White Matter Organization and Cortical Thickness Differ Among Active Duty Service Members With Chronic Mild, Moderate, and Severe Traumatic Brain Injury.

Abstract This study compared findings from whole-brain diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) among 90 Active Duty Service Members with chronic mild traumatic brain injury (TBI; n = 52), chronic moderate-to-severe TBI (n = 17), and TBI-negative controls (n = 21). Data were collected on a Philips Ingenia 3T MRI with DTI in 32 directions. Results demonstrated that history of TBI was associated with differences in white matter microstructure, white matter volume, and cortical thickness in both mild TBI and moderate-to-severe TBI groups relative to controls. However, the presence, pattern, and distribution of these findings varied substantially depending on the injury severity. Spatially-defined forms of DTI fractional anisotropy (FA) analyses identified altered white matter organization within the chronic moderate-to-severe TBI group, but they did not provide clear evidence of abnormalities within the chronic mild TBI group. In contrast, DTI FA "pothole" analyses identified widely distributed areas of decreased FA throughout the white matter in both the chronic mild TBI and chronic moderate-to-severe TBI groups. Additionally, decreased white matter volume was found in several brain regions for the chronic moderate-to-severe TBI group compared with the other groups. Greater number of DTI FA potholes and reduced cortical thickness were also related to greater severity of self-reported symptoms. In sum, this study expands upon a growing body of literature using advanced imaging techniques to identify potential effects of brain injury in military Service Members. These findings may differ from work in other TBI populations due to varying mechanisms and frequency of injury, as well as a potentially higher level of functioning in the current sample related to the ability to maintain continued Active Duty status after injury. In conclusion, this study provides DTI and volumetric MRI findings across the spectrum of TBI severity. These results provide support for the use of DTI and volumetric MRI to identify differences in white matter microstructure and volume related to TBI. In particular, DTI FA pothole analysis may provide greater sensitivity for detecting subtle forms of white matter injury than conventional DTI FA analyses.

Associations of mTBI and post-traumatic stress to amygdala structure and functional connectivity in military Service Members.

Introduction: Traumatic brain injury (TBI) is one of the highest public health priorities, especially among military personnel where comorbidity with post-traumatic stress symptoms and resulting consequences is high. Brain injury and post-traumatic stress symptoms are both characterized by dysfunctional brain networks, with the amygdala specifically implicated as a region with both structural and functional abnormalities. Methods: This study examined the structural volumetrics and resting state functional connectivity of 68 Active Duty Service Members with or without chronic mild TBI (mTBI) and comorbid symptoms of Post-Traumatic Stress (PTS). Results and discussion: Structural analysis of the amygdala revealed no significant differences in volume between mTBI and healthy comparison participants with and without post-traumatic stress symptoms. Resting state functional connectivity with bilateral amygdala revealed decreased anterior network connectivity and increased posterior network connectivity in the mTBI group compared to the healthy comparison group. Within the mTBI group, there were significant regions of correlation with amygdala that were modulated by PTS severity, including networks implicated in emotional processing and executive functioning. An examination of a priori regions of amygdala connectivity in the default mode network, task positive network, and subcortical structures showed interacting influences of TBI and PTS, only between right amygdala and right putamen. These results suggest that mTBI and PTS are associated with hypo-frontal and hyper-posterior amygdala connectivity. Additionally, comorbidity of these conditions appears to compound these neural activity patterns. PTS in mTBI may change neural resource recruitment for information processing between the amygdala and other brain regions and networks, not only during emotional processing, but also at rest.

Functional Brain Connectivity During Narrative Processing Relates to Transportation and Story Influence.

Engaging with narratives involves a complex array of cognitive and affective processes. These processes make stories persuasive in ways that standard arguments are not, though the underlying reasons for this remain unclear. Transportation theory proposes a potential explanation for this: narratives are processed in a way which makes individuals feel immersed in the world of a story, which in turn leads people to resonate emotionally with the events of the story. Recent fMRI studies have shown that the posterior medial cortex (PMC) and anterior insula (AI) play important roles in understanding the meaning of stories and experiencing the feelings they produce. In this study, we aimed to explore the AI's and PMC's role in narrative processing by measuring their functional connectivity with the rest of the brain during story listening, and how connectivity changes as a function of narrative transportation and the persuasiveness of the story. We analyzed data from 36 right-handed subjects who listened to two stories, obtained from podcasts, inside the fMRI scanner. After the scan, subjects were asked a series of questions, including a measure of how transported into the story they felt, how likely they would be to donate to causes related to the messages of the stories. We used searchlight multivariate pattern analysis (MVPA) to classify functional connectivity maps using seeds in both the AI and PMC and to compare these maps between participants who differed in transportation and prosocial intention. We found that connectivity to various regions successfully distinguished between high and low ratings on each of these behavioral measures with accuracies over 75%. However, only one pattern of connectivity was consistent across both stories: PMC-inferior frontal gyrus connectivity successfully distinguished high and low ratings of narrative transportation in both stories. All other findings were not consistent across stories. Instead, we found that patterns of connectivity may relate more to the specific content of the story rather than to a universal way in which narratives are processed.

Brain bases of recovery following cognitive rehabilitation for traumatic brain injury: a preliminary study.

Many patients with traumatic brain injury (TBI) have persistent cognitive deficits, including decreased attention and working memory. This preliminary study examined fMRI data from a clinical trial implementing a 4-week virtual reality driving intervention to assess how sustained training can improve deficits related to traumatic brain injury. Previously-reported behavioral findings showed improvements in working memory and processing speed in those who received the intervention; this report explores the brain bases of these effects by comparing neural activity related to working memory (n-back task) and resting state connectivity before and after the intervention. In the baseline visit (n = 24), working memory activity was prominent in bilateral DLPFC and prefrontal cortex, anterior insula, medial superior frontal gyrus, left thalamus, bilateral supramarginal / angular gyrus, precuneus, and left posterior middle temporal gyrus. Following intervention, participants showed less global activation on the n-back task, with regions of activity only in the bilateral middle frontal cortex, posterior middle frontal gyrus, and supramarginal gyrus. Activity related to working memory load was reduced for the group that went through the intervention (n = 7) compared to the waitlist control group (n = 4). These results suggest that successful cognitive rehabilitation of working memory in TBI may be associated with increased efficiency of brain networks, evidenced by reduced activation of brain activity during cognitive processing. These results highlight the importance of examining brain activity related to cognitive rehabilitation of attention and working memory after brain injury.

Clinical validation of an optimized multimodal neurocognitive assessment of chronic mild TBI.

OBJECTIVE: Previous laboratory-based studies have shown that neurocognitive eye-tracking metrics are sensitive to chronic effects of mild traumatic brain injury (mTBI), even in individuals with normal performance on traditional neuropsychological measures. In this study, we sought to replicate and extend these findings in a military medical environment. We expected that metrics from the multimodal Fusion n-Back test would successfully distinguish chronic mTBI participants from controls, particularly eye movement metrics from the more cognitively challenging "1-Back" subtest. METHODS: We compared performance of participants with chronic mTBI (n = 46) and controls (n = 33) on the Fusion n-Back test and a battery of conventional neuropsychological tests. Additionally, we examined test reliability and the impact of potential confounds to neurocognitive assessment. RESULTS: Our results supported hypotheses; Fusion 1-Back metrics were successful in multimodal (saccadic and manual) classification of chronic mTBI versus control. In contrast, conventional neuropsychological measures could not distinguish these groups. Additional findings demonstrated the reliability of Fusion n-Back test metrics and provided evidence that saccadic metrics are resistant to confounding influences of age, intelligence, and psychiatric symptoms. INTERPRETATION: The Fusion n-Back test could provide advantages in differential diagnosis for complex brain injury populations. Additionally, the rapid administration of this test could be valuable for screening patients in clinical settings where longer test batteries are not feasible.

Neurocognitive Driving Rehabilitation in Virtual Environments (NeuroDRIVE): A pilot clinical trial for chronic traumatic brain injury.

BACKGROUND: Virtual reality (VR) technology may provide an effective means to integrate cognitive and functional approaches to TBI rehabilitation. However, little is known about the effectiveness of VR rehabilitation for TBI-related cognitive deficits. In response to these clinical and research gaps, we developed Neurocognitive Driving Rehabilitation in Virtual Environments (NeuroDRIVE), an intervention designed to improve cognitive performance, driving safety, and neurobehavioral symptoms. OBJECTIVE: This pilot clinical trial was conducted to examine feasibility and preliminary efficacy of NeuroDRIVE for rehabilitation of chronic TBI. METHODS: Eleven participants who received the intervention were compared to six wait-listed participants on driving abilities, cognitive performance, and neurobehavioral symptoms. RESULTS: The NeuroDRIVE intervention was associated with significant improvements in working memory and visual search/selective attention- two cognitive skills that represented a primary focus of the intervention. By comparison, no significant changes were observed in untrained cognitive areas, neurobehavioral symptoms, or driving skills. CONCLUSIONS: Results suggest that immersive virtual environments can provide a valuable and engaging means to achieve some cognitive rehabilitation goals, particularly when these goals are closely matched to the VR training exercises. However, additional research is needed to augment our understanding of rehabilitation for driving skills, cognitive performance, and neurobehavioral symptoms in chronic TBI.

