European Journal of Neuroscience

IntroductionThyroid hormones modulate the brain structure during neurogenesis and impact cognition and emotions during the lifetime. It is, therefore, important to understand their association with relevant brain structures during the aging process. MethodsA subset of 1348 older adults from the Alzheimers Disease Neuroimaging Initiative (ADNI) was included. Linear regression was used to study the association between serum thyroid stimulating hormone (TSH) and the Amygdala, Hippocampus, and Entorhinal cortex volumes. Sex and neurodegeneration-related stratifications and comparative bilateral volumetric analyses were performed. ResultsFemales represented 667 (49%) of included cases, and 522 (38.72 %) were healthy controls (HC). A significant positive association was observed between TSH and total Hippocampus volume in mild cognitive impairment (MCI) (adj.{beta}=92 (23, 161), p- value=0.009), while a negative association in dementia participants remained statistically significant ({beta}=-177 (-295, -60), p-value=0.003 and adj.{beta}=-141 (-250, -32), p-value=0.012). There was a significant association between TSH and total Entorhinal cortex volume in the total study population ({beta}=44 (3.9, 85), p-value=0.032 and adj.{beta}=40 (5.1, 75), p-value=0.025). Stratification showed significant associations only in MCI ({beta}=80 (21, 138), p-value=0.007, and adj.{beta}=83 (27, 138), p-value=0.003), and males (adj.{beta}=54 (1.9, 106), p-value=0.042). Similar statistically significant associations were found only in the left Entorhinal cortex. The association between TSH and total Amygdala volume was positive in HC ({beta}=37 (1.6, 73), p- value=0.041) and negative in dementia participants ({beta}=-67 (-128, -6.4), p-value=0.030). None of those results remained statistically significant after adjusting the models. The bilateral volumetric analysis showed significant results only in the right Amygdala and dementia group. ConclusionsDepending on the stratum and side of the volumetric analysis, significant associations were observed between TSH and Hippocampus, Amygdala, and Entorhinal cortex volumes. It is, therefore, crucial to consider the role of sex, neurodegeneration, and laterality when exploring the thyroid-brain interaction in older adults. HighlightsO_LIHigher TSH levels are associated with lower Hippocampus volume on both sides in the dementia group. C_LIO_LILower TSH levels are associated with lower left Entorhinal cortex volume in the mild cognitive impairment and male strata. C_LIO_LIHigher TSH levels are associated with lower right Amygdala volume in the dementia group. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/24314757v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1fc4bd8org.highwire.dtl.DTLVardef@d76a84org.highwire.dtl.DTLVardef@922fbaorg.highwire.dtl.DTLVardef@17b7e7b_HPS_FORMAT_FIGEXP M_FIG C_FIG

Prader-Willi Syndrome (PWS) is a rare genetic condition with multifaceted physical, behavioural and cognitive difficulties that is characterized by hyperphagia and low executive functioning. Food-seeking behaviours may be moderated by hormonal, cognitive, and psychological factors, and are thought to be mediated in part by functional brain abnormalities. Here, we used an experimental protocol integrating eyes opens resting state magnetoencephalography (MEG) - a high-resolution neurophysiological imaging technique - and neuropsychological profiling to understand the relationship between executive functioning, and intrinsic brain activity & functional connectivity in a prospective, cross-sectional cohort with PWS, and a sex-, age- and BMI-matched control group. We observed lower executive functioning in PWS as well as functional dysconnectivity across multiple channels of brain synchrony - in other words, across multiple frequency bands that mediate communication within and between brain networks - in the visual, attentional, and the default mode networks. Moreover, we found brain-wide changes in the topological structure of brain networks in those with PWS, with increased hubness of functional networks, but decreased centrality. However, none of these measures survived multiple comparison correction after correlating with neuropsychological outcomes, although there were moderate effect sizes (degree of association). This is the first study to combine neuropsychology and neurophysiological imaging to show that functional synchrony in multiple brain networks is dysregulated in PWS.

