The spatiotemporal dynamics of autobiographical memory: neural correlates of recall, emotional intensity, and reliving.

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.

Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging.

OBJECTIVE: The authors sought to increase understanding of the brain mechanisms involved in cigarette addiction by identifying neural substrates modulated by visual smoking cues in nicotine-deprived smokers. METHOD: Event-related functional magnetic resonance imaging (fMRI) was used to detect brain activation after exposure to smoking-related images in a group of nicotine-deprived smokers and a nonsmoking comparison group. Subjects viewed a pseudo-random sequence of smoking images, neutral nonsmoking images, and rare targets (photographs of animals). Subjects pressed a button whenever a rare target appeared. RESULTS: In smokers, the fMRI signal was greater after exposure to smoking-related images than after exposure to neutral images in mesolimbic dopamine reward circuits known to be activated by addictive drugs (right posterior amygdala, posterior hippocampus, ventral tegmental area, and medial thalamus) as well as in areas related to visuospatial attention (bilateral prefrontal and parietal cortex and right fusiform gyrus). In nonsmokers, no significant differences in fMRI signal following exposure to smoking-related and neutral images were detected. In most regions studied, both subject groups showed greater activation following presentation of rare target images than after exposure to neutral images. CONCLUSIONS: In nicotine-deprived smokers, both reward and attention circuits were activated by exposure to smoking-related images. Smoking cues are processed like rare targets in that they activate attentional regions. These cues are also processed like addictive drugs in that they activate mesolimbic reward regions.

The neural basis of naming impairments in Alzheimer's disease revealed through positron emission tomography.

The naming impairments in Alzheimer's disease (AD) have been attributed to a variety of cognitive processing deficits, including impairments in semantic memory, visual perception, and lexical access. To further understand the underlying biological basis of the naming failures in AD, the present investigation examined the relationship of various classes of naming errors to regional brain measures of cerebral glucose metabolism as measured with 18 F-Fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). Errors committed on a visual naming test were categorized according to a cognitive processing schema and then examined in relationship to metabolism within specific brain regions. The results revealed an association of semantic errors with glucose metabolism in the frontal and temporal regions. Language access errors, such as circumlocutions, and word blocking nonresponses were associated with decreased metabolism in areas within the left hemisphere. Visuoperceptive errors were related to right inferior parietal metabolic function. The findings suggest that specific brain areas mediate the perceptual, semantic, and lexical processing demands of visual naming and that visual naming problems in dementia are related to dysfunction in specific neural circuits.

Validation of ICDPIC software injury severity scores using a large regional trauma registry.

BACKGROUND: Administrative or quality improvement registries may or may not contain the elements needed for investigations by trauma researchers. International Classification of Diseases Program for Injury Categorisation (ICDPIC), a statistical program available through Stata, is a powerful tool that can extract injury severity scores from ICD-9-CM codes. We conducted a validation study for use of the ICDPIC in trauma research. METHODS: We conducted a retrospective cohort validation study of 40,418 patients with injury using a large regional trauma registry. ICDPIC-generated AIS scores for each body region were compared with trauma registry AIS scores (gold standard) in adult and paediatric populations. A separate analysis was conducted among patients with traumatic brain injury (TBI) comparing the ICDPIC tool with ICD-9-CM embedded severity codes. Performance in characterising overall injury severity, by the ISS, was also assessed. RESULTS: The ICDPIC tool generated substantial correlations in thoracic and abdominal trauma (weighted κ 0.87-0.92), and in head and neck trauma (weighted κ 0.76-0.83). The ICDPIC tool captured TBI severity better than ICD-9-CM code embedded severity and offered the advantage of generating a severity value for every patient (rather than having missing data). Its ability to produce an accurate severity score was consistent within each body region as well as overall. CONCLUSIONS: The ICDPIC tool performs well in classifying injury severity and is superior to ICD-9-CM embedded severity for TBI. Use of ICDPIC demonstrates substantial efficiency and may be a preferred tool in determining injury severity for large trauma datasets, provided researchers understand its limitations and take caution when examining smaller trauma datasets.

Less wiring, more firing: low-performing older adults compensate for impaired white matter with greater neural activity.

