Differences in Brain Architecture in Remote Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is brain trauma from an external impact with a loss of consciousness less than 30 min. Mild TBI results in several biopsychosocial impairments, with pronounced cognitive deficits thought to resolve within 3 months of injury. Previous research suggests that these impairments are due to a temporary inability to appropriately allocate neural resources in response to cognitive demands. Our study questioned this assumption and instead hypothesized that mTBI was associated with long-term neural disruptions and compromised brain structure integrity. By extension, we investigated the likelihood that functional restitution and cognitive resolution following mTBI may be due to some form of neurofunctional reorganization. To this end, we examined abnormalities in resting state functional connectivity and structure (volume, thickness, and fractional anisotropy) in two groups of mTBI-those with 1-10 years time post-injury (mTBI1-10), and those with 20-65 years time post-injury, relative to age-, sex-, and education-matched controls. We observed abnormalities in brain architecture only in the mTBI1-10 group, characterized by functional hypo-activation in the right frontal pole, smaller frontal pole volume, and lesser fractional anisotropy in the genu of the corpus callosum that extended near the right frontal pole. This frontal region is laterally specialized to regulate function specific to socio-emotional processes. Collectively, neural disruptions and structural insult in mTBI may persist up to 10 years following injury, but injury-related pathology may resolve with longer recovery time. Disruption to frontal-dependent function that supports socio-emotional processes also may interfere with cognitive functioning, as in the case of chronic mTBI.

Relational memory and self-efficacy measures reveal distinct profiles of subjective memory concerns in older adults.

OBJECTIVE: Subjective memory concerns (SMCs) in healthy older adults are associated with future decline and can indicate preclinical dementia. However, SMCs may be multiply determined, and often correlate with affective or psychosocial variables rather than with performance on memory tests. Our objective was to identify sensitive and selective methods to disentangle the underlying causes of SMCs. METHOD: Because preclinical dementia pathology targets the hippocampus, we hypothesized that performance on hippocampally dependent relational memory tests would correlate with SMCs. We thus administered a series of memory tasks with varying dependence on relational memory processing to 91 older adults, along with questionnaires assessing depression, anxiety, and memory self-efficacy. We used correlational, regression, and mediation analyses to compare the variance in SMCs accounted for by these measures. RESULTS: Performance on the task most dependent on relational memory processing showed a stronger negative association with SMCs than did other memory performance metrics. SMCs were also negatively associated with memory self-efficacy. These 2 measures, along with age and education, accounted for 40% of the variance in SMCs. Self-efficacy and relational memory were uncorrelated and independent predictors of SMCs. Moreover, self-efficacy statistically mediated the relationship between SMCs and depression and anxiety, which can be detrimental to cognitive aging. CONCLUSIONS: These data identify multiple mechanisms that can contribute to SMCs, and suggest that SMCs can both cause and be caused by age-related cognitive decline. Relational memory measures may be effective assays of objective memory difficulties, while assessing self-efficacy could identify detrimental affective responses to cognitive aging. (PsycINFO Database Record

The role of nutrition on cognition and brain health in ageing: a targeted approach.

Animal experiments and cross-sectional or prospective longitudinal research in human subjects suggest a role for nutrition in cognitive ageing. However, data from randomised controlled trials (RCT) that seek causal evidence for the impact of nutrients on cognitive ageing in humans often produce null results. Given that RCT test hypotheses in a rigorous fashion, one conclusion could be that the positive effects of nutrition on the aged brain observed in other study designs are spurious. On the other hand, it may be that the design of many clinical trials conducted thus far has been less than optimal. In the present review, we offer a blueprint for a more targeted approach to the design of RCT in nutrition, cognition and brain health in ageing that focuses on three key areas. First, the role of nutrition is more suited for the maintenance of health rather than the treatment of disease. Second, given that cognitive functions and brain regions vary in their susceptibility to ageing, those that especially deteriorate in senescence should be focal points in evaluating the efficacy of an intervention. Third, the outcome measures that assess change due to nutrition, especially in the cognitive domain, should not necessarily be the same neuropsychological tests used to assess gross brain damage or major pathological conditions. By addressing these three areas, we expect that clinical trials of nutrition, cognition and brain health in ageing will align more closely with other research in this field, and aid in revealing the true nature of nutrition's impact on the aged brain.

