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Background: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. Most patients are older and have associated multiple comorbidities. Topical and systemic corticosteroids are considered the first-line treatment for BP, and immunosuppressants are used as steroid-sparing treatments. However, both have side-effects and contraindications, which are even more common in this older population. New treatments targeting interleukins and receptors related to BP pathogenesis have been proposed to decrease these side-effects while achieving equal or better effectiveness and response rates. Omalizumab is a monoclonal antibody that targets IgE and has been proposed for the treatment of BP due to the evidence that IgE autoantibodies play an essential role in BP pathogenesis., Objectives: To assess the efficacy and safety of omalizumab for the treatment of BP., Methods: We carried out a multicentre, retrospective, observational study including patients diagnosed with BP who received omalizumab for ≥ 3 months from 15 tertiary hospitals in Spain. IgE levels prior to treatment were measured, and we evaluated the possible correlation with clinical response. We excluded patients treated with omalizumab for < 3 months, as we consider this duration to be insufficient for a comprehensive assessment of its efficacy. To evaluate the effectiveness of the treatment, we used the percentage of body surface area improvement., Results: We included 36 patients. The vast majority had associated multiple comorbidities, and all patients had used other systemic therapies apart from corticosteroids before omalizumab. In total, 83% experienced some kind of treatment response and 42% of all patients treated achieved complete response. We did not find any correlation between higher IgE levels and a better response (P = 0.2). All patients tolerated omalizumab without reported side-effects., Conclusions: Omalizumab is a good therapeutic alternative for BP as it provided clinical response in most patients, and nearly one-half of the cases achieved complete response. It showed no side-effects, which is crucial in older patients with BP., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Exercise reduces adiposity, but its influence on bone marrow fat fraction (BMFF) is unknown; nor is it known whether a reduction in liver fat content mediates this reduction., Objectives: (i) To determine whether incorporating exercise into a lifestyle program reduces the lumbar spine (LS)-BMFF, and (ii), to investigate whether changes in liver fat mediate any such effect., Design: Ancillary analysis of a two-arm, parallel, non-randomized clinical trial., Setting: Primary care centres in Vitoria-Gasteiz (Spain)., Participants: A total of 116 children with overweight/obesity were assigned to a 22-week family-based lifestyle program (control group [n=57]) or the same program plus an exercise intervention (exercise group [n=59]., Interventions: The compared interventions consisted of a family-based lifestyle program (two 90-minute sessions/month) and the same program plus supervised exercise (three 90-minute sessions/week)., Main Outcomes and Measures: The primary outcome examined was the change in LS-BMFF between baseline and 22 weeks, as estimated by MRI. The effect of changes in hepatic fat on LS-BMFF were also recorded., Results: Mean weight loss difference between groups was 1.4±0.5 kg favour of the exercise group. Only the children in the exercise group experienced a reduction in LS-BMFF (effect size [Cohen d] -0.42, CI: -0.86, -0.01). Importantly, 40.9% of the reductions in LS-BMFF were mediated by changes in percentage hepatic fat (indirect effect: β=-0.104, 95%CI=-0.213, -0.019). The impact of changes in hepatic fat on LS-BMFF was independent of weight loss., Conclusions and Relevance: The addition of exercise to a family-based lifestyle program designed to reduce cardiometabolic risk improves bone health by reducing LS-BMFF in children with overweight or obesity. This beneficial effect on bone marrow appears to be mediated by reductions in liver fat., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Despite the progress toward gender equality in events like the Olympic Games and other institutionalized competitions, and the rising number of women engaging in