The reliable neuroimaging finding that older adults often show greater activity (over-recruitment) than younger adults is typically attributed to compensation. Yet, the neural mechanisms of over-recruitment in older adults (OAs) are largely unknown. Rodent electrophysiology studies have shown that as number of afferent fibers within a circuit decreases with age, the fibers that remain show higher synaptic field potentials (less wiring, more firing). Extrapolating to system-level measures in humans, we proposed and tested the hypothesis that greater activity in OAs compensates for impaired white-matter connectivity. Using a neuropsychological test battery, we measured individual differences in executive functions associated with the prefrontal cortex (PFC) and memory functions associated with the medial temporal lobes (MTLs). Using event-related functional magnetic resonance imaging, we compared activity for successful versus unsuccessful trials during a source memory task. Finally, we measured white-matter integrity using diffusion tensor imaging. The study yielded 3 main findings. First, low-executive OAs showed greater success-related activity in the PFC, whereas low-memory OAs showed greater success-related activity in the MTLs. Second, low-executive OAs displayed white-matter deficits in the PFC, whereas low-memory OAs displayed white-matter deficits in the MTLs. Finally, in both prefrontal and MTL regions, white-matter decline and success-related activations occurred in close proximity and were negatively correlated. This finding supports the less-wiring-more-firing hypothesis, which provides a testable account of compensatory over-recruitment in OAs.

Magnetic resonance imaging of graded skeletal muscle injury in live rats.

INTRODUCTION: Increasing number of stretch-shortening contractions (SSCs) results in increased muscle injury. METHODS: Fischer Hybrid rats were acutely exposed to an increasing number of SSCs in vivo using a custom-designed dynamometer. Magnetic resonance imaging (MRI) imaging was conducted 72 hours after exposure when rats were infused with Prohance and imaged using a 7T rodent MRI system (GE Epic 12.0). Images were acquired in the transverse plane with typically 60 total slices acquired covering the entire length of the hind legs. Rats were euthanized after MRI, the lower limbs removed, and tibialis anterior muscles were prepared for histology and quantified stereology. RESULTS: Stereological analyses showed myofiber degeneration, and cellular infiltrates significantly increased following 70 and 150 SSC exposure compared to controls. MRI images revealed that the percent affected area significantly increased with exposure in all SSC groups in a graded fashion. Signal intensity also significantly increased with increasing SSC repetitions. DISCUSSION: These results suggest that contrast-enhanced MRI has the sensitivity to differentiate specific degrees of skeletal muscle strain injury, and imaging data are specifically representative of cellular histopathology quantified via stereological analyses.

Lack of evidence for ectopic sprouting of genetically labeled Aβ touch afferents in inflammatory and neuropathic trigeminal pain.

BACKGROUND: Mechanical and in particular tactile allodynia is a hallmark of chronic pain in which innocuous touch becomes painful. Previous cholera toxin B (CTB)-based neural tracing experiments and electrophysiology studies had suggested that aberrant axon sprouting from touch sensory afferents into pain-processing laminae after injury is a possible anatomical substrate underlying mechanical allodynia. This hypothesis was later challenged by experiments using intra-axonal labeling of A-fiber neurons, as well as single-neuron labeling of electrophysiologically identified sensory neurons. However, no studies have used genetically labeled neurons to examine this issue, and most studies were performed on spinal but not trigeminal sensory neurons which are the relevant neurons for orofacial pain, where allodynia oftentimes plays a dominant clinical role. FINDINGS: We recently discovered that parvalbumin::Cre (Pv::Cre) labels two types of Aβ touch neurons in trigeminal ganglion. Using a Pv::CreER driver and a Cre-dependent reporter mouse, we specifically labeled these Aβ trigeminal touch afferents by timed taxomifen injection prior to inflammation or infraorbital nerve injury (ION transection). We then examined the peripheral and central projections of labeled axons into the brainstem caudalis nucleus after injuries vs controls. We found no evidence for ectopic sprouting of Pv::CreER labeled trigeminal Aβ axons into the superficial trigeminal noci-receptive laminae. Furthermore, there was also no evidence for peripheral sprouting. CONCLUSIONS: CreER-based labeling prior to injury precluded the issue of phenotypic changes of neurons after injury. Our results suggest that touch allodynia in chronic orofacial pain is unlikely caused by ectopic sprouting of Aβ trigeminal afferents.

Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.

