Exploring the psychopathological profile of fibromyalgia: insights from the personality assessment inventory and its association with disease impact.

Background: Fibromyalgia (FM) is a complex rheumatic disorder characterized by chronic nociplastic pain and central sensitization. Psychopathological conditions can influence FM symptoms, which worsen their condition. However, not all patients with FM have psychopathological disorders, indicating a heterogeneous population. Objective: To investigate the psychopathological profile and personality disorders in patients with FM and its relationship impact on this disease. Methods: An observational and cross-sectional comparative study was conducted with a sample of 90 women, mean age 48.7 years (SD = 8.12), from Hospital del Mar, Barcelona. The Personality Assessment Inventory (PAI) and the Fibromyalgia Impact Questionnaire (FIQ) were used for assessment. Results: FM patients predominantly exhibited psychopathological profiles resembling affective disorders (37.7%) and Cluster C personality disorders (58.8%). The severity of FM's impact was related to affective disorder symptoms, hypervigilance, derealization, somatization, and Cluster B personality disorder (emotional instability). Different rheumatic symptoms correlated with specific psychopathological patterns. Increased somatic symptoms on the FIQ were related to an unstable and dependent personality, while heightened emotional symptoms on the FIQ were associated with avoidance, borderline traits, and passive-aggressive reactions. Conclusion: Recognizing psychopathological aspects is crucial for managing FM. The PAI is a valuable tool for establishing its psychopathological multidimensional profile, which predominantly shows an affective spectrum conditions and comorbid Cluster C personality disorder, exacerbating the disease's impact.

Psychometric Properties and Normative Data of the Spanish UPPS-P Impulsive Behavior Scale in Adolescents.

Impulsivity is a multidimensional construct linked to a broad spectrum of psychopathological and neuropsychological disorders. The UPPS-P model has emerged as a valuable tool for assessing impulsivity from a multi-dimensional perspective. Despite its relevance, few studies have examined the psychometric properties of the UPPS-P scale scores in a large, representative sample of adolescents. This study aims to evaluate the psychometric properties of the Spanish UPPS-P in adolescents and to establish normative data for this population in Spain. To this end, 9024 students aged 11-19 from 66 different Spanish high schools were included. The fit for the expected 5-factor model, assessed through confirmatory factor analysis, was inadequate (CFI and TLI ≤ .85, RMSEA = .063), but becomes satisfactory when employing the more flexible ESEM approach (CFI and TLI ≥ .94, RMSEA = .038), which was invariant across gender and age. Internal consistency reliability was satisfactory (ω = .83 to .94). Convergent validity with the Barratt Impulsiveness Scale-11-A total score was good (r = .53 to .60). We provide population norms of the UPPS-P, which may help practitioners to interpret the UPPS-P scores of adolescents from the general population in Spain. Subsequent research should explore implications for both clinical and non-clinical settings.

Functional structure of local connections and differentiation of cerebral cortex areas in the neonate.

Neuroimaging research on functional connectivity can provide valuable information on the developmental differentiation of the infant cerebral cortex into its functional areas. We examined healthy neonates to comprehensively map brain functional connectivity using a combination of local measures that uniquely capture the rich spatial structure of cerebral cortex functional connections. Optimal functional MRI scans were obtained in 61 neonates. Local functional connectivity maps were based on Iso-Distance Average Correlation (IDAC) measures. Single distance maps and maps combining three distinct IDAC measures were used to assess different levels of cortical area functional differentiation. A set of brain areas showed higher connectivity than the rest of the brain parenchyma in each local distance map. These areas were consistent with those supporting basic aspects of the neonatal repertoire of adaptive behaviors and included the sensorimotor, auditory and visual cortices, the frontal operculum/anterior insula (relevant for sucking, swallowing and the sense of taste), paracentral lobule (processing anal and urethral sphincter activity), default mode network (relevant for self-awareness), and limbic-emotional structures such as the anterior cingulate cortex, amygdala and hippocampus. However, the results also indicate that brain areas presumed to be actively developing may not necessarily be mature. In fact, combined distance, second-level maps confirmed that the functional differentiation of the cerebral cortex into functional areas in neonates is far from complete. Our results provide a more comprehensive understanding of the developing brain systems, while also highlighting the substantial developmental journey that the neonatal brain must undergo to reach adulthood.

Mapping alterations in the local synchrony of the cerebral cortex in schizophrenia.

BACKGROUND: Observations from different fields of research coincide in indicating that a defective gamma-aminobutyric acid (GABA) interneuron system may be among the primary factors accounting for the varied clinical expression of schizophrenia. GABA interneuron deficiency is locally expressed in the form of neural activity desynchronization. We mapped the functional anatomy of local synchrony in the cerebral cortex in schizophrenia using functional connectivity MRI. METHODS: Data from 86 patients with schizophrenia and 137 control subjects were obtained from publicly available repositories. Resting-state functional connectivity maps based on Iso-Distant Average Correlation measures across three distances were estimated detailing the local functional structure of the cerebral cortex. RESULTS: Patients with schizophrenia showed weaker local functional connectivity (i.e., lower MRI signal synchrony) in (i) prefrontal lobe areas, (ii) somatosensory, auditory, visual, and motor cortices, (iii) paralimbic system at the anterior insula and anterior cingulate cortex, and (iv) hippocampus. The distribution of the defect in cortical area synchrony largely coincided with the synchronization effect of the GABA agonist alprazolam previously observed using identical functional connectivity measures. There was also a notable resemblance between the anatomy of our findings and cortical areas showing higher density of parvalbumin (prefrontal lobe and sensory cortices) and somatostatin (anterior insula and anterior cingulate cortex) GABA interneurons in humans. CONCLUSIONS: Our results thus provide detail of the functional anatomy of synchrony changes in the cerebral cortex in schizophrenia and suggest which elements of the interneuron system are affected. Such information could ultimately be relevant in the search for specific treatments.

The effects of exposure to road traffic noise at school on central auditory pathway functional connectivity.

As the world becomes more urbanized, more people become exposed to traffic and the risks associated with a higher exposure to road traffic noise increase. Excessive exposure to environmental noise could potentially interfere with functional maturation of the auditory brain in developing individuals. The aim of the present study was to assess the association between exposure to annual average road traffic noise (LAeq) in schools and functional connectivity of key elements of the central auditory pathway in schoolchildren. A total of 229 children from 34 representative schools in the city of Barcelona with ages between 8 and 12 years (49.2% girls) were evaluated. LAeq was obtained as the mean of 2-consecutive day measurements inside classrooms before lessons started following standard procedures to obtain an indicator of long-term road traffic noise levels. A region-of-interest functional connectivity Magnetic Resonance Imaging (MRI) approach was adopted. Functional connectivity maps were generated for the inferior colliculus, medial geniculate body of the thalamus and primary auditory cortex as key levels of the central auditory pathway. Road traffic noise in schools was significantly associated with stronger connectivity between the inferior colliculus and a bilateral thalamic region adjacent to the medial geniculate body, and with stronger connectivity between the medial geniculate body and a bilateral brainstem region adjacent to the inferior colliculus. Such a functional connectivity strengthening effect did not extend to the cerebral cortex. The anatomy of the association implicating subcortical relays suggests that prolonged road traffic noise exposure in developing individuals may accelerate maturation in the basic elements of the auditory pathway. Future research is warranted to establish whether such a faster maturation in early pathway levels may ultimately reduce the developing potential in the whole auditory system.

Central Sensitization and Chronic Pain Personality Profile: Is There New Evidence? A Case-Control Study.

BACKGROUND: Personality traits are relevant for pain perception in persistent pain disorders, although they have not been studied in depth in sensitized and nonsensitized patients with knee osteoarthritis (OA). OBJECTIVE: To explain and compare the personality profile of patients with OA, with and without central sensitization (CS), and fibromyalgia (FM). SETTING: Participants were selected at the Rheumatology Department in two major hospitals in Spain. PARTICIPANTS: Case-control study where the sample consists of 15 patients with OA and CS (OA-CS), 31 OA without CS (OA-noCS), 47 FM, and 22 controls. We used a rigorous and systematic process that ensured the sample strictly fulfilled all the inclusion/exclusion criteria, so the sample is very well delimited. PRIMARY OUTCOME MEASURES: Personality was assessed by the Temperament and Character Inventory of Cloninger. RESULTS: The percentile in harm-avoidance dimension for the FM group is higher compared to OA groups and controls. The most frequent temperamental profiles in patients are cautious, methodical, and explosive. Patients with FM are more likely to report larger scores in harm-avoidance, with an increase in logistic regression adjusted odds ratio (ORadj) between 4.2% and 70.2%. CONCLUSIONS: Harm-avoidance seems to be the most important dimension in personality patients with chronic pain, as previously found. We found no differences between OA groups and between sensitized groups, but there are differences between FM and OA-noCS, so harm-avoidance might be the key to describe personality in patients with CS rather than the presence of prolonged pain, as found in the literature before.

Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Effects of remifentanil on brain responses to noxious stimuli during deep propofol sedation.

BACKGROUND: The safety of anaesthesia has improved as a result of better control of anaesthetic depth. However, conventional monitoring does not inform on the nature of nociceptive processes during unconsciousness. A means of inferring the quality of potentially painful experiences could derive from analysis of brain activity using neuroimaging. We have evaluated the dose effects of remifentanil on brain response to noxious stimuli during deep sedation and spontaneous breathing. METHODS: Optimal data were obtained in 26 healthy subjects. Pressure stimulation that proved to be moderately painful before the experiment was applied to the thumbnail. Functional MRI was acquired in 4-min periods at low (0.5 ng ml-1), medium (1 ng ml-1), and high (1.5 ng ml-1) target plasma concentrations of remifentanil at a stable background infusion of propofol adjusted to induce a state of light unconsciousness. RESULTS: At low remifentanil doses, we observed partial activation in brain areas processing sensory-discriminative and emotional-affective aspects of pain. At medium doses, relevant changes were identified in structures highly sensitive to general brain arousal, including the brainstem, cerebellum, thalamus, auditory and visual cortices, and the frontal lobe. At high doses, no significant activation was observed. CONCLUSIONS: The response to moderately intense focal pressure in pain-related brain networks is effectively eliminated with safe remifentanil doses. However, the safety margin in deep sedation-analgesia would be narrowed in minimising not only nociceptive responses, but also arousal-related biological stress.

Effectiveness of antitussives, anticholinergics, and honey versus usual care in adults with uncomplicated acute bronchitis: a multiarm randomized clinical trial.

BACKGROUND: Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking. OBJECTIVE: We compared the effectiveness of 3 symptomatic therapies and usual care in acute bronchitis. METHODS: Multicenter, pragmatic, multiarm parallel group, open randomized trial in primary care (ClinicalTrials.gov, Identifier: NCT03738917) was conducted in Catalonia. Patients ≥18 with uncomplicated acute bronchitis, with cough<3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough (7-point Likert scale), were randomized to usual care, dextromethorphan 15 mg t.i.d., ipratropium bromide inhaler 20 µg 2 puffs t.i.d, or 30 mg of honey t.i.d., all taken for up to 14 days. The main outcome measure was the number of days with moderate-to-severe cough. A symptom diary was given. A second visit was scheduled at days 2-3 for assessing evolution, with 2 more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance, and complications. RESULTS: We failed to achieve the sample size scheduled due to the COVID-19 pandemic. We finally recruited 194 patients. The median number of days with moderate-to-severe cough (score ≥ 3) in the usual care arm was 5 (interquartile range [IQR], 4, 8.75), 5 in the ipratropium bromide arm (IQR, 3, 8), 5 in the dextromethorphan arm (IQR, 4, 9.75), and 6 in the honey arm (IQR, 3.5, 7). The same results were obtained in the Kaplan-Meier survival analysis for the median survival time of each arm with the usual care as the reference group. CONCLUSION: The symptomatic treatment evaluated has shown to be ineffective against cough.

Cough is the most frequent symptom reported by patients with lower respiratory tract infections. Despite being a defense mechanism, cough is unpleasant and negatively affects sleep and overall well-being. Accordingly, many patients with acute cough seek medical help to mitigate symptoms and reduce their duration despite the typically self-limiting nature of the condition. In this randomized clinical trial, we explored the benefit of 3 common symptomatic treatments recommended in some guidelines for relieving this symptom during the course of uncomplicated acute bronchitis, a cough suppressant, an inhaler, and honey intake. Although the total number of patients initially expected could not be achieved due to the disruption caused by the COVID-19 pandemic, the results of our study demonstrate a lack of efficacy of these products as the number of days of severe-to-moderate cough was similar in the 3 arms and comparable to the group of patients allocated to usual care.

Distinctive alterations in the functional anatomy of the cerebral cortex in pain-sensitized osteoarthritis and fibromyalgia patients.

BACKGROUND: Pain-sensitized osteoarthritis and fibromyalgia patients characteristically show nociceptive system augmented responsiveness as a common feature. However, sensitization can be originally related to the peripheral injury in osteoarthritis patients, whereas pain and bodily discomfort spontaneously occur in fibromyalgia with no apparent origin. We investigated the distinct functional repercussion of pain sensitization in the cerebral cortex in both conditions. METHODS: Thirty-one pain-sensitized knee osteoarthritis patients and 38 fibromyalgia patients were compared with matched control groups. And new samples of 34 sensitized knee osteoarthritis and 63 fibromyalgia patients were used to directly compare each condition. A combined measure of local functional connectivity was estimated to map functional alterations in the cerebral cortex at rest. RESULTS: In osteoarthritis, weaker local connectivity was identified in the insula, which is a cortical area processing important aspects of the brain response to painful stimulation. In contrast, fibromyalgia patients showed weaker connectivity in the sensorimotor cortex extensively affecting the cortical representation of the body. CONCLUSIONS: In osteoarthritis, weaker insular cortex connectivity is compatible with reduced neural activity during metabolic recovery after repeated activation. In the fibromyalgia neurophysiological context, weaker connectivity may better express both reduced neural activity and increased excitability, particularly affecting the sensorimotor cortex in patients with spontaneous body pain. Such a combination is compatible with a central gain enhancement mechanism, where low sensory tolerance results from the over-amplification of central sensory reception to compensate a presumably weak sensory input. We propose that deficient proprioception could be a factor contributing to weak sensory input.

Neurogenetics of Dynamic Connectivity Patterns Associated With Obsessive-Compulsive Symptoms in Healthy Children.

Background: Obsessive-compulsive symptoms (OCSs) during childhood predispose to obsessive-compulsive disorder and have been associated with changes in brain circuits altered in obsessive-compulsive disorder samples. OCSs may arise from disturbed glutamatergic neurotransmission, impairing cognitive oscillations and promoting overstable functional states. Methods: A total of 227 healthy children completed the Obsessive Compulsive Inventory-Child Version and underwent a resting-state functional magnetic resonance imaging examination. Genome-wide data were obtained from 149 of them. We used a graph theory-based approach and characterized associations between OCSs and dynamic functional connectivity (dFC). dFC evaluates fluctuations over time in FC between brain regions, which allows characterizing regions with stable connectivity patterns (attractors). We then compared the spatial similarity between OCS-dFC correlation maps and mappings of genetic expression across brain regions to identify genes potentially associated with connectivity changes. In post hoc analyses, we investigated which specific single nucleotide polymorphisms of these genes moderated the association between OCSs and patterns of dFC. Results: OCSs correlated with decreased attractor properties in the left ventral putamen and increased attractor properties in (pre)motor areas and the left hippocampus. At the specific symptom level, increased attractor properties in the right superior parietal cortex correlated with ordering symptoms. In the hippocampus, we identified two single nucleotide polymorphisms in glutamatergic neurotransmission genes (GRM7, GNAQ) that moderated the association between OCSs and attractor features. Conclusions: We provide evidence that in healthy children, the association between dFC changes and OCSs may be mapped onto brain circuits predicted by prevailing neurobiological models of obsessive-compulsive disorder. Moreover, our findings support the involvement of glutamatergic neurotransmission in such brain network changes.

Shape analysis of subcortical structures in obsessive-compulsive disorder and the relationship with comorbid anxiety, depression, and medication use: A meta-analysis by the OCD Brain Imaging Consortium.

OBJECTIVE: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients have highlighted the important role of deep gray matter structures. Less work has however focused on subcortical shape in OCD patients. METHODS: Here we pooled brain MRI scans from 412 OCD patients and 368 controls to perform a meta-analysis utilizing the ENIGMA-Shape protocol. In addition, we investigated modulating effects of medication status, comorbid anxiety or depression, and disease duration on subcortical shape. RESULTS: There was no significant difference in shape thickness or surface area between OCD patients and healthy controls. For the subgroup analyses, OCD patients with comorbid depression or anxiety had lower thickness of the hippocampus and caudate nucleus and higher thickness of the putamen and pallidum compared to controls. OCD patients with comorbid depression had lower shape surface area in the thalamus, caudate nucleus, putamen, hippocampus, and nucleus accumbens and higher shape surface area in the pallidum. OCD patients with comorbid anxiety had lower shape surface area in the putamen and the left caudate nucleus and higher shape surface area in the pallidum and the right caudate nucleus. Further, OCD patients on medication had lower shape thickness of the putamen, thalamus, and hippocampus and higher thickness of the pallidum and caudate nucleus, as well as lower shape surface area in the hippocampus and amygdala and higher surface area in the putamen, pallidum, and caudate nucleus compared to controls. There were no significant differences between OCD patients without co-morbid anxiety and/or depression and healthy controls on shape measures. In addition, there were also no significant differences between OCD patients not using medication and healthy controls. CONCLUSIONS: The findings here are partly consistent with prior work on brain volumes in OCD, insofar as they emphasize that alterations in subcortical brain morphology are associated with comorbidity and medication status. Further work is needed to understand the biological processes contributing to subcortical shape.

Exposure to road traffic noise and cognitive development in schoolchildren in Barcelona, Spain: A population-based cohort study.

BACKGROUND: Road traffic noise is a prevalent and known health hazard. However, little is known yet about its effect on children's cognition. We aimed to study the association between exposure to road traffic noise and the development of working memory and attention in primary school children, considering school-outdoor and school-indoor annual average noise levels and noise fluctuation characteristics, as well as home-outdoor noise exposure. METHODS AND FINDINGS: We followed up a population-based sample of 2,680 children aged 7 to 10 years from 38 schools in Barcelona (Catalonia, Spain) between January 2012 to March 2013. Children underwent computerised cognitive tests 4 times (n = 10,112), for working memory (2-back task, detectability), complex working memory (3-back task, detectability), and inattentiveness (Attention Network Task, hit reaction time standard error, in milliseconds). Road traffic noise was measured indoors and outdoors at schools, at the start of the school year, using standard protocols to obtain A-weighted equivalent sound pressure levels, i.e., annual average levels scaled to human hearing, for the daytime (daytime LAeq, in dB). We also derived fluctuation indicators out of the measurements (noise intermittency ratio, %; and number of noise events) and obtained individual estimated indoor noise levels (LAeq) correcting for classroom orientation and classroom change between years. Home-outdoor noise exposure at home (Lden, i.e., EU indicator for the 24-hour annual average levels) was estimated using Barcelona's noise map for year 2012, according to the European Noise Directive (2002). We used linear mixed models to evaluate the association between exposure to noise and cognitive development adjusting for age, sex, maternal education, socioeconomical vulnerability index at home, indoor or outdoor traffic-related air pollution (TRAP) for corresponding school models or outdoor nitrogen dioxide (NO2) for home models. Child and school were included as nested random effects. The median age (percentile 25, percentile 75) of children in visit 1 was 8.5 (7.8; 9.3) years, 49.9% were girls, and 50% of the schools were public. School-outdoor exposure to road traffic noise was associated with a slower development in working memory (2-back and 3-back) and greater inattentiveness over 1 year in children, both for the average noise level (e.g., ‒4.83 points [95% CI: ‒7.21, ‒2.45], p-value < 0.001, in 2-back detectability per 5 dB in street levels) and noise fluctuation (e.g., ‒4.38 [‒7.08, ‒1.67], p-value = 0.002, per 50 noise events at street level). Individual exposure to the road traffic average noise level in classrooms was only associated with inattentiveness (2.49 ms [0, 4.81], p-value = 0.050, per 5 dB), whereas indoor noise fluctuation was consistently associated with all outcomes. Home-outdoor noise exposure was not associated with the outcomes. Study limitations include a potential lack of generalizability (58% of mothers with university degree in our study versus 50% in the region) and the lack of past noise exposure assessment. CONCLUSIONS: We observed that exposure to road traffic noise at school, but not at home, was associated with slower development of working memory, complex working memory, and attention in schoolchildren over 1 year. Associations with noise fluctuation indicators were more evident than with average noise levels in classrooms.

One Year of Recombinant Human Growth Hormone Treatment in Adults with Prader-Willi Syndrome Improves Body Composition, Motor Skills and Brain Functional Activity in the Cerebellum.

We compared body composition, biochemical parameters, motor function, and brain neural activation in 27 adults with Prader-Willi syndrome and growth-hormone deficiency versus age-and sex-matched controls and baseline versus posttreatment values of these parameters after one year of recombinant human growth hormone (rhGH) treatment. To study body composition, we analyzed percentage of fat mass, percentage of lean mass, and muscle-mass surrogate variables from dual X-ray absorptiometry. Biochemical parameters analyzed included IGF-I, glucose metabolism, and myokines (myostatin, irisin, and IL6). To explore muscle function, we used dynamometer-measured handgrip strength, the Timed Up and Go (TUG) test, and the Berg Balance Scale (BBS). To study brain activation, we acquired functional magnetic resonance images during three motor tasks of varying complexity. After one year of treatment, we observed an increase in lean mass and its surrogates, a decrease in fat mass, improvements in TUG test and BBS scores, and increased neural activation in certain cerebellar areas. The treatment did not significantly worsen glucose metabolism, and no side-effects were reported. Our findings support the benefits of rhGH treatment in adults with Prader-Willi syndrome and growth-hormone deficiency on body composition and suggest that it may also improve balance and brain neural activation.

The neurologic pain signature responds to nonsteroidal anti-inflammatory treatment vs placebo in knee osteoarthritis.

INTRODUCTION: Many drug trials for chronic pain fail because of high placebo response rates in primary endpoints. Neurophysiological measures can help identify pain-linked pathophysiology and treatment mechanisms. They can also help guide early stop/go decisions, particularly if they respond to verum treatment but not placebo. The neurologic pain signature (NPS), an fMRI-based measure that tracks evoked pain in 40 published samples and is insensitive to placebo in healthy adults, provides a potentially useful neurophysiological measure linked to nociceptive pain. OBJECTIVES: This study aims to validate the NPS in knee osteoarthritis (OA) patients and test the effects of naproxen on this signature. METHODS: In 2 studies (50 patients, 64.6 years, 75% females), we (1) test the NPS and other control signatures related to negative emotion in knee OA pain patients; (2) test the effect of placebo treatments; and (3) test the effect of naproxen, a routinely prescribed nonsteroidal anti-inflammatory drug in OA. RESULTS: The NPS was activated during knee pain in OA (d = 1.51, P < 0.001) and did not respond to placebo (d = 0.12, P = 0.23). A single dose of naproxen reduced NPS responses (vs placebo, NPS d = 0.34, P = 0.03 and pronociceptive NPS component d = 0.38, P = 0.02). Naproxen effects were specific for the NPS and did not appear in other control signatures. CONCLUSION: This study provides preliminary evidence that fMRI-based measures, validated for nociceptive pain, respond to acute OA pain, do not appear sensitive to placebo, and are mild-to-moderately sensitive to naproxen.

Tapentadol effects on brain response to pain in sensitized patients with knee osteoarthritis.

OBJECTIVE: Pain sensitization, in the form of knee tenderness and anatomically spread hyperalgesia, is notably common in patients with knee OA and is often refractory to conventional interventions. Tapentadol, as an opioid receptor agonist and noradrenaline reuptake inhibitor, has been proposed as a potentially effective symptomatic treatment for pain-sensitized OA patients. We empirically tested whether tapentadol could attenuate brain response to painful stimulation on the tender knee using functional MRI. METHODS: Painful pressure stimulation was applied to the articular interline and the tibial surface, a commonly sensitized site surrounding the joint. Thirty patients completed the crossover trial designed to compare prolonged release tapentadol and placebo effects administered over 14 days. RESULTS: We found no effects in the direction of the prediction. Instead, patients administered with tapentadol showed stronger activation in response to pressure on the tender site in the right prefrontal cortex and somatosensory cortices. The somatosensory effect was compatible with the spread of neural activation around the knee cortical representation. Consistent with the functional MRI findings, the patients showed higher clinical ratings of pain sensitization under tapentadol and a significant positive association was identified between the number of tapentadol tablets and the evoked subjective pain. CONCLUSION: The tapentadol effect paradoxically involved both the spread of the somatosensory cortex response and a stronger activation in prefrontal areas with a recognized role in the appraisal of pain sensations. Further studies are warranted to explore how OA patients may benefit from powerful analgesic drugs without the associated risks of prolonged use. TRIAL REGISTRATION: EudraCT, https://eudract.ema.europa.eu, 2016-005082-31.

Effects of Mixing Energy Drinks With Alcohol on Driving-Related Skills.

BACKGROUND: Energy drinks (EDs) reduce sleepiness and fatigue and improve driving performance whereas alcohol does just the opposite. Although it is a trendy combination among young people, the effects of alcohol mixed with EDs on driving performance have been poorly studied. The aim was to assess if there is an interaction between the effects of both drinks on driving-related skills as well as perceptions about driving ability. METHODS: We conducted a randomized, double-blind, and placebo-controlled 4-way crossover clinical trial. Participants were 16 healthy volunteers. Interventions of 60 g of ethanol and 750 mL of Red Bull (RB) were administered in 2 separated doses. Conditions were alcohol + RB placebo, alcohol + RB, alcohol placebo + RB, and both placebos. Objective performance was assessed using a tracking test and simple reaction time, N-Back, and movement estimation tasks. Additionally, willingness to drive, other subjective effects, and ethanol and caffeine blood concentrations were also measured. RESULTS: Alcohol increased the time outside the road in the tracking test and increased simple reaction time, but the addition of RB had no main or interaction effects on performance. Nonetheless, driving-related skills after alcohol + RB were better than after alcohol alone. Willingness to drive increased with the combination of drinks. RB also reduced alcohol-induced sedation whereas drunkenness did not change. These effects were seen even though alcohol + RB increased alcohol (14.8%) and caffeine plasma concentrations (17.6%). CONCLUSIONS: Mixing EDs with alcohol predisposes consumers to drive under alcohol influence, perhaps in part because EDs counteract its detrimental effects on driving-related skills. Clinicaltrials.gov: NCT02771587.

Mapping the neural systems driving breathing at the transition to unconsciousness.

After falling asleep, the brain needs to detach from waking activity and reorganize into a functionally distinct state. A functional MRI (fMRI) study has recently revealed that the transition to unconsciousness induced by propofol involves a global decline of brain activity followed by a transient reduction in cortico-subcortical coupling. We have analyzed the relationships between transitional brain activity and breathing changes as one example of a vital function that needs the brain to readapt. Thirty healthy participants were originally examined. The analysis involved the correlation between breathing and fMRI signal upon loss of consciousness. We proposed that a decrease in ventilation would be coupled to the initial decline in fMRI signal in brain areas relevant for modulating breathing in the awake state, and that the subsequent recovery would be coupled to fMRI signal in structures relevant for controlling breathing during the unconscious state. Results showed that a slight reduction in breathing from wakefulness to unconsciousness was distinctively associated with decreased activity in brain systems underlying different aspects of consciousness including the prefrontal cortex, the default mode network and somatosensory areas. Breathing recovery was distinctively coupled to activity in deep brain structures controlling basic behaviors such as the hypothalamus and amygdala. Activity in the brainstem, cerebellum and hippocampus was associated with breathing variations in both states. Therefore, our brain maps illustrate potential drives to breathe, unique to wakefulness, in the form of brain systems underlying cognitive awareness, self-awareness and sensory awareness, and to unconsciousness involving structures controlling instinctive and homeostatic behaviors.

Hunger and Satiety Peptides: Is There a Pattern to Classify Patients with Prader-Willi Syndrome?

Hyperphagia is one of the main problems of patients with Prader-Willi syndrome (PWS) to cope with everyday life. The underlying mechanisms are not yet well understood. Gut-brain hormones are an interrelated network that may be at least partially involved. We aimed to study the hormonal profile of PWS patients in comparison with obese and healthy controls. Thirty adult PWS patients (15 men; age 27.5 ± 8.02 years; BMI 32.4 ± 8.14 kg/m2), 30 obese and 30 healthy controls were studied before and after eating a hypercaloric liquid diet. Plasma brain-derived neurotrophic factor (BDNF), leptin, total and active ghrelin, peptide YY (PYY), pancreatic polypeptide (PP), Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and amylin were determined at times 0', 30', 60' and 120'. Cluster analysis was used. When considering all peptides together, two clusters were established according to fasting hormonal standardized concentrations. Cluster 1 encompassed most of obese (25/30) and healthy controls (28/30). By contrast, the majority of patients with PWS were located in Cluster 2 (23/27) and presented a similar fasting profile with hyperghrelinemia, high levels of leptin, PYY, GIP and GLP-1, compared to Cluster 1; that may reflect a dysfunction of these hunger/satiety hormones. When peptide behavior over the time was considered, PP concentrations were not sustained postprandially from 60 min onwards in Cluster 2. BDNF and amylin did not help to differentiate the two clusters. Thus, cluster analysis could be a good tool to distinguish and characterize the differences in hormone responses between PWS and obese or healthy controls.