Reliability and minimal detectable change of dynamic temporal summation and conditioned pain modulation using a single experimental paradigm.

BACKGROUND: Quantitative sensory tests (QST) are frequently used to explore alterations in somatosensory systems. Static and dynamic QST like pain threshold and temporal summation (TS) and conditioned pain modulation (CPM) are commonly used to evaluate excitatory and inhibitory mechanisms involved in pain processing. The aim of the present study was to document the reliability and the minimal detectable change (MDC) of these dynamic QST measurements using a standardized experimental paradigm. MATERIAL AND METHODS: Forty-six (46) pain-free participants took part in 2 identical sessions to collect TS and CPM outcomes. Mechanical (pressure pain threshold [PPT]) and thermal (constant 2-minute heat pain stimulation [HPS]) nociceptive stimuli were applied as test stimuli, before and after a cold-water bath (conditioning stimulus). TS was interpreted as the change in pain perception scores during HPS. CPM were determined by calculating the difference in pain perception between pre- and post- water bath for both PPT and HPS. Relative and absolute reliability were analyzed with intra-class correlation coefficient (ICC2, k), standard error of the measurements (SEMeas) and MDC. RESULTS: Results revealed a good to excellent relative reliability for static QST (ICC ≥ 0.73). For TS, a poor to moderate relative reliability depending on the calculation methods (ICC = 0.25 ≤ ICC ≤ 0.59), and a poor relative reliability for CPM (ICC = 0.16 ≤ ICC ≤ 0.37), both when measured with mechanical stimulation (PPT) and thermal stimulation (HPS). Absolute reliability varied from 0.73 to 7.74 for static QST, 11 to 22 points for TS and corresponded to 11.42 points and 1.56 points for thermal and mechanical-induced CPM, respectively. MDC analyses revealed that a change of 1.58 to 21.46 point for static QST, 31 to 52 points for TS and 4 to 31 points for CPM is necessary to be interpreted as a real change. CONCLUSION: Our approach seems well-suited to clinical use. Although our method shows equivalent relative and absolute reliability compared to other protocols, we found that the reliability of endogenous pain modulation mechanisms is vulnerable, probably due to its dynamic nature.

A novel methodology utilizing microchip implants to monitor individual activity and body temperature for assessing knee pain in group-housed rats.

The pain assessment in animals is challenging as they cannot verbally express the site and severity of pain. In this study, we tried a small implantable actimeter, "Nanotag", to monitor spontaneous locomotor activity and body temperature in animals suffering from a chemical-induced rat knee arthritis as compared to naïve and steroid-treated rats. Nanotag could detect the decrease in locomotor activity quickly after the arthritis induction and anti-inflammation analgesic treatment by intra-articular injection of steroid significantly improved locomotor activity. These changes were in the same line with those of a conventional knee pain evaluation method (incapacitance test). Nanotag can be utilized as the non-interventional, continuous, and completely objective monitoring the amount of pain in rat knee arthritis model. This traditional yet innovative method may be universally applicable to various pain models and species, making it a worthwhile device for research across diverse fields.

Psychopathy, pain, and pain empathy: A psychophysiological study.

The present study examined whether people higher in psychopathy experienced less self-reported and psychophysiological nociceptive pressure than people lower in psychopathy. We also examined whether psychopathy affects empathy for others' pain via self-reported and psychophysiological measures. Three hundred and sixty-nine students (18-78 years; M = 26, SD = 9.34) were screened for psychopathic traits using the Youth Psychopathy Inventory (YPI). Stratified sampling was used to recruit 49 adults residing in the highest (n = 23) and lowest (n = 26) 20% of the psychopathy spectrum. Using skin conductance response (SCR) and self-report responses, participants responded to individually adjusted intensities of pneumatic pressure and others' pain images and completed self-reported psychopathy and empathy measures (Triarchic Psychopathy Measure, TriPm; Interpersonal Reactivity Index, IRI). People higher in psychopathy self-reported feeling less nociceptive pressure compared to people lower in psychopathy, yet we did not find any differences in SCR to nociceptive pressure. However, when viewing other people in pain, the high psychopathy group displayed lower SCR and lower self-reported empathy compared to those lower in psychopathy. Our results suggest psychopathic traits relate to problems empathising with others' pain, as well as the perception of nociceptive pressure. We also show support for the theory of dual harm which has been receiving increasing attention. Consequently, psychopathy interventions should focus both on recognising and empathising with the pain of others.

Empathy incites a stable prosocial decision bias.

Empathy toward suffering individuals serves as potent driver for prosocial behavior. However, it remains unclear whether prosociality induced by empathy for another person's pain persists once that person's suffering diminishes. To test this, participants underwent functional magnetic resonance imaging while performing a binary social decision task that involved allocation of points to themselves and another person. In block one, participants completed the task after witnessing frequent painful stimulation of the other person, and in block two, after observing low frequency of painful stimulation. Drift-diffusion modeling revealed an increased initial bias toward making prosocial decisions in the first block compared with baseline that persisted in the second block. These results were replicated in an independent behavioral study. An additional control study showed that this effect may be specific to empathy as stability was not evident when prosocial decisions were driven by a social norm such as reciprocity. Increased neural activation in dorsomedial prefrontal cortex was linked to empathic concern after witnessing frequent pain and to a general prosocial decision bias after witnessing rare pain. Altogether, our findings show that empathy for pain elicits a stable inclination toward making prosocial decisions even as their suffering diminishes.

Neural pathways that compel us to scratch an itch.

Itch is a unique sensory experience that is responded to by scratching. How pruritogens, which are mechanical and chemical stimuli with the potential to cause itch, engage specific pathways in the peripheral and central nervous system has been a topic of intense investigation over the last few years. Studies employing recently developed molecular, physiological, and behavioral techniques have delineated the dedicated mechanisms that transmit itch information to the brain. This review outlines the genetically defined and evolutionary conserved circuits for itch ranging from the skin-innervating peripheral neurons to the cortical neurons that drive scratching. Moreover, scratch suppression of itch is attributed to the concurrent activation of pain and itch pathways. Hence, we discuss the similarities between circuits driving pain and itch.

Unpacking the relationship between Big Five personality traits and experimental pain: A systematic review and meta-analysis.

Pain is essential for survival, but individual responses to painful stimuli vary, representing a complex interplay between sensory, cognitive, and affective factors. Individual differences in personality traits and in pain perception covary but it is unclear which traits play the most significant role in understanding the pain experience and whether this depends on pain modality. A systematic search identified 1534 records (CINAHL, MEDLINE, PsycInfo, PubMed and Web of Science), of which 22 were retained and included in a systematic review. Only studies from the pressure pain domain (n=6) could be compared in a formal meta-analysis to evaluate the relationship between Big Five traits and experimental pain. Pressure pain tolerance correlated positively with Extraversion and negatively with Neuroticism with a trivial effect size (<0.1). While these findings suggest personality might be only weakly related to pain in healthy individuals, we emphasize the need to consider standardization, biases, and adequate sample sizes in future research, as well as additional factors that might affect experimental pain sensitivity.

Posttraumatic headache: pain related evoked potentials (PREP) and conditioned pain modulation (CPM) to assess the pain modulatory function.

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

An externally validated resting-state brain connectivity signature of pain-related learning.

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Measuring pain intensity through physical interaction in an experimental model of cold-induced pain: A method comparison study.

OBJECTIVES: Assessment of pain is challenging given its subjective nature. Standard pain assessment tools have limitations. We aimed to compare the verbal numeric rating scale (NRS) and Grasp, a novel handheld electronic device that reports pain by squeezing. METHODS: To compare Grasp and NRS, healthy adult volunteers were invited to undergo two subsequent standardised tests of cold-triggered pain using a cold pressor test (CPT) at a temperature of 3°C. Pain intensity was in a randomised manner reported by NRS (scale 0-10) or by squeezing Grasp (0-3 V) during the two CPTs. A third CPT was performed 1 to 14 days later where subjects reported pain by Grasp a second time in order to study the association of repeated Grasp measurements. Acceptable association was a priori considered as mean Kendall's τ-b coefficient (τ-b) ≥ 0.7. The subjects reported their experience of using Grasp in a purpose-made questionnaire. RESULTS: In total, 102 subjects were included, and 96 subjects (56 females) completed all three tests. The association of pain intensity reported by Grasp and NRS was moderate with a mean τ-b of 0.53 (95% confidence interval [CI] 0.47-0.58). The association between the repeated Grasp measurements was weak with a mean τ-b of 0.43 (95% CI 0.37-0.48). Most subjects reported that Grasp was intuitive and easy to use. CONCLUSIONS: Pain intensity reported by squeezing Grasp did not show acceptable association with pain intensity reported by NRS during CPTs. The association between pain intensity reported by Grasp during two CPTs on separate days was weak. Further improvements of the Grasp ball are needed before use in clinical settings.

Do we empathize humanoid robots and humans in the same way? Behavioral and multimodal brain imaging investigations.