MAPKKK dual leucine zipper-bearing kinases (DLKs) are regulators of synaptic development and axon regeneration. The mechanisms underlying their activation are not fully understood. Here, we show that C. elegans DLK-1 is activated by a Ca(2+)-dependent switch from inactive heteromeric to active homomeric protein complexes. We identify a DLK-1 isoform, DLK-1S, that shares identical kinase and leucine zipper domains with the previously described long isoform DLK-1L but acts to inhibit DLK-1 function by binding to DLK-1L. The switch between homo- or heteromeric DLK-1 complexes is influenced by Ca(2+) concentration. A conserved hexapeptide in the DLK-1L C terminus is essential for DLK-1 activity and is required for Ca(2+) regulation. The mammalian DLK-1 homolog MAP3K13 contains an identical C-terminal hexapeptide and can functionally complement dlk-1 mutants, suggesting that the DLK activation mechanism is conserved. The DLK activation mechanism is ideally suited for rapid and spatially controlled signal transduction in response to axonal injury and synaptic activity.

The role of stimulus salience and attentional capture across the neural hierarchy in a stop-signal task.

Inhibitory motor control is a core function of cognitive control. Evidence from diverse experimental approaches has linked this function to a mostly right-lateralized network of cortical and subcortical areas, wherein a signal from the frontal cortex to the basal ganglia is believed to trigger motor-response cancellation. Recently, however, it has been recognized that in the context of typical motor-control paradigms those processes related to actual response inhibition and those related to the attentional processing of the relevant stimuli are highly interrelated and thus difficult to distinguish. Here, we used fMRI and a modified Stop-signal task to specifically examine the role of perceptual and attentional processes triggered by the different stimuli in such tasks, thus seeking to further distinguish other cognitive processes that may precede or otherwise accompany the implementation of response inhibition. In order to establish which brain areas respond to sensory stimulation differences by rare Stop-stimuli, as well as to the associated attentional capture that these may trigger irrespective of their task-relevance, we compared brain activity evoked by Stop-trials to that evoked by Go-trials in task blocks where Stop-stimuli were to be ignored. In addition, region-of-interest analyses comparing the responses to these task-irrelevant Stop-trials, with those to typical relevant Stop-trials, identified separable activity profiles as a function of the task-relevance of the Stop-signal. While occipital areas were mostly blind to the task-relevance of Stop-stimuli, activity in temporo-parietal areas dissociated between task-irrelevant and task-relevant ones. Activity profiles in frontal areas, in turn, were activated mainly by task-relevant Stop-trials, presumably reflecting a combination of triggered top-down attentional influences and inhibitory motor-control processes.

Neuroimaging assessment of early and late neurobiological sequelae of traumatic brain injury: implications for CTE.

Traumatic brain injury (TBI) has been increasingly accepted as a major external risk factor for neurodegenerative morbidity and mortality. Recent evidence indicates that the resultant chronic neurobiological sequelae following head trauma may, at least in part, contribute to a pathologically distinct disease known as Chronic Traumatic Encephalopathy (CTE). The clinical manifestation of CTE is variable, but the symptoms of this progressive disease include impaired memory and cognition, affective disorders (i.e., impulsivity, aggression, depression, suicidality, etc.), and diminished motor control. Notably, mounting evidence suggests that the pathology contributing to CTE may be caused by repetitive exposure to subconcussive hits to the head, even in those with no history of a clinically evident head injury. Given the millions of athletes and military personnel with potential exposure to repetitive subconcussive insults and TBI, CTE represents an important public health issue. However, the incidence rates and pathological mechanisms are still largely unknown, primarily due to the fact that there is no in vivo diagnostic tool. The primary objective of this manuscript is to address this limitation and discuss potential neuroimaging modalities that may be capable of diagnosing CTE in vivo through the detection of tau and other known pathological features. Additionally, we will discuss the challenges of TBI research, outline the known pathology of CTE (with an emphasis on Tau), review current neuroimaging modalities to assess the potential routes for in vivo diagnosis, and discuss the future directions of CTE research.

Effects of chronic mild traumatic brain injury on white matter integrity in iraq and afghanistan war veterans

Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events. © 2012 Wiley Periodicals, Inc.

Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery.

BACKGROUND: Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. METHODS: The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. RESULTS: The median postoperative nadir platelet count was 121 × 10/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 × 10/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). CONCLUSION: The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery.