Age-related differences in functional connectivity associated with pain modulation.

Growing evidence suggests that aging is associated with impaired endogenous pain modulation, and that this likely underlies the increased transition from acute to chronic pain in older individuals. Resting-state functional connectivity (rsFC) offers a valuable tool to examine the neural mechanisms behind these age-related changes in pain modulation. RsFC studies generally observe decreased within-network connectivity due to aging, but its relevance for pain modulation remains unknown. We compared rsFC within a set of brain regions involved in pain modulation between young and older adults and explored the relationship with the efficacy of distraction from pain. This revealed several age-related increases and decreases in connectivity strength. Importantly, we found a significant association between lower pain relief and decreased strength of three connections in older adults, namely between the periaqueductal gray and right insula, between the anterior cingulate cortex (ACC) and right insula, and between the ACC and left amygdala. These findings suggest that the functional integrity of the pain control system is critical for effective pain modulation, and that its function is compromised by aging.

Baseline heart rate variability predicts placebo hypoalgesia in men, but not women.

Introduction: Placebo hypoalgesic effects vary greatly across individuals, making them challenging to control for in clinical trials and difficult to use in treatment. We investigated the potential of resting vagally-mediated heart rate variability (vmHRV) to help predict the magnitude of placebo responsiveness. Methods: In two independent studies (total N = 77), we administered a placebo paradigm after measuring baseline HRV. In Study I, we delivered heat pain to the forearm, on skin patches treated with "real" and "control" cream (identical inactive creams). In Study II, electrical pulses to the forearm were modulated by sham transcutaneous electrical nerve stimulation. We combined data from both studies to evaluate the relationship between vagally-mediated HRV (vmHRV) parameters and the placebo response size, while also assessing sex differences in this relationship. Results and Discussion: This revealed a positive association between vmHRV and the degree of pain relief, and this effect was driven by men. These results not only reveal new insights into the (sex-specific) mechanisms of placebo hypoalgesia, but also suggest that measuring vmHRV may be helpful in predicting placebo responsiveness. Given that placebo hypoalgesic effects contribute substantially to treatment outcomes, such a non-invasive and easily obtained predictor would be valuable in the context of personalized medicine.

Better Executive Functions Are Associated With More Efficient Cognitive Pain Modulation in Older Adults: An fMRI Study.

Growing evidence suggests that aging is associated with less efficient endogenous pain modulation as demonstrated by reduced conditioned pain modulation, and that these changes may be mediated by differences in frontal functioning. Yet, little is known about potential age-related changes in cognitive pain modulation, such as distraction from pain. In a first session, 30 healthy young (19-35 years) and 30 healthy older (59-82 years) adults completed a battery of neuropsychological tests. In a second session, we acquired functional brain images while participants completed a working memory task with two levels of cognitive load (high vs. low) and concurrently received individually adjusted heat stimuli (warm vs. painful). In both age groups, completing the high load task was associated with a significant reduction in the perceived intensity and unpleasantness of painful stimuli and a reduction in activation of brain regions involved in pain processing. Group comparisons revealed that young adults showed a stronger de-activation of brain regions involved in pain processing during the high load vs. the low load task, such as the right insula, right mid cingulate cortex and left supramarginal gyrus, compared to older adults. Older adults, on the other hand, showed an increased activation in the anterior cingulate cortex during the high load vs. low load task, when compared to young adults. Covariate analyses indicated that executive functions significantly predicted neural pain modulation in older adults: Better executive functions were associated with a more pronounced de-activation of the insula, thalamus and primary somatosensory cortex and increased activation of prefrontal regions during the high vs. low load task. These findings suggest that cognitive pain modulation is altered in older age and that the preservation of executive functions may have beneficial effects on the efficacy of distraction from pain.

Anterior Cingulate Cortex Activity During Rest Is Related to Alterations in Pain Perception in Aging.

Alterations in the affective component of pain perception are related to the development of chronic pain and may contribute to the increased vulnerability to pain observed in aging. The present study analyzed age-related changes in resting-state brain activity and their possible relation to an increased pain perception in older adults. For this purpose, we compared EEG current source density and fMRI functional-connectivity at rest in older (n = 20, 66.21 ± 3.08 years) and younger adults (n = 21, 20.71 ± 2.30 years) and correlated those brain activity parameters with pain intensity and unpleasantness ratings elicited by painful stimulation. We found an age-related increase in beta2 and beta3 activity in temporal, frontal, and limbic areas, and a decrease in alpha activity in frontal areas. Moreover, older participants displayed increased functional connectivity in the anterior cingulate cortex (ACC) and the insula with precentral and postcentral gyrus. Finally, ACC beta3 activity was positively correlated with pain intensity and unpleasantness ratings in older, and ACC-precentral/postcentral gyrus connectivity was positively correlated with unpleasantness ratings in older and younger participants. These results reveal that ACC resting-state hyperactivity is a stable trait of brain aging and may underlie their characteristic altered pain perception.

Brief mindfulness training can mitigate the influence of prior expectations on pain perception.

BACKGROUND: Recent neuroimaging evidence suggests that mindfulness practice may mitigate the biasing influence of prior cognitive and emotional expectations on pain perception. The current study tested this hypothesis using a pain-cueing paradigm, which has reliably been shown to elicit conditioned hypoalgesic and hyperalgesic effects. Specifically, we aimed to investigate whether the instructed use of a mindfulness compared to a suppression strategy differentially modulates the magnitudes of conditioned hypoalgesia and hyperalgesia. METHODS: Sixty-two healthy non-meditators were assigned to listen to either brief mindfulness or suppression instructions, in between the conditioning and testing phases of a pain-cueing task. Participants provided ratings of anticipatory anxiety, pain intensity and pain unpleasantness throughout the task. They also completed trait and state self-report measures of mindfulness and pain catastrophizing. RESULTS: Results indicated that the paradigm was successful in inducing conditioned hyperalgesic and hypoalgesic effects. Importantly, while we found evidence of cue-induced hyperalgesia in both groups, only the suppression group reported cue-induced hypoalgesia. No group differences in pain ratings were found for unconditioned (novel-cued) stimuli. CONCLUSIONS: These findings provide partial support for recently proposed predictive processing models, which posit that mindfulness may lead to a prioritization of current sensory information over previous expectations. We explore potential explanations for the asymmetrical group differences in conditioned hypoalgesia versus conditioned hyperalgesia, and discuss our results in light of recent neuroimaging insights into the neuropsychological mechanisms of mindfulness and expectancy-driven pain modulation. SIGNIFICANCE: The current study provides novel insights into the working mechanisms of mindfulness-driven pain modulation. Our data suggest that brief mindfulness training may reduce the influence of prior beliefs and expectations on pain perception. This finding adds to growing evidence suggesting that mindfulness may alleviate pain via neuropsychological mechanisms opposite to those typically observed in conditioning/placebo procedures and other cognitive manipulations. These unique mechanisms underline the potential of mindfulness as an alternative to traditional cognitive pain regulatory strategies.

Intact pain modulation through manipulation of controllability and expectations in aging.

BACKGROUND: Pain expectation and controllability can modulate pain processing. However, little is known about age-related effects on these cognitive factors involved in pain control. This study assessed age-related brain changes associated with pain expectation and controllability. METHODS: 17 healthy older adults (9 men; 65.65 ± 4.34 years) and 18 healthy younger adults (8 men; 20.56 ± 5.56 years) participated in the study. Pain evoked potentials and pain ratings were recorded while participants received painful electrical stimuli under two different conditions of pain controllability over the intensity of the stimulation (self-controlled vs. computer controlled) and two conditions of pain expectations (high vs. low pain). RESULTS: Although the intensity of the painful stimulation was kept constant, all participants showed reduced pain perception in the controllable and low pain expectancy conditions. However, older participants showed reduced amplitudes of pain evoked potentials in the time window between 150 and 500 ms after stimulus onset as compared to younger participants. Moreover, younger participants showed greater negative amplitudes from 80 to 150 ms after stimulus onset for uncontrollable versus controllable pain. CONCLUSIONS: These results suggest that although cognitive pain modulation is preserved during ageing, neural processing of pain is reduced in older adults. SIGNIFICANCE: This research describes the impact of age on cognitive pain modulation evoked by the manipulation of pain controllability and pain expectations. Our findings constitute a first step in the understanding of the greater vulnerability of older individuals to chronic pain. Moreover, we show that older adults can benefit from cognitive pain control mechanisms to increase the efficacy of pain treatments.

When Less Is More: Investigating Factors Influencing the Distraction Effect of Virtual Reality From Pain.

Virtual reality (VR) is a powerful method of redirecting attention away from pain. Yet, little is known about which factors modulate the size of this distraction effect. The aim of this study was to investigate the role of cognitive load and inter-individual differences in the cognitive and affective domain on heat pain thresholds during a VR game. Ninety healthy participants (mean age ± SD: 23.46 ± 3.28; 50% identified as male and 50% as female) played a low and high load version of a VR game while heat pain thresholds and heart rate were recorded. The effects of cognitive load were assessed by computing the difference in pain thresholds between the high and low load condition for each participant. In addition, we computed the difference in heart rate variability (HRV) measures between both conditions to explore whether these would be correlated with the difference in heat pain thresholds. Prior to the VR session, participants completed questionnaires about their emotional distress, pain-related cognitions, and different executive functioning tasks. Contrary to our expectations, not all participants benefitted from a higher load in terms of distraction from pain. Logistic regression analysis revealed that participants who reported more emotional distress were more likely to exhibit higher pain thresholds in the low relative to the high load condition. Accordingly, these participants tended to show marginally higher HRV in the low compared to the high load condition. Our study demonstrates that the potential benefits of an increased cognitive load in VR on pain sensitivity depends on individual differences in affective state.

Alterations in Neural Responses and Pain Perception in Older Adults During Distraction.

OBJECTIVE: Although it is acknowledged that pain may be modulated by cognitive factors, little is known about the effect of aging on these control processes. The present study investigated electroencephalographical correlates of pain processing and its cognitive modulation in healthy older individuals. METHODS: For this purpose, the impact of distraction on pain was evaluated in 21 young (9 men; 20.71 [2.30]) and 20 older (10 men; 66.80 [4.14]) adults. Participants received individually adjusted electrical pain stimuli in a high-distraction condition (one-back task) and in a low-distraction condition (simple letter response task). Pain-related evoked potentials and pain ratings were analyzed. RESULTS: Both groups rated pain as less intense (F(1,39) = 13.954, p < .001) and less unpleasant (F(1,39) = 10.111, p = .003) when it was experienced during the high- rather than the low-distraction condition. However, in comparison to younger participants, older adults gave higher unpleasantness ratings to painful stimulation (F(1,39) = 4.233, p = .046), accompanied by attenuated neural responses (N1-P1 and P3 amplitudes), regardless of the distraction condition (F(1,38) = 6.028 [p = .019] and F(1,38) = 6.669 [p = .014], respectively). CONCLUSIONS: Older participants felt pain relief through distraction, like younger participants. However, we also found that aging may enhance affective aspects of pain perception. Finally, our results show that aging is characterized by reduced neural processing of painful stimuli. This phenomenon could be related to the increased vulnerability of older participants to develop chronic pain.

Distraction from pain: The role of selective attention and pain catastrophizing.

BACKGROUND: Previous research has demonstrated the efficacy of cognitive engagement in reducing concurrent pain. However, little is known about the role of individual differences in inhibitory control abilities and negative pain-related cognitions in modulating the magnitude of this type of distraction from pain. METHODS: In a pain distraction paradigm, 41 participants completed a working memory task with both a demanding high load condition (2-back) and an easy low load condition (0-back), while receiving warm or painful thermal stimuli to their left forearm. To control for individual differences in sensitivity to pain and perceived task difficulty, nociceptive stimulus intensity and task speed were individually calibrated. Additionally, participants completed a set of cognitive inhibition tasks (flanker, go/nogo, Stroop) and questionnaires about negative pain-related cognitions (fear of pain, pain catastrophizing) prior to the distraction paradigm. RESULTS: As expected, engaging in the high load condition significantly reduced perceived intensity and unpleasantness of nociceptive stimuli, compared to the low load condition. The size of the distraction effect correlated significantly with better cognitive inhibition and selective attention abilities, as measured by the flanker task. A moderation analysis revealed a significant interaction between pain catastrophizing and performance in the flanker task in predicting the distraction effect size: Participants who performed well on the flanker task showed more pain reduction, but only when they were average to high pain catastrophizers. CONCLUSIONS: Selective attention abilities and pain catastrophizing seem to be important factors in explaining individual differences in the size of the analgesic response to a distractive task. SIGNIFICANCE: Understanding which factors influence the effectiveness of cognitive engagement in distracting from pain could help to optimize its therapeutic application in patient care. This study shows that a complex interplay of cognitive inhibition abilities, specifically selective attention, and negative pain-related cognitions, such as pain catastrophizing, modulate the magnitude of the distraction effect.

Age-Related Changes in Pain Perception Are Associated With Altered Functional Connectivity During Resting State.

Aging affects pain experience and brain functioning. However, how aging leads to changes in pain perception and brain functional connectivity has not yet been completely understood. To investigate resting-state and pain perception changes in old and young participants, this study employed region of interest (ROI) to ROI resting-state functional connectivity (rsFC) analysis of imaging data by using regions implicated in sensory and affective dimensions of pain, descending pain modulation, and the default-mode networks (DMNs). Thirty-seven older (66.86 ± 4.04 years; 16 males) and 38 younger healthy participants (20.74 ± 4.15 years; 19 males) underwent 10 min' eyes-closed resting-state scanning. We examined the relationship between rsFC parameters with pressure pain thresholds. Older participants showed higher pain thresholds than younger. Regarding rsFC, older adults displayed increased connectivity of pain-related sensory brain regions in comparison to younger participants: increased rsFC between bilateral primary somatosensory area (SI) and anterior cingulate cortex (ACC), and between SI(L) and secondary somatosensory area (SII)-(R) and dorsolateral prefrontal cortex (PFC). Moreover, decreased connectivity in the older compared to the younger group was found among descending pain modulatory regions: between the amygdala(R) and bilateral insula(R), thalamus(R), ACC, and amygdala(L); between the amygdala(L) and insula(R) and bilateral thalamus; between ACC and bilateral insula, and between periaqueductal gray (PAG) and bilateral thalamus. Regarding the DMN, the posterior parietal cortex and lateral parietal (LP; R) were more strongly connected in the older group than in the younger group. Correlational analyses also showed that SI(L)-SII(R) rsFC was positively associated with pressure pain thresholds in older participants. In conclusion, these findings suggest a compensatory mechanism for the sensory changes that typically accompanies aging. Furthermore, older participants showed reduced functional connectivity between key nodes of the descending pain inhibitory pathway.

The role of cognitive reappraisal in placebo analgesia: an fMRI study.

Placebo analgesia (PA) depends crucially on the prefrontal cortex (PFC), which is assumed to be responsible for initiating the analgesic response. Surprisingly little research has focused on the psychological mechanisms mediated by the PFC and underlying PA. One increasingly accepted theory is that cognitive reappraisal-the reinterpretation of the meaning of adverse events-plays an important role, but no study has yet addressed the possible functional relationship with PA. We studied the influence of individual differences in reappraisal ability on PA and its prefrontal mediation. Participants completed a cognitive reappraisal ability task, which compared negative affect evoked by pictures in a reappraise versus a control condition. In a subsequent fMRI session, PA was induced using thermal noxious stimuli and an inert skin cream. We found a region in the left dorsolateral PFC, which showed a positive correlation between placebo-induced activation and (i) the reduction in participants' pain intensity ratings; and (ii) cognitive reappraisal ability scores. Moreover, this region showed increased placebo-induced functional connectivity with the periaqueductal grey, indicating its involvement in descending nociceptive control. These initial findings thus suggest that cognitive reappraisal mechanisms mediated by the dorsolateral PFC may play a role in initiating pain inhibition in PA.

The neural basis of age-related changes in motor imagery of gait: an fMRI study.

BACKGROUND: Aging is often associated with modifications of gait. Recent studies have revealed a strong relationship between gait and executive functions in healthy and pathological aging. We hypothesized that modification of gait due to aging may be related to changes in frontal lobe function. METHODS: Fourteen younger (27.0±3.6 years) and 14 older healthy adults (66.0±3.5 years) performed a motor imagery task of gait as well as a matched visual imagery task. Task difficulty was modulated to investigate differential activation for precise control of gait. Task performance was assessed by recording motor imagery latencies, eye movements, and electromyography during functional magnetic resonance imaging scanning. RESULTS: Our results showed that both healthy older and young adults recruited a network of brain regions comprising the bilateral supplementary motor cortex and primary motor cortex, right prefrontal cortex, and cerebellum, during motor imagery of gait. We observed an age-related increase in brain activity in the right supplementary motor area (BA6), the right orbitofrontal cortex (BA11), and the left dorsolateral frontal cortex (BA10). Activity in the left hippocampus was significantly modulated by task difficulty in the elderly participants. Executive functioning correlated with magnitude of increases in right primary motor cortex (BA4) during the motor imagery task. CONCLUSIONS: Besides demonstrating a general overlap in brain regions recruited in young and older participants, this study shows age-related changes in cerebral activation during mental imagery of gait. Our results underscore the importance of executive function (dorsolateral frontal cortex) and spatial navigation or memory function (hippocampus) in gait control in elderly individuals.

The influence of individual motor imagery ability on cerebral recruitment during gait imagery.

Motor imagery (MI) is often used in combination with neuroimaging techniques to study the cognitive control of gait. However, imagery ability (IA) varies widely across individuals, potentially influencing the pattern of cerebral recruitment during MI. The aim of the current study was to investigate this effect of IA on the neural correlates of gait control using functional magnetic resonance imaging (fMRI). Twenty healthy young subjects were subdivided into a good and bad imagers group, on the basis of their performance on two mental chronometry tests. For the whole group, MI activated a bilateral network of areas highly consistent with previous studies, encompassing primary motor cortex (BA 4), supplementary motor area, and other frontal and parietal areas, anterior insula, and cerebellum. Compared to bad imagers, good imagers showed higher activation in the right BA 4, left prefrontal cortex (BA 10), right thalamus, and bilateral cerebellum. Good imagers thus appear better able to recruit motor areas during MI, but also activate a prefrontal executive area (BA 10), which integrates information from the body and the environment and participates in higher-order gait control. These differences were found even though the two groups did not differ in other imagery abilities according to a standard questionnaire for vividness of motor and visual imagery. Future studies on MI should take into account these effects, and control for IA when comparing different populations, using appropriate measures. A better understanding of the neural mechanisms that underlie MI ability is crucial to accurately evaluate locomotor skills in clinical measures and neurorehabilitation techniques.

Associative and semantic memory deficits in amnestic mild cognitive impairment as revealed by functional magnetic resonance imaging.

OBJECTIVE: To identify the neural underpinnings of cognitive deficits associated with memory problems in amnestic mild cognitive impairment (aMCI). BACKGROUND: Functional magnetic resonance imaging (fMRI) is increasingly used to assess patients with aMCI and could potentially help predict conversion to Alzheimer disease, but imaging results so far have been inconsistent in identifying brain activation patterns in aMCI. There is an immediate need to identify the neural substrates of different memory components that are affected by aMCI. METHODS: We used fMRI to study 13 patients with aMCI and 15 healthy age-matched controls during an associative memory encoding and recognition task. The picture-pair memory task encompassed different types of recognition trials to investigate recollection versus familiarity, and manipulated the relationship between paired pictures to investigate semantic processing. RESULTS: Brain activation during both encoding and recognition was lower in patients than controls, with greatest implications in the medial temporal lobe during encoding. Patients also had much greater impairment of associative recollection than recognition based on familiarity, along with a failure to recruit regions that normally respond to violations of learned associations. Finally, patients' impaired semantic encoding was reflected by deficient activation of a left frontotemporal network responsible for elaborate semantic processes. CONCLUSIONS: We show that a simple fMRI task may be sensitive to deficits in different memory components in aMCI and could thus prove useful in the development of an fMRI tool to assess and monitor patients.

Ipsilateral hyperschematia without spatial neglect after right frontal lesion.

The disorder is described as a size distortion involving the side of space. We report the case of a woman with an ipsilateral hyperschematia without neglect after a right frontal lesion. The patient has exhibited a disproportionate enlargement of the right-hand side of objects and added more left-sided petals to the drawn daisy. This pathologic behavior is independent from spatial neglect and from classic frontal perseverations. Our data support the presence of a spatial component to the perception of object size and a specific sub-component of space distortion.

Investigating multitasking in high-functioning adolescents with autism spectrum disorders using the Virtual Errands Task.

Using a modified version of the Virtual Errands Task (VET; McGeorge et al. in Presence-Teleop Virtual Environ 10(4):375-383, 2001), we investigated the executive ability of multitasking in 18 high-functioning adolescents with ASD and 18 typically developing adolescents. The VET requires multitasking (Law et al. in Acta Psychol 122(1):27-44, 2006) because there is a limited amount of time in which to complete the errands. ANCOVA revealed that the ASD group completed fewer tasks, broke more rules and rigidly followed the task list in the order of presentation. Our findings suggest that executive problems of planning inflexibility, inhibition, as well as difficulties with prospective memory (remembering to carry out intentions) may lie behind multitasking difficulties in ASD.

Evidence for a workspace model of working memory from semantic implicit processing in neglect.

Three experiments tested the hypothesis that activation of semantic memory from perceptual input does not require initial retention of the perceptual material in working memory as assumed by a widely held view of information processing. In Expt 1, two brain-damaged patients with left-sided unilateral spatial neglect were tested. They were asked to listen to and read a series of familiar (British) and unfamiliar (foreign) proverbs and to choose which proverb was the best match to a depicted figure shown with the target object(s) on the left (neglected side) of the patients' visual field. Expt 2 simulated the testing conditions for the neglect patients with healthy participants using subliminal presentation of one half of each picture. Using different materials, Expt 3 replicated the outcomes of Expts 1 and 2 with a third neglect patient and a new group of controls. In all three experiments, participants appeared to be unaware of target features; however they selected familiar, but not unfamiliar, target proverbs above chance. The results showing implicit processing of semantic material can be explained by a model in which working memory is a separate system that deals with activated contents of semantic memory, and in which there is direct activation of semantic memory from perception without intermediate stages of processing in working memory.

Pharmacological interventions in primary care: hopes and illusions.

Alzheimer's disease is a neurodegenerative disease characterized by senile plaques, neurofibrillary tangles, synaptic loss, neuronal death and cholinergic deficits, causing cognitive, behavioral and psychological deficits, as well as a functional impairment that results in serious caregiver distress and a great economic burden worldwide. High hopes rose with the development of symptomatic treatments,resulting from randomized controlled trials using cholinergic enhancers or cholinesterase inhibitors, such as donepezil, galantamine and rivastigmine. When memantine, an NMDA antagonist,was approved and the first phase III antiamyloid immunization was launched, many clinicians eagerly anticipated the first disease-modifying drugs in their daily practice. For the treatment of behavioral and psychological symptoms of dementia (BPSD), atypical antipsychotics and new-generation antidepressants also seemed to offer great promises, mainly because of their good tolerance and side effect profiles. Hopes, however, were followed by desillusions: subsequent studies demonstrated that cholinesterase inhibitors and memantine had only modest and short-lived effects on cognition and BPSD, and the effect of antipsychotics on BPSD appeared questionable. Disease-modifying drugs such as antiamyloid immunization or amyloid clearance medication had to be abandoned for safety reasons or absence of efficacy. Although the early treatment of vascular risk factors is increasingly recognized in Alzheimer's disease prevention because of their implication in the amyloid cascade, randomized controlled trials have yielded largely negative results. Therefore,pharmacological as well as fundamental research that better underpins the complex pathophysiology of this devastating disease constitutes one of the biggest challenges of the 21st century.

Selective interference with image retention and generation: evidence for the workspace model.

We address three types of model of the relationship between working memory (WM) and long-term memory (LTM): (a) the gateway model, in which WM acts as a gateway between perceptual input and LTM; (b) the unitary model, in which WM is seen as the currently activated areas of LTM; and (c) the workspace model, in which perceptual input activates LTM, and WM acts as a separate workspace for processing and temporary retention of these activated traces. Predictions of these models were tested, focusing on visuospatial working memory and using dual-task methodology to combine two main tasks (visual short-term retention and image generation) with two interference tasks (irrelevant pictures and spatial tapping). The pictures selectively disrupted performance on the generation task, whereas the tapping selectively interfered with the retention task. Results are consistent with the predictions of the workspace model.