physical exercise programs, scientific studies focused on establishing specific nutritional recommendations for female athletes and other physically active women are scarce., Objective: This systematic review aimed to compile the scientific evidence available for addressing the question "What dietary strategies, including dietary and supplementation approaches, can improve sports performance, recovery, and health status in female athletes and other physically active women?", Data Sources: The Pubmed, Web of Science, and Scopus databases were searched., Data Extraction: The review process involved a comprehensive search strategy using keywords connected by Boolean connectors. Data extracted from the selected studies included information on the number of participants and their characteristics related to sport practice, age, and menstrual function., Data Analysis: A total of 71 studies were included in this review: 17 focused on the analysis of dietary manipulation, and 54 focused on the effects of dietary supplementation. The total sample size was 1654 participants (32.5% categorized as competitive athletes, 30.7% as highly/moderately trained, and 37.2% as physically active/recreational athletes). The risk of bias was considered moderate, mainly for reasons such as a lack of access to the study protocol, insufficient description of how the hormonal phase during the menstrual cycle was controlled for, inadequate dietary control during the intervention, or a lack of blinding of the researchers., Conclusion: Diets with high carbohydrate (CHO) content enhance performance in activities that induce muscle glycogen depletion. In addition, pre-exercise meals with a high glycemic index or rich in CHOs increase CHO metabolism. Ingestion of 5-6 protein meals interspersed throughout the day, with each intake exceeding 25 g of protein favors anabolism of muscle proteins. Dietary supplements taken to enhance performance, such as caffeine, nitric oxide precursors, β-alanine, and certain sport foods supplements (such as CHOs, proteins, or their combination, and micronutrients in cases of nutritional deficiencies), may positively influence sports performance and/or the health status of female athletes and other physically active women., Systematic Review Registration: PROSPERO registration no. CRD480674., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Hepatic steatosis is associated with decreased bone mineral density (BMD). Bone marrow fat fraction (BMFF) could play a role in this relationship in children with obesity., Objective: The objectives of this work were (i) to examine the relationship between the lumbar spine (LS) BMFF and BMD, and (ii) to explore the mediating role of LS-BMFF on the relationship between percentage hepatic fat with LS-BMD in preadolescent children with overweight/obesity., Methods: Hepatic fat and LS-BMFF (magnetic resonance imaging) and areal LS-BMD (LS-aBMD, dual-energy x-ray absorptiometry) were measured in 106 children (aged 10.6 ± 1.1 years, 53.8% girls) with overweight/obesity., Results: LS-BMFF was inversely associated with LS-aBMD (r = -0.313; P = .001) and directly related with percentage hepatic fat (r = 0.276; P = .005). LS-BMFF was significantly greater in children with than without hepatic steatosis (P = .003; Cohen's d: 0.61; 95% CI, -0.21 to 1.0), while no significant difference was seen between children with overweight and those with obesity (P = .604; Cohen's d: 0.16; 95% CI, -0.21-0.55). Mediating analysis indicated that LS-BMFF is an important mediator (50%) in the association of hepatic fat with lower LS-aBMD (indirect effect: β = -.076; 95% CI, -0.143 to -0.015)., Conclusion: These findings suggest that hepatic steatosis, rather than overall excess adiposity, is associated with greater bone marrow adipose tissue in preadolescent children with overweight/obesity, which in turn, is related to lower BMD. Hepatic steatosis could be a potential biomarker of osteoporosis risk, and a therapeutic target for interventions that aim to reduce not only hepatic steatosis, but for those designed to improve bone health in such children., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Visual mental imagery refers to our ability to experience visual images in the absence of sensory stimulation. Studies have shown that visual mental imagery can