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Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that is often accompanied by both visceral and somatic hyperalgesia (enhanced pain from colorectal and somatic stimuli). Neural mechanisms of both types of hyperalgesia have been analyzed by neuroimaging studies of IBS patients and animal analog studies of “IBS-like” rats with delayed rectal and somatic hypersensitivity. Results from these studies suggest that pains associated with both visceral and widespread secondary cutaneous hyperalgesia are dynamically maintained by tonic impulse input from the non-inflamed colon and/or rectum and by brain-to-spinal cord facilitation. Enhanced visceral and somatic pains are accompanied by enhanced pain-related brain activity in IBS patients as compared to normal control subjects; placebos can normalize both their hyperalgesia and enhanced brain activity. That pain in IBS which is likely to be at least partly maintained by peripheral impulse input from the colon/rectum is supported by results showing that local rectal–colonic anesthesia normalizes visceral and somatic hyperalgesia in IBS patients and visceral and somatic hypersensitivity in “IBS-like” rats. Yet these forms of hyperalgesia are also highly modifiable by placebo and nocebo factors (e.g., expectations of relief or distress, respectively). Our working hypothesis is that synergistic interactions occur between placebo/nocebo factors and enhanced afferent processing so as to enhance, maintain, or reduce hyperalgesia in IBS. This explanatory model may be relevant to other persistent pain conditions.

Although neural activity associated with emotion is becoming better understood, the influence of affective parameters on brain activity reflecting cognitive functioning in humans remains poorly characterized. We examined affective influences on working memory (WM) and tested the hypotheses that (i) dorsolateral prefrontal cortex (DLPFC) activity reflecting WM is influenced by the emotion-evoking qualities of task-relevant stimuli, but only when brought \"on-line\" by task demands, and (ii) DLPFC and orbitofrontal cortex (OFC) activities are inversely related as a function of emotional valence. Participants performed two tasks while event-related functional MRI measured brain activity; one task required active maintenance of stimulus representations in WM, and the other task required target detection responses with no demand for WM. Stimuli were standardized emotional (pleasant and unpleasant) and neutral pictures. Emotional stimuli differentially influenced DPFC and OFC activity during WM; DLPFC was influenced by emotional valence, enhanced by pleasant and reduced by unpleasant, compared to neutral stimuli, only when task conditions required WM. OFC was valence-sensitive during both tasks, greater to arousing than neutral stimuli when WM demand was low and in inverse relationship to DLPFC with high WM demand. Further, DLPFC and OFC activities are inversely related with respect to emotional valence during the WM task. The results are consistent with the hypothesis that the intrinsic valence of task-relevant stimuli maintained in WM modulates DLPFC activity but only when the DLPFC is required for task demands. Findings suggest a conceptualization of DLPFC and its involvement in WM that takes into account a role for affective parameters.

Working memory is responsible for the short-term storage and online manipulation of information necessary for higher cognitive functions, such as language, planning and problem-solving 1,2 . Traditionally, working memory has been divided into two types of processes: executive control (governing the encoding manipulation and retrieval of information in working memory) and active maintenance (keeping information available 'online'). It has also been proposed that these two types of processes may be subserved by distinct cortical structures, with the prefrontal cortex housing the executive control processes, and more posterior regions housing the content-specific buffers (for example verbal versus visuospatial) responsible for active maintenance 3,4 . However, studies in non-human primates suggest that dorsolateral regions of the prefrontal cortex may also be involved in active maintenance 5–8 . We have used functional magnetic resonance imaging to examine brain activation in human subjects during performance of a working memory task. We used the temporal resolution of this technique to examine the dynamics of regional activation, and to show that prefrontal cortex along with parietal cortex appears to play a role in active maintenance.

Event-related potential (ERP) studies have previously found that scalp topographies of attention-related ERP components show frontal shifts with age, suggesting an increased need for compensatory frontal activity to assist with top-down facilitation of attention. However, the precise neural time course of top-down attentional control in aging is not clear. In this study, 20 young (mean: 22 years) and 14 older (mean: 64 years) adults completed a three-stimulus visual oddball task while high-density ERPs were acquired. Colorful, novel distracters were presented to engage early visual processing. Relative to young controls, older participants exhibited elevations in occipital early posterior positivity (EPP), approximately 100 ms after viewing colorful distracters. Neural source models for older adults implicated unique patterns of orbitofrontal cortex (OFC; BA 11) activity during early visual novelty processing (100 ms), which was positively correlated with subsequent activations in primary visual cortex (BA 17). Older adult EPP amplitudes and OFC activity were associated with performance on tests of complex attention and executive function. These findings are suggestive of age-related, compensatory neural changes that may driven by a combination of weaker cortical efficiency and increased need for top-down control over attention. Accordingly, enhanced early OFC activity during visual attention may serve as an important indicator of frontal lobe integrity in healthy aging.

The present study compared young and older adults on behavioral and neural correlates of three attentional networks (alerting, orienting, and executive control). Nineteen young and 16 older neurologically-healthy adults completed the Attention Network Test (ANT) while behavioral data (reaction time and error rates) and 64-channel event-related potentials (ERPs) were acquired. Significant age-related RT differences were observed across all three networks; however, after controlling for generalized slowing, only the alerting network remained significantly reduced in older compared with young adults. ERP data revealed that alerting cues led to enhanced posterior N1 responses for subsequent attentional targets in young adults, but this effect was weakened in older adults. As a result, it appears that older adults did not benefit fully from alerting cues, and their lack of subsequent attentional enhancements may compromise their ability to be as responsive and flexible as their younger counterparts. N1 alerting deficits were associated with several key neuropsychological tests of attention that were difficult for older adults. Orienting and executive attention networks were largely similar between groups. Taken together, older adults demonstrated behavioral and neural alterations in alerting, however, they appeared to compensate for this reduction, as they did not significantly differ in their abilities to use spatially informative cues to aid performance (e.g., orienting), or successfully resolve response conflict (e.g., executive control). These results have important implications for understanding the mechanisms of age-related changes in attentional networks.

Patients with chronic pain exhibit altered default mode network (DMN) activity. This preliminary project questioned whether comorbid disease states are associated with further brain alterations. Thirteen women with fibromyalgia (FM) only and 26 women with fibromyalgia with comorbid chronic insomnia (FMI) underwent a single night of ambulatory polysomnography and completed a sleep diary each morning for 14 days prior to performing a neuroimaging protocol. Novel imaging analyses were utilized to identify regions associated with significantly disordered sleep that were more active in task-negative periods than task-oriented periods in participants with FMI, when compared to participants with FM. It was hypothesized that core DMN areas (ie, cingulate cortex, inferior parietal lobule, medial prefrontal cortex, medial temporal cortex, precuneus) would exhibit increased activity during task-negative periods. Analyses revealed that significantly disordered sleep significantly contributed to group differences in the right cingulate gyrus, left lentiform nucleus, left anterior cingulate, left superior gyrus, medial frontal gyrus, right caudate, and the left inferior parietal lobules. Results suggest that FMI may alter some brain areas of the DMN, above and beyond FM. However, future work will need to investigate these results further by controlling for chronic insomnia only before conclusions can be made regarding the effect of FMI comorbidity on the DMN.

Pain requires the integration of sensory, cognitive, and affective information. The use of placebo is a common methodological ploy in many fields, including pain. Neuroimaging studies of pain and placebo analgesia (PA) have yet to identify a mechanism of action. Because PA must result from higher order processes, it is likely influenced by cognitive and affective dimensions of the pain experience. A network of brain regions involved in these processes includes the anterior and posterior insula (A-Ins, P-Ins), dorsal anterior cingulate cortex (DACC), dorsolateral prefrontal cortex (DLPFC), and the supplementary motor area (SMA). We used connectivity analyses to investigate the underlying mechanisms associated with Placebo analgesia in a group of chronic pain patients. Structural equation models (SEM) of fMRI data evaluated the inter-regional connectivity of these regions across three conditions: (1) initial Baseline (B1), (2) placebo (PA), and (3) Placebo Match (PM). SEM results of B1 data in the left hemisphere confirmed hypothesized regional relationships. However, inter-regional relationships were dynamic and the network models varied across hemispheres and conditions. Deviations from the B1 model in the PA and PM conditions correspond to our manipulation of expectation for pain. The dynamic changes in inter-regional influence across conditions are interpreted in the context of a self-reinforcing feedback loop involved in the induction and maintenance of PA. Although it is likely that placebo analgesia results partly from afferent inhibition of a nociceptive signal, the mechanisms likely involve the interaction of a cognitive–affective network with input from both hemispheres.

Fibromyalgia patients frequently report cognitive abnormalities. As the hippocampus plays an important role in learning and memory, we determined whether individuals with fibromyalgia had smaller hippocampal volume compared with healthy control participants. T1-weighted structural magnetic resonance imaging (MRI) scans were acquired from 40 female participants with fibromyalgia and 22 female healthy controls. The volume of the hippocampus was estimated using the software FreeSurfer. An analysis of covariance model controlling for potentially confounding factors of age, whole brain size, MRI signal quality, and Beck Depression Inventory scores were used to determine significant group differences. Fibromyalgia participants had significantly smaller hippocampi in both left (F[1,56]=4.55, P=0.037, η (2) p=0.08) and right hemispheres (F[1,56]=5.89, P=0.019, η (2) p=0.10). No significant effect of depression was observed in either left or right hemisphere hippocampal volume (P=0.813 and P=0.811, respectively). Potential mechanisms for reduced hippocampal volume in fibromyalgia include abnormal glutamate excitatory neurotransmission and glucocorticoid dysfunction; these factors can lead to neuronal atrophy, through excitotoxicity, and disrupt neurogenesis in the hippocampus. Hippocampal atrophy may play a role in memory and cognitive complaints among fibromyalgia patients.

Impairments of attention and executive functions are common sequelae of traumatic brain injury (TBI). The anterior cingulate is implicated in conflict-related task performance, such as the Stroop, and is susceptible to TBI-related injury due to its frontal location and proximity to the rough surface of the falx cerebri. We investigated the relationship between cingulate cortex volume and performance on tasks of selective attention and cognitive flexibility (single-trial Stroop and Auditory Consonant Trigrams [ACT]). Participants consisted of 12 adults with severe TBI and 18 controls. T1-weighted volumetric MRI data were analyzed using automated cortical reconstruction, segmentation, parcellation, and volume measurement. Cortical volume reductions were prominent bilaterally in frontal, temporal, and inferior parietal regions. Specific regional reduction of the cingulate cortex was observed only for cortical volume of right caudal anterior cingulate (cACC). The TBI group performed significantly worse than control participants on the Stroop and ACT tasks. Findings suggest that atrophy of the right cACC may contribute to reduced performance on executive function tasks, such as the Stroop and ACT, although this is likely but one node of an extensive brain network involved in these cognitive processes. (JINS, 2013, 19, 1–12)

Traumatic brain injury (TBI) is often associated with enduring impairments in high-level cognitive functioning, including working memory (WM). We examined WM function in predominantly chronic patients with mild, moderate and severe TBI and healthy comparison subjects behaviorally and, in a small subset of moderate-to-severe TBI patients, with event-related functional magnetic resonance imaging (fMRI), using a visual n-back task that parametrically varied WM load. TBI patients showed severity-dependent and load-related WM deficits in performance accuracy, but not reaction time. Performance of mild TBI patients did not differ from controls; patients with moderate and severe TBI were impaired, relative to controls and mild TBI patients, but only at higher WM-load levels. fMRI results show that TBI patients exhibit altered patterns of activation in a number of WM-related brain regions, including the dorsolateral prefrontal cortex and Broca's area. Examination of the pattern of behavioral responding and the temporal course of activations suggests that WM deficits in moderate-to-severe TBI are due to associative or strategic aspects of WM, and not impairments in active maintenance of stimulus representations. Overall, results demonstrate that individuals with moderate-to-severe TBI exhibit WM deficits that are associated with dysfunction within a distributed network of brain regions that support verbally mediated WM. (JINS, 2004, 10, 724–741.)