Rheumatoid arthritis (RA) is a chronic autoinflammatory disease that affects 1-2% of the world population and is characterized by widespread joint inflammation. IL-1 is an important mediator of cartilage destruction in rheumatic diseases1, but our understanding of the upstream mechanisms leading to IL-1β production in rheumatoid arthritis is limited by the absence of suitable RA mouse models in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the RA-susceptibility gene A20/TNFAIP3 in mice (A20myel-KO mice) triggers a spontaneous erosive polyarthritis that resembles RA in patients2. Notably, RA in A20myel-KO mice was not rescued by tumor necrosis factor receptor 1 (TNF-R1) deletion, but we showed it to crucially rely on interleukin-1 receptor (IL-1R) signaling. Macrophages lacking A20 had increased basal and LPS-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1β. As a result, A20-deficiency in macrophages significantly enhanced Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and IL-1β secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes was not altered. Importantly, increased Nlrp3 inflammasome activation contributed to RA pathology in vivo, because deletion of Nlrp3 and caspase-1 markedly protected against RA-associated inflammation and cartilage destruction in A20myel-KO mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20myel-KO mice as the first experimental model to study the role of inflammasomes in RA pathology.
inflammasome; Nlrp3; A20; caspase-1; IL1R1
Post-traumatic stress disorder (PTSD) affects the functional recruitment and connectivity between neural regions during autobiographical memory (AM) retrieval that overlap with default and control networks. Whether such univariate changes relate to potential differences in the contribution of large-scale neural networks supporting cognition in PTSD is unknown. In the current functional MRI (fMRI) study we employ independent component analysis to examine the influence the engagement of neural networks during the recall of personal memories in PTSD (15 participants) compared to non-trauma exposed, healthy controls (14 participants). We found that the PTSD group recruited similar neural networks when compared to controls during AM recall, including default network subsystems and control networks, but there were group differences in the spatial and temporal characteristics of these networks. First, there were spatial differences in the contribution of the anterior and posterior midline across the networks, and with the amygdala in particular for the medial temporal subsystem of the default network. Second, there were temporal differences in the relationship of the medial prefrontal subsystem of the default network, with less temporal coupling of this network during AM retrieval in PTSD relative to controls. These findings suggest that spatial and temporal characteristics of the default and control networks potentially differ in PTSD versus healthy controls, and contribute to altered recall of personal memory.
PTSD; Memory; Default Network; Control Network; Independent Component Analysis
Memory can be modified when reactivated, but little is known about how the properties and extent of reactivation can selectively affect subsequent memory. We developed a novel museum paradigm to directly investigate reactivation-induced plasticity for personal memories. Participants reactivated memories triggered by photos taken from a camera they wore during a museum tour and made relatedness judgments on novel photos taken from a different tour of the same museum. Subsequent recognition memory for events at the museum was better for memories that were highly reactivated (i.e., the retrieval cues during reactivation matched the encoding experience) than for memories that were reactivated at a lower level (i.e., the retrieval cues during reactivation mismatched the encoding experience), but reactivation also increased false recognition of photographs depicting stops that were not experienced during the museum tour. Reactivation thus enables memories to be selectively enhanced and distorted via updating, thereby supporting the dynamic and flexible nature of memory.
memory; false memory; autobiographical memory; episodic memory; long-term memory
Older adults recall less episodically rich autobiographical memories (AM), however, the neural basis of this effect is not clear. Using functional MRI, we examined the effects of age during search and elaboration phases of AM retrieval. Our results suggest that the age-related attenuation in the episodic richness of AMs is associated with difficulty in the strategic retrieval processes underlying recovery of information during elaboration. First, age effects on AM activity were more pronounced during elaboration than search, with older adults showing less sustained recruitment of the hippocampus and ventrolateral prefrontal cortex (VLPFC) for less episodically rich AMs. Second, there was an age-related reduction in the modulation of top-down coupling of the VLPFC on the hippocampus for episodically rich AMs. In sum, the present study shows that changes in the sustained response and coupling of the hippocampus and PFC underlie age-related reductions in episodic richness of the personal past.
