Enabling brain-wide mapping of directed functional connectivity at 3T via layer-dependent fMRI with draining-vein suppression.

Layer-dependent functional magnetic resonance imaging (fMRI) offers a compelling avenue for investigating directed functional connectivity (FC). To construct a comprehensive map of brain-wide directed FC, several technical criteria must be met, including sub-mm spatial resolution, adequate temporal resolution, functional sensitivity, global brain coverage, and high spatial specificity. Although gradient echo (GE)-based echo planar imaging (EPI) is commonly used for rapid fMRI acquisition, it faces significant challenges due to the draining-vein effect, particularly when utilizing blood oxygen level-dependent (BOLD) contrast. In this study, we mitigated this effect by incorporating velocity-nulling (VN) gradients into a GE-BOLD fMRI sequence, opting for a 3T magnetic field strength over 7T. We also integrated several advanced techniques, such as simultaneous multi-slice (SMS) acceleration and NORDIC denoising, to enhance temporal resolution, spatial coverage, and signal sensitivity. Collectively, the VN fMRI method exhibited notable spatial specificity, as evidenced by the identification of double-peak activation patterns within the primary motor cortex (M1) during a finger-tapping task. Additionally, the technique demonstrated BOLD sensitivity in the lateral geniculate nucleus (LGN). Furthermore, our VN fMRI technique displayed superior robustness when compared to conventional fMRI approaches across participants. Our findings of directed FC elucidate several layer-specific functional relationships between different brain regions and align closely with existing literature. Given the widespread availability of 3T scanners, this technical advancement has the potential for significant impact across multiple domains of neuroscience research.

Mild traumatic brain injury history is associated with lower brain network resilience in soldiers.

Special Operations Forces combat soldiers sustain frequent blast and blunt neurotrauma, most often classified as mild traumatic brain injuries. Exposure to repetitive mild traumatic brain injuries is associated with persistent behavioural, cognitive, emotional and neurological symptoms later in life. Identifying neurophysiological changes associated with mild traumatic brain injury exposure, in the absence of present-day symptoms, is necessary for detecting future neurological risk. Advancements in graph theory and functional MRI have offered novel ways to analyse complex whole-brain network connectivity. Our purpose was to determine how mild traumatic brain injury history, lifetime incidence and recency affected whole-brain graph theoretical outcome measures. Healthy male Special Operations Forces combat soldiers (age = 33.2 ± 4.3 years) underwent multimodal neuroimaging at a biomedical research imaging centre using 3T Siemens Prisma or Biograph MRI scanners in this cross-sectional study. Anatomical and functional scans were preprocessed. The blood-oxygen-level-dependent signal was extracted from each functional MRI time series using the Big Brain 300 atlas. Correlations between atlas regions were calculated and Fisher z-transformed to generate subject-level correlation matrices. The Brain Connectivity Toolbox was used to obtain functional network measures for global efficiency (the average inverse shortest path length), local efficiency (the average global efficiency of each node and its neighbours), and assortativity coefficient (the correlation coefficient between the degrees of all nodes on two opposite ends of a link). General linear models were fit to compare mild traumatic brain injury lifetime incidence and recency. Nonparametric ANOVAs were used for tests on non-normally distributed data. Soldiers with a history of mild traumatic brain injury had significantly lower assortativity than those who did not self-report mild traumatic brain injury (t148 = 2.44, P = 0.016). The assortativity coefficient was significantly predicted by continuous mild traumatic brain injury lifetime incidence [F1,144 = 6.51, P = 0.012]. No differences were observed between recency groups, and no global or local efficiency differences were observed between mild traumatic brain injury history and lifetime incidence groups. Brain networks with greater assortativity have more resilient, interconnected hubs, while those with lower assortativity indicate widely distributed, vulnerable hubs. Greater lifetime mild traumatic brain injury incidence predicted lower assortativity in our study sample. Less resilient brain networks may represent a lack of physiological recovery in mild traumatic brain injury patients, who otherwise demonstrate clinical recovery, more vulnerability to future brain injury and increased risk for accelerated age-related neurodegenerative changes. Future longitudinal studies should investigate whether decreased brain network resilience may be a predictor for long-term neurological dysfunction.