BackgroundReduced inhibitory control is associated with obesity and neuroimaging studies indicate that diminished prefrontal cortex activity influence eating behavior and metabolism. The hypothalamus regulates energy homeostasis and is functionally connected to cortical and subcortical regions especially the frontal areas. ObjectivesWe tested network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in appetite control. MethodsIn a randomized, double-blind parallel group design, 44 adults with overweight or obesity (BMI 30.6 kg/m2, 52.3 % female) received active (anodal or cathodal) or sham 12-channel net-tDCS on the hypothalamus appetite-control network for 25 minutes on three consecutive days while performing a Stop-Signal-Task to measure response inhibition. Before and after stimulation, state questionnaires assessed changes in desire to eat and food craving. Directly after stimulation, participants received a breakfast buffet to evaluate ad-libitum food intake. An oral glucose tolerance test was conducted at follow-up. Resting-state functional MRI was obtained at baseline and follow-up. ResultsThe Stop-Signal Reaction Time (SSRT) was shorter in both active groups versus sham, indicating improved response inhibition. Additionally, a stronger increase in hypothalamic functional connectivity was associated with shorter SSRT. Caloric intake of sweet food was lower in the anodal group versus sham, but no main effects between groups were observed on total and macronutrient intake, food craving ratings and desire to eat. At follow-up, no differences were observed between groups on peripheral metabolism. ConclusionOur study suggests that modulating hypothalamic functional network connectivity patterns via net-tDCS may improve food choice and inhibitory control. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/24318873v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1869c1forg.highwire.dtl.DTLVardef@73e837org.highwire.dtl.DTLVardef@192b3bcorg.highwire.dtl.DTLVardef@5632d0_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIActive net-tDCS groups showed better inhibitory control compared to the sham group. C_LIO_LIStronger increase in hypothalamic functional connectivity associated with better inhibitory control after active net-tDCS. C_LIO_LINo differences were found between the active net-tDCS and sham groups for total kilocaloric intake. C_LIO_LIAnodal net-tDCS showed lower sweet food intake compared to the sham group. C_LI

Aberrant resting-state static functional connectivity of the brain regions, which could be evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA) including rheumatoid arthritis and spondyloarthritis. This static methods for assessing brain functional connections would be too simple to estimate the whole picture of resting-state brain function because it fluctuates over time. The effects of resting-state brain connectivity dynamics for clinical course are unknown in patients with IA. Therefore, we aimed to evaluate dynamic functional connectivity for clinical courses of IA in the context of therapeutic responsiveness to biologics using resting-state fMRI data of 64 patients with IA consisting of two cohorts. We determined representative whole-brain dynamic functional connectivity patterns by k-means++ cluster analysis, and evaluated the association of their occurrence probability and therapeutic outcomes with biologics. We determined four distinct clusters of dynamic functional connectivity in IA patients. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients global assessment. This finding was validated by the second cohort. The whole-brain functional coordination of the cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared to -ineffective patients. In conclusion, dynamic functional connectivity, in particular, frequent emergence of corticocortical connections was associated with clinical outcomes in patients with IA. The coherence of corticocortical interactions might affect modulation of pain, which would be relevant to therapeutic satisfaction. SUMMARYO_LIEffects of resting-state dynamic connectivity on clinical course of inflammatory arthritis regarding therapeutic responsiveness to biologics were assessed by functional magnetic resonance. C_LIO_LIOccurrence probability of corticocortical functional connectivity pattern was associated with favorable therapeutic response in disease activity and patients global assessment in inflammatory arthritis. C_LI

Peripheral neuropathy (PN) is the most common complication of diabetes. It is characterized by sensory loss which often causes major health consequences including foot ulceration, chronic pain, poor mobility and increased risk of falls. However, present treatments do not counteract the cause of the disease, namely lack of sensory feedback, but rather aim at partial and temporal symptoms relief (e.g. analgesics for pain or creams for ulcers healing). Electrical stimulation is a promising solution for sensory restoration, but it is yet unknown if it can elicit perceivable sensations in PN damaged nerves and whether it could lead to any health or functional benefits. To this aim, we designed a wearable sensory neuroprosthesis providing targeted neurostimulation at the ankle level (NeuroStep) restoring feet lost sensations. We tested it in 14 participants with PN, evaluating its effects on functional outcomes and pain, and the cortical activation related to the restored sensations. Our system was able to restore lost sensations in all participants. The nerves of PN participants resulted significantly less excitable and sensitive than healthy individuals (N=22). Thanks to the neurostimulation, participants improved cadence and functional gait, with even stronger improvements in individuals with higher risk of falls. A full day of NeuroStep use led to a clinically significant reduction of 30.4% {+/-} 9.2% in neuropathic pain. Restored sensations activated cortical patterns, as measured via fMRI, similar to the naturally located foot sensations, thus not requiring training by the user. NeuroStep restores intuitive sensations in PN participants, improving mobility and decreasing pain, possibly replacing multiple inefficient treatments. It holds potential to drastically improve patients quality of life thanks to functional and health benefits, while paving the way to new effective neuromodulation treatments.

Video gaming often sparks controversy, though negative effects are mainly linked to gaming disorder, not gaming itself. Research shows that gaming disorder is associated with reduced executive functioning and greater reliance on habitual processes, while recreational gaming may relate to enhanced cognitive functions. However, comprehensive comparisons of cognitive profiles across gaming behaviors remain scarce. Therefore, we aimed to compare the cognitive functioning of non-gamers (NG), recreational gamers (RG), and gaming disorder risk individuals (GDR). Based on the Internet Gaming Disorder Test scores, 114 participants were classified into NG, RG, or GDR groups. Executive functions were assessed using the Go/No-Go, Counting Span, Digit Span, Card Sorting, 1-back and 2-back tasks. Habit learning was measured with the Alternating Serial Reaction Time task. The GDR group showed reduced working memory, performing worse on the Digit Span task than the NG group, and worse on the Counting Span task than both NG and RG groups. Conversely, the RG group displayed enhanced attention-related performance. No group differences emerged in other executive functions or overall habit learning. Interaction analyses revealed a negative relationship between habit learning and inhibitory control/updating across groups, supporting competition theory, while a positive link between working memory and habit learning in NG and GDR groups suggests possible compensatory mechanisms. Overall, this study underscores that cognitive impairments are linked to gaming disorder rather than gaming itself, while recreational gaming may offer cognitive benefits. These findings provide insights into the distinct cognitive profiles of recreational gamers and those at risk of gaming disorder. HighlightsO_LICognitive profiles differ for gaming disorder vs. recreational gaming. C_LIO_LIWorking memory is impaired in individuals at risk of gaming disorder. C_LIO_LIRecreational gaming is linked to enhanced attention-related performance. C_LIO_LIExecutive functions and habits compete with each other, regardless of gaming. C_LIO_LICognitive systems show both competitive and compensatory links. C_LI

Aims/HypothesisType 2 diabetes has a well-established link to cognitive impairment in older adults; however, studies often do not control for adiposity and co-morbid conditions which might mediate this cognitive impairment. To overcome these limitations, we investigated the relation between prediabetes and cognition in youth with overweight/obesity while controlling for adiposity in a cross-sectional ancillary study to the Pathogenesis of Youth Onset Diabetes (PYOD) study. We reasoned that if glucose control directly impacts brain health, then cognitive function should be worse in youth with versus without prediabetes. We also predicted that this effect should be greater on tasks that depend on dopaminergic function, such as working memory and that it may be related to central insulin sensitivity. MethodsWe evaluated 69 youth with overweight/obesity for anthropomorphic and metabolic measures, abdominal adiposity, comprehensive cognitive testing, and the effects of intranasal insulin on cognition, resting state brain activity, and functional connectivity. Oral glucose tolerance tests classified 22 participants as having prediabetes (preT2D+) and 44 participants as having normal glucose control (preT2D-). ResultsGroups did not differ in age, sex, race, diet, or adiposity measures. IQ was significantly lower (p=0.032) in the preT2D+ group compared to the preT2D-group. The preT2D+ group performed worse than the preT2D-group in tasks of working memory (p<.0.001), reaction time (p=0.01), and visuospatial processing (p=0.02). After considering IQ as a model covariate, only spatial working memory showed a significant difference between groups (p=0.002). Insulin sensitivity across the entire sample was negatively correlated with processing speed in two tasks (reaction time index: p=0.022; and trail making test A: p=0.022) and with the sensitivity of the intraparietal sulcus to intranasal insulin administration. Administration of intranasal insulin showed no effect on cognition within or between groups. However, the extent to which intranasal insulin administration influenced caudate functional connectivity with the right intraparietal sulcus (p(FWE) =0.018) and bilateral medial precuneus (p(FWE) =0.03) was correlated with performance on the spatial working memory task. Conclusions/interpretationWe find evidence for the presence of global cognitive impairment in youth with prediabetes that cannot be accounted for by adiposity, as well as a specific deficit in spatial working memory that is not attributable to global cognitive impairment. We identified associations between central insulin sensitivity and both cognition and peripheral insulin sensitivity; however, central insulin sensitivity did not appear to account for the effect of prediabetes on cognition. These findings show that the association between peripheral glucose intolerance and cognition exists early in the course of the disease, prior to the onset of significant comorbid conditions and independently of adiposity. It also suggests the involvement of both generalized and specific mechanisms contributing to cognitive change. Research in ContextO_LIWhat is already known about this subject? (maximum of 3 bullet points) O_LIType 2 diabetes and prediabetes have been associated with an increased risk of dementia and cognitive impairment on dopaminergic tasks C_LIO_LIThe mechanism of this cognitive impairment and if it is dissociable from adiposity or comorbid conditions related to old age is unknown C_LIO_LIIt is unclear whether youth with prediabetes are at risk for cognitive impairment from impaired insulin sensitivity/glucose regulation C_LI C_LI O_LIWhat is the key question? (one bullet point only; formatted as a question) O_LIDo youth with prediabetes show cognitive impairment independent of adiposity, and is this related to insulin sensitivity of dopaminergic systems? C_LI C_LI O_LIWhat are the new findings? (maximum of 3 bullet points) O_LIYouth with prediabetes show global cognitive impairment, as well as particular impairment of spatial working memory, independent of adiposity C_LIO_LIInsulin sensitivity of caudate functional connectivity with right intraparietal sulcus and bilateral precuneus is correlated with prior performance on a spatial working memory task C_LI C_LI O_LIHow might this impact on clinical practice in the foreseeable future? (one bullet point only) O_LIThese findings provide evidence that suggests that youth with prediabetes are at risk for cognitive impairment, indicating early detection and treatment of impaired insulin sensitivity is crucial. C_LI C_LI

Fibromyalgia is associated with elevated levels of comorbid anxiety and depression, together impacting brain morphology possibly reflecting common underlying biological processes. The present study aims to determine the difference in regional myelination in females with fibromyalgia compared to females who do not experience chronic pain and determine the role of the severity of comorbid anxiety and depressive symptoms experienced to mediate this difference in brain myelination. Thirty-three females with and 33 females without (Controls) fibromyalgia were included, for which the severity of depressive and anxiety symptoms were recorded using the Hamilton Anxiety/Depression Rating scales (HAMA/HAMD). Whole-brain three-dimensional T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging scans were collected, and T1w/T2w ratio (myelin maps) derived. Mediation analyses were performed with anxiety and depressive symptoms as mediators of the T1w/T2w ratio differences among the groups. Compared to the control group, the fibromyalgia group lower T1w/T2w values in the left cerebellar lobule VI (pFWEc=0.030) and left cerebellar lobule VIII (pFWEc=0.029). These T1w/T2w values were significantly negatively associated with severity of anxiety and depressive symptoms (all p<0.001). Mediation analyses indicated that the severity of anxiety (but not depressive) symptoms mediated the group difference in T1w/T2w values in cerebellar lobule VI (p=0.012), but not VIII (p=0.813). Lowered cerebellar myelination may reflect chronic states of low-grade inflammation, resulting from the long-term consequences of living with fibromyalgia and related anxiety and depressive symptoms. This remains speculative, and future studies integrating peripheral biological markers of inflammation are warranted to confirm this interpretation.

IntroductionUnderstanding the particularities of thyroid-cognition interactions in the elderly is crucial in assessing the risks and evaluating therapeutic options. MethodsCross-sectional analyses where participants from Alzheimers Disease Neuroimaging Initiative (ADNI) with mild cognitive impairment (MCI) and healthy controls (HC), with complete neurocognitive tests, thyroid stimulating hormone (TSH) <10 {micro}IU/mL, and geriatric depression scale (GDS) <5 were eligible. Linear and logistic regression models, including testing for non-linearity, were performed. Sex and neurodegeneration-related stratifications were explored. ResultsOf the total 1845 participants, with a median age of 73 (IQR: 68, 78); 887 (48%) were females, and 1056 (57%) had MCI. The median TSH level was 1.70 {micro}IU/mL (IQR: 1.15, 2.40). There was a significant association between TSH and cognition only in males (adj. {beta}Males: -0.40; 95% CI: -0.74, -0.07; p-value: 0.019). The odds of being diagnosed with MCI at baseline decreased with higher TSH levels in the total study population (adj. ORTotal: 0.87; 95% CI: 0.79, 0.95; p-value: 0.002), and in males (adj. ORMales: 0.80; 95% CI: 0.70, 0.92; p-value: 0.001). The median TSH value was a significant cutoff in this association. ConclusionsThe association between thyroid function and cognitive decline in the elderly is subject to a sex-driven effect modification and depends on a cutoff value. Plain English summaryThe thyroid-brain association starts at very early stages of the nervous system development and plays a central role in cognition. During the aging process, the thyroid maintains an important role in modulating mental health well-being and associated risks. Older persons are at higher risk of hypothyroidism (lower functioning of thyroid hormone), which is a risk factor for reversible cognitive impairment and dementia. The current study explored the association between thyroid stimulating hormone, a central biomarker of thyroid function, and cognitive function in the elderly. People with dementia, depression, and overt hypothyroidism were excluded to better assess the risks beyond those well-established risk factors. Using different advanced statistical methods, a significant association between thyroid function and cognitive impairment was observed only in males but not females. The association was particularly relevant in older males with lower TSH levels under the median TSH value. Sex-related mechanisms and the reversibility of the association after appropriate intervention are still unclear. It is therefore important to explore thyroid-brain interactions in males and females separately and use methods testing for non-linear associations. The study design based on a cross-sectional analysis of baseline data does not imply causation and randomized longitudinal studies are needed. HighlightsO_LIADAS13 total score was negatively correlated with TSH levels in a statistically significant manner only in males. C_LIO_LIHigher TSH levels predicted significantly lower ADAS13 scores only in males. C_LIO_LILower TSH levels were significantly associated with higher odds of mild cognitive impairment only in males. C_LIO_LIThe median TSH value was a significant cutoff point in the association between thyroid function and mild cognitive impairment. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/24309827v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@10a6486org.highwire.dtl.DTLVardef@14dd678org.highwire.dtl.DTLVardef@13b86e7org.highwire.dtl.DTLVardef@115da96_HPS_FORMAT_FIGEXP M_FIG C_FIG

Adult-onset craniopharyngioma (AoC) is a rare intracranial tumour associated with long-term physical and psychological difficulties. Although prior questionnaire-based studies suggest impairments in social and emotional functioning, no research has experimentally examined social interaction perception in this population. This study employed an online experimental task combined with automated linguistic analysis to explore differences in social interaction perception between AoC patients and healthy volunteers (HVs). Nineteen AoC patients and twenty matched HVs viewed 30 short, naturalistic video clips depicting everyday social interactions. After each video, participants were asked to describe what they saw in as much detail as possible. Responses were analysed using Linguistic Inquiry and Word Count (LIWC) software to assess emotional and social language use across eight pre-registered categories. AoC participants used a higher proportion of social and emotional language across six categories (e.g., affect, social behaviour) despite producing shorter responses overall. Inferential statistics found no significant differences between groups, and Bayesian analysis confirmed there were no differences in the use of pro-social or emotion words between AoC participants and HVs. Contrary to hypotheses, AoC patients did not significantly differ from HVs in their linguistic descriptions of social interactions. This may indicate preserved social interaction perception or may reflect task or sample limitations. Future studies should explore the influence of hypothalamic involvement and oxytocin in social functioning in AoC.

BackgroundCocaine use disorder (CUD) is a worldwide public health condition which is suggested to induce pathological changes in macro- and microstructure. Repetitive transcranial magnetic stimulation (rTMS) has gained attention to induce a reduction in CUD symptoms. Here, we sought to elucidate whether rTMS induces changes on white-matter (WM) microstructure in frontostriatal circuits after two weeks of therapy in patients with CUD, and to test whether baseline WM microstructure of the same circuits has an effect on clinical improvement. This study consisted of a 2-week, parallel group, double-blind, randomized controlled clinical trial (acute phase) (sham [n=23] and active [n=27]), in which patients received two daily sessions of rTMS on the left dorsolateral prefrontal cortex (lDLPFC) as an add-on treatment. T1-weighted and HARDI-DWI at baseline and two weeks after served to evaluate WM microstructure. After active rTMS, results showed a significant increase in neurite density compared to sham rTMS in WM-tracts connecting left DLPFC with left and right vmPFC. Similarly, rTMS showed reduction in orientation dispersion in WM tracts connecting left DLPFC with left caudate nucleus, left thalamus and left vmPFC. Results also showed a greater reduction in craving VAS after rTMS when baseline ICVF was low in WM tracts connecting left caudate nucleus with substantia nigra, left pallidum, and left thalamus with substantia nigra and left pallidum. Our results evidence rTMS-induced WM microstructural changes in fronto-striato-thalamic circuits and support its efficacy as a therapeutic tool in the treatment of CUD. Further, individual clinical improvement may rely on the patients individual structural connectivity integrity. HighlightsO_LIWhite matter microstructural changes between fronto-striato-thalamic regions after 2 weeks of rTMS. C_LIO_LIWhether rTMS would induce microstructural changes may depend on the baseline integrity of the connections between the striatum, thalamus, and the substantia nigra. C_LIO_LIOur results highlight rTMS as a potential therapeutic tool in the treatment of CUD, due to its ability to modulate altered brain microstructure. C_LI

Smoking is a severe addictive health risk behavior and notorious for the high likelihood of relapse after attempted cessation. Such an addictive pattern in smoking has been associated with neurobiological changes in the brain. However, little is known whether the neural changes associated with chronic smoking persist after a long period of successful abstinence. To address this question, we examined resting state EEG (rsEEG) in heavy smokers who have been smoking for 20 years or more, past-smokers who have been successfully abstaining for 20 years or more, and non-smokers. Compared with chronic current- or past-smokers, non-smokers showed higher relative power in theta frequency band, showcasing long-lasting effects of smoking on the brain. A few rsEEG features in alpha frequency band also revealed reversible impacts of smoking, such that only current-smokers, but not past-smokers, showed distinctively higher patterns than non-smokers in their relative power, EEG reactivity--power changes between eyes-closed and eyes-open conditions--, and coherence between channels. Furthermore, rsEEG feature differences between current- and past-smokers were accounted for by individuals self-reported smoking history and nicotine dependence. These data suggest long-lasting impacts of chronic smoking on the brain that are dissociable from the neural changes reversible with long-term abstinence.

BackgroundSchizophrenia (SCZ) and bipolar disorder (BD) are both associated with several autoimmune disorders including rheumatoid arthritis(RA). However, a causal association of SCZ and BD on RA is controversial and elusive. In the present study, we aimed to investigate the causal association of SCZ and BD with RA by using the Mendelian randomization (MR) approach. MethodsA two-sample MR (2SMR) study including the inverse-variance weighted(IVW), weighted median, simple mode, weighted mode and MR-Egger methods were performed. We used summary-level genome-wide association study(GWAS) data in which BD and SCZ are the exposure and RA the outcome. We used data from the Psychiatric Genomics Consortium(PGC) for BD(n= 41,917) and SCZ(n= 33,426) and RA GWAS dataset(n= 2,843) from the European ancestry for RA. ResultsWe found 48 and 52 independent single nucleotide polymorphisms (SNPs, r2 <0.001)) that were significant for respectively BD and SCZ (p <5x10-8). Subsequently, these SNPs were utilized as instrumental variables(IVs) in 2SMR analysis to explore the causality of BD and SCZ on RA. The two out of five MR methods showed a statistically significant inverse causal association between BD and RA: weighted median method(odds ratio (OR), 0.869, [95% CI, 0.764-0.989]; P= 0.034) and inverse-variance weighted(IVW) method (OR, 0.810, [95% CI, 0.689-0.953]; P= 0.011). However, we did not find any significant association of SCZ with RA (OR, 1.008, [95% CI, 0.931-1.092]; P= 0.829, using the IVW method). ConclusionsThese results provide support for an inverse causal association between BD and RA. Further investigation is needed to explain the underlying protective mechanisms in the development of RA. Key messagesO_LIMendelian randomization can offer strong insight into the cause-effect relationships in rheumatology. C_LIO_LIBipolar disorder had a protective effect on rheumatoid arthritis. C_LIO_LIThere is no inverse causal association between schizophrenia and rheumatoid arthritis contrary to the findings from observational studies. C_LI

ObjectiveThe neurotrophic protein brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain function and is affected by acute and chronic stress. We here investigate the patterns of BDNF and cortisol stress reactivity and recovery under the standardized stress protocol of the TSST and the effect of perceived chronic stress on the basal BDNF levels in healthy young men. MethodsTwenty-nine lean young men underwent the Trier Social Stress Test (TSST) and a resting condition. Serum BDNF and cortisol were measured before and repeatedly after both conditions. The perception of chronic stress was assessed by the Trier Inventory for Chronic Stress (TICS). ResultsAfter the TSST, there was a significant increase over time for BDNF and cortisol. Stronger increase in cortisol in response to stress was linked to an accelerated BDNF decline after stress. Basal resting levels of BDNF was significantly predicted by chronic stress perception. ConclusionsThe increased BDNF level following psychosocial stress suggest a stress-induced neuroprotective mechanism. The presumed interplay between BDNF and the HPA-axis indicates an antagonistic relationship of cortisol on BDNF recovery post-stress. Chronically elevated high cortisol levels, as present in chronic stress, could thereby contribute to reduced neurogenesis, and an increased risk of neurodegenerative conditions in persons suffering from chronic stress. HighlightsO_LIAcute psychosocial stress increases serum BDNF and cortisol C_LIO_LIStress-induced cortisol secretion may accelerate the decline of BDNF after stress. C_LIO_LIChronic stress is linked to lower basal serum BDNF levels C_LI

BackgroundMethamphetamine use disorder (MUD) is known to have profound effects on brain structure and cognitive functions. Understanding the extent of these neurobiological changes during the early abstinence period is crucial for developing targeted rehabilitation strategies. ObjectiveThis study aimed to investigate structural brain alterations, and cognitive functions, in early abstinent methamphetamine users compared with healthy controls. MethodsA total of 27 participants were included, comprising 13 participants with MUD in early abstinence (<30 days - mean age: 37.4 {+/-} 9 years, 66% female) and 14 age- and sex-matched healthy controls (mean age: 39.2 {+/-} 11.1 years, 74% female). All subjects underwent brain MRI scans using a 3T scanner, acquiring T1-weighted and myelin-sensitive imaging data. They also completed the Tower of London (TOL) cognitive assessment to evaluate executive functioning. Grey matter volumetric analysis was performed using T1-weighted images, and both regional and global myelin measures were quantified for group comparison. ResultsBehaviourally, MUD participants demonstrated significantly longer execution times for correct solutions (p=0.01), required more attempts to solve problems (p=0.02), and achieved fewer correct solutions on the first attempt (p=0.01). Neuroimaging analyses revealed significant cortical thinning in the left lateral occipital and right lingual cortices among MUD participants. Additionally, cortical volumes of the right superior frontal and lingual cortex were significantly reduced in the MUD group. Vertex-wise analysis further showed a negative correlation between duration of methamphetamine use and the volume of multiple cortical regions. ConclusionsThese findings indicate that methamphetamine use is linked to poorer executive function, and cortical changes, while the absence of group differences in myelin measures suggests that grey-matter is more vulnerable to meth-induced damage than white-matter.

BackgroundThere is growing evidence linking cocaine consumption with a broad spectrum of neurocognitive deficits. Despite of evidence suggesting that the route of administration should be taken into account to assess the short and long term effects of cocaine consumption, to our knowledge no study to date has characterized clinically relevant neuropsychological variables along with physiological variables separately in populations of individuals with histories of smoked cocaine dependence (SCD) and insufflated cocaine hydrochloride dependence (ICD). MethodsThe present study examined a sample of (a) 25 participants who fulfilled criteria for SCD, (b) 22 participants who fulfilled criteria for ICD, and (c) 25 healthy controls matched by age, gender, education, and socioeconomic status. An exhaustive neuropsychological battery was used to assess different cognitive domains (attention, executive functions, fluid intelligence, memory, language and social cognition). We complemented this neuropsychological assessment with the acquisition and analysis of structural (MRI) and functional (fMRI) neuroimaging data. ResultsDifferent routes of administration led to equally different profiles of neurocognitive impairment, with the SCD group being specifically associated with deficits in attention and executive functions. Consistent with risk models, executive function-attention deficit is better explained for age and age onset of consumption initiation. SCD also presented reduced grey matter density relative to ICD in the bilateral caudate, a key area for executive functions and attention. Connectivity between left caudate and inferior frontal regions mediates performance-structure association. ConclusionsCocaine routes of administration are associated to a differential profile that may not be due direct effects of stimulant action but also driven by cognitive and biological differences in key executive functioning and attention areas. This point the critical importance of the routes of administration. This information could inform clinical management and should be taken into account in clinical research.

Cocaine use disorder (CUD) is described as a compulsive urge to seek and consume cocaine despite the inimical consequences. MRI studies from different modalities have shown that CUD patients exhibit structural and/or functional connectivity pathology among several brain regions. Nevertheless, both connectivities are commonly studied and analyzed separately, which may potentially obscure its relationship between them, and with the clinical pathology. Here, we compare and contrast structural and functional brain networks in CUD patients and healthy controls (HC) using multimodal fusion. The sample consisted of 63 (8 females) CUD patients and 42 (9 females) healthy controls (HC), recruited as part of the SUDMEX CONN database. For this, we computed a battery of graph-based measures from multi-shell diffusion-weighted imaging and resting state fc-fMRI to quantify local and global connectivity. Then we used multimodal canonical component analysis plus joint independent component analysis (mCCA+jICA) to compare between techniques, and evaluate group differences and its association with clinical alteration. Unimodal results showed a striatal decrease in the participation coefficient, but applied supervised data fusion revealed other regions with cocaine-related alterations in joint functional communication. When performing multimodal fusion analysis, we observed a higher centrality of the interrelationship and a lower participation coefficient in patients with CUD. In contrast to the unimodal approach, the multimodal fusion method was able to reveal latent information about brain regions involved in impairment due to cocaine abuse. The present results could help in understanding the pathology of CUD in order to develop better pre-treatment/post-treatment intervention designs.

Tobacco smoking is one of the leading causes of preventable death and disease worldwide. Most smokers want to quit, but relapse rates are high. To improve current smoking cessation treatments, a better understanding of the underlying mechanisms of nicotine dependence and related craving behavior is needed. Studies on cue-driven cigarette craving have been a particularly useful tool for investigating the neural mechanisms of drug craving. Here, functional neuroimaging studies in humans have identified a core network of craving-related brain responses to smoking cues that comprises of amygdala, anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex, and ventral striatum. However, most functional Magnetic Resonance Imaging (fMRI) cue-reactivity studies do not adjust their stimuli for emotional valence, a factor assumed to confound craving-driven brain responses to smoking cues. Here, we investigated the influence of emotional valence on key addiction brain areas by disentangling craving- and valence-related brain responses with parametric modulators in 32 smokers. For one of the suggested key regions for addiction, the amygdala, we observed significantly stronger brain responses to the valence aspect of the presented images than to the craving aspect. Our results emphasize the need for carefully selecting stimulus material for cue-reactivity paradigms, in particular with respect to emotional valence. Further, they can help designing future research on teasing apart the diverse psychological dimensions that comprise nicotine dependence, and, therefore, can lead to a more precise mapping of craving-associated brain areas, an important step towards more tailored smoking cessation treatments.

BackgroundEnhanced temporal summation (TS), measured through self-reported pain ratings, has been interpreted as indicative of central sensitisation in fibromyalgia. Greater TS in patients, however, has not been universally observed. It is also unclear whether increased pain report maintains beyond the TS period. MethodsIn this study, we measured TS through continuously reported pain ratings. Fibromyalgia-diagnosed patients (n = 17) and matched pain-free controls (n = 13) rated painful transcutaneous electrical stimulation of various intensity levels in 18 one-minute-long blocks. Pain was rated on a 101-point visual analogue scale. The resulting continuous response was divided into TS (< 15s) and adaptation (15 - 60s) periods. Average pain values were extracted for each period alongside the timing of key events such as maximal pain ratings. The difference in temporal summation and adaptation measures between fibromyalgia and control participants was analysed using mixed-effects modelling. ResultsThe average pain ratings for TS and adaptation periods were not significantly associated with fibromyalgia diagnosis but were with stimulation intensity. The same was true for the magnitude of the maximal rating during TS and the slope leading to that peak rating. The presence of fibromyalgia, however, did predict the time of the maximal TS rating, as well as the value and the time of the maximal adaptation rating. ConclusionsOur study did not find homogeneously increased TS pain ratings. Instead, by utilising continuous pain data we demonstrate for the first time that the time of TS peak rating, as well as the magnitude and time of adaptation peak rating are linked to fibromyalgia diagnosis.

Obesity and metabolic dysfunction are among the strongest risk factors for poor brain and mental health, yet the neural mechanisms linking metabolism, brain, and behaviour remains poorly understood. Here, we provide the first evidence for two distinct large-scale brain network configurations--one associated with metabolic health and another with obesity-- identified using resting-state fMRI data and metabolic phenotypes from a large community cohort (N = 564). While obesity was linked to enhanced coupling between subcortical reward and higher-order cortical networks, metabolic health was characterized by functional integration among default mode, salience, and frontoparietal control regions (metabolic health functional connectivity; MHFC). The MHFC network mediated the relationship between eating restraint and metabolic health, independent on individuals body weight and metabolic status, and it was replicated with data from a different time point. Longitudinal analysis showed that change of MHFC strength predicted metabolic indicators over time, suggesting a role for this network as a potential marker of metabolic resilience. These findings reveal a neurobiological pathway through which executive and interoceptive regulatory systems contribute to metabolic health, offering new insights into the brain mechanisms linking eating behaviour, metabolism, and brain function.