Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study.

BACKGROUND AIMS: Spinal cord injury (SCI) represents a devastating condition leading to severe disability related to motor, sensory and autonomic dysfunction. Stem cell transplantation is considered a potential emerging therapy to stimulate neuroplastic and neuroregenerative processes after SCI. In this clinical trial, the authors investigated the safety and clinical recovery effects of intrathecal infusion of expanded Wharton jelly mesenchymal stromal cells (WJ-MSCs) in chronic complete SCI patients. METHODS: The authors designed a randomized, double-blind, crossover, placebo-controlled, phase 1/2a clinical trial (NCT03003364). Participants were 10 patients (7 males, 3 females, age range, 25-47 years) with chronic complete SCI (American Spinal Injury Association A) at dorsal level (T3-11). Patients were randomly assigned to receive a single dose of intrathecal ex vivo-expanded WJ-MSCs (10 × 106 cells) from human umbilical cord or placebo and were then switched to the other arm at 6 months. Clinical evaluation (American Spinal Injury Association impairment scale motor and sensory score, spasticity, neuropathic pain, electrical perception and pain thresholds), lower limb motor evoked potentials (MEPs) and sensory evoked potentials (SEPs), Spinal Cord Independence Measure and World Health Organization Quality of Life Brief Version were assessed at baseline, 1 month, 3 months and 6 months after each intervention. Urodynamic studies and urinary-specific quality of life (Qualiveen questionnaire) as well as anorectal manometry, functional assessment of bowel dysfunction (Rome III diagnostic questionnaire) and severity of fecal incontinence (Wexner score) were conducted at baseline and at 6 months after each intervention. RESULTS: Intrathecal transplantation of WJ-MSCs was considered safe, with no significant side effects. Following MSC infusion, the authors found significant improvement in pinprick sensation in the dermatomes below the level of injury compared with placebo. Other clinically relevant effects, such as an increase in bladder maximum capacity and compliance and a decrease in bladder neurogenic hyperactivity and external sphincter dyssynergy, were observed only at the individual level. No changes in motor function, spasticity, MEPs, SEPs, bowel function, quality of life or independence measures were observed. CONCLUSIONS: Intrathecal transplantation of human umbilical cord-derived WJ-MSCs is a safe intervention. A single intrathecal infusion of WJ-MSCs in patients with chronic complete SCI induced sensory improvement in the segments adjacent to the injury site.

Botulinum toxin type-A infiltration of the external anal sphincter to treat outlet constipation in motor incomplete spinal cord injury: pilot cohort study.

BACKGROUND: Outlet constipation is a major problem in spinal cord injury (SCI) patients. We aimed to study the efficacy of external anal sphincter (EAS) infiltration with type-A botulinum toxin (BTX-A) in motor incomplete SCI patients with outlet constipation. METHODS: Double blind, randomized, placebo controlled, comparative study in 16 motor incomplete SCI subjects. Patients were randomly assigned toreceive100 UI of BTX-A (n = 9) or physiologic serum infiltration (n = 7) in the EAS under electromyographic guidance. Outcome measures included a questionnaire for clinical bowel function evaluation, colonic transit time and anorectal manometry. All assessments were done at baseline, 1 and 3 months after treatment. RESULTS: Fourteen patients completed the study. In the BTX-A group we observed an improvement of subjective perception of bowel function (p = 0.01), constipation (p = 0.02) and neurogenic bowel dysfunction score (p = 0.02). The anorectal manometry revealed are duction of EAS voluntary contraction pressure (p = 0.01). No changes were observed in the placebo group. No significant side effects were observed in none of the groups. CONCLUSION: BTX-A infiltration of the EAS is a safe technique that in motor incomplete SCI, decreases the EAS contraction and the anal canal pressure during straining, and improves outlet constipation symptoms. Future studies in larger populations are needed.

Effects of different vibration frequencies on spinal cord reflex circuits and thermoalgesic perception.

OBJECTIVES: We studied the effect of different vibration frequencies on spinal cord excitability and heat pain perception. We hypothesized that the effects of vibration on spinal cord reflexes, and, also those on heat pain perception, depend on vibration frequency. METHODS: In 9 healthy subjects, we applied vibration over the tibialis anterior muscle at three different frequencies (50, 150, or 250 Hz) on spinal cord reflex excitably, tested with the H reflex and the T wave in the soleus muscle, as well as on sensory and pain perception, tested by measuring warm perception (WT) and heat pain perception thresholds, (HPT) in sites rostral and caudal to vibration. Exams were carried out before, during, and after vibration. RESULTS: The amplitude of the H reflex and T wave significantly decreased during vibration in comparison to baseline. Low frequencies (50 and 150Hz) induced greater reflex suppression than high frequency (250Hz). No significant changes were observed on WT and HPT. CONCLUSIONS: The effects of vibratory stimulation can be summarized as frequency-related suppression of the spinal cord excitability without an effect on warm and heat pain perception. The present results may help to design vibration-related interventions intended to diminish spinal cord reflex excitability in spastic patients.

Divergent effects of conditioned pain modulation on subjective pain and nociceptive-related brain activity.

BACKGROUND AND OBJECTIVES: Pain is a complex experience involving both nociceptive and affective-cognitive mechanisms. The present study evaluated whether modulation of pain perception, employing a conditioned pain modulation (CPM) paradigm, is paralleled by changes in contact heat-evoked potentials (CHEPs), a brain response to nociceptive stimuli. METHODS: Participants were 25 healthy, pain-free, college students (12 males, 13 females, mean age 19.24 ± 0.97 years). Twenty computer-controlled heat stimuli were delivered to the non-dominant forearm and CHEPs were recorded at Cz using a 32-channel EEG system. After each stimulus, participants rated the intensity of the heat pain using the 0-100 numerical rating scale. The latency and amplitude of N2, P2 components as well as single-sweep spectral analysis of individual CHEPs were measured offline. For CPM, participants had to submerge their dominant foot into a neutral (32 °C) or noxious (0 °C) water bath. CHEPs and heat pain ratings were recorded in 3 different conditions: without CPM, after neutral CPM (32 °C) and after noxious CPM (0 °C). RESULTS: The noxious CPM induced a facilitatory pain response (p = 0.001) with an increase in heat pain following noxious CPM compared to neutral CPM (p = 0.001) and no CPM (p = 0.001). Changes in CHEPs did not differ between conditions when measured as N2-P2 peak-to-peak amplitude (p = 0.33) but the CPM significantly suppressed the CHEPs-related delta power (p = 0.03). Changes in heat pain in the noxious CPM were predicted by trait catastrophizing variables (p = 0.04). CONCLUSION: The current study revealed that pain facilitatory CPM is related to suppression of CHEPs delta power which could be related to dissociation between brain responses to noxious heat and pain perception.

Cumulative Childhood Adversity as a Risk Factor for Common Chronic Pain Conditions in Young Adults.

OBJECTIVE: Multiple and specific types of childhood adverse events are risk factors for chronic pain conditions. Although both can covary, no study has evaluated one aspect while controlling for the other. Therefore, the current study examined whether more adverse events would be a risk factor for common chronic pain conditions and pain medication use in young adults after controlling for different adversity types such as physical, emotional, and sexual traumatic events or vice versa. METHODS: This cross-sectional study recruited 3,073 undergraduates (72% female, mean age = 18.8 years, SD = 1.4 years) who completed the survey for current health status and early life traumatic events. RESULTS: More adverse events were associated with a 1.2-1.3-fold increase in the odds of any chronic pain, chronic back pain, headache, and dysmenorrhea with adjusting for adversity types, but they were not associated with the risk of comorbid pain conditions and use of pain medications. In contrast, specific adversity types were unrelated to chronic pain conditions when controlling for the number of adverse events. CONCLUSIONS: Cumulative childhood adverse events may be a more relevant risk factor for chronic pain conditions than the experience of a specific type of adverse event. Clinicians and researchers need to evaluate cumulative childhood adversity when assessing its link to chronic pain.

Generalized Pain Sensitization and Endogenous Oxytocin in Individuals With Symptoms of Migraine: A Cross-Sectional Study.

OBJECTIVE: The current study examined pain and neurogenic inflammation responses to topical capsaicin during the interictal period (between headache) and their relationship with plasma oxytocin in individuals with migraine. BACKGROUND: Individuals with migraine can experience generalized (extracephalic) hyperalgesia, which can persist even between headache attacks. Elevated levels of plasma and cerebrospinal fluid oxytocin have been observed during migraine attacks, oxytocin levels being positively associated with the intensity of migraine symptoms. However, whether oxytocin plays a role in the mechanisms of generalized pain sensitization and neurogenic inflammation during the interictal period has not been studied yet. Understanding migraineurs' interictal pain phenotype and endogenous oxytocin might help identify individuals who would benefit from intranasal oxytocin treatment. METHODS: Thirty-two subjects with migraine and 26 healthy controls underwent pain testing. The current study compared capsaicin-induced pain, central sensitization (areas of secondary mechanical allodynia and hyperalgesia), and neurogenic inflammation (capsaicin-induced flare) responses on the nondominant volar forearm between migraineurs and healthy controls. Additionally, we studied plasma oxytocin levels and their relationship to migraine symptoms, experimental pain and affect. RESULTS: The results indicated a significant group effect (P = .019): Migraineurs reported greater capsaicin-induced pain unpleasantness (M = 1.2, SD = 1.4) on a 0-10 scale and showed larger areas of flare (LnM = 2.8, SD = 0.4) than healthy controls (M = 0.5, SD = 0.8; LnM = 2.6, SD = 0.4; ps < .032). In a subgroup analysis, enhanced capsaicin-induced pain unpleasantness was found in the chronic (P = .007), but not the episodic (Ps > .200), migraineurs. The oxytocin levels were elevated in migraineurs and accounted for 18% of the group difference in capsaicin-induced pain unpleasantness. Within migraineurs, interictal oxytocin levels were negatively associated with psychological distress (Ps < .030). However, during the interictal period, pain sensitivity in extracephalic regions and plasma oxytocin levels were unrelated to migraine symptom parameters (Ps > .074). Lastly, the results found no group difference in areas of secondary mechanical allodynia and hyperalgesia (Ps >.298). CONCLUSION: The current study revealed that individuals with migraine exhibit enhanced extracephalic capsaicin-induced pain unpleasantness and flare responses during interictal periods. In addition, migraineurs, especially those with chronic migraine, had slightly elevated interictal oxytocin levels compared to controls, which was associated with their affective component of experimental pain. Therefore, treatment targeting affective pain during the interictal period may help to reduce generalized pain in migraine. Furthermore, endogenous increases in oxytocin may be a compensatory mechanism that may help decrease affective distress in migraineurs. The therapeutic effects of intranasal oxytocin may benefit migraineurs by reducing their affective distress.

Motor Cortex Plasticity during Unilateral Finger Movement with Mirror Visual Feedback.

Plasticity is one of the most important physiological mechanisms underlying motor recovery from brain lesions. Rehabilitation methods, such as mirror visual feedback therapy, which are based on multisensory integration of motor, cognitive, and perceptual processes, are considered effective methods to induce cortical reorganization. The present study investigated 3 different types of visual feedback (direct, mirrored, and blocked visual feedback: DVF, MVF, and BVF, resp.) on M1 cortex excitability and intracortical inhibition/facilitation at rest and during phasic unimanual motor task in 11 healthy individuals. The excitability of the ipsilateral M1 cortex and the intracortical facilitation increased during motor task performance in the DVF and MVF but not in the BVF condition. In addition, MVF induced cortical disinhibition of the ipsilateral hemisphere to the index finger performing the motor task, which was greater when compared to the BVF and restricted to the homologue first dorsal interosseous muscle. The visual feedback is relevant to M1 cortex excitability modulation but the MVF plays a crucial role in promoting changes in intracortical inhibition in comparison to BVF. Altogether, it can be concluded that a combination of motor training with MVF therapy may induce more robust neuroplastic changes through multisensory integration that is relevant to motor rehabilitation.

Influence of spinal cord lesion level and severity on H-reflex excitability and recovery curve.

INTRODUCTION: Changes in spinal reflexes can result from alterations in the spinal cord and descending pathways. We studied whether H-reflex excitability and its recovery depend on the level and/or severity of spinal cord injury (SCI). METHODS: The soleus Hmax and Mmax responses and the H-reflex recovery curve (HRC) at interstimulus intervals (ISIs) ranging from 50 to 1,000 ms were recorded in 38 SCI individuals and 18 healthy subjects. RESULTS: Amplitude of Mmax correlated with level and severity of lesion (smaller amplitude correlated with more severe SCI or with more caudal lesion). Hmax/Mmax correlated only with age in the SCI group. HRC was increased significantly in complete SCI at ISIs < 500 ms and in incomplete SCI at ISIs > 200 ms with respect to healthy subjects. CONCLUSIONS: The changes in spinal reflexes as measured by the H-reflex and its recovery curve after SCI depend on the severity, but not on the level of the lesion.

Long-term use of intrathecal baclofen reduces neuropathic pain and its interference with general activity in spinal cord injury individuals.

INTRODUCTION: Long-term analgesic effect of intrathecal baclofen was reported in individuals with spinal cord injury. We conducted a prospective study to evaluate the effect of intrathecal baclofen on subtypes of neuropathic pain and its interference with general activity. MATERIALS AND METHODS: Nine spinal cord injury individuals who presented with severe spasticity and moderate to severe neuropathic pain received intrathecal baclofen via an implanted pump. We applied the ASIA Impairment Scale to assess spinal cord injury severity. Neuropathic pain was evaluated by numerical rating scale, Neuropathic Pain Symptom Inventory, and Brief Pain Inventory. Evaluations were performed at baseline and after at least 6 months of continuous intrathecal baclofen treatment. RESULTS: Intrathecal baclofen led to significant pain reduction as measured by numerical rating scale, Neuropathic Pain Symptom Inventory, and Brief Pain Inventory (p < 0.05). Improvements were significant for paroxysmal pain and dysesthesia and for pain interference with general activity, as assessed by the Brief Pain Inventory (p < 0.05). There was a significant relationship between the time since spinal cord injury and changes in paroxysmal pain as well as in the total Neuropathic Pain Symptom Inventory score (p < 0.05). The baclofen dose correlated also to the percentage changes in neuropathic pain improvement and sleep (p < 0.003). CONCLUSIONS: The present results provide evidence that intrathecal baclofen effectively reduces neuropathic pain, particularly paroxysmal pain and dysesthesia, and improves pain interference and overall well-being in individuals with spinal cord injury. Clinicians should be aware of this less well-known beneficial effect of intrathecal baclofen and should consider such a treatment option for better control of neuropathic pain in individuals with spinal cord injury.

Diagnostic challenges of functional neurological disorders after covid-19 disease or vaccination: case series and review of the literature.

BACKGROUND: Functional neurological disorders have rarely been described in patients recovering from Covid-19 or after vaccination but they are probably under diagnosed. MATERIAL AND METHODS: Six patients referred for rehabilitation of persistent symptoms and/or sequelae of Coronavirus disease 2019 (COVID-19) were diagnosed with functional neurological disorders. A literature review was conducted to identify reported cases of functional neurological disorders after Covid-19 infection or vaccination. RESULTS: In the current case series, patients diagnosed with functional neurological disorders presented high variability of clinical symptoms including hemiplegia, lower limb unilateral or bilateral paralysis, myoclonus, dystonia, tremor and sensory impairment. Four patients were young females with mild Covid-19 infection without hospital admission. Their neurological symptoms developed over the course of 4 weeks after the beginning of Covid-19 symptoms or vaccine administration with normal ancillary exams. One patient presented overlapping functional neurological symptoms and mild impairment of the left common peroneal nerve after prolonged ICU stay. In addition, all patients in our case series reported other non-motor symptoms such as fatigue, cognitive impairment and diffuse pain or dysesthesia, which are compatible with post Covid-19 condition. CONCLUSIONS: It is important that clinicians recognize functional neurological symptoms and consider it as a differential diagnosis in patients with neurological complications of Covid-19 infection and vaccination.

Transcutaneous Spinal Cord Stimulation Improves Respiratory Muscle Strength and Function in Subjects with Cervical Spinal Cord Injury: Original Research.

(1) Background: Respiratory muscle weakness is common following cervical spinal cord injury (cSCI). Transcutaneous spinal cord stimulation (tSCS) promotes the motor recovery of the upper and lower limbs. tSCS improved breathing and coughing abilities in one subject with tetraplegia. Objective: We therefore hypothesized that tSCS applied at the cervical and thoracic levels could improve respiratory function in cSCI subjects; (2) Methods: This study was a randomized controlled trial. Eleven cSCI subjects received inspiratory muscle training (IMT) alone. Eleven cSCI subjects received tSCS combined with IMT (six of these subjects underwent IMT alone first and then they were given the opportunity to receive tSCS + IMT). The subjects evaluated their sensation of breathlessness/dyspnea and hypophonia compared to pre-SCI using a numerical rating scale. The thoracic muscle strength was assessed by maximum inspiratory (MIP), expiratory pressure (MEP), and spirometric measures. All assessments were conducted at baseline and after the last session. tSCS was applied at C3-4 and Th9-10 at a frequency of 30 Hz for 30 min on 5 consecutive days; (3) Results: Following tSCS + IMT, the subjects reported a significant improvement in breathlessness/dyspnea and hypophonia (p < 0.05). There was also a significant improvement in MIP, MEP, and forced vital capacity (p < 0.05). Following IMT alone, there were no significant changes in any measurement; (4) Conclusions: Current evidence supports the potential of tSCS as an adjunctive therapy to accelerate and enhance the rehabilitation process for respiratory impairments following SCI. However, further research is needed to validate these results and establish the long-term benefits of tSCS in this population.

Morphological instability leading to formation of porous anodic oxide films.

Electrochemical oxidation of metals, in solutions where the oxide is somewhat soluble, produces anodic oxides with highly regular arrangements of pores. Although porous aluminium and titanium oxides have found extensive use in functional nanostructures, pore initiation and self-ordering are not yet understood. Here we present an analysis that examines the roles of oxide dissolution and ionic conduction in the morphological stability of anodic films. We show that patterns of pores with a minimum spacing are possible only within a narrow range of the oxide formation efficiency (the fraction of oxidized metal atoms retained in the film), which should exist when the metal ion charge exceeds two. Experimentally measured efficiencies, over diverse anodizing conditions on both aluminium and titanium, lie within the different ranges predicted for each metal. On the basis of these results, the relationship between dissolution chemistry and the conditions for pore initiation can now be understood in quantitative terms.

Neuropathic pain intensity, unpleasantness, coping strategies, and psychosocial factors after spinal cord injury: an exploratory longitudinal study during the first year.

OBJECTIVE: To determine the temporal relationship between pain-related coping strategies and psychosocial factors with non-evoked neuropathic pain (NP) intensity and unpleasantness in patients during the subacute phase of spinal cord injury (SCI). DESIGN: Exploratory longitudinal study of NP from 2 to 12 months. SETTING: Hospital Nacional de Parapléjicos, Toledo, Spain. SUBJECTS: A maximum of 26 patients with early symptoms of NP after SCI with a neurological level above the Th10 spinal level. OUTCOME MEASURES: Multidimensional Pain Inventory-Spinal Cord Injury Version, Coping Strategies Questionnaire, General 7-day pain intensity and unpleasantness rated with a visual analog scale, Spearman correlation analysis. RESULTS: PAIN-related coping strategies and psychosocial factors remained stable from 2 to 12 months after SCI. Initially pain intensity and unpleasantness were rated independently, but at 6 months were intercorrelated along with "pain severity,""life interference," and "catastrophizing.""Coping self-statements" and "solicitous responses from others" were frequently adopted, compared with "ignoring pain sensations" and "catastrophising." Perception of "pain severity" correlated with "support,""solicitous responses from others,""distracting responses from others," and "life control" at 6 months, while pain intensity and unpleasantness were related to "coping self-statements,""catastrophizing,""distancing from pain," and "praying." CONCLUSIONS: Pilot longitudinal data suggest that pain-related coping strategies are adopted early after subacute SCI, and correlate with both pain intensity and unpleasantness. Future longitudinal studies of SCI with sufficient sample size will be instrumental to determine the causal relationship between psychosocial factors and coping strategies on pain.

Multidisciplinary outpatient rehabilitation of physical and neurological sequelae and persistent symptoms of covid-19: a prospective, observational cohort study.

PURPOSE: This prospective, observational cohort study investigated the effects of multidisciplinary rehabilitation of post Covid-19 sequelae and persistent symptoms and their impact on patients' functioning and quality of life. METHODS: From 58 patients referred for neurorehabilitation, 43 were eligible for and participated in the present study. Before and after 8 weeks of rehabilitation, patients underwent physical, neuropsychological and respiratory evaluations and assessment of functional independence, impact of fatigue and quality of life. RESULTS: Forty of 43 individuals (52 ± 11.4 years, 24 male) completed the rehabilitation program. Fatigue (87.5%), dyspnea and/or shortness of breath (62.5%), and cognitive impairment (37.5%) were reported by both previously hospitalized and home-confined patients. Neurological sequelae (35.5%) were present only in hospitalized patients. After 8 weeks of rehabilitation, patients reported significant improvements in motor functional independence, upper and lower limb functionality, impact of fatigue on daily activities, respiratory muscle strength, cognitive performance, and quality of life. CONCLUSIONS: Post Covid-19 patients present with heterogeneous neurological, physical, and respiratory impairments requiring a multidisciplinary rehabilitation approach to reduce disability and improve functionality and quality of life. A comprehensive assessment of clinical profiles and responses to rehabilitation may facilitate the identification of rehabilitation candidates and help to design effective rehabilitation interventions.Implication for rehabilitationPost Covid-19 patients present multiple, heterogeneous neurological, physical and respiratory impairments that are observed in both previously hospitalized and home-confined patients.Eight weeks of multidisciplinary rehabilitation may significantly reduce disability and improve functionality and quality of life.A comprehensive assessment of their clinical profile and response to rehabilitation may facilitate the identification of rehabilitation candidates and help to design more effective rehabilitation interventions.

Long-interval intracortical inhibition in primary motor cortex related to working memory in middle-aged adults.

Introduction: Excitability of the primary motor cortex measured with TMS has been associated with cognitive dysfunctions in patient populations. However, only a few studies have explored this relationship in healthy adults, and even fewer have considered the role of biological sex. Methods: Ninety-seven healthy middle-aged adults (53 male) completed a TMS protocol and a neuropsychological assessment. Resting Motor Threshold (RMT) and Long-Interval Intracortical Inhibition (LICI) were assessed in the left motor cortex and related to attention, episodic memory, working memory, reasoning, and global cognition composite scores to evaluate the relationship between cortical excitability and cognitive functioning. Results: In the whole sample, there was a significant association between LICI and cognition; specifically, higher motor inhibition was related to better working memory performance. When the sample was broken down by biological sex, LICI was only associated with working memory, reasoning, and global cognition in men. No associations were found between RMT and cognitive functions. Conclusion: Greater intracortical inhibition, measured by LICI, could be a possible marker of working memory in healthy middle-aged adults, and biological sex plays a critical role in this association.

Local Prefrontal Cortex TMS-Induced Reactivity Is Related to Working Memory and Reasoning in Middle-Aged Adults.

INTRODUCTION: The prefrontal cortex (PFC) plays a crucial role in cognition, particularly in executive functions. Cortical reactivity measured with Transcranial Magnetic Stimulation combined with Electroencephalography (TMS-EEG) is altered in pathological conditions, and it may also be a marker of cognitive status in middle-aged adults. In this study, we investigated the associations between cognitive measures and TMS evoked EEG reactivity and explored whether the effects of this relationship were related to neurofilament light chain levels (NfL), a marker of neuroaxonal damage. METHODS: Fifty two healthy middle-aged adults (41-65 years) from the Barcelona Brain Health Initiative cohort underwent TMS-EEG, a comprehensive neuropsychological assessment, and a blood test for NfL levels. Global and Local Mean-Field Power (GMFP/LMFP), two measures of cortical reactivity, were quantified after left prefrontal cortex (L-PFC) stimulation, and cognition was set as the outcome of the regression analysis. The left inferior parietal lobe (L-IPL) was used as a control stimulation condition. RESULTS: Local reactivity was significantly associated with working memory and reasoning only after L-PFC stimulation. No associations were found between NfL and cognition. These specific associations were independent of the status of neuroaxonal damage indexed by the NfL biomarker and remained after adjusting for age, biological sex, and education. CONCLUSION: Our results demonstrate that TMS evoked EEG reactivity at the L-PFC, but not the L-IPL, is related to the cognitive status of middle-aged individuals and independent of NfL levels, and may become a valuable biomarker of frontal lobe-associated cognitive function.

What's going on following acute covid-19? Clinical characteristics of patients in an out-patient rehabilitation program.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients present long-lasting physical and neuropsychological impairment, which may require rehabilitation. OBJECTIVES: The current cross-sectional study characterizes post COVID-19 sequelae and persistent symptoms in patients in an outpatient rehabilitation program. METHODS: Thirty patients [16 post-ICU and 14 non-ICU; median age = 54(43.8-62) years; 19 men] presenting sequelae and/or persistent symptoms (>3 months after acute COVID-19) were selected of 41 patients referred for neurorehabilitation. Patients underwent physical, neuropsychological and respiratory evaluation and assessment of impact of fatigue and quality of life. RESULTS: The main reasons for referral to rehabilitation were: fatigue (86.6%), dyspnea (66.7%), subjective cognitive impairment (46.7%) and neurological sequelae (33.3%). Post-ICU patient presented sequelae of critical illness myopathy and polyneuropathy, stroke and encephalopathy and lower forced vital capacity compared to non-ICU patients. Cognitive impairment was found in 63.3% of patients, with a similar profile in both sub-groups. Increased physical fatigue, anxiety and depression and low quality of life were prevalent irrespective of acute COVID-19 severity. CONCLUSIONS: The variability of post COVID-19 physical and neuropsychological impairment requires a complex screening process both in ICU and non-ICU patients. The high impact of persistent symptoms on daily life activities and quality of life, regardless of acute infection severity, indicate need for rehabilitation.

Cognitive Reserve as a Protective Factor of Mental Health in Middle-Aged Adults Affected by Chronic Pain.

Chronic pain is associated with worse mental health and cognitive impairment, which can be a cause or a consequence of brain structure and function alterations, e.g., maladaptive plasticity, antinociceptive system dysregulation. Cognitive reserve reflects the effectiveness of the internal connections of the brain and it has been shown to be a protective factor in brain damage, slowing cognitive aging or reducing the risk of mental health disorders. The current study explored the impact of chronic pain on psychosocial factors, mental health, and cognition. Furthermore, we aimed to examine the role of cognitive reserve in the relationship between mental health and chronic pain clinical characteristics in middle-aged adults. The study group consisted of 477 volunteers from the Barcelona Brain Health Initiative who completed online surveys on pain, mental health, cognitive reserve, and psychosocial factors (sleep and quality of life). We described the differences in sociodemographic data, psychosocial factors, mental health, and self-perceived cognitive impairment, and neuropsychological assessment, between participants reporting pain compared with those without pain, as well as the main characteristics of the chronic pain group. Finally, to study the role of cognitive reserve in the modulation of the relationship between chronic pain and mental health, we compared variables between subgroups of participants with high/low pain intensity and cognitive reserve. The results showed that chronic pain was reported by 45.5% of middle-aged adults. Our results revealed that participants with chronic pain were older and had worse health status than people without pain. The presence of chronic pain affected working memory, mental health, and daily life activities. Moreover, cognitive reserve moderated the influence of pain intensity on mental health, resulting in less mental health affection in people suffering from high pain intensity with high cognitive reserve. In conclusion, the construct of the cognitive reserve could explain differential susceptibility between chronic pain and its mental health association and be a powerful tool in chronic pain assessment and treatment, principally due to its modifiable nature.

Associations Between Cardiorespiratory Fitness, Cardiovascular Risk, and Cognition Are Mediated by Structural Brain Health in Midlife.

Background Evidence in older adults suggests that higher cardiorespiratory fitness and lower cardiovascular risk are associated with greater cognition. However, given that changes in the brain that lead to cognitive decline begin decades before the onset of symptoms, understanding the mechanisms by which modifiable cardiovascular factors are associated with brain health in midlife is critical and can lead to the development of strategies to promote and maintain brain health as we age. Methods and Results In 501 middle-aged (aged 40-65 years) adult participants of the BBHI (Barcelona Brain Health Initiative), we found differential associations among cardiorespiratory fitness, cardiovascular risk, and cognition and cortical thickness. Higher cardiorespiratory fitness was significantly associated with better visuospatial abilities and frontal loading abstract problem solving (ß=3.16, P=0.049) in the older middle-aged group (aged 55-65 years). In contrast, cardiovascular risk was negatively associated with better visuospatial reasoning and problem-solving abilities (ß=-0.046, P=0.002), flexibility (ß=-0.054, P<0.001), processing speed (ß=-0.115, P<0.001), and memory (ß=-0.120, P<0.001). Cortical thickness in frontal regions mediated the relationship between cardiorespiratory fitness and cognition, whereas cortical thickness in a disperse network spanning multiple cortical regions across both hemispheres mediated the relationship between cardiovascular risk and cognition. Conclusions The relationships between modifiable cardiovascular factors, cardiorespiratory fitness, and cardiovascular risk, and cognition are present in healthy middle-aged adults. These relationships are also mediated by brain structure highlighting a potential mechanistic pathway through which higher cardiorespiratory fitness and lower cardiovascular risk can positively impact cognitive function in midlife.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.