How?" mand-for-information frames to children with autism.

The current study extends the mand-for-information literature by examining a method to teach mand-for-information frames, targeting 2 frames for the "How?" mand ("How do I?" and "How many?"). Using separate behavior chains to target the 2 frames, we taught 3 children with autism to emit mands for information with 1 behavior chain and assessed generalization with the remaining behavior chains. Behavior chains that the participants were unable to perform independently and that produced a desirable outcome for the participant (e.g., tornado water) were used to contrive the relevant motivating operation. For all 3 participants, mands for information generalized across motivating operations and response topographies.