Humanoid robots have been designed to look more and more like humans to meet social demands. How do people empathize humanoid robots who look the same as but are essentially different from humans? We addressed this issue by examining subjective feelings, electrophysiological activities, and functional magnetic resonance imaging signals during perception of pain and neutral expressions of faces that were recognized as patients or humanoid robots. We found that healthy adults reported deceased feelings of understanding and sharing of humanoid robots' compared to patients' pain. Moreover, humanoid robot (vs. patient) identities reduced long-latency electrophysiological responses and blood oxygenation level-dependent signals in the left temporoparietal junction in response to pain (vs. neutral) expressions. Furthermore, we showed evidence that humanoid robot identities inhibited a causal input from the right ventral lateral prefrontal cortex to the left temporoparietal junction, contrasting the opposite effect produced by patient identities. These results suggest a neural model of modulations of empathy by humanoid robot identity through interactions between the cognitive and affective empathy networks, which provides a neurocognitive basis for understanding human-robot interactions.

Modulating Neural Circuits of Pain in Preclinical Models: Recent Insights for Future Therapeutics.

Chronic pain is a pathological state defined as daily pain sensation over three consecutive months. It affects up to 30% of the general population. Although significant research efforts have been made in the past 30 years, only a few and relatively low effective molecules have emerged to treat chronic pain, with a considerable translational failure rate. Most preclinical models have focused on sensory neurotransmission, with particular emphasis on the dorsal horn of the spinal cord as the first relay of nociceptive information. Beyond impaired nociceptive transmission, chronic pain is also accompanied by numerous comorbidities, such as anxiety-depressive disorders, anhedonia and motor and cognitive deficits gathered under the term "pain matrix". The emergence of cutting-edge techniques assessing specific neuronal circuits allow in-depth studies of the connections between "pain matrix" circuits and behavioural outputs. Pain behaviours are assessed not only by reflex-induced responses but also by various or more complex behaviours in order to obtain the most complete picture of an animal's pain state. This review summarises the latest findings on pain modulation by brain component of the pain matrix and proposes new opportunities to unravel the mechanisms of chronic pain.

The impact of pain on daily activities in patients with idiopathic inflammatory myopathies: Report from the OMERACT myositis working group.

BACKGROUND: International focus groups with patients with idiopathic inflammatory myopathies (IIM) conducted by the OMERACT Myositis Working Group over the years demonstrated the pain as an important symptom experienced by these patients. In this study, we aimed to examine the frequency and degree of pain interference, the aspects of daily life impacted by pain, and the factors associated with pain interference in adults with IIM. METHODS: This was a prospective observational study with two visits. The patients who fulfilled the probable/definite IIM (ACR/EULAR Myositis Classification Criteria) were enrolled. Pain interference was assessed with PROMIS pain interference form (6a). Myositis core set measures and PROMIS fatigue (7a) and physical function (8b) were obtained at both visits. Logistic regression and linear mixed models were performed to assess the association between pain interference and other parameters. RESULTS: A total of 129 patients with IIM (60 % females) were recruited from U.S., South Korea, Netherlands, Sweden, and Australia. Approximately 71 % reported pain interference. The patients in the greater pain interference group were more likely to be female, had significantly worse patient/physician global disease activity, fatigue, and physical function than those in the lower pain interference group. The most commonly impacted life aspect was household chores. Manual muscle testing, patient/physician global disease activity, fatigue, and physical function were all significantly associated with pain interference score >60. CONCLUSION: The majority of the patients with IIM experience the impact of pain on their daily activities, particularly household chores. Myositis disease activity, duration, and subtype could be associated with greater pain interference.

Noise or signal? Spontaneous activity of dorsal horn neurons: patterns and function in health and disease.

Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or "noise" in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment.

Feeling older, feeling pain? Reciprocal between-person and within-person associations of pain and subjective age in the second half of life.

Experiencing pain in middle adulthood and old age might be interpreted as a sign of aging and make people feel older, whereas feeling older has behavioral, motivational, and physiological consequences that might increase the risk of pain. We investigated between-person and within-person associations between pain, subjective age, and chronological age in middle-aged and older adults. Data from the German Ageing Survey were used (n = 13,874 who provided more than 32,000 observations, baseline mean age = 62.3 years). The observation period comprised up to 13 years (M = 4 years) and five (M = 2.4) measurement occasions. Based on the longitudinal multilevel regression models, we found significant between-person and within-person effects in both directions, which were small but robust when controlling for sociodemographic variables, depressive symptoms, and number of chronic diseases. At the between-person level, participants reporting overall more severe pain also felt older than others. Likewise, those who felt overall older than others reported more pain. At the within-person level, when participants experienced more pain than they usually do, they also reported feeling older than usual. Likewise, on measurement occasions when participants reported feeling older than usual, they reported more pain than usual. Additionally, those with overall stronger pain exhibited steeper age-related increases in their subjective age than those with less severe pain. Our findings suggest that an older subjective age may operate as both antecedent and consequence of pain, and pain might prompt a steeper increase in subjective age over time. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The location of pain in cluster headache: Data from the International Cluster Headache Questionnaire.