Aging; fMRI; Autobiographical memory; Hippocampus; Prefrontal Cortex; Episodic Memory Retrieval; Effective Connectivity
Emotional processes are enhanced in aging, such that aging is characterized by superior emotional regulation. This article provides a brief review of the neural bases supporting this effect with a focus on functional neuroimaging studies of perception and episodic memory. The most consistent finding across these studies is that older adults show an alteration in the recruitment of the amygdala, but greater recruitment of the frontal cortex. These Fronto-amygdalar Age-related Differences in Emotion (FADE) may reflect emotional regulation strategies mediated by frontal brain regions that dampen emotion-related activations in the amygdala.
fMRI; Affect; Frontal cortex; Amygdala; Older adults; Emotional regulation
Aging is associated with preserved enhancement of emotional memory, as well as with age-related reductions in memory for negative stimuli, but the neural networks underlying such alterations are not clear. We used a subsequent-memory paradigm to identify brain activity predicting enhanced emotional memory in young and older adults. Activity in the amygdala predicted enhanced emotional memory, with subsequent-memory activity greater for negative stimuli than for neutral stimuli, across age groups, a finding consistent with an overall enhancement of emotional memory. However, older adults recruited greater activity in anterior regions and less activity in posterior regions in general for negative stimuli that were subsequently remembered. Functional connectivity of the amygdala with the rest of the brain was consistent with age-related reductions in memory for negative stimuli: Older adults showed decreased functional connectivity between the amygdala and the hippocampus, but increased functional connectivity between the amygdala and dorsolateral prefrontal cortices. These findings suggest that age-related differences in the enhancement of emotional memory might reflect decreased connectivity between the amygdala and typical subsequent-memory regions, as well as the engagement of regulatory processes that inhibit emotional responses.
Previous evidence has suggested both preserved emotional function in aging and age-related differences in emotional processing, but the neural networks underlying such processing alterations in the context of preserved affective function are not clear. Using event-related fMRI, we scanned young and older adults while they made valence ratings for emotional pictures. Behavioral results showed a similar pattern of emotional evaluation, but older adults experienced negatively valenced pictures as being less negative. Consistent with behavioral findings, we identified common activity in the right amygdala, but age-related differences in the functional connectivity of this region with the rest of the brain. Compared to young adults, older adults had greater functional connectivity between the right amygdala and ventral anterior cingulate cortex, possibly reflecting increased emotional regulation. Conversely, older adults showed decreased functional connectivity with posterior brain regions, likely reflecting decreased perceptual processing. Thus, age-related differences in evaluating negatively valenced stimuli might reflect decreased perceptual processing of these stimuli, as well as the engagement of control processes that inhibit the response to negative emotion.
Aging; Emotion; fMRI
Memory is prone to distortions that can have serious consequences in everyday life. Here we integrate emerging evidence that several types of memory distortions – imagination inflation, gist-based and associative memory errors, and post-event misinformation – reflect adaptive cognitive processes that contribute to the efficient functioning of memory, but produce distortions as a consequence of doing so. We consider recent cognitive and neuroimaging studies that link these distortions with adaptive processes, including simulation of future events, semantic and contextual encoding, creativity, and memory updating. We also discuss new evidence concerning factors that can influence the occurrence of memory distortions, such as sleep and retrieval conditions, as well as conceptual issues related to the development of an adaptive perspective.
Gender differences are frequently observed in autobiographical memory (AM). Few studies, however, have investigated the neural basis of potential gender differences in AM. In the present functional MRI (fMRI) study we investigated gender differences in AMs elicited using dynamic visual images vs. verbal cues. We used a novel technology called a SenseCam, a wearable device that automatically takes thousands of photographs. SenseCam differs considerably from other prospective methods of generating retrieval cues because it does not disrupt the ongoing experience. This allowed us to control for potential gender differences in emotional processing and elaborative rehearsal, while manipulating how the AMs were elicited. We predicted that males would retrieve more richly experienced AMs elicited by the SenseCam images vs. the verbal cues, whereas females would show equal sensitivity to both cues. The behavioral results indicated that there were no gender differences in subjective ratings of reliving, importance, vividness, emotion and uniqueness, suggesting that gender differences in brain activity were not due to differences in these measures of phenomenological experience. Consistent with our predictions, the fMRI results revealed that males showed a greater difference in functional activity associated with the rich experience of SenseCam vs. Verbal Cues, than did females.
How do separate neural networks interact to support complex cognitive processes such as remembrance of the personal past? Autobiographical memory (AM) retrieval recruits a consistent pattern of activation that potentially comprises multiple neural networks. However, it is unclear how such large-scale neural networks interact and are modulated by properties of the memory retrieval process. In the present functional MRI (fMRI) study, we combined independent component analysis (ICA) and dynamic causal modeling (DCM) to understand the neural networks supporting AM retrieval. ICA revealed four task-related components consistent with the previous literature: 1) Medial Prefrontal Cortex (PFC) Network, associated with self-referential processes, 2) Medial Temporal Lobe (MTL) Network, associated with memory, 3) Frontoparietal Network, associated with strategic search, and 4) Cingulooperculum Network, associated with goal maintenance. DCM analysis revealed that the medial PFC network drove activation within the system, consistent with the importance of this network to AM retrieval. Additionally, memory accessibility and recollection uniquely altered connectivity between these neural networks. Recollection modulated the influence of the medial PFC on the MTL network during elaboration, suggesting that greater connectivity among subsystems of the default network supports greater re-experience. In contrast, memory accessibility modulated the influence of frontoparietal and MTL networks on the medial PFC network, suggesting that ease of retrieval involves greater fluency among the multiple networks contributing to AM. These results show the integration between neural networks supporting AM retrieval and the modulation of network connectivity by behavior.
Episodic Memory; Autobiographical Memory; Retrieval; Large-Scale Brain Network; fMRI; Functional Neuroimaging
Self-projection, the capacity to re-experience the personal past and to mentally infer another person’s perspective, has been linked to the medial prefrontal cortex (mPFC). In particular, ventral mPFC is associated with inferences about one’s own self, whereas dorsal mPFC is associated with inferences about another individual. In the present functional MRI study we examined self-projection using a novel camera technology, which employs a sensor and timer to automatically take hundreds of photographs when worn, in order to create dynamic visuospatial cues taken from a first-person perspective. This allowed us to ask participants to self-project into the personal past or into the life of another person. We predicted that self-projection to the personal past would elicit greater activity in the ventral mPFC, whereas self-projection of another perspective would rely on dorsal mPFC. There were three main findings supporting this prediction. First, we found that self-projection to the personal past recruited greater ventral mPFC, whereas observing another person’s perspective recruited dorsal mPFC. Second, activity in ventral vs. dorsal mPFC was sensitive to parametric modulation on each trial by the ability to relive the personal past or to understand another’s perspective, respectively. Third, task-related functional connectivity analysis revealed that ventral mPFC contributed to the medial temporal lobe network linked to memory processes, whereas dorsal mPFC contributed to the frontoparietal network linked to controlled processes. In sum, these results suggest that ventral-dorsal subregions of the anterior midline are functionally dissociable and may differentially contribute to self-projection of self vs. other.
Post-traumatic stress disorder (PTSD) affects regions that support autobiographical memory (AM) retrieval, such as the hippocampus, amygdala and ventral medial prefrontal cortex (PFC). However, it is not well understood how PTSD may impact the neural mechanisms of memory retrieval for the personal past. We used a generic cue method combined with parametric modulation analysis and functional MRI (fMRI) to investigate the neural mechanisms affected by PTSD symptoms during the retrieval of a large sample of emotionally intense AMs. There were three main results. First, the PTSD group showed greater recruitment of the amygdala/hippocampus during the construction of negative versus positive emotionally intense AMs, when compared to controls. Second, across both the construction and elaboration phases of retrieval the PTSD group showed greater recruitment of the ventral medial PFC for negatively intense memories, but less recruitment for positively intense memories. Third, the PTSD group showed greater functional coupling between the ventral medial PFC and the amygdala for negatively intense memories, but less coupling for positively intense memories. In sum, the fMRI data suggest that there was greater recruitment and coupling of emotional brain regions during the retrieval of negatively intense AMs in the PTSD group when compared to controls.