Associations of lifetime concussion history and repetitive head impact exposure with resting-state functional connectivity in former collegiate American football players: An NCAA 15-year follow-up study.

The objective of this study was to examine associations of lifetime concussion history (CHx) and an advanced metric of lifetime repetitive head impact exposure with resting-state functional connectivity (rsFC) across the whole-brain and among large-scale functional networks (Default Mode; Dorsal Attention; and Frontoparietal Control) in former collegiate football players. Individuals who completed at least one year of varsity collegiate football were eligible to participate in this observational cohort study (n = 48; aged 36-41 years; 79.2% white/Caucasian; 12.5±4.4 years of football played; all men). Individuals were excluded if they reported history/suspicion of psychotic disorder with active symptoms, contraindications to participation in study procedures (e.g., MRI safety concern), or inability to travel. Each participant provided concussion and football playing histories. Self-reported concussion history was analyzed in two different ways based on prior research: dichotomous "High" (≥3 concussions; n = 28) versus "Low" (<3 concussions; n = 20); and four ordinal categories (0-1 concussion [n = 19]; 2-4 concussions [n = 8]; 5-7 concussions [n = 9]; and ≥8 concussions [n = 12]). The Head Impact Exposure Estimate (HIEE) was calculated from football playing history captured via structured interview. Resting-state fMRI and T1-weighted MRI were acquired and preprocessed using established pipelines. Next, rsFC was calculated using the Seitzman et al., (2020) 300-ROI functional atlas. Whole-brain, within-network, and between-network rsFC were calculated using all ROIs and network-specific ROIs, respectively. Effects of CHx and HIEE on rsFC values were examined using separate multivariable linear regression models, with a-priori α set to 0.05. We observed no statistically significant associations between rsFC outcomes and either CHx or HIEE (ps ≥ .12). Neither CHx nor HIEE were associated with neural signatures that have been observed in studies of typical and pathological aging. While CHx and repetitive head impacts have been associated with changes in brain health in older former athletes, our preliminary results suggest that associations with rsFC may not be present in early midlife former football players.

Episodic memory impairment in children and adolescents at risk for schizophrenia: A role for context processing.

People with schizophrenia experience episodic memory impairments that have been theorized to reflect deficits in processing context (e.g., spatio-temporal features tied to a specific event). Although past research has reported episodic memory impairments in young people at-risk for schizophrenia, the extent to which these impairments reflect context processing deficits remains unknown. We addressed this gap in the literature by examining whether children and adolescents at risk for schizophrenia exhibit context processing deficits during free recall, a memory task with high contextual demands. Our sample included three groups (N = 58, 9-16 years old) varying in risk for schizophrenia:16 high-risk, unaffected first-degree relatives of patients with schizophrenia, bipolar disorder, and/or schizoaffective disorder, 22 clinical control participants with a comorbid disorder (ADHD and/or an anxiety disorder), and 20 healthy control participants. Participants first completed a free recall task and then completed a recognition memory task. Based on established theories of episodic memory, we assumed that context processing played a more pivotal role in free recall than recognition memory. Consequently, if schizophrenia risk is associated with context processing deficits, then memory impairment should be present in free recall measures that are most sensitive to context processing (i.e., recall accuracy and temporal contiguity). Consistent with this prediction, free recall accuracy and temporal contiguity were lower for the high-risk group than the healthy controls, whereas recognition memory was comparable across groups. These findings suggest that episodic memory impairments associated with schizophrenia in unaffected, first-degree relatives may reflect context processing deficits.

Head Impact Exposure, Gray Matter Volume, and Moderating Effects of Estimated Intelligence Quotient and Educational Attainment in Former Athletes at Midlife.