improve episodic memory. However, we have limited understanding of the neural mechanisms underlying this improvement. Using electroencephalography, we examined the neural processes associated with the retrieval of previously generated visual mental images, focusing on how the vividness at generation can modulate retrieval processes. Participants viewed word stimuli referring to common objects, forming a visual mental image of each word and rating the vividness of the mental image. This was followed by a surprise old/new recognition task. We compared retrieval performance for items rated as high- versus low-vividness at encoding. High-vividness items were retrieved with faster reaction times and higher confidence ratings in the memory judgment. While controlling for confidence, neural measures indicated that high-vividness items produced an earlier decrease in alpha-band activity at retrieval compared with low-vividness items, suggesting an earlier memory reinstatement. Even when low-vividness items were remembered with high confidence, they were not retrieved as quickly as high-vividness items. These results indicate that when highly vivid mental images are encoded, the speed of their retrieval occurs more rapidly, relative to low-vivid items., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Attention can be directed externally toward sensory information or internally toward self-generated information. Using electroencephalography (EEG), we investigated the attentional processes underlying the formation and encoding of self-generated mental images into episodic memory. Participants viewed flickering words referring to common objects and were tasked with forming visual mental images of the objects and rating their vividness. Subsequent memory for the presented object words was assessed using an old-new recognition task. Internally-directed attention during image generation was indexed as a reduction in steady-state visual evoked potentials (SSVEPs), oscillatory EEG responses at the frequency of a flickering stimulus. The results yielded 3 main findings. First, SSVEP power driven by the flickering word stimuli decreased as subjects directed attention internally to form the corresponding mental image. Second, SSVEP power returned to pre-imagery baseline more slowly for low- than high-vividness later remembered items, suggesting that longer internally-directed attention is required to generate subsequently remembered low-vividness images. Finally, the event-related-potential difference due to memory was more sustained for subsequently remembered low- versus high-vividness items, suggesting that additional conceptual processing may have been needed to remember the low-vividness visual images. Taken together, the results clarify the neural mechanisms supporting the encoding of self-generated information., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While it is broadly accepted that attention modulates memory, the contribution of specific rapid attentional processes to successful encoding is largely unknown. To investigate this issue, we leveraged the high temporal resolution of electroencephalographic recordings to directly link a cascade of visuo-attentional neural processes to successful encoding: namely (1) the N2pc (peaking ~200 ms), which reflects stimulus-specific attentional orienting and allocation, (2) the sustained posterior-contralateral negativity (post-N2pc), which has been associated with sustained visual processing, (3) the contralateral reduction in oscillatory alpha power (contralateral reduction in alpha > 200 ms), which has also been independently related to attentionally sustained visual processing. Each of these visuo-attentional processes was robustly predictive of successful encoding, and, moreover, each enhanced memory independently of the classic, longer-latency, conceptually related, difference-due-to memory (Dm) effect. Early latency midfrontal theta power also promoted successful encoding, with at least part of this influence being mediated by the later latency Dm effect. These findings markedly expand current knowledge by helping to elucidate the intimate relationship between attentional modulations of perceptual processing and effective encoding for later memory retrieval., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

During demanding cognitive tasks, older adults (OAs) frequently show greater prefrontal cortex (PFC) activity than younger adults (YAs). This age-related increase in PFC activity is often associated with enhanced cognitive performance, suggesting functional compensation. However, the brain is a complex network of interconnected regions, and it is unclear how network connectivity of PFC regions differs for OAs versus YAs. To investigate this, we examined the age-related difference on the functional brain networks mediating episodic memory retrieval. YAs and OAs participants encoded and recalled visual scenes, and age-related differences in network topology during memory retrieval were investigated as a function of memory performance. We measured both changes in functional integration and reconfiguration in connectivity patterns. The study yielded three main findings. First, PFC regions were more functionally integrated with the rest of the brain network in OAs. Critically, this age-related increase in PFC integration was associated with better retrieval performance. Second, PFC regions showed stronger performance-related reconfiguration of connectivity patterns in OAs. Finally, the PFC reconfiguration increases in OAs tracked reconfiguration reductions in the medial temporal lobe (MTL)-a core episodic memory region, suggesting that PFC connectivity in OAs may be compensating for MTL deficits., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

It is generally assumed that the encoding of a single event generates multiple memory representations, which contribute differently to subsequent episodic memory. We used functional magnetic resonance imaging (fMRI) and representational similarity analysis to examine how visual and semantic representations predicted subsequent memory for single item encoding (e.g., seeing an orange). Three levels of visual representations corresponding to early, middle, and late visual processing stages were based on a deep neural network. Three levels of semantic representations were based on normative observed ("is round"), taxonomic ("is a fruit"), and encyclopedic features ("is sweet"). We identified brain regions where each representation type predicted later perceptual memory, conceptual memory, or both (general memory). Participants encoded objects during fMRI, and then completed both a word-based conceptual and picture-based perceptual memory test. Visual representations predicted subsequent perceptual memory in visual cortices, but also facilitated conceptual and general memory in more anterior regions. Semantic representations, in turn, predicted perceptual memory in visual cortex, conceptual memory in the perirhinal and inferior prefrontal cortex, and general memory in the angular gyrus. These results suggest that the contribution of visual and semantic representations to subsequent memory effects depends on a complex interaction between representation, test type, and storage location., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A common approach in memory research is to isolate the function(s) of individual brain regions, such as the hippocampus, without addressing how those regions interact with the larger network. To investigate the properties of the hippocampus embedded within large-scale networks, we used functional magnetic resonance imaging and graph theory to characterize complex hippocampal interactions during the active retrieval of vivid versus dim visual memories. The study yielded 4 main findings. First, the right hippocampus displayed greater communication efficiency with the network (shorter path length) and became a more convergent structure for information integration (higher centrality measures) for vivid than dim memories. Second, vivid minus dim differences in our graph theory measures of interest were greater in magnitude for the right hippocampus than for any other region in the 90-region network. Moreover, the right hippocampus significantly reorganized its set of direct connections from dim to vivid memory retrieval. Finally, beyond the hippocampus, communication throughout the whole-brain network was more efficient (shorter global path length) for vivid than dim memories. In sum, our findings illustrate how multivariate network analyses can be used to investigate the roles of specific regions within the large-scale network, while also accounting for global network changes., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A fundamental principle in memory research is that memory is a function of the similarity between encoding and retrieval operations. Consistent with this principle, many neurobiological models of declarative memory assume that memory traces are stored in cortical regions, and the hippocampus facilitates the reactivation of these traces during retrieval. The present investigation tested the novel prediction that encoding-retrieval similarity can be observed and related to memory at the level of individual items. Multivariate representational similarity analysis was applied to functional magnetic resonance imaging data collected during encoding and retrieval of emotional and neutral scenes. Memory success tracked fluctuations in encoding-retrieval similarity across frontal and posterior cortices. Importantly, memory effects in posterior regions reflected increased similarity between item-specific representations during successful recognition. Mediation analyses revealed that the hippocampus mediated the link between cortical similarity and memory success, providing crucial evidence for hippocampal-cortical interactions during retrieval. Finally, because emotional arousal is known to modulate both perceptual and memory processes, similarity effects were compared for emotional and neutral scenes. Emotional arousal was associated with enhanced similarity between encoding and retrieval patterns. These findings speak to the promise of pattern similarity measures for evaluating memory representations and hippocampal-cortical interactions.

Studies of cognitive and neural aging have recently provided evidence of a shift from an early- to late-onset cognitive control strategy, linked with temporally extended activity in the prefrontal cortex (PFC). It has been uncertain, however, whether this age-related shift is unique to PFC and executive control tasks or whether the functional location might vary depending on the particular cognitive processes that are altered. The present study tested whether an early-to-late shift in aging (ELSA) might emerge in the medial temporal lobes (MTL) during a protracted context memory task comprising both anticipatory cue (retrieval preparation) and retrieval probe (retrieval completion) phases. First, we found reduced MTL activity in older adults during the early retrieval preparation phase coupled with increased MTL activity during the late retrieval completion phase. Second, we found that functional connectivity between MTL and PFC regions was higher during retrieval preparation in young adults but higher during retrieval completion in older adults, suggesting an important interactive relationship between the ELSA pattern in MTL and PFC. Taken together, these results critically suggest that aging results in temporally lagged activity even in regions not typically associated with cognitive control, such as the MTL.

Contralateral recruitment remains a controversial phenomenon in both the clinical and normative populations. To investigate the neural correlates of this phenomenon, we explored the tendency for older adults to recruit prefrontal cortex (PFC) regions contralateral to those most active in younger adults. Participants were scanned with diffusion tensor imaging and functional magnetic rresonance imaging during a lateralized word matching task (unilateral vs. bilateral). Cross-hemispheric communication was measured behaviorally as greater accuracy for bilateral than unilateral trials (bilateral processing advantage [BPA]) and at the neural level by functional and structural connectivity between contralateral PFC. Compared with the young, older adults exhibited 1) greater BPAs in the behavioral task, 2) greater compensatory activity in contralateral PFC during the bilateral condition, 3) greater functional connectivity between contralateral PFC during bilateral trials, and 4) a positive correlation between fractional anisotropy in the corpus callosum and both the BPA and the functional connectivity between contralateral PFC, indicating that older adults' ability to distribute processing across hemispheres is constrained by white matter integrity. These results clarify how older adults' ability to recruit extra regions in response to the demands of aging is mediated by existing structural architecture, and how this architecture engenders corresponding functional changes that allow subjects to meet those task demands.

The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496-1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

According to the consolidation hypothesis, enhanced memory for emotional information reflects the modulatory effect of the amygdala on the medial temporal lobe (MTL) memory system during consolidation. Although there is evidence that amygdala-MTL connectivity enhances memory for emotional stimuli, it remains unclear whether this enhancement increases over time, as consolidation processes unfold. To investigate this, we used functional magnetic resonance imaging to measure encoding activity predicting memory for emotionally negative and neutral pictures after short (20-min) versus long (1-week) delays. Memory measures distinguished between vivid remembering (recollection) and feelings of knowing (familiarity). Consistent with the consolidation hypothesis, the persistence of recollection over time (long divided by short) was greater for emotional than neutral pictures. Activity in the amygdala predicted subsequent memory to a greater extent for emotional than neutral pictures. Although this advantage did not vary with delay, the contribution of amygdala-MTL connectivity to subsequent memory for emotional items increased over time. Moreover, both this increase in connectivity and amygdala activity itself were correlated with individual differences in recollection persistence for emotional but not neutral pictures. These results suggest that the amygdala and its connectivity with the MTL are critical to sustaining emotional memories over time, consistent with the consolidation hypothesis.

A consistent finding from functional neuroimaging studies of cognitive aging is an age-related reduction in occipital activity coupled with increased frontal activity. This posterior-anterior shift in aging (PASA) has been typically attributed to functional compensation. The present functional magnetic resonance imaging sought to 1) confirm that PASA reflects the effects of aging rather than differences in task difficulty; 2) test the compensation hypothesis; and 3) investigate whether PASA generalizes to deactivations. Young and older participants were scanned during episodic retrieval and visual perceptual tasks, and age-related changes in brain activity common to both tasks were identified. The study yielded 3 main findings. First, inconsistent with a difficulty account, the PASA pattern was found across task and confidence levels when matching performance among groups. Second, supporting the compensatory hypothesis, age-related increases in frontal activity were positively correlated with performance and negatively correlated with the age-related occipital decreases. Age-related increases and correlations with parietal activity were also found. Finally, supporting the generalizability of the PASA pattern to deactivations, aging reduced deactivations in posterior midline cortex but increased deactivations in medial frontal cortex. Taken together, these findings demonstrate the validity, function, and generalizability of PASA, as well as its importance for the cognitive neuroscience of aging.

We sought to map the time course of autobiographical memory retrieval, including brain regions that mediate phenomenological experiences of reliving and emotional intensity. Participants recalled personal memories to auditory word cues during event-related functional magnetic resonance imaging (fMRI). Participants pressed a button when a memory was accessed, maintained and elaborated the memory, and then gave subjective ratings of emotion and reliving. A novel fMRI approach based on timing differences capitalized on the protracted reconstructive process of autobiographical memory to segregate brain areas contributing to initial access and later elaboration and maintenance of episodic memories. The initial period engaged hippocampal, retrosplenial, and medial and right prefrontal activity, whereas the later period recruited visual, precuneus, and left prefrontal activity. Emotional intensity ratings were correlated with activity in several regions, including the amygdala and the hippocampus during the initial period. Reliving ratings were correlated with activity in visual cortex and ventromedial and inferior prefrontal regions during the later period. Frontopolar cortex was the only brain region sensitive to emotional intensity across both periods. Results were confirmed by time-locked averages of the fMRI signal. The findings indicate dynamic recruitment of emotion-, memory-, and sensory-related brain regions during remembering and their dissociable contributions to phenomenological features of the memories.

The neural correlates of true memory formation (TMF) and false memory formation (FMF) were investigated using functional magnetic resonance imaging (fMRI). Using a parametric subsequent memory paradigm, encoding activity was analyzed as a function of whether it predicted subsequent hits to targets (TMF activity) or subsequent false alarms to critical lures (FMF activity). The fMRI analyses yielded 3 main findings. First, the left prefrontal cortex (PFC) was involved in both TMF and FMF activities. This finding is consistent with the evidence that semantic elaboration, which has been associated with left PFC, tends to enhance both true and false remembering. Second, the left posterior medial temporal lobes (MTLs) contributed to TMF but not to FMF activity. This finding is consistent with the notion that MTL is involved in the storage of a consciously, but not unconsciously, processed event. Third, late visual regions were engaged in both TMF and FMF activities, whereas early visual areas were involved primarily in TMF activity. This dissociation indicates that elaborative perceptual processing, but not basic sensory processing, contributes to false remembering. Taken together, the results suggest that FMF is an unintended consequence, or by-product, of elaborative semantic and visual encoding processes.

Event-related functional magnetic resonance imaging was used to study the effects of healthy aging on hippocampal and rhinal memory functions. Memory for past events can be based on retrieval accompanied by specific contextual details (recollection) or on the feeling that an event is old or new without the recovery of contextual details (familiarity). There is evidence that recollection is more dependent on hippocampus, whereas familiarity is more dependent on the rhinal cortex, and that healthy aging has greater effects on recollection than on familiarity. However, little evidence is available about the neural correlates of these effects. Here, we isolated activity associated with recollection and familiarity by distinguishing between linear and quasi-exponential "perceived oldness" functions derived from recognition confidence levels. The main finding was a double dissociation within the medial temporal lobes between recollection-related activity in hippocampus, which was reduced by aging, and familiarity-related activity in rhinal cortex, which was increased by aging. In addition, age dissociations were found within parietal and posterior midline regions. Finally, aging reduced functional connectivity within a hippocampal-retrosplenial/parietotemporal network but increased connectivity within a rhinal-frontal network. These findings indicate that older adults compensate for hippocampal deficits by relying more on rhinal cortex, possibly through a top-down frontal modulation. This finding has important clinical implications because early Alzheimer's disease impairs both hippocampus and rhinal cortex.

In the episodic retrieval (ER) domain, activations in right dorsolateral prefrontal cortex (DLPFC) are often attributed to postretrieval monitoring. Yet, right DLPFC activations are also frequently found during nonmemory tasks. To investigate the role of this region across different cognitive functions, we directly compared brain activity during ER and visual perception (VP) using event-related functional magnetic resonance imaging. In the ER task, participants decided whether words were old or new, whereas in the VP task, they decided which of the two colored screen areas was larger. In both tasks, each decision was followed by a confidence rating. The main finding was that right DLPFC (Brodmann area 46/10) activity was greater for low- than for high-confidence decisions in both tasks, demonstrating a general role in decision making. Even when reaction times (RTs) were included in the model, confidence remained the significant predictor of activity, suggesting that right DLPFC is involved in discontinuous evaluation rather than in continuous monitoring. In contrast, activity in anterior cingulate cortex was not only greater for low-confidence decisions but also increased with RT, reflecting a role in continuous conflict monitoring. Overall, the results demonstrate how direct cross-function comparisons clarify the generality and specificity of the functions of various brain regions.