PTSD; Autobiographical Memory; Episodic Memory; fMRI; Functional Neuroimaging
Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α-1,2-oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c+MHC-IIintCD40int dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination.
Mycobacterium; SapM; tuberculosis; vaccine; BCG
Objectives. To compare the ability of different cyclodextrin polysulphate (CDPS) derivatives to affect human articular cartilage cell metabolism in vitro.
Methods. OA chondrocytes were cultured in alginate and exposed to 5 µg/ml of 2,3,6-tri-O-methyl-β-cyclodextrin (ME-CD), 2,3-di-O-methyl-6-sulphate-β-cyclodextrin (ME-CD-6-S), 2,6-di-O-methyl-3-sulphate-β-cyclodextrin (ME-CD-3-S), (2-carboxyethyl)-β-CDPS (CE-CDPS), (2-hydroxypropyl)-β-CDPS (HP-CDPS), 6-monoamino-6-monodeoxy-β-CDPS (MA-CDPS) or β-CDPS for 5 days. Effects on IL-1-driven chondrocyte extracellular matrix (ECM) metabolism were assayed by analysis of the accumulation of aggrecan in the interterritorial matrix, IL-6 secretion and qPCR. MA-CDPS, HP-CDPS, CE-CDPS and CDPS were analysed for their in vitro effect on coagulation and their ability to activate platelets in an in vitro assay to detect possible cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies.
Results. The monosulphated cyclodextrins ME-CD-6-S and -3-S failed to affect aggrecan synthesis and IL-6 secretion by the OA chondrocytes. Polysulphated cyclodextrins MA-CDPS, HP-CDPS, CE-CDPS and CDPS at 5 µg/ml concentrations, on the other hand, significantly induced aggrecan production and repressed IL-6 release by the chondrocytes in culture. aPTT and PT for all derivatives were lengthened for polysaccharide concentrations >50 µg/ml. Five micrograms per millilitre of β-CDPS concentrations that significantly modulated ECM ground substance production in vitro did not affect aPTT or PT. Furthermore, CE-CDPS, in contrast to MA-CDPS, HP-CDPS and CDPS, did not significantly activate platelets, suggesting a minimal potential to induce HIT thromboembolic accidents in vivo.
Conclusions. CE-CDPS is a new, structurally adjusted, sulphated β-cyclodextrin derivative with preserved chondroprotective capacity and a promising safety profile.
Chondroprotection; Osteoarthritis; Cyclodextrin polysulphates
When autobiographical memories are elicited with word cues, personal events from middle childhood to early adulthood are overrepresented compared to events from other periods. It is, however, unclear whether these memories are also associated with greater recollection. In this online study, we examined whether autobiographical memories from adolescence and early adulthood are recollected more than memories from other lifetime periods. Participants rated personal events that were elicited with cue words on reliving or vividness. Consistent with previous studies, most memories came from the period in which the participants were between 6 and 20 years old. The memories from this period were not relived more or recalled more vividly than memories from other lifetime periods, suggesting that they do not involve more recollection. Recent events had higher levels of reliving and vividness than remote events, and older adults reported a stronger recollective experience than younger adults.
Recollection; Vividness; Autobiographical memory; Reminiscence bump; Aging
Disease severity in collagen-induced arthritis (CIA) is commonly assessed by clinical scoring of paw swelling and histological examination of joints. Although this is an accurate approach, it is also labour-intensive and the application of less invasive and less time-consuming methods is of great interest. However, it is still unclear which of these methods represents the most discriminating measure of disease activity.
We undertook a comparative analysis in which different measurements of inflammation and tissue damage in CIA were studied on an individual mouse level. We compared the current gold standard methods - clinical scoring and histological examination - with alternative methods based on scoring of X-ray or micro-computed tomography (CT) images and investigated the significance of systemically expressed proteins, involved in CIA pathogenesis, that have potential as biomarkers.
Linear regression analysis revealed a marked association of serum matrix metalloproteinase (MMP)-3 levels with all features of CIA including inflammation, cartilage destruction and bone erosions. This association was improved by combined detection of MMP-3 and anti-collagen IgG2a antibody concentrations. In addition, combined analysis of both X-ray and micro-CT images was found to be predictive for cartilage and bone damage. Most remarkably, validation analysis using an independent data set proved that variations in disease severity, induced by different therapies, could be accurately represented by predicted values based on the proposed parameters.
Our analyses revealed that clinical scoring, combined with serum MMP-3, anti-collagen IgG2a measurement and scoring of X-ray and micro-CT images, yields a comprehensive insight into the different aspects of disease activity in CIA.
Previous functional neuroimaging studies of temporal-order memory have investigated memory for laboratory stimuli that are causally unrelated and poor in sensory detail. In contrast, the present functional MRI (fMRI) study investigated temporal-order memory for autobiographical events that were causally interconnected and rich in sensory detail. Participants took photographs at many campus locations over a period of several hours, and the following day they were scanned while making temporal-order judgments to pairs of photographs from different locations. By manipulating the temporal lag between the two locations in each trial, we compared the neural correlates associated with reconstruction processes, which we hypothesized depended on recollection and contribute mainly to short lags, and distance processes, which we hypothesized to depend on familiarity and contribute mainly to longer lags. Consistent with our hypotheses, parametric fMRI analyses linked shorter lags to activations in regions previously associated with recollection (left prefrontal, parahippocampal, precuneus, and visual cortices) and longer lags with regions previously associated with familiarity (right prefrontal cortex). The hemispheric asymmetry in prefrontal cortex activity fits very well with evidence and theories regarding the contributions of left vs. right prefrontal cortex to memory (recollection vs. familiarity processes) and cognition (systematic vs. heuristic processes). In sum, using a novel photo-paradigm this study provided the first evidence regarding the neural correlates of temporal-order for autobiographical events.
Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease.
We investigated age-related effects in recall of emotional and neutral autobiographical memories. Protocols were scored according to episodic and non-episodic detail categories using the Autobiographical Interview. Young adults recalled a greater number of episodic details compared to older adults, whereas older adults recalled more semantic details, replicating previous findings. Both young and older adults’ emotional memories contained more overall detail than neutral ones, with the enhancement from emotion-specific to episodic details, but this did not alter the effect of age group on the pattern of episodic and semantic details. However, the age effect on episodic details was attenuated for neutral autobiographical memories. The findings suggest that age differences for emotional autobiographical recollection might reflect a more general pattern of age-related changes in memory, with impaired recall of episodic components and relative sparing of semantic aspects of autobiographical memory in older adults when compared to young adults.
As imaging centers produce higher resolution research scans, the number of man-hours required to process regional data has become a major concern. Comparison of automated vs. manual methodology has not been reported for functional imaging. We explored validation of using automation to delineate regions of interest on positron emission tomography (PET) scans. The purpose of this study was to ascertain improvements in image processing time and reproducibility of a semi-automated brain region extraction (SABRE) method over manual delineation of regions of interest (ROIs).
We compared 2 sets of partial volume corrected serotonin 1a receptor binding potentials (BPs) resulting from manual vs. semi-automated methods. BPs were obtained from subjects meeting consensus criteria for frontotemporal degeneration and from age- and gender-matched healthy controls. Two trained raters provided each set of data to conduct comparisons of inter-rater mean image processing time, rank order of BPs for 9 PET scans, intra- and inter-rater intraclass correlation coefficients (ICC), repeatability coefficients (RC), percentages of the average parameter value (RM%), and effect sizes of either method.
SABRE saved approximately 3 hours of processing time per PET subject over manual delineation (p < .001). Quality of the SABRE BP results was preserved relative to the rank order of subjects by manual methods. Intra- and inter-rater ICC were high (>0.8) for both methods. RC and RM% were lower for the manual method across all ROIs, indicating less intra-rater variance across PET subjects' BPs.
SABRE demonstrated significant time savings and no significant difference in reproducibility over manual methods, justifying the use of SABRE in serotonin 1a receptor radioligand PET imaging analysis. This implies that semi-automated ROI delineation is a valid methodology for future PET imaging analysis.