Repetitive head impact (RHI) exposure has been associated with differences in brain structure among younger active athletes, most often within the hippocampus. Studies of former athletes at early-midlife are limited. We investigated the association between RHI exposure and gray matter (GM) structure, as well as moderating factors, among former athletes in early-midlife. Former collegiate football players (n = 55; age = 37.9 + 1.5 years) completed magnetic resonance imaging to quantify GM morphometry and extensive structured interviews of RHI history (Head Impact Exposure Estimate). Linear regression models tested the association between RHI exposure and GM structures of interest. Interactions were tested for moderators: two estimates of intelligence quotient (IQ) (single word reading and picture vocabulary) and education history. Greater RHI exposure was associated with smaller hippocampal volume, ß = -0.36, p = 0.004. Conversely, RHI exposure was not significantly associated with other GM outcomes ps > 0.05. Education history significantly moderated the association between RHI exposure and hippocampal volume, ß = 0.31, p = 0.047. Among those with a bachelor's degree, greater RHI exposure was significantly associated with smaller hippocampal volumes, ß = -0.58, p < 0.001. For those with graduate/professional degrees, the association between RHI and hippocampal volume was not significant, ß = -0.33, p = 0.134. Consistent with studies involving younger, active athletes, smaller hippocampal volumes were selectively associated with greater RHI exposure among former collegiate football players at midlife. This relationship was moderated by higher levels of education. Future longitudinal studies are needed to investigate the course of possible changes that can occur between early-midlife and older ages, as well as the continued protective effect of education and other potential influential factors.

Differential Role for Hippocampal Subfields in Alzheimer's Disease Progression Revealed with Deep Learning.

Mild cognitive impairment (MCI) is often considered the precursor of Alzheimer's disease. However, MCI is associated with substantially variable progression rates, which are not well understood. Attempts to identify the mechanisms that underlie MCI progression have often focused on the hippocampus but have mostly overlooked its intricate structure and subdivisions. Here, we utilized deep learning to delineate the contribution of hippocampal subfields to MCI progression. We propose a dense convolutional neural network architecture that differentiates stable and progressive MCI based on hippocampal morphometry with an accuracy of 75.85%. A novel implementation of occlusion analysis revealed marked differences in the contribution of hippocampal subfields to the performance of the model, with presubiculum, CA1, subiculum, and molecular layer showing the most central role. Moreover, the analysis reveals that 10.5% of the volume of the hippocampus was redundant in the differentiation between stable and progressive MCI.

The association between hippocampal volume and memory in pathological aging is mediated by functional redundancy.

Hippocampal neurodegeneration, a primary component of Alzheimer's disease pathology, relates to poor cognition; however, the mechanisms underlying this relationship are not well understood. Using a sample of cognitively normal older adults and individuals with mild cognitive impairment, this study aims to determine the topological properties of functional networks accompanying hippocampal atrophy in aging, along with their association to cognition and clinical progression. We considered two conceptually differing topological properties: redundancy (the existence of alternative channels of functional commutation) and local efficiency (the efficiency of local information exchange). Hippocampal redundancy, but not local efficiency, mediated the association between low hippocampal volume and low memory in both the whole sample and in ß-amyloid positive participants. Additionally, participants with high hippocampal volume, redundancy, and memory clustered separately from those with low values on all three measures, with the latter group showing higher conversion rates to dementia within three years. Together, these results demonstrate that reduced hippocampal redundancy is one mechanism through which hippocampal atrophy associates with memory impairment in healthy and pathological aging.

Brainwide functional networks associated with anatomically- and functionally-defined hippocampal subfields using ultrahigh-resolution fMRI.

The hippocampus is critical for learning and memory and may be separated into anatomically-defined hippocampal subfields (aHPSFs). Hippocampal functional networks, particularly during resting state, are generally analyzed using aHPSFs as seed regions, with the underlying assumption that the function within a subfield is homogeneous, yet heterogeneous between subfields. However, several prior studies have observed similar resting-state functional connectivity (FC) profiles between aHPSFs. Alternatively, data-driven approaches investigate hippocampal functional organization without a priori assumptions. However, insufficient spatial resolution may result in a number of caveats concerning the reliability of the results. Hence, we developed a functional Magnetic Resonance Imaging (fMRI) sequence on a 7 T MR scanner achieving 0.94 mm isotropic resolution with a TR of 2 s and brain-wide coverage to (1) investigate the functional organization within hippocampus at rest, and (2) compare the brain-wide FC associated with fine-grained aHPSFs and functionally-defined hippocampal subfields (fHPSFs). This study showed that fHPSFs were arranged along the longitudinal axis that were not comparable to the lamellar structures of aHPSFs. For brain-wide FC, the fHPSFs rather than aHPSFs revealed that a number of fHPSFs connected specifically with some of the functional networks. Different functional networks also showed preferential connections with different portions of hippocampal subfields.

Accrual of functional redundancy along the lifespan and its effects on cognition.

Despite the necessity to understand how the brain endures the initial stages of age-associated cognitive decline, no brain mechanism has been quantitatively specified to date. The brain may withstand the effects of cognitive aging through redundancy, a design feature in engineered and biological systems, which entails the presence of substitute elements to protect it against failure. Here, we investigated the relationship between functional network redundancy and age over the human lifespan and their interaction with cognition, analyzing resting-state functional MRI images and cognitive measures from 579 subjects. Network-wide redundancy was significantly associated with age, showing a stronger link with age than other major topological measures, presenting a pattern of accumulation followed by old-age decline. Critically, redundancy significantly mediated the association between age and executive function, with lower anti-correlation between age and cognition in subjects with high redundancy. The results suggest that functional redundancy accrues throughout the lifespan, mitigating the effects of age on cognition.

Lower functional hippocampal redundancy in mild cognitive impairment.

With an increasing prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) in response to an aging population, it is critical to identify and understand neuroprotective mechanisms against cognitive decline. One potential mechanism is redundancy: the existence of duplicate elements within a system that provide alternative functionality in case of failure. As the hippocampus is one of the earliest sites affected by AD pathology, we hypothesized that functional hippocampal redundancy is protective against cognitive decline. We compared hippocampal functional redundancy derived from resting-state functional MRI networks in cognitively normal older adults, with individuals with early and late MCI, as well as the relationship between redundancy and cognition. Posterior hippocampal redundancy was reduced between cognitively normal and MCI groups, plateauing across early and late MCI. Higher hippocampal redundancy was related to better memory performance only for cognitively normal individuals. Critically, functional hippocampal redundancy did not come at the expense of network efficiency. Our results provide support that hippocampal redundancy protects against cognitive decline in aging.

Subtyping of mild cognitive impairment using a deep learning model based on brain atrophy patterns.

Trajectories of cognitive decline vary considerably among individuals with mild cognitive impairment (MCI). To address this heterogeneity, subtyping approaches have been developed, with the objective of identifying more homogeneous subgroups. To date, subtyping of MCI has been based primarily on cognitive measures, often resulting in indistinct boundaries between subgroups and limited validity. Here, we introduce a subtyping method for MCI based solely upon brain atrophy. We train a deep learning model to differentiate between Alzheimer's disease (AD) and cognitively normal (CN) subjects based on whole-brain MRI features. We then deploy the trained model to classify MCI subjects based on whole-brain gray matter resemblance to AD-like or CN-like patterns. We subsequently validate the subtyping approach using cognitive, clinical, fluid biomarker, and molecular imaging data. Overall, the results suggest that atrophy patterns in MCI are sufficiently heterogeneous and can thus be used to subtype individuals into biologically and clinically meaningful subgroups.

Implicit associative memory remains intact with age and extends to target-distractor pairs.

In this study, we use a novel, implicit memory paradigm to test forhyper-binding, or older adults' tendency to form non-target associations. Participants viewed pictures of objects superimposed with text and made speeded categorization judgments about the objects across three blocks varying in binding demand. During the no- and some-binding blocks, participants decided if the pictured object alone could fit inside a drawer while ignoring superimposed non-words and words, respectively. During the full-binding block, participants decided if both items could fit inside a drawer together. At test, participants viewed intact and rearranged pairs from encoding and decided if both items could fit in a drawer together. Across two experiments, older adults responded faster to intact than rearranged pairs from both the some- and full-binding blocks, while young adults showed no difference in RTs. These findings suggest that implicit associative memory is preserved with age and extends to non-target information.

Domain general processes moderate age-related performance differences on the mnemonic similarity task.

Several prominent domain general theories (e.g., processing speed and inhibitory function) have been developed to explain cognitive changes associated with aging. A bias to "pattern complete" in aging has also been suggested to account for some of the age-related changes in episodic memory. The current experiments test whether domain-general processes of cognitive aging moderate age-related performance decrements on the mnemonic similarity task, a task thought to rely on hippocampal pattern separation and completion. The study phase of the mnemonic similarity task, a memory task with old, new, and similar trials at recognition, was manipulated to assess the contribution of processing speed (Experiment 1 - different encoding times) and inhibitory function (Experiment 2 - item-level directed forgetting) to age-related performance differences in a sample of 100 healthy younger and older adults. Both experiments exhibited significant interactions between age group and encoding manipulation, replicating a decrement in performance in older adults, and indicating that processing speed and inhibitory function moderate this effect. Results suggest that age-related differences in performance on the mnemonic similarity task can at least partially be accounted for by experimental manipulations of domain general processes that also decline with age.

Affect in the Aging Brain: A Neuroimaging Meta-Analysis of Older Vs. Younger Adult Affective Experience and Perception.

We report the first functional neuroimaging meta-analysis on age-related differences in adult neural activity during affect. We identified and coded experimental contrasts from 27 studies (published 1997-2018) with 490 older adults (55-87 years, M age = 69 years) and 470 younger adults (18-39 years, M age = 24 years). Using multilevel kernel density analysis, we assessed functional brain activation contrasts for older vs. younger adult affect across in-scanner tasks (i.e., affect induction and perception). Relative to older adults, younger adults showed more reliable activation in subcortical structures (e.g., amygdala, thalamus, caudate) and in relatively more posterior aspects of specific brain structures (e.g., posterior insula, mid- and posterior cingulate). In contrast, older adults exhibited more reliable activation in the prefrontal cortex and more anterior aspects of specific brain structures (e.g., anterior insula, anterior cingulate). Meta-analytic coactivation network analyses further revealed that in younger adults, the amygdala and mid-cingulate were more central, locally efficient network nodes, whereas in older adults, regions in the superior and medial prefrontal cortex were more central, locally efficient network nodes. Collectively, these findings help characterize age differences in the brain basis of affect and provide insights for future investigations into the neural mechanisms underlying affective aging.

Age-related differences in recognition in associative memory.

Aging is often accompanied by associative memory changes, although their precise nature remains unclear. This study examines how recognition of item position in the context of associative memory differs between younger and older adults. Participants studied word pairs (A-B, C-D) and were later tested with intact (A-B), reversed (D-C), recombined (A-D), and recombined and reversed (B-C) pairs. When participants were instructed to respond "Old" to both intact and reversed pairs, and "New" to recombined, and recombined and reversed pairs, older adults showed worse recognition for recombined and reversed pairs relative to younger adults (Experiment 1). This finding also emerged when flexible retrieval demands were increased by asking participants to respond "Old" only to intact pairs (Experiment 2). These results suggest that as conditions for flexible retrieval become more demanding, older adults may show worse recognition in associative memory tasks relative to younger adults.

Neural Correlates of Enhanced Memory for Meaningful Associations with Age.

Evidence suggests that age differences in associative memory are attenuated for associations that are consistent with prior knowledge. Such knowledge structures have traditionally been associated with the default network (DN), which also shows reduced modulation with age. In the present study, we investigated whether DN activity and connectivity patterns could account for this age-related effect. Younger and older adults underwent functional magnetic resonance imaging as they learned realistic and unrealistic prices of common grocery items. Both groups showed greater activity in the DN during the encoding of realistic, relative to unrealistic, prices. Moreover, DN activity at encoding and retrieval and its connectivity with an attention control network at encoding were associated with enhanced memory for realistic prices. Finally, older adults showed overactivation of control regions during retrieval of realistic prices relative to younger adults. Our findings suggest that DN activity and connectivity patterns (traditionally viewed as indicators of cognitive failure with age), and additional recruitment of control regions, might underlie older adults' enhanced memory for meaningful associations.

Age differences in memory for meaningful and arbitrary associations: A memory retrieval account.