It is controversial whether the effects of aging on various cognitive functions have the same common cause or several different causes. To investigate this issue, we scanned younger and older adults with functional magnetic resonance imaging (fMRI) while performing three different tasks: working memory, visual attention and episodic retrieval. There were three main results. First, in all three tasks, older adults showed weaker occipital activity and stronger prefrontal and parietal activity than younger adults. The occipital reduction is consistent with the view that sensory processing decline is a common cause in cognitive aging, and the prefrontal increase may reflect functional compensation. Secondly, older adults showed more bilateral patterns of prefrontal activity than younger adults during working memory and visual attention tasks. These findings are consistent with the Hemispheric Asymmetry Reduction in Older Adults (HAROLD) model. Finally, compared to younger adults, older adults showed weaker hippocampal formation activity in all three tasks but stronger parahippocampal activity in the episodic retrieval task. The former finding suggests that age-related hippocampal deficits may have a global effect in cognition, and the latter is consistent with an age-related increase in familiarity-based recognition. Taken together, the results indicate that both common and specific factors play an important role in cognitive aging.

Isolated retrograde amnesia is defined as impaired recollection of experiences pre-dating brain injury with relatively preserved anterograde learning and memory. We present findings from a patient (M.L.) with isolated retrograde amnesia following severe traumatic brain injury (TBI) that address hypotheses of the interrelationships of focal neuropathology, episodic memory and the self. M.L. is densely amnesic for experiences predating his injury, but shows normal anterograde memory performance on a variety of standard tests of recall and recognition. The cognitive processes underlying this performance were examined with the remember/know technique, which permits separation of episodic from non-episodic contributions to memory tests by quantifying subjects' reports of re-experiencing aspects of the encoding episode. The results demonstrated that M.L. does not episodically re-experience post-injury events to the same extent as control subjects, although he can use familiarity or other non-episodic processes to distinguish events he has experienced from those he has not experienced. M.L.'s MRI showed damage to the right ventral frontal cortex and underlying white matter, including the uncinate fasciculus, a frontotemporal band of fibres previously hypothesized to mediate retrieval of specific events from one's personal past. Recent functional neuroimaging evidence of an association between right frontal lobe functioning and episodic retrieval demands suggest that M.L.'s memory deficits are related to this focal injury. This hypothesis was supported by right frontal polar hypoactivation in M.L. in response to episodic retrieval demands when he was examined with a cognitive activation H2(15)O PET paradigm that reliably activated this frontal region in both healthy controls and patients with TBI carefully matched to M.L. (but without isolated retrograde amnesia). He also showed increased left inferomedial temporal activation relative to control subjects, suggesting that his spared anterograde memory is mediated through increased reliance on medial temporal lobe structures. Re-experiencing events as part of one's past is based on autonoetic awareness, i.e. awareness of oneself as a continuous entity across time. This form of awareness also supports the formulation of future goals and the implementation of a behavioural guidance system to achieve them. The findings from this study converge to suggest that M.L. has impaired autonoetic awareness attributable to right ventral frontal lobe injury, including right frontal-temporal disconnection. Reorganized brain systems mediate certain preserved cognitive operations in M.L., but without the normal complement of information concerning the self with respect to both past and future events.

A sensory-sensory learning paradigm was used to measure neural changes in humans during acquisition of an association between an auditory and visual stimulus. Three multivariate partial least-squares (PLS) analyses of positron emission tomography data identified distributed neural systems related to (i) processing the significance of the auditory stimulus, (ii) mediating the acquisition of the behavioral response, and (iii) the spatial overlap between these two systems. The system that processed the significance of the tone engaged primarily right hemisphere regions and included dorsolateral prefrontal cortex, putamen, and inferior parietal and temporal cortices. Activity changes in left occipital cortex were also identified, most likely reflecting the learned expectancy of the upcoming visual event. The system related to behavior was similar to that which coded the significance of the tone, including dorsal occipital cortex. The PLS analysis of the concordance between these two systems showed substantial regional overlap, and included occipital, dorsolateral prefrontal, and limbic cortices. However, activity in dorsomedial prefrontal cortex was strictly related to processing the auditory stimulus and not to behavior. Taken together, the PLS analyses identified a system that contained a sensory-motor component (comprised of occipital, temporal association and sensorimotor cortices) and a medial prefrontallimbic component, that as a group simultaneously embodied the learning-related response to the stimuli and the subsequent change in behavior.