William M. Perlstein

Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia

BACKGROUND Schizophrenic patients show deficits in working memory (WM) and inhibition of prepotent responses. We examined brain activity while subjects performed tasks that placed demands on WM and overriding prepotent response tendencies, testing predictions that both processes engage overlapping prefrontal cortical (PFC) regions and that schizophrenic patients show reduced PFC activity and performance deficits reflecting both processes. METHODS Functional magnetic resonance imaging data were acquired while 16 schizophrenic and 15 healthy subjects performed the N-Back task that varied WM load and a version of the AX-CPT that required overriding a prepotent response tendency. RESULTS Both tasks engaged overlapping cortical networks (e.g., bilateral dorsolateral PFC, Brocas area, parietal cortex). Increased WM load monotonically increased activity; preparation to override a prepotent response produced greater and more enduring activity. Group differences on each task emerged in a right dorsolateral PFC region: schizophrenic subjects showed lesser magnitude increases under conditions of high WM and prepotent response override demands, with concomitant performance impairments. CONCLUSIONS Schizophrenic patients exhibit PFC-mediated deficits in WM and preparation to override prepotent responses. Findings are consistent with the operation of a single underlying PFC-mediated cognitive control mechanism and with physiologic dysfunction of the dorsolateral PFC in schizophrenic patients reflecting impairments in this mechanism.

Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients

Abstract Previous experiments found that placebos produced small decreases in neural activity of pain‐related areas of the brain, yet decreases were only statistically significant after termination of stimuli and in proximity to when subjects rated them. These changes could reflect report bias rather than analgesia. This functional magnetic resonance imaging (fMRI) study examined whether placebo analgesia is accompanied by reductions in neural activity in pain‐related areas of the brain during the time of stimulation. Brain activity of irritable bowel syndrome patients was measured in response to rectal distension by a balloon barostat. Large reductions in pain and in brain activation within pain‐related regions (thalamus, somatosensory cortices, insula, and anterior cingulate cortex) occurred during the placebo condition. Results indicate that decreases in activity were related to placebo suggestion and a second factor (habituation/attention/conditioning). Although many factors influence placebo analgesia, it is accompanied by reduction in pain processing within the brain in clinically relevant conditions.

Dissociation in human prefrontal cortex of affective influences on working memory-related activity

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.

Brain Activity Related to Temporal Summation of C-fiber Evoked Pain

Abstract Temporal summation of “second pain” (TSSP) is considered to be the result of C‐fiber‐evoked responses of dorsal horn neurons, termed ‘windup’. This phenomenon is dependent on stimulus frequency (⩾0.33 Hz) and relevant for central sensitization and chronic pain. Previous brain imaging studies have only been used to characterize neural correlates of second pain but not its temporal summation. We utilized functional magnetic resonance imaging (fMRI) in healthy volunteers to measure brain responses associated with TSSP. Region of interest analysis was used to assess TSSP related brain activation. Eleven pain‐free normal subjects underwent fMRI scanning during repetitive heat pulses to the right foot at 0.33 and 0.17 Hz. Stimulus intensities were adjusted to each individual’s heat sensitivity to achieve comparable TSSP ratings of moderate pain in all subjects. As predicted, experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. fMRI statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including contralateral thalamus (THAL), S1, bilateral S2, anterior and posterior insula (INS), mid‐anterior cingulate cortex (ACC), and supplemental motor areas (SMA). TSSP ratings were significantly correlated with brain activation in somatosensory areas (THAL, S1, left S2), anterior INS, and ACC. These results show that neural responses related to TSSP are evoked in somatosensory processing areas (THAL, S2), as well as in multiple areas that serve other functions related to pain, such as cognition (ACC, PFC), affect (INS, ACC, PAG), pre‐motor activity (SMA, cerebellum), and pain modulation (rostral ACC).

Parametric manipulation of working memory load in traumatic brain injury: behavioral and neural correlates.

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 Brocas 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.

Age-related changes in word retrieval: Role of bilateral frontal and subcortical networks

Healthy older adults frequently report word-finding difficulties, yet the underlying cause of these problems is not well understood. This study examined whether age-related changes in word retrieval are related to changes in areas of the frontal lobes thought to subserve word retrieval or changes in areas of the inferior temporal lobes thought to be involved in semantic knowledge. Twenty younger and 20 older healthy adults named aloud photographs during event-related fMRI. Results showed that in the face of equivalent naming accuracy, older adults activated a larger frontal network than younger adults during word retrieval, but there were no activity differences between groups in the fusiform gyrus, suggesting that the substrates for word retrieval but not for semantic knowledge change with aging. Additionally, correlations between BOLD response and naming accuracy and response latency were found in several frontal and subcortical regions in older adults. Findings are discussed in the context of possible compensatory mechanisms invoked to maintain performance in healthy aging, and suggest that increased involvement of the right hemisphere is not universally beneficial to performance.

Brain activity associated with slow temporal summation of C-fiber evoked pain in fibromyalgia patients and healthy controls.

Temporal summation of “second pain” (TSSP) is the result of C‐fiber‐evoked responses of dorsal‐horn neurons, termed “windup”. This phenomenon is dependent on stimulus frequency (≥0.33Hz) and relevant for central sensitization as well as chronic pain. Whereas, our previous functional magnetic resonance imaging (fMRI) study characterized neural correlates of TSSP in 11 healthy volunteers, the present study was designed to compare brain responses associated with TSSP across these healthy participants and 13 fibromyalgia (FM) patients. Volume‐of‐interest analysis was used to assess TSSP‐related brain activation. All participants underwent fMRI‐scanning during repetitive heat pulses at 0.33Hz and 0.17Hz to the right foot. Stimulus intensities were adjusted to each individuals heat sensitivity to achieve comparable TSSP‐ratings of moderate pain in all subjects. Experimental pain ratings showed robust TSSP during 0.33Hz but not 0.17Hz stimuli. When stimulus strength was adjusted to induce equivalent levels of TSSP, no differences in activation of pain‐related brain regions occurred across NC and FM groups. Subsequently, the fMRI‐data of both groups were combined to increase the power of our statistical comparisons. fMRI‐statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including ipsilateral and contralateral thalamus, medial thalamus, S1, bilateral S2, mid‐ and posterior insula, rostral and mid‐anterior cingulate cortex. However, the stimulus temperatures necessary to evoke equivalent levels of TSSP and corresponding brain activity were less in FM patients. These results suggest that enhanced neural mechanisms of TSSP in FM are reflected at all pain related brain areas, including posterior thalamus, and are not the result of selective enhancement at cortical levels.

Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia

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.

Gray Matter Volumes of Pain-Related Brain Areas Are Decreased in Fibromyalgia Syndrome

UNLABELLED Fibromyalgia (FM) is a chronic, widespread musculoskeletal pain disorder that is very prevalent in the general population (approximately 5%). Accumulating evidence suggests that FM is associated with central pain processing abnormalities, ie, central sensitization. Several previous studies of chronic pain patients, including FM, have shown gray matter atrophy of brain areas associated with sensory and affective pain processing. These findings, however, have not been confirmed in all FM studies. In this study, we investigated gray matter volumes of brain areas associated with pain-related areas of FM patients identified by functional brain imaging. Using voxel-based morphometric (VBM) analysis of magnetic resonance brain images, we compared 19 pain-related brain areas of 14 female FM patients and 11 healthy controls (NC). We found that FM patients had significantly less gray matter volumes than NC in 3 of these brain regions, including the anterior and mid-cingulate, as well as mid-insular cortices. Importantly, FM patients demonstrated neither global gray matter atrophy nor gray matter changes associated with depression, as shown in some studies. Using a more stringent analysis than other VBM studies, we provide evidence for decreased gray matter volumes in a number of pain-related brain areas in FM. Although the mechanisms for these gray matter changes are presently unclear, they may contribute to some of the core features of this chronic disorder including affective disturbances and chronic widespread pain. PERSPECTIVE Increasing evidence supports the association of chronic pain with accelerated gray matter atrophy in pain disorders like low back pain, IBS, and FM syndrome. However, cause-effect relationships between chronic pain and decreased gray matter volumes have not been established yet and will require future prospective studies.

Temporal dissociation of components of cognitive control dysfunction in severe TBI: ERPs and the cued-Stroop task.

Cognitive control comprises two essential interactive component processes: a regulative component supporting the activation and implementation of control and an evaluative component that monitors the need for regulative control and signals when adjustments in control are necessary. Survivors of severe traumatic brain injury (TBI) experience cognitive control impairments, but the specific nature of these impairments is poorly characterized. Using event-related potentials (ERPs) acquired in the context of a trial-by-trial task-switching version of the Stroop task we temporally dissociated the regulative and evaluative processes in order to shed light on the potential roles of these components in TBI-related cognitive control impairment. Behaviorally, TBI patients showed a specific performance deficit suggestive of a failure to implement cognitive control in the service of processing conflict information. ERP findings showed that TBI patients were impaired in both the implementation of control and subsequent detection and processing of conflict. TBI patients were also impaired on a measure of working memory capacity, a measure that correlated with the ability to implement regulative control and overcome conflict. These findings suggest that patients with predominantly chronic severe TBI patients are impaired on both regulative and evaluative components of cognitive control, and may have implications for the design and evaluation of behavioral and pharmacological remediation strategies.