OBJECTIVE: To identify the most common locations of cluster headache pain from an international, non-clinic-based survey of participants with cluster headache, and to compare these locations to other cluster headache features as well as to somatotopic maps of peripheral, brainstem, thalamic, and cortical areas. BACKGROUND: Official criteria for cluster headache state pain in the orbital, supraorbital, and/or temporal areas, yet studies have noted pain extending beyond these locations, and the occipital nerve appears relevant, given the effectiveness of suboccipital corticosteroid injections and occipital nerve stimulation. Furthermore, cranial autonomic features vary between patients, and it is not clear if the trigeminovascular reflex is dermatome specific (e.g., do patients with maxillary or V2 division pain have more rhinorrhea?). Finally, functional imaging studies show early activation of the posterior hypothalamus in a cluster headache attack. However, the first somatosensory area to be sensitized is unclear; the first area can be hypothesized based on the complete map of pain locations. METHODS: The International Cluster Headache Questionnaire was an internet-based cross-sectional survey that included a clickable pain map of the face. These data were compared to several other datasets: (1) a meta-analysis of 22 previous publications of pain location in cluster headache (consisting of 6074 patients); (2) four cephalic dermatome maps; (3) participants' survey responses for demographics, autonomic features, and effective medications; and (4) previously published somatotopic maps of the brainstem, thalamus, primary somatosensory cortex, and higher order somatosensory cortex. RESULTS: One thousand five hundred eighty-nine participants completed the pain map portion of the survey, and the primary locations of pain across all respondents was the orbital, periorbital, and temporal areas with a secondary location in the lower occiput; these primary and secondary locations were consistent with our meta-analysis of 22 previous publications. Of the four cephalic dermatomes (V1, V2, V3, and a combination of C2-3), our study found that most respondents had pain in two or more dermatomes (range 85.7% to 88.7%, or 1361-1410 of 1589 respondents, across the four dermatome maps). Dermatomes did not correlate with their respective autonomic features or with medication effectiveness. The first area to be sensitized in the canonical somatosensory pathway is either a subcortical (brainstem or thalamus) or higher order somatosensory area (parietal ventral or secondary somatosensory cortices) because the primary somatosensory cortex (area 3b) and somatosensory area 1 have discontinuous face and occipital regions. CONCLUSIONS: The primary pain locations in cluster headache are the orbital, supraorbital, and temporal areas, consistent with the official International Classification of Headache Disorders criteria. However, activation of the occiput in many participants suggests a role for the occipital nerve, and the pain locations suggest that somatosensory sensitization does not start in the primary somatosensory cortex.

Sex differences in mechanisms of pain hypersensitivity.

The introduction of sex-as-a-biological-variable policies at funding agencies around the world has led to an explosion of very recent observations of sex differences in the biology underlying pain. This review considers evidence of sexually dimorphic mechanisms mediating pain hypersensitivity, derived from modern assays of persistent pain in rodent animal models. Three well-studied findings are described in detail: the male-specific role of spinal cord microglia, the female-specific role of calcitonin gene-related peptide (CGRP), and the female-specific role of prolactin and its receptor. Other findings of sex-specific molecular involvement in pain are subjected to pathway analyses and reveal at least one novel hypothesis: that females may preferentially use Th1 and males Th2 T cell activity to mediate chronic pain.

Dissecting shared pain representations to understand their behavioral and clinical relevance.

Accounts of shared representations posit that the experience of pain and pain empathy rely on similar neural mechanisms. Experimental research employing novel analytical and methodological approaches has made significant advances in both the identification and targeted manipulation of such shared experiences and their neural underpinnings. This revealed that painful experiences can be shared on different representational levels, from pain-specific to domain-general features, such as negative affect and its regulation. In view of direct links between such representations and social behaviors such as prosocial behavior, conditions characterized by aberrant pain processing may come along with heavy impairments in the social domain, depending on the affected representational level. This has wide potential implications in light of the high prevalence of pain-related clinical conditions, their management, and the overuse of pain medication. In this review and opinion paper, we aim to chart the path toward a better understanding of the link between shared affect and prosocial behavior.

Predictors of pain intensity in carpal tunnel syndrome: Development and validation of a model.

OBJECTIVE: Pain often accompanies carpal tunnel syndrome and affects patients' health-related quality of life. The aim was to develop and validate a predictive model for the pain intensity of carpal tunnel syndrome using demographic, clinical, electrophysiological, and ultrasound findings. METHODS: We conducted a secondary analysis of data from a large sample of patients (May 2017 to December 2022) with carpal tunnel syndrome. A total of 520 (53.0 %) mild, 276 (28.1 %) moderate, and 186 (18.9 %) severe syndromes were included in the complete data set of 982 hands (61.1 % female). The mean age was 57.8 (10.7) years and the median duration [interquartile range] of the symptoms was 4 [2,10] months. A regression model was developed and validated to predict pain intensity on a numerical rating scale using a tree-based machine learning algorithm. RESULTS: The validation of the regression model showed good performance with a root mean squared error, R-squared, and mean absolute error of 1.35, 0.42, and 1.05, respectively. Overall, the top significant predictors of pain intensity were compound motor nerve action potential latency, nocturnal pain, and thenar weakness. These were followed by the cross-sectional area of the median nerve, sensory nerve action potential, bowing of the flexor retinaculum, disease duration, and body mass index. We did not find strong associations between the median nerve transcarpal latency, age, sex, and diabetes with the pain intensity of carpal tunnel syndrome. CONCLUSION: Our model showed good performance in predicting the subjective pain intensity of carpal tunnel syndrome, even in the context of non-linear relations.

Moving in pain - A preliminary study evaluating the immediate effects of experimental knee pain on locomotor biomechanics.

Pain changes how we move, but it is often confounded by other factors due to disease or injury. Experimental pain offers an opportunity to isolate the independent effect of pain on movement. We used cutaneous electrical stimulation to induce experimental knee pain during locomotion to study the short-term motor adaptions to pain. While other models of experimental pain have been used in locomotion, they lack the ability to modulate pain in real-time. Twelve healthy adults completed the single data collection session where they experienced six pain intensity conditions (0.5, 1, 2, 3, 4, 5 out of 10) and two pain delivery modes (tonic and phasic). Electrodes were placed over the lateral infrapatellar fat pad and medial tibial condyle to deliver the 10 Hz pure sinusoid via a constant current electrical stimulator. Pain intensity was calibrated prior to each walking bout based on the target intensity and was recorded using an 11-point numerical rating scale. Knee joint angles and moments were recorded over the walking bouts and summarized in waveform and discrete outcomes to be compared with baseline walking. Knee joint angles changed during the swing phase of gait, with higher pain intensities resulting in greater knee flexion angles. Minimal changes in joint moments were observed but there was a consistent pattern of decreasing joint stiffness with increasing pain intensity. Habituation was limited across the 30-90 second walking bouts and the electrical current needed to deliver the target pain intensities showed a positive linear relationship. Experimental knee pain shows subtle biomechanical changes and favourable habituation patterns over short walking bouts. Further exploration of this model is needed in real-world walking conditions and over longer timeframes to quantify motor adaptations.

Investigating physiological symptoms associated with mental health symptoms in youth with cerebral palsy: An observational study.

Over 50 % of children and youth with cerebral palsy (CP) experience mental health challenges, with anxiety and depression most common. Youth with CP also experience several physiological symptoms such as fatigue, pain, sedentary lifestyle, and sleep disturbances that impact their daily living; however, little is known about the impact of these symptoms on mental health outcomes in these youth. This study addressed this gap and examined the individual and cumulative impacts of physiological symptoms on anxiety and depression symptoms in youth with CP. Forty youth with CP aged 8 to 18 years, and their caregiver, participated in this cross-sectional observational study. Pain, fatigue, anxiety, and depressive symptoms were measured using caregiver- and self-reported questionnaires and participants wore accelerometers for seven consecutive days, providing non-invasive physical activity and sleep pattern data. Youth with CP experienced substantial physiological symptoms and elevated anxiety and depression symptoms. Linear regression models determined that all physiological factors were predictive of caregiver-reported youth anxiety (R2 = 0.23) and youth depressive symptoms (R2 = 0.48). Fatigue, pain severity, sleep efficiency, and physical activity outcomes individually and cumulatively contributed to caregiver-reported youth anxiety and depression symptoms. These findings highlight the important role of physiological symptoms as potential risk factors and potential targets for intervention for mental health issues for in youth with CP.