Competition and Cooperation among Relational Memory Representations.

Mnemonic processing engages multiple systems that cooperate and compete to support task performance. Exploring these systems' interaction requires memory tasks that produce rich data with multiple patterns of performance sensitive to different processing sub-components. Here we present a novel context-dependent relational memory paradigm designed to engage multiple learning and memory systems. In this task, participants learned unique face-room associations in two distinct contexts (i.e., different colored buildings). Faces occupied rooms as determined by an implicit gender-by-side rule structure (e.g., male faces on the left and female faces on the right) and all faces were seen in both contexts. In two experiments, we use behavioral and eye-tracking measures to investigate interactions among different memory representations in both younger and older adult populations; furthermore we link these representations to volumetric variations in hippocampus and ventromedial PFC among older adults. Overall, performance was very accurate. Successful face placement into a studied room systematically varied with hippocampal volume. Selecting the studied room in the wrong context was the most typical error. The proportion of these errors to correct responses positively correlated with ventromedial prefrontal volume. This novel task provides a powerful tool for investigating both the unique and interacting contributions of these systems in support of relational memory.

Central adiposity is negatively associated with hippocampal-dependent relational memory among overweight and obese children.

OBJECTIVE: To assess associations between adiposity and hippocampal-dependent and hippocampal-independent memory forms among prepubertal children. STUDY DESIGN: Prepubertal children (age 7-9 years; n = 126), classified as non-overweight (<85th percentile body mass index [BMI]-for-age [n = 73]) or overweight/obese (≥85th percentile BMI-for-age [n = 53]), completed relational (hippocampal-dependent) and item (hippocampal-independent) memory tasks. Performance was assessed with both direct (behavioral accuracy) and indirect (preferential disproportionate viewing [PDV]) measures. Adiposity (ie, percent whole-body fat mass, subcutaneous abdominal adipose tissue, visceral adipose tissue, and total abdominal adipose tissue) was assessed by dual-energy X-ray absorptiometry. Backward regression identified significant (P < .05) predictive models of memory performance. Covariates included age, sex, pubertal timing, socioeconomic status (SES), IQ, oxygen consumption, and BMI z-score. RESULTS: Among overweight/obese children, total abdominal adipose tissue was a significant negative predictor of relational memory behavioral accuracy, and pubertal timing together with SES jointly predicted the PDV measure of relational memory. In contrast, among non-overweight children, male sex predicted item memory behavioral accuracy, and a model consisting of SES and BMI z-score jointly predicted the PDV measure of relational memory. CONCLUSION: Regional, but not whole-body, fat deposition was selectively and negatively associated with hippocampal-dependent relational memory among overweight/obese prepubertal children.

Relating hippocampus to relational memory processing across domains and delays.

The hippocampus has been implicated in a diverse set of cognitive domains and paradigms, including cognitive mapping, long-term memory, and relational memory, at long or short study-test intervals. Despite the diversity of these areas, their association with the hippocampus may rely on an underlying commonality of relational memory processing shared among them. Most studies assess hippocampal memory within just one of these domains, making it difficult to know whether these paradigms all assess a similar underlying cognitive construct tied to the hippocampus. Here we directly tested the commonality among disparate tasks linked to the hippocampus by using PCA on performance from a battery of 12 cognitive tasks that included two traditional, long-delay neuropsychological tests of memory and two laboratory tests of relational memory (one of spatial and one of visual object associations) that imposed only short delays between study and test. Also included were different tests of memory, executive function, and processing speed. Structural MRI scans from a subset of participants were used to quantify the volume of the hippocampus and other subcortical regions. Results revealed that the 12 tasks clustered into four components; critically, the two neuropsychological tasks of long-term verbal memory and the two laboratory tests of relational memory loaded onto one component. Moreover, bilateral hippocampal volume was strongly tied to performance on this component. Taken together, these data emphasize the important contribution the hippocampus makes to relational memory processing across a broad range of tasks that span multiple domains.

Physical activity and cardiorespiratory fitness are beneficial for white matter in low-fit older adults.

Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with better cognitive function in late life, but the neural correlates for these relationships are unclear. To study these correlates, we examined the association of both PA and CRF with measures of white matter (WM) integrity in 88 healthy low-fit adults (age 60-78). Using accelerometry, we objectively measured sedentary behavior, light PA, and moderate to vigorous PA (MV-PA) over a week. We showed that greater MV-PA was related to lower volume of WM lesions. The association between PA and WM microstructural integrity (measured with diffusion tensor imaging) was region-specific: light PA was related to temporal WM, while sedentary behavior was associated with lower integrity in the parahippocampal WM. Our findings highlight that engaging in PA of various intensity in parallel with avoiding sedentariness are important in maintaining WM health in older age, supporting public health recommendations that emphasize the importance of active lifestyle.

Identifying and characterizing the effects of nutrition on hippocampal memory.

In this review we provide evidence linking relational memory to the hippocampus, as well as examples of sensitive relational memory tasks that may help characterize the subtle effects of nutrition on learning and memory. Research into dietary effects on cognition is in its nascent stages, and many studies have cast a wide net with respect to areas of cognition to investigate. However, it may be that nutrition will have a disproportionate effect on particular cognitive domains. Thus, researchers interested in nutrition-cognition interactions may wish to apply a more targeted approach when selecting cognitive domains. We suggest that hippocampus-based relational memory may be extraordinarily sensitive to the effects of nutrition. The hippocampus shows unique plastic capabilities, making its structure and function responsive to an array of lifestyle factors and environmental conditions, including dietary intake. A major function of the hippocampus is relational memory, defined as learning and memory for the constituent elements and facts that comprise events. Here we identify several sensitive tests of relational memory that may be used to examine what may be subtle effects of nutrition on hippocampus and memory. We then turn to the literature on aerobic exercise and cognition to provide examples of translational research programs that have successfully applied this targeted approach centering on the hippocampus and sensitive relational memory tools. Finally, we discuss selected findings from animal and human research on nutrition and the hippocampus and advocate for the role of relational memory tasks in future research.

Very mild Alzheimer׳s disease is characterized by increased sensitivity to mnemonic interference.

Early pathology and tissue loss in Alzheimer׳s disease (AD) occurs in the hippocampus, a brain region that has recently been implicated in relational processing irrespective of delay. Thus, tasks that involve relational processing will especially tax the hippocampal memory system, and should be sensitive to even mild dysfunction typical of early AD. Here we used a short-lag, short-delay memory task previously shown to be sensitive to hippocampal integrity in an effort to discriminate cognitive changes due to healthy aging from those associated with very mild AD. Young adults, healthy older adults, and individuals with very mild AD (N=30 for each group) participated in our investigation, which entailed attempting to find an exact match to a previously presented target among a series of stimuli that varied in perceptual similarity to the target stimulus. Older adults with very mild AD were less accurate than healthy older adults, who, in turn, were impaired relative to young adults. Older adults with very mild AD were also particularly susceptible to interference from intervening lure stimuli. A measure based on this finding was able to explain additional variance in differentiating those in the very mild stage of AD from healthy older adults after accounting for episodic memory and global cognition composite scores in logistic regression models. Our findings suggest that cognitive changes in early stage AD reflect aging along with an additional factor potentially centered on sensitivity to interference, thereby supporting multifactorial models of aging.

Dietary lipids are differentially associated with hippocampal-dependent relational memory in prepubescent children.

BACKGROUND: Studies in rodents and older humans have shown that the hippocampus-a brain structure critical to relational/associative memory-has remarkable plasticity as a result of lifestyle factors (eg, exercise). However, the effect of dietary intake on hippocampal-dependent memory during childhood has remained unexamined. OBJECTIVE: We investigated the cross-sectional relation of dietary components characteristic of the Western diet, including saturated fatty acids (SFAs), omega-3 (n-3) fatty acids, and refined sugar, with hippocampal-dependent relational memory in prepubescent children. DESIGN: Participants aged 7-9 y (n = 52) reported their dietary intake by using the Youth-Adolescent Food-Frequency Questionnaire and completed memory tasks designed to assess relational (hippocampal-dependent) and item (hippocampal-independent) memory. Performance on the memory tasks was assessed with both direct (accuracy) and indirect (eye movement) measures. RESULTS: Partial correlations adjusted for body mass index showed a positive relation between relational memory accuracy and intake of omega-3 fatty acids and a negative relation of both relational and item memory accuracy with intake of SFAs. Potential confounding factors of age, sex, intelligence quotient, socioeconomic status, pubertal timing, and aerobic fitness (maximal oxygen volume) were not significantly related to any of the dietary intake measures. Eye movement measures of relational memory (preferential viewing to the target stimulus) showed a negative relation with intake of added sugar. CONCLUSIONS: SFA intake was negatively associated with both forms of memory, whereas omega-3 fatty acid intake was selectively positively associated with hippocampal-dependent relational memory. These findings are among the first to show a link between habitual dietary intake and cognitive health as pertaining to hippocampal function in childhood. The Fitness Improves Thinking Kids (FITKids) and FITKids2 trials were registered at www.clinicaltrials.gov as NCT01334359 and NCT01619826, respectively.

History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in life.

Evidence suggests that a history of head trauma is associated with memory deficits later in life. The majority of previous research has focused on moderate-to-severe traumatic brain injury (TBI), but recent evidence suggests that even a mild TBI (mTBI) can interact with the aging process and produce reductions in memory performance. This study examined the association of mTBI with memory and the brain by comparing young and middle-aged adults who have had mTBI in their recent (several years ago) and remote (several decades ago) past, respectively, with control subjects on a face-scene relational memory paradigm while they underwent functional magnetic resonance imaging (fMRI). Hippocampal volumes were also examined from high-resolution structural images. Results indicated middle-aged adults with a head injury in their remote past had impaired memory compared to gender, age, and education matched control participants, consistent with previous results in the study of memory, aging, and TBI. The present findings extended previous results by demonstrating that these individuals also had smaller bilateral hippocampi, and had reduced neural activity during memory performance in cortical regions important for memory retrieval. These results indicate that a history of mTBI may be one of the many factors that negatively influence cognitive and brain health in aging.

Aerobic fitness enhances relational memory in preadolescent children: the FITKids randomized control trial.

It is widely accepted that aerobic exercise enhances hippocampal plasticity. Often, this plasticity co-occurs with gains in hippocampal-dependent memory. Cross-sectional work investigating this relationship in preadolescent children has found behavioral differences in higher versus lower aerobically fit participants for tasks measuring relational memory, which is known to be critically tied to hippocampal structure and function. The present study tested whether similar differences would arise in a clinical intervention setting where a group of preadolescent children were randomly assigned to a 9-month after school aerobic exercise intervention versus a wait-list control group. Performance measures included eye-movements as a measure of memory, based on recent work linking eye-movement indices of relational memory to the hippocampus. Results indicated that only children in the intervention increased their aerobic fitness. Compared to the control group, those who entered the aerobic exercise program displayed eye-movement patterns indicative of superior memory for face-scene relations, with no differences observed in memory for individual faces. The results of this intervention study provide clear support for the proposed linkage among the hippocampus, relational memory, and aerobic fitness, as well as illustrating the sensitivity of eye-movement measures as a means of assessing memory.

Expectation and surprise determine neural population responses in the ventral visual stream.

Visual cortex is traditionally viewed as a hierarchy of neural feature detectors, with neural population responses being driven by bottom-up stimulus features. Conversely, "predictive coding" models propose that each stage of the visual hierarchy harbors two computationally distinct classes of processing unit: representational units that encode the conditional probability of a stimulus and provide predictions to the next lower level; and error units that encode the mismatch between predictions and bottom-up evidence, and forward prediction error to the next higher level. Predictive coding therefore suggests that neural population responses in category-selective visual regions, like the fusiform face area (FFA), reflect a summation of activity related to prediction ("face expectation") and prediction error ("face surprise"), rather than a homogenous feature detection response. We tested the rival hypotheses of the feature detection and predictive coding models by collecting functional magnetic resonance imaging data from the FFA while independently varying both stimulus features (faces vs houses) and subjects' perceptual expectations regarding those features (low vs medium vs high face expectation). The effects of stimulus and expectation factors interacted, whereby FFA activity elicited by face and house stimuli was indistinguishable under high face expectation and maximally differentiated under low face expectation. Using computational modeling, we show that these data can be explained by predictive coding but not by feature detection models, even when the latter are augmented with attentional mechanisms. Thus, population responses in the ventral visual stream appear to be determined by feature expectation and surprise rather than by stimulus features per se.

Differential age-related decline in conflict-driven task-set shielding from emotional versus non-emotional distracters.

While normal aging is associated with a marked decline in cognitive abilities, such as memory and executive functions, recent evidence suggests that control processes involved in regulating responses to emotional stimuli may remain well-preserved in the elderly. However, neither the precise nature of these preserved control processes, nor their domain-specificity with respect to comparable non-emotional control processes, are currently well-established. Here, we tested the hypothesis of domain-specific preservation of emotional control in the elderly by employing two closely matched behavioral tasks that assessed the ability to shield the processing of task-relevant stimulus information from competition by task-irrelevant distracter stimuli that could be either non-emotional or emotional in nature. The efficacy of non-emotional versus emotional task-set shielding, gauged via the 'conflict adaptation effect', was compared between cohorts of healthy young adults, healthy elderly adults, and individuals diagnosed with probable Alzheimer's disease (PRAD), age-matched to the elderly subjects. It was found that, compared to the young adult cohort, the healthy elderly displayed deficits in task-set shielding in the non-emotional but not in the emotional task, whereas PRAD subjects displayed impaired performance in both tasks. These results provide new evidence that healthy aging is associated with a domain-specific preservation of emotional control functions, specifically, the shielding of a current task-set from interference by emotional distracter stimuli. This selective preservation of function supports the notion of partly dissociable affective control mechanisms, and may either reflect different time-courses of degeneration in the neuroanatomical circuits mediating task-set maintenance in the face of non-emotional versus emotional distracters, or a motivational shift towards affective processing in the elderly.

Search for a threatening target triggers limbic guidance of spatial attention.

The ability to actively locate potential threats in our environment is highly adaptive. To investigate mediating neural mechanisms, we designed a visual search task in which central cues signaled future location and emotional expression (angry or neutral) of a target face. Cues predicting angry targets accelerated subsequent attention shifts, indicating that endogenous signals predicting threatening events can prime the spatial attention network. Functional imaging showed that spatially informative cues activated the fusiform gyrus (FG) as well as frontoparietal components of the spatial attention network, including intraparietal sulcus (IPS) and frontal eye field (FEF), whereas cues predicting angry faces also activated limbic areas, including the amygdala. Anatomically overlapping, additive effects of spatial and emotional cuing were identified in the IPS, FEFs, and FG, regions that also displayed augmented connectivity with the amygdala after cues predicting angry faces. These data highlight a key role for the frontoparietal spatial attention network in the compilation of a salience map that combines the spatial coordinates of an event with its motivational relevance. Furthermore, they suggest that active search for a threatening stimulus elicits amygdala input to the spatial attention network and inferotemporal visual areas, facilitating the rapid detection of upcoming motivationally significant events.

Neural integration of top-down spatial and feature-based information in visual search.

Visual search is aided by previous knowledge regarding distinguishing features and probable locations of a sought-after target. However, how the human brain represents and integrates concurrent feature-based and spatial expectancies to guide visual search is currently not well understood. Specifically, it is not clear whether spatial and feature-based search information is initially represented in anatomically segregated regions, nor at which level of processing expectancies regarding target features and locations may be integrated. To address these questions, we independently and parametrically varied the degree of spatial and feature-based (color) cue information concerning the identity of an upcoming visual search target while recording blood oxygenation level-dependent (BOLD) responses in human subjects. Search performance improved with the amount of spatial and feature-based cue information, and cue-related BOLD responses showed that, during preparation for visual search, spatial and feature cue information were represented additively in shared frontal, parietal, and cingulate regions. These data show that representations of spatial and feature-based search information are integrated in source regions of top-down biasing and oculomotor planning before search onset. The purpose of this anticipatory integration could lie with the generation of a "top-down salience map," a search template of primed target locations and features. Our results show that this role may be served by the intraparietal sulcus, which additively integrated a spatially specific activation gain in relation to spatial cue information with a spatially global activation gain in relation to feature cue information.

Neural repetition suppression reflects fulfilled perceptual expectations.

Stimulus-evoked neural activity is attenuated on stimulus repetition (repetition suppression), a phenomenon that is attributed to largely automatic processes in sensory neurons. By manipulating the likelihood of stimulus repetition, we found that repetition suppression in the human brain was reduced when stimulus repetitions were improbable (and thus, unexpected). Our data suggest that repetition suppression reflects a relative reduction in top-down perceptual 'prediction error' when processing an expected, compared with an unexpected, stimulus.