Older adults typically show poor associative memory performance relative to younger adults. This age-related effect, however, is mediated by the meaningfulness of the materials used, such that age differences are minimized with the use of information that is consistent with prior knowledge. While this effect has been interpreted as facilitative learning through schematic support, the role of memory retrieval on this effect has yet to be explored. Using an associative memory paradigm that varied the extent of controlled retrieval for previously studied meaningful or arbitrary associations, older and younger adults in the present study retrieved realistic and unrealistic grocery item prices in a speeded, or in a slow, more control-based retrieval condition. There were no age differences in memory for realistic (meaningful) prices in either condition; however, younger adults showed better memory than older adults for unrealistic prices in the controlled retrieval condition only. These results suggest that age differences in memory for arbitrary associations can, at least partly, be accounted for by age reductions in strategic, controlled retrieval. (PsycINFO Database Record

Effects of Career Duration, Concussion History, and Playing Position on White Matter Microstructure and Functional Neural Recruitment in Former College and Professional Football Athletes.

Purpose To better understand the relationship between exposure to concussive and subconcussive head impacts, white matter integrity, and functional task-related neural activity in former U.S. football athletes. Materials and Methods Between 2011 and 2013, 61 cognitively unimpaired former collegiate and professional football players (age range, 52-65 years) provided informed consent to participate in this cross-sectional study. Participants were stratified across three crossed factors: career duration, concussion history, and primary playing position. Fractional anisotropy (FA) and blood oxygen level-dependent (BOLD) percent signal change (PSC) were measured with diffusion-weighted and task-related functional magnetic resonance imaging, respectively. Analyses of variance of FA and BOLD PSC were used to determine main or interaction effects of the three factors. Results A significant interaction between career duration and concussion history was observed; former college players with more than three concussions had lower FA in a broadly distributed area of white matter compared with those with zero to one concussion (t29 = 2.774; adjusted P = .037), and the opposite was observed for former professional players (t29 = 3.883; adjusted P = .001). A separate interaction between concussion history and position was observed: Nonspeed players with more than three concussions had lower FA in frontal white matter compared with those with zero to one concussion (t25 = 3.861; adjusted P = .002). Analysis of working memory-task BOLD PSC revealed a similar interaction between concussion history and position (all adjusted P < .004). Overall, former players with lower FA tended to have lower BOLD PSC across three levels of a working memory task. Conclusion Career duration and primary playing position seem to modify the effects of concussion history on white matter structure and neural recruitment. The differences in brain structure and function were observed in the absence of clinical impairment, which suggested that multimodal imaging may provide early markers of onset of traumatic neurodegenerative disease. © RSNA, 2017 Online supplemental material is available for this article.

Single-nucleotide polymorphisms are associated with cognitive decline at Alzheimer's disease conversion within mild cognitive impairment patients.

INTRODUCTION: The growing public threat of Alzheimer's disease (AD) has raised the urgency to quantify the degree of cognitive decline during the conversion process of mild cognitive impairment (MCI) to AD and its underlying genetic pathway. The aim of this article was to test genetic common variants associated with accelerated cognitive decline after the conversion of MCI to AD. METHODS: In 583 subjects with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI; ADNI-1, ADNI-Go, and ADNI-2), 245 MCI participants converted to AD at follow-up. We tested the interaction effects between individual single-nucleotide polymorphisms and AD diagnosis trajectory on the longitudinal Alzheimer's Disease Assessment Scale-Cognition scores. RESULTS: Our findings reveal six genes, including BDH1, ST6GAL1, RAB20, PDS5B, ADARB2, and SPSB1, which are directly or indirectly related to MCI conversion to AD. DISCUSSION: This genome-wide association study sheds light on a genetic mechanism of longitudinal cognitive changes during the transition period from MCI to AD.

The effect of presentation rate on implicit sequence learning in aging.

Implicit sequence learning is thought to be preserved in aging when the to-be learned associations are first-order; however, when associations are second-order, older adults (OAs) tend to experience deficits as compared to young adults (YAs). Two experiments were conducted using a first (Experiment 1) and second-order (Experiment 2) serial-reaction time task. Stimuli were presented at a constant rate of either 800 milliseconds (fast) or 1200 milliseconds (slow). Results indicate that both age groups learned first-order dependencies equally in both conditions. OAs and YAs also learned second-order dependencies, but the learning of lag-2 information was significantly impacted by the rate of presentation for both groups. OAs showed significant lag-2 learning in slow condition while YAs showed significant lag-2 learning in the fast condition. The sensitivity of implicit sequence learning to the rate of presentation supports the idea that OAs and YAs different processing speeds impact the ability to build complex associations across time and intervening events.