Spatiotemporal mixed modeling of multi-subject task fMRI via method of moments

Estimating spatiotemporal models for multi-subject fMRI is computationally challenging. We propose a mixed model for localization studies with spatial random effects and time-series errors. We develop method-of-moment estimators that leverage population and spatial information and are scalable to massive datasets. In simulations, subject-specific estimates of activation are considerably more accurate than the standard voxel-wise general linear model. Our mixed model also allows for valid population inference. We apply our model to cortical data from motor and theory of mind tasks from the Human Connectome Project (HCP). The proposed method results in subject-specific predictions that appear smoother and less noisy than those from the popular single-subject univariate approach. In particular, the regions of motor cortex associated with a left-hand finger-tapping task appear to be more clearly delineated. Subject-specific maps of activation from task fMRI are increasingly used in pre-surgical planning for tumor removal and in locating targets for transcranial magnetic stimulation. Our findings suggest that using spatial and population information is a promising avenue for improving clinical neuroimaging

Distribution of lactate dehydrogenase in healthy and degenerative canine stifle joint cartilage

In dogs, degenerative joint diseases (DJD) have been shown to be associated with increased lactate dehydrogenase (LDH) activity in the synovial fluid. The goal of this study was to examine healthy and degenerative stifle joints in order to clarify the origin of LDH in synovial fluid. In order to assess the distribution of LDH, cartilage samples from healthy and degenerative knee joints were investigated by means of light and transmission electron microscopy in conjunction with immunolabeling and enzyme cytochemistry. Morphological analysis confirmed DJD. All techniques used corroborated the presence of LDH in chondrocytes and in the interterritorial matrix of healthy and degenerative stifle joints. Although enzymatic activity of LDH was clearly demonstrated in the territorial matrix by means of the tetrazolium-formazan reaction, immunolabeling for LDH was missing in this region. With respect to the distribution of LDH in the interterritorial matrix, a striking decrease from superficial to deeper layers was present in healthy dogs but was missing in affected joints. These results support the contention that LDH in synovial fluid of degenerative joints originates from cartilage. Therefore, we suggest that (1) LDH is transferred from chondrocytes to ECM in both healthy dogs and dogs with degenerative joint disease and that (2) in degenerative joints, LDH is released from chondrocytes and the ECM into synovial fluid through abrasion of cartilage as well as through enhanced diffusion as a result of increased water content and degradation of collage

Oxytocin alters patterns of brain activity and amygdalar connectivity by age during dynamic facial emotion identification

Aging is associated with increased difficulty in facial emotion identification, possibly due to age-related network change. The neuropeptide oxytocin (OT) facilitates emotion identification, but this is understudied in aging. To determine the effects of OT on dynamic facial emotion identification across adulthood, 46 young and 48 older participants self-administered intranasal OT or a placebo in a randomized, double-blind procedure. Older participants were slower and less accurate in identifying emotions. Although there was no behavioral treatment effect, partial least squares analysis supported treatment effects on brain patterns during emotion identification that varied by age and emotion. For young participants, OT altered the processing of sadness and happiness, whereas for older participants, OT only affected the processing of sadness (15.3% covariance, p\ua0= 0.004). Furthermore, seed partial least squares analysis showed that older participants in the OT group recruited a large-scale amygdalar network that was positively correlated for anger, fear, and happiness, whereas older participants in the placebo group recruited a smaller, negatively correlated network (7% covariance, p\ua0= 0.002). Advancing the literature, these findings show that OT alters brain activity and amygdalar connectivity by age and emotion

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed

The association between past and future oriented thinking: Evidence from autism spectrum disorder

A number of recently developed theories (e.g., the constructive episodic simulation, self-projection, and scene construction hypotheses) propose that the ability to simulate possible future events (sometimes referred to as episodic future thinking, prospection, or foresight) depends on the same neurocognitive system that is implicated in the recall of past events (episodic memory). In this paper, we argue that autism spectrum disorder (ASD) offers an ideal test of such theories, given that it is a developmental disorder that is characterized by impairments in episodic memory. Each of these theories would predict concomitant impairments in episodic future thinking among individuals with ASD. We review evidence concerning episodic future thinking in ASD, as well as studies of prospective memory (remembering to do something in the future), planning, navigation, and theory of mind, which some theories suggest also rely on the same mechanism as episodic future thinking

Fractionating the anterior temporal lobe : MVPA reveals differential responses to input and conceptual modality

Words activate cortical regions in accordance with their modality of presentation (i.e., written vs. spoken), yet there is a long-standing debate about whether patterns of activity in any specific brain region capture modality-invariant conceptual information. Deficits in patients with semantic dementia highlight the anterior temporal lobe (ATL) as an amodal store of semantic knowledge but these studies do not permit precise localisation of this function. The current investigation used multiple imaging methods in healthy participants to examine functional dissociations within ATL. Multi-voxel pattern analysis identified spatially segregated regions: a response to input modality in anterior superior temporal gyrus (aSTG) and a response to meaning in more ventral anterior temporal lobe (vATL). This functional dissociation was supported by resting-state connectivity that found greater coupling for aSTG with primary auditory cortex and vATL with the default mode network. A meta-analytic decoding of these connectivity patterns implicated aSTG in processes closely tied to auditory processing (such as phonology and language) and vATL in meaning-based tasks (such as comprehension or social cognition). Thus we provide converging evidence for the segregation of meaning and input modality in the ATL

Neural Correlates of Ongoing Conscious Experience: Both Task-Unrelatedness and Stimulus-Independence Are Related to Default Network Activity

The default mode network (DMN) is a set of brain regions that consistently shows higher activity at rest compared to tasks requiring sustained focused attention toward externally presented stimuli. The cognitive processes that the DMN possibly underlies remain a matter of debate. It has alternately been proposed that DMN activity reflects unfocused attention toward external stimuli or the occurrence of internally generated thoughts. The present study aimed at clarifying this issue by investigating the neural correlates of the various kinds of conscious experiences that can occur during task performance. Four classes of conscious experiences (i.e., being fully focused on the task, distractions by irrelevant sensations/perceptions, interfering thoughts related to the appraisal of the task, and mind-wandering) that varied along two dimensions (“task-relatedness” and “stimulus-dependency”) were sampled using thought-probes while the participants performed a go/no-go task. Analyses performed on the intervals preceding each probe according to the reported subjective experience revealed that both dimensions are relevant to explain activity in several regions of the DMN, namely the medial prefrontal cortex, posterior cingulate cortex/precuneus, and posterior inferior parietal lobe. Notably, an additive effect of the two dimensions was demonstrated for midline DMN regions. On the other hand, lateral temporal regions (also part of the DMN) were specifically related to stimulus-independent reports. These results suggest that midline DMN regions underlie cognitive processes that are active during both internal thoughts and external unfocused attention. They also strengthen the view that the DMN can be fractionated into different subcomponents and reveal the necessity to consider both the stimulus-dependent and the task-related dimensions of conscious experiences when studying the possible functional roles of the DMN

Top-down modulation of visual processing and knowledge after 250 ms supports object constancy of category decisions

People categorize objects slowly when visual input is highly impoverished instead of optimal. While bottom-up models may explain a decision with optimal input, perceptual hypothesis testing (PHT) theories implicate top-down processes with impoverished input. Brain mechanisms and the time course of PHT are largely unknown. This event-related potential study used a neuroimaging paradigm that implicated prefrontal cortex in top-down modulation of occipitotemporal cortex. Subjects categorized more impoverished and less impoverished real and pseudo objects. PHT theories predict larger impoverishment effects for real than pseudo objects because top-down processes modulate knowledge only for real objects, but different PHT variants predict different timing. Consistent with parietal-prefrontal PHT variants, around 250 ms, the earliest impoverished real object interaction started on an N3 complex, which reflects interactive cortical activity for object cognition. N3 impoverishment effects localized to both prefrontal and occipitotemporal cortex for real objects only. The N3 also showed knowledge effects by 230 ms that localized to occipitotemporal cortex. Later effects reflected (a) word meaning in temporal cortex during the N400, (b) internal evaluation of prior decision and memory processes and secondary higher-order memory involving anterotemporal parts of a default mode network during posterior positivity (P600), and (c) response related activity in posterior cingulate during an anterior slow wave (SW) after 700 ms. Finally, response activity in supplementary motor area during a posterior SW after 900 ms showed impoverishment effects that correlated with RTs. Convergent evidence from studies of vision, memory, and mental imagery which reflects purely top-down inputs, indicates that the N3 reflects the critical top-down processes of PHT. A hybrid multiple-state interactive, PHT and decision theory best explains the visual constancy of object cognition

Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques

Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials