Novel method for assessing age-related differences in the temporal summation of pain

Temporal summation (TS) of pain protocols typically involve the delivery of brief repetitive noxious stimuli held at a constant intensity and measuring the consequent increase in the perceived intensity of pain sensations. To date, no studies have examined the effect of a TS protocol on the perceived spatial dimensions of the pain experience and its interaction with age. This study used a new TS protocol that examined changes in the perceived size of the painful area in 22 younger adults and 20 older adults. Four trials of ten brief heat pulses delivered at a constant intensity were administered on the volar forearm. Interpulse intervals (IPIs) were 2.5 seconds or 3.5 seconds. Subjects rated the peak pain intensity (trials 1 and 3) or the size of the painful area (trials 2 and 4) after each pulse on a 0-100 scale. The magnitude of summation was calculated for each trial. Three seconds and 6 seconds after delivering the last heat pulse, the subjects rated the intensity or the size of any remaining pain (aftersensations). The results indicated that older adults compared to younger adults exhibited significantly greater summation of size ratings for the 2.5-second and 3.5-second IPI trials and size of pain aftersensations at 3 seconds following the 2.5-second IPI TS trial. These results suggest that aging is associated with enhanced endogenous facilitation of the perceived size of pain. The potential clinical and mechanistic implications of enhanced TS of size of pain remain unknown and warrant further investigation

Loss of Temporal Inhibition of Nociceptive Information Is Associated With Aging and Bodily Pain

An age-related decline in endogenous pain inhibitory processes likely places older adults at an increased risk for chronic pain. Limited research indicates that older adults may be characterized by deficient offset analgesia, an inhibitory temporal sharpening mechanism that increases the detectability of minor decreases in noxious stimulus intensity. The primary purpose of the study was to examine age differences in offset analgesia in community-dwelling younger, middle-aged, and older adults. An additional aim of the study was to determine whether the magnitude of offset analgesia predicted self-reported bodily pain. Eighty-seven younger adults, 42 middle-aged adults, and 60 older adults completed 4 offset analgesia trials and 3 constant temperature trials in which a noxious heat stimulus was applied to the volar forearm for 40 seconds. The offset trials consisted of 3 continuous phases: an initial 10-second painful stimulus, either a 1.0°C or .4°C increase in temperature from the initial 10-second painful stimulus for 10 seconds, and either a 1.0°C or .4°C decrease back to the initial testing temperature for 20 seconds. During each trial, subjects rated pain intensity continuously using an electronic visual analog scale (0–100). All subjects also completed the Short-Form Health Survey-36 including the Bodily Pain subscale. The results indicated that older and middle-aged adults showed reduced offset analgesia compared with younger adults in the 1.0°C and .4°C offset trials. Furthermore, the magnitude of offset analgesia predicted self-reported bodily pain, with those exhibiting reduced offset analgesia reporting greater bodily pain. Dysfunction of this endogenous inhibitory system could increase the risk of developing chronic pain for middle-aged and older adults. Perspective Older and middle-aged adults showed reduced offset analgesia compared with younger adults. The significant association between reduced offset analgesia and pain in daily life supports the notion that pain modulatory deficits are associated with not just a chronic pain condition but with the experience of pain in general

Feasibility of brain age predictions from clinical T1-weighted MRIs

An individual's brain predicted age minus chronological age (brain-PAD) obtained from MRIs could become a biomarker of disease in research studies. However, brain age reports from clinical MRIs are scant despite the rich clinical information hospitals provide. Since clinical MRI protocols are meant for specific clinical purposes, performance of brain age predictions on clinical data need to be tested. We explored the feasibility of using DeepBrainNet, a deep network previously trained on research-oriented MRIs, to predict the brain ages of 840 patients who visited 15 facilities of a health system in Florida. Anticipating a strong prediction bias in our clinical sample, we characterized it to propose a covariate model in group-level regressions of brain-PAD (recommended to avoid Type I, II errors), and tested its generalizability, a requirement for meaningful brain age predictions in new single clinical cases. The best bias-related covariate model was scanner-independent and linear in age, while the best method to estimate bias-free brain ages was the inverse of a scanner-independent and quadratic in brain age function. We demonstrated the feasibility to detect sex-related differences in brain-PAD using group-level regression accounting for the selected covariate model. These differences were preserved after bias correction. The Mean-Average Error (MAE) of the predictions in independent data was ∼8 years, 2-3 years greater than reports for research-oriented MRIs using DeepBrainNet, whereas an R2 (assuming no bias) was 0.33 and 0.76 for the uncorrected and corrected brain ages, respectively. DeepBrainNet on clinical populations seems feasible, but more accurate algorithms or transfer-learning retraining is needed

Reliability of pain intensity clamping using response-dependent thermal stimulation in healthy volunteers

BACKGROUND: Pain intensity clamping uses the REsponse-Dependent Stimulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point which is continuously monitored from a subject's real-time pain ratings. REDSTIM blinds subjects regarding the pain intensity set-point, supporting its use for assessing intervention efficacy. By maintaining the pain intensity at a constant level, a potential decrease in pain sensitivity can be detected by an increase in thermode temperature (unknown to the subject) and not by pain ratings alone. Further, previously described sensitizing and desensitizing trends within REDSTIM provide a novel insight into human pain mechanisms overcoming limitations of conventional testing methods. The purpose of the present study was to assess the test-retest reliability of pain intensity clamping using REDSTIM during three separate sessions. METHODS: We used a method for testing changes in pain sensitivity of human subjects (REDSTIM) where the stimulus temperature is modulated to clamp pain intensity near a desired set-point. Temperature serves as the response variable and is used to infer pain sensitivity. Several measures were analyzed for reliability including average temperature and area under the curve (AUC). Intraclass correlation coefficients were calculated for each measure at pain rating set-points of 20/100 and 35/100. RESULTS: Sixteen healthy individuals (mean age = 21.6 ± 3.9) participated in three experiments two days apart at both pain rating set-points. Most reliability coefficients were in the moderate to substantial range (r's = 0.79 to 0.94) except for the negative AUC (r = 0.52), but only at the 20/100 pain rating set-point. CONCLUSIONS: The present study supports the test-retest reliability of pain intensity clamping using the REDSTIM methodology while providing a novel tool to examine human pain modulatory mechanisms and overcoming common shortcomings of conventional quantitative sensory testing methods

Increased spatial dimensions of repetitive heat and cold stimuli in older women

Protocols of temporal summation (TS) of pain typically involve the delivery of brief repetitive noxious pulses of a constant intensity while measuring the perceived intensity of pain after each pulse. The size percept of noxious repetitive stimulation has been poorly characterized. Furthermore, no studies have investigated age differences in TS of cold pain. The current study examined TS of pain intensity and the perceived size of the painful area during repetitive noxious heat and cold pulses in healthy younger (n = 104) and older adults (n = 40). Trials of 10 brief repetitive noxious heat or cold pulses were delivered to the upper extremities. Participants rated the perceived size of the painful area or intensity of pain after each pulse. The magnitude of change for the size percept and intensity for pain were calculated for each trial. The results indicated that older adults experienced greater TS of the size percept of cold stimuli compared with younger adults. Additionally, older women experienced greater TS of the size percept of heat stimuli compared with older men and all younger participants. No overall age or sex differences were found in the TS of pain intensity for cold or heat trials. These results suggest dysfunctional modulation of the spatial percept of the painful stimuli by older adults, and in particular older women, during repetitive noxious thermal pulses

Toward MR protocol-agnostic, unbiased brain age predicted from clinical-grade MRIs

The difference between the estimated brain age and the chronological age ('brain-PAD') could become a clinical biomarker. However, most brain age models were developed for research-grade high-resolution T1-weighted MRIs, limiting their applicability to clinical-grade MRIs from various protocols. We adopted a dual-transfer learning strategy to develop a model agnostic to modality, resolution, or slice orientation. We retrained a convolutional neural network (CNN) using 6281 clinical MRIs from 1559 patients, among 7 modalities and 8 scanner models. The CNN was trained to estimate brain age from synthetic research-grade magnetization-prepared rapid gradient-echo MRIs (MPRAGEs) generated by a 'super-resolution' method. The model failed with T2-weighted Gradient-Echo MRIs. The mean absolute error (MAE) was 5.86-8.59 years across the other modalities, still higher than for research-grade MRIs, but comparable between actual and synthetic MPRAGEs for some modalities. We modeled the "regression bias" in brain age, for its correction is crucial for providing unbiased summary statistics of brain age or for personalized brain age-based biomarkers. The bias model was generalizable as its correction eliminated any correlation between brain-PAD and chronological age in new samples. Brain-PAD was reliable across modalities. We demonstrate the feasibility of brain age predictions from arbitrary clinical-grade MRIs, thereby contributing to personalized medicine

Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation

The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0-100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain

Systemic Inflammation Mediates Age-Related Cognitive Deficits

The association between systemic inflammation and cognitive deficits is well-documented. Further, previous studies have shown that systemic inflammation levels increase with age. The present study took a novel approach by examining the extent to which systemic inflammation levels mediated age-related cognitive decline. Forty-seven young and 46 older generally healthy adults completed two cognitive tasks measuring processing speed and short-term memory, respectively. Serum concentrations of three inflammatory biomarkers (including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP)) were measured in each participant. Both cognitive measures showed age-related deficits. In addition, levels of IL-6 and TNF-α were elevated with age. IL-6 partially mediated the difference in processing speed between the young and the older participant age group; there was no mediation effect for TNF-α and CRP. Considering chronological age, IL-6 partially accounted for age-related impairment in processing speed within older but not young participants. No effects were found for short-term memory. Evidence from this research supports the role of inflammatory processes in age-related cognitive decline. Processes involved in this mediation and differences in inflammatory influence on specific cognitive functions are discussed

Brain-predicted age difference mediates the association between PROMIS sleep impairment, and self-reported pain measure in persons with knee pain

Knee pain, the most common cause of musculoskeletal pain (MSK), constitutes a severe public health burden. Its neurobiological causes, however, remain poorly understood. Among many possible causes, it has been proposed that sleep problems could lead to an increase in chronic pain symptomatology, which may be driven by central nervous system changes. In fact, we previously found that brain cortical thickness mediated the relationship between sleep qualities and pain severity in older adults with MSK. We also demonstrated a significant difference in a machine-learning-derived brain-aging biomarker between participants with low-and high-impact knee pain. Considering this, we examined whether brain aging was associated with self-reported sleep and pain measures, and whether brain aging mediated the relationship between sleep problems and knee pain. Exploratory Spearman and Pearson partial correlations, controlling for age, sex, race and study site, showed a significant association of brain aging with sleep related impairment and self-reported pain measures. Moreover, mediation analysis showed that brain aging significantly mediated the effect of sleep related impairment on clinical pain and physical symptoms. Our findings extend our prior work demonstrating advanced brain aging among individuals with chronic pain and the mediating role of brain-aging on the association between sleep and pain severity. Future longitudinal studies are needed to further understand whether the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain

Functional Integrity of Somatosensory Pathways in the Neuropathic Pain Conditions After Spinal Cord Injury

Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect a person’s quality of life and is often refractory to currently available treatments. In order to advance the field and find effective therapeutic avenues; signs, symptoms, and biomarkers in humans should be identified and related to specific pain-generating mechanisms. The present work utilizes quantitative sensory testing (QST) and magnetic resonance spectroscopy (MRS) to evaluate the relationship between the functional integrity of the dorsal column-medial lemniscus pathway (DCML), the spinothalamic tract (STT), and metabolic markers of neuronal loss and glial activation in the thalamus of persons with/without NP after SCI. This work was based on the hypothesis that the presence/severity of NP after SCI is dependent both on function of ascending somatosensory pathways and changes in neuronal and glial markers in the thalamus. The results indicate that NP is associated with a decreased afferent DCML input to the thalamus resulting in a loss of inhibitory neurons and that residual function from STT afferents may contribute to thalamic glial activation and NP. Based on this work, in combination with previous studies in animals and humans, it can be proposed that NP after SCI partly results from the combination of residual STT function and loss of neuronal inhibition leading to neuronal hyperexcitability in the spinal cord and the thalamus. Thus, the presence of NP in chronic SCI is dependent on several underlying mechanisms which may be measured in human subjects with methods such as QST and MRS. Clinical implications and recommendations for further research are enclosed