Community violence exposure in early adolescence: Longitudinal associations with hippocampal and amygdala volume and resting state connectivity.

Community violence exposure is a common stressor, known to compromise youth cognitive and emotional development. In a diverse, urban sample of 22 adolescents, participants reported on community violence exposure (witnessing a beating or illegal drug use, hearing gun shots, or other forms of community violence) in early adolescence (average age 12.99), and underwent a neuroimaging scan 3-5 years later (average age 16.92). Community violence exposure in early adolescence predicted smaller manually traced left and right hippocampal and amygdala volumes in a model controlling for age, gender, and concurrent community violence exposure, measured in late adolescence. Community violence continued to predict hippocampus (but not amygdala) volumes after we also controlled for family aggression exposure in early adolescence. Community violence exposure was also associated with stronger resting state connectivity between the right hippocampus (using the manually traced structure as a seed region) and bilateral frontotemporal regions including the superior temporal gyrus and insula. These resting state connectivity results held after controlling for concurrent community violence exposure, SES, and family aggression. Although this is the first study focusing on community violence in conjunction with brain structure and function, these results dovetail with other research linking childhood adversity with smaller subcortical volumes in adolescence and adulthood, and with altered frontolimbic resting state connectivity. Our findings suggest that even community-level exposure to neighborhood violence can have detectable neural correlates in adolescents.

Longitudinal Associations Between Family Aggression, Externalizing Behavior, and the Structure and Function of the Amygdala.

Using longitudinal data from 21 adolescents, we assessed family aggression (via mother, father, and youth report) in early adolescence, externalizing behavior in mid-adolescence, and magnetic resonance imaging (MRI) data in late adolescence. Amygdalae were manually traced, and used as seed regions for resting state analyses. Both family aggression and subsequent externalizing behavior predicted larger right amygdala volumes and stronger amygdala-frontolimbic/salience network connectivity and weaker amygdala-posterior cingulate connectivity. Externalizing behavior in mid-adolescence mediated associations between family aggression in early adolescence and resting state connectivity between the amygdala and the subgenual anterior cingulate cortex, medial prefrontal cortex, orbitofrontal cortex, and posterior cingulate cortex in late adolescence. Family adversity and adolescent behavior problems may share common neural correlates.

Decoding the neural representation of story meanings across languages.

Drawing from a common lexicon of semantic units, humans fashion narratives whose meaning transcends that of their individual utterances. However, while brain regions that represent lower-level semantic units, such as words and sentences, have been identified, questions remain about the neural representation of narrative comprehension, which involves inferring cumulative meaning. To address these questions, we exposed English, Mandarin, and Farsi native speakers to native language translations of the same stories during fMRI scanning. Using a new technique in natural language processing, we calculated the distributed representations of these stories (capturing the meaning of the stories in high-dimensional semantic space), and demonstrate that using these representations we can identify the specific story a participant was reading from the neural data. Notably, this was possible even when the distributed representations were calculated using stories in a different language than the participant was reading. Our results reveal that identification relied on a collection of brain regions most prominently located in the default mode network. These results demonstrate that neuro-semantic encoding of narratives happens at levels higher than individual semantic units and that this encoding is systematic across both individuals and languages. Hum Brain Mapp 38:6096-6106, 2017. © 2017 Wiley Periodicals, Inc.

Corrigendum: Associations between Family Adversity and Brain Volume in Adolescence: Manual vs. Automated Brain Segmentation Yields Different Results.

[This corrects the article on p. 398 in vol. 10, PMID: 27656121.].

I know I've seen you before: Distinguishing recent-single-exposure-based familiarity from pre-existing familiarity.

This study examines how individuals differentiate recent-single-exposure-based familiarity from pre-existing familiarity. If these are two distinct cognitive processes, are they supported by the same neural bases? This study examines how recent-single-exposure-based familiarity and multiple-previous-exposure-based familiarity are supported and represented in the brain using functional MRI. In a novel approach, we first behaviorally show that subjects can divide retrieval of items in pre-existing memory into judgments of recollection and familiarity. Then, using functional magnetic resonance imaging, we examine the differences in blood oxygen level dependent activity and regional connectivity during judgments of recent-single-exposure-based and pre-existing familiarity. Judgments of these two types of familiarity showed distinct regions of activation in a whole-brain analysis, in medial temporal lobe (MTL) substructures, and in MTL substructure functional-correlations with other brain regions. Specifically, within the MTL, perirhinal cortex showed increased activation during recent-single-exposure-based familiarity while parahippocampal cortex showed increased activation during judgments of pre-existing familiarity. We find that recent-single-exposure-based and pre-existing familiarity are represented as distinct neural processes in the brain; this is supported by differing patterns of brain activation and regional correlations. This spatially distinct regional brain involvement suggests that the two separate experiences of familiarity, recent-exposure-based familiarity and pre-existing familiarity, may be cognitively distinct.

Processing Narratives Concerning Protected Values: A Cross-Cultural Investigation of Neural Correlates.

Narratives are an important component of culture and play a central role in transmitting social values. Little is known, however, about how the brain of a listener/reader processes narratives. A receiver's response to narration is influenced by the narrator's framing and appeal to values. Narratives that appeal to "protected values," including core personal, national, or religious values, may be particularly effective at influencing receivers. Protected values resist compromise and are tied with identity, affective value, moral decision-making, and other aspects of social cognition. Here, we investigated the neural mechanisms underlying reactions to protected values in narratives. During fMRI scanning, we presented 78 American, Chinese, and Iranian participants with real-life stories distilled from a corpus of over 20 million weblogs. Reading these stories engaged the posterior medial, medial prefrontal, and temporo-parietal cortices. When participants believed that the protagonist was appealing to a protected value, signal in these regions was increased compared with when no protected value was perceived, possibly reflecting the intensive and iterative search required to process this material. The effect strength also varied across groups, potentially reflecting cultural differences in the degree of concern for protected values.

Neural correlates of maintaining one's political beliefs in the face of counterevidence.

People often discount evidence that contradicts their firmly held beliefs. However, little is known about the neural mechanisms that govern this behavior. We used neuroimaging to investigate the neural systems involved in maintaining belief in the face of counterevidence, presenting 40 liberals with arguments that contradicted their strongly held political and non-political views. Challenges to political beliefs produced increased activity in the default mode network-a set of interconnected structures associated with self-representation and disengagement from the external world. Trials with greater belief resistance showed increased response in the dorsomedial prefrontal cortex and decreased activity in the orbitofrontal cortex. We also found that participants who changed their minds more showed less BOLD signal in the insula and the amygdala when evaluating counterevidence. These results highlight the role of emotion in belief-change resistance and offer insight into the neural systems involved in belief maintenance, motivated reasoning, and related phenomena.

Corrigendum: Associations between Family Adversity and Brain Volume in Adolescence: Manual vs. Automated Brain Segmentation Yields Different Results.

[This corrects the article on p. 398 in vol. 10, PMID: 27656121.].

Associations between Family Adversity and Brain Volume in Adolescence: Manual vs. Automated Brain Segmentation Yields Different Results.

Associations between brain structure and early adversity have been inconsistent in the literature. These inconsistencies may be partially due to methodological differences. Different methods of brain segmentation may produce different results, obscuring the relationship between early adversity and brain volume. Moreover, adolescence is a time of significant brain growth and certain brain areas have distinct rates of development, which may compromise the accuracy of automated segmentation approaches. In the current study, 23 adolescents participated in two waves of a longitudinal study. Family aggression was measured when the youths were 12 years old, and structural scans were acquired an average of 4 years later. Bilateral amygdalae and hippocampi were segmented using three different methods (manual tracing, FSL, and NeuroQuant). The segmentation estimates were compared, and linear regressions were run to assess the relationship between early family aggression exposure and all three volume segmentation estimates. Manual tracing results showed a positive relationship between family aggression and right amygdala volume, whereas FSL segmentation showed negative relationships between family aggression and both the left and right hippocampi. However, results indicate poor overlap between methods, and different associations were found between early family aggression exposure and brain volume depending on the segmentation method used.

Elaboration versus suppression of cued memories: influence of memory recall instruction and success on parietal lobe, default network, and hippocampal activity.

Functional imaging studies of episodic memory retrieval consistently report task-evoked and memory-related activity in the medial temporal lobe, default network and parietal lobe subregions. Associated components of memory retrieval, such as attention-shifts, search, retrieval success, and post-retrieval processing also influence regional activity, but these influences remain ill-defined. To better understand how top-down control affects the neural bases of memory retrieval, we examined how regional activity responses were modulated by task goals during recall success or failure. Specifically, activity was examined during memory suppression, recall, and elaborative recall of paired-associates. Parietal lobe was subdivided into dorsal (BA 7), posterior ventral (BA 39), and anterior ventral (BA 40) regions, which were investigated separately to examine hypothesized distinctions in sub-regional functional responses related to differential attention-to-memory and memory strength. Top-down suppression of recall abolished memory strength effects in BA 39, which showed a task-negative response, and BA 40, which showed a task-positive response. The task-negative response in default network showed greater negatively-deflected signal for forgotten pairs when task goals required recall. Hippocampal activity was task-positive and was influenced by memory strength only when task goals required recall. As in previous studies, we show a memory strength effect in parietal lobe and hippocampus, but we show that this effect is top-down controlled and sensitive to whether the subject is trying to suppress or retrieve a memory. These regions are all implicated in memory recall, but their individual activity patterns show distinct memory-strength-related responses when task goals are varied. In parietal lobe, default network, and hippocampus, top-down control can override the commonly identified effects of memory strength.

Search-Related Suppression of Hippocampus and Default Network Activity during Associative Memory Retrieval.

Episodic memory retrieval involves the coordinated interaction of several cognitive processing stages such as mental search, access to a memory store, associative re-encoding, and post-retrieval monitoring. The neural response during memory retrieval is an integration of signals from multiple regions that may subserve supportive cognitive control, attention, sensory association, encoding, or working memory functions. It is particularly challenging to dissociate contributions of these distinct components to brain responses in regions such as the hippocampus, which lies at the interface between overlapping memory encoding and retrieval, and "default" networks. In the present study, event-related functional magnetic resonance imaging (fMRI) and measures of memory performance were used to differentiate brain responses to memory search from subcomponents of episodic memory retrieval associated with successful recall. During the attempted retrieval of both poorly and strongly remembered word pair associates, the hemodynamic response was negatively deflected below baseline in anterior hippocampus and regions of the default network. Activations in anterior hippocampus were functionally distinct from those in posterior hippocampus and negatively correlated with response times. Thus, relative to the pre-stimulus period, the hippocampus shows reduced activity during intensive engagement in episodic memory search. Such deactivation was most salient during trials that engaged only pre-retrieval search processes in the absence of successful recollection or post-retrieval processing. Implications for interpretation of hippocampal fMRI responses during retrieval are discussed. A model is presented to interpret such activations as representing modulation of encoding-related activity, rather than retrieval-related activity. Engagement in intensive mental search may reduce neural and attentional resources that are otherwise tonically devoted to encoding an individual's stream of experience into episodic memory.

Reaction time, memory strength, and fMRI activity during memory retrieval: Hippocampus and default network are differentially responsive during recollection and familiarity judgments.

Retrieval is often subdivided into recollection and familiarity. Memory-strength and reaction time (RT) differ for each, complicating fMRI studies of these processes. Recollection leads to greater activity in the hippocampus and default network (DN). Increased DN activity with recollection is thought to reflect self-referential processes, but prior studies have not accounted for varying RT, which modulates DN activity and is consistently faster for recollection than familiarity. This study examined the influence of RT and memory-strength on recollection and familiarity activity. The results show the hippocampus functionally dissociated from DN during retrieval. DN was generally influenced by RT and signal was suppressed when subjects were task-engaged in recollection or familiarity; suppression was greater for slower trials of either type. The hippocampus showed a positive deflection of fMRI activity only for recollection trials; activation was greater for slower recollection trials, but RT did not influence hippocampal activity during familiarity trials.

Parietal activity in episodic retrieval measured by fMRI and MEG.

Understanding the functional role of the left lateral parietal cortex in episodic retrieval requires characterization of both spatial and temporal features of activity during memory tasks. In a recent study using magnetoencephalography (MEG), we described an early parietal response in a cued-recall task. This response began within 100 milliseconds (ms) of the retrieval cue and lasted less than 400 ms. Spatially, the effect reached significance in all three anatomically defined left lateral parietal subregions included in the study. Here we present a multimodal analysis of both hemodynamic and electrophysiologic responses in the same cued-recall paradigm. Functional MRI (fMRI) was used to more precisely reveal the portion of the parietal cortex with the greatest response. The MEG data set was then reanalyzed to show the early MEG time course of the region identified by fMRI. We found that the hemodynamic response is greatest within the intraparietal sulcus. Further, the MEG pattern in this region shows a strong response during the first 300 ms following the cue to retrieve. Finally, when individual-dipole MEG activity is analyzed for the left cortical surface over the early 300-millisecond time window, significant recall-related activity is limited to a relatively small portion of the left hemisphere that overlaps the region identified by fMRI in the intraparietal sulcus.