BACKGROUND: In autism spectrum condition (ASC), altered predictions (priors) or prediction errors have been hypothesized to increase the influence of bottom-up sensory input, relative to top-down prior knowledge. Such alterations could account for several autistic features, but their empirical basis is unclear. In neurotypical individuals (NT), multiple neuroimaging meta-analyses have aimed to outline domain-general ‘prediction networks’ of the brain. However, there has not been a similar meta-analysis in autism.METHODS: We searched the literature for functional magnetic resonance imaging and magnetoencephalography studies with autistic participants. The contrasts that explicitly or implicitly involved the processing of priors/predictions and prediction errors were selected. Contrasts were divided into those that reported stronger activation in the ASC group compared to the NT group, and vice versa. We then tested the convergence of differences between the groups in two activation likelihood estimation meta-analyses.RESULTS: Activation differences in eight contrasts reporting stronger activation in ASC compared to NT (139 ASC; 150 NT) did not result in significant convergence. Activation differences in 13 contrasts reporting stronger activation in NT compared to ASC (261 ASC; 289 NT) converged in a cluster in the medial frontal gyrus/cingulate gyrus. Additionally, we identified 38 contrasts without significant group differences.CONCLUSION: We found converging activation differences (from contrasts reporting stronger activation in NT compared to ASC) in an area associated with error monitoring and uncertainty estimation. Our results are generally consistent with notions of altered priors/predictions or prediction errors in autism, pointing to differences at high levels of the information-processing hierarchy. However, we recommend a cautious interpretation, given the limited number of available contrasts and the high proportion of null results.

OBJECTIVE:This study investigated the effects of tumor necrosis factor α (TNFα) blockade treatment, adalimumab (ADA), on cerebral pain processing in relevant brain regions in patients with rheumatoid arthritis (RA). Its secondary aim was to identify pretreatment markers in cerebral pain processing that might predict treatment response. METHODS:A total of 25 patients with RA were randomly allocated treatment with 40 mg ADA (n = 14) or placebo (PBO) (n = 11) injected subcutaneously. During functional magnetic resonance imaging (fMRI), patients underwent individually calibrated pressure-pain stimulation on the most inflamed interphalangeal joint and on an unaffected control site before and after four weeks of treatment. RESULTS:The ADA but not the PBO group showed significant changes in subjective, clinician-rated, and objective measures. Both groups exhibited significant activations in pain-relevant brain regions during the fMRI task. Cerebral activations did not change following treatment nor did they correlate pre- or post-treatment with changes in systemic inflammation (measured as the change in erythrocyte sedimentation rate [ΔESR]). Baseline cerebral activations did not correlate with treatment response in terms of ΔESR nor with pain or fatigue outcomes. However, in an exploratory analysis, five baseline activation clusters in the ADA group, and one in the PBO group, correlated positively with changes in swollen joint count (P < 0.001). CONCLUSIONS:Our study did not observe any associations between treatment with TNFα inhibitors and changes in cerebral pain processing, indicating that this treatment may not have a clear central effect.

ABSTRACT Background Individuals who engage in non‐suicidal self‐injury (NSSI) exhibit reduced pain sensitivity compared to the general population. It has been argued that this hypoalgesic characteristic may be attributable to hyper‐effective pain modulation. However, empirical support for this theory remains inconsistent. The aim of the study was to use a combined offset analgesia (OA) and onset hyperalgesia (OH) protocol to investigate if women with NSSI have a propensity to inhibit nociceptive signals to a higher degree (stronger OA response) and facilitate nociceptive signals to a lesser degree (weaker OH response), compared to a control group. Methods Data was collected from 76 women, 18–35 age (37 with NSSI and 39 healthy controls). The OA and OH protocol were combined with functional magnetic resonance imaging (fMRI). Results The NSSI group displayed a weaker OH response, compared to the control group. This suggests that women with NSSI do not facilitate nociceptive signals to the same extent as healthy women. However, there were no significant differences between the groups regarding OA. Across all participants, we observed stronger activation in the primary sensory cortex during the OH condition, compared to the control condition. Conclusions The results offer partial support for the general hypothesis that women with NSSI demonstrate enhanced pain modulation. The fMRI finding requires replication.

Synesthesia is a variation in conscious experience where certain sensory stimuli automatically trigger additional sensations, such as smell, taste, or color. Synesthesia has been associated with autism and sensory hypersensitivity and there is preliminary evidence for an association with psychiatric conditions, including obsessive-compulsive disorder.Traditionally, synesthesia is defined by both the subjective conscious experience of synesthesia and consistency of synesthetic experiences determined via an objective test. However, self-report does not always converge with test results, and it is currently unknown whether these two synesthetic markers relate differently to neurodevelopmental and psychiatric characteristics. We systematically assessed this question in 584 twins. Both traditionally defined synesthesia and synesthesia defined only by self-report showed similar association patterns with autistic, obsessive-compulsive and sensory hypersensitive characteristics. When comparing twins to their co-twins (controlling familial factors shared within pairs), we found that all associations with self-reported synesthesia attenuated below significance. When traditionally defined synesthetes were compared to their non-synesthetic co-twins, only the association with sensory hypersensitivity remained significant.Our findings suggest that autistic and obsessive-compulsive characteristics are associated with subjective rather than objective markers of synesthesia, and that this association is influenced by familial factors shared by twins. Meanwhile, environmental factors influenced the relationship between sensory hypersensitivity and synesthesia, and for this association, both subjective and objective markers were essential. These results add to the ongoing discussion about the utility of objective markers for defining synesthesia, and the role of genetic and environmental influences on synesthesia and its link to neurodevelopmental and psychiatric characteristics.

Traditional case-control studies show that obsessive-compulsive disorder (OCD) is associated with disturbances in cortico-striatal-thalamo-cortical (CSTC) brain circuits. Whether these findings represent underlying familial vulnerabilities (i.e. shared genetic and environmental factors) or are the result of acquired non-shared environmental influences, such as chronic stress or lifestyle factors, is unknown. Using a unique sample of monozygotic twin pairs discordant for lifetime OCD diagnoses (14 pairs, 28 twins) and resting-state functional MRI, we examined the contribution of non-shared environmental influences to CSTC functional connectivity while strictly controlling for shared genetic and environmental factors. Further, we examined familial vulnerability effects by comparing the unaffected co-twins of OCD-affected twins to a sample of control twins (14 pairs, 28 twins). Non-shared environmental influences were statistically significantly associated with thalamostriatal hypoconnectivity, whereas familial vulnerability was significantly associated with heightened connectivity between the striatum and the medial orbitofrontal cortex. These findings suggest that non-shared environmental and familial factors may differentially relate to distinct CSTC circuit disturbances in OCD.

BACKGROUND:Neonatal hypoxic-ischemic encephalopathy (HIE) injures the infant brain during the basic formation of the developing functional connectome. This study aimed to investigate long-term changes in the functional connectivity (FC) networks of the adolescent brain following neonatal HIE treated with therapeutic hypothermia (TH). METHODS:This prospective, population-based cohort study included all infants (n = 66) with TH-treated neonatal HIE in Stockholm during 2007-2009 and a control group (n = 43) of children with normal neonatal course. Assessment with resting-state functional magnetic resonance imaging (fMRI) was performed at Karolinska Institutet, Stockholm at age 9-12 years. RESULTS:fMRI data met quality criteria for 35 children in the HIE-cohort (mean [SD] age at MRI: 11.2 [0.74] years, 46% male) and 30 children in the control group (mean [SD] age at MRI: 10.1 [0.78] years, 53% male). Adverse outcome was present in 40% of children in the HIE-cohort. Non-parametric statistical analysis failed to detect any significant (p < 0.001) alterations of FC networks in the HIE-cohort, nor between children in the HIE-cohort with or without neurological symptoms. CONCLUSION:Findings of persistent alterations in specific functional networks did not remain significant after correction for multiple comparisons in this cohort of adolescent children exposed to TH-treated neonatal HIE. IMPACT:Neonatal hypoxic-ischemic encephalopathy (HIE) could not be associated with alterations in functional connectivity in this cohort of adolescent children. Findings of aberrant connectivity identified in two functional networks were no longer significant after correction for multiple comparisons. Larger, multi-center studies are needed to understand whether network abnormalities persist long term and are related to outcomes in neonatal HIE.

Long-term effects of lumbar disc herniation treatment on brain function are poorly understood, and it is unclear when surgery should be recommended over non-operative treatment. The overall aim of the present study was to determine potential long-term effects on brain networks among individuals who received either surgical or non-operative treatment for lumbar disc herniation in adolescence. Brain network connectivity was assessed for individuals who received surgical treatment or non-operative treatment, and controls with no history of lumbar disc herniation. Prior to analysis, brain connectivity measures between groups were determined as main outcome, using functional magnetic resonance imaging. On average 12 years after treatment onset, the surgically treated cohort exhibited distinctly different functional brain connectivity, compared with both non-operative treatment and controls. The difference was neither attributed to self-reported pain, nor lumbar spine morphology. The findings suggest that surgical treatment for lumbar disc herniation in adolescence may be associated with a long-term imprint on the functional brain connectome.

Functional neuroimaging studies have shown that a set of cortical brain regions is typically engaged during noxious stimulation and pain perception in humans. Other studies have focused on cortical brain activation patterns in patients suffering from chronic pain conditions such as fibromyalgia. Recent work has shown that functional MRI signals are also present in white matter. In this study, we present an analysis of white and grey matter functional MRI activation during a block-designed pain stimulus task in cohorts of fibromyalgia patients and healthy controls. Task data and resting-state functional MRI data were collected from female fibromyalgia patients (N = 54) and controls (N = 56). Pain-stimulation task-based functional MRI included noxious pressure of the left shin as well as an appraisal of pain intensity. White and grey matter brain activities related to pain stimulation were analysed in 29 white matter and 200 grey matter regions-of-interest using time-locked activation analysis. In the healthy cohort, we present evidence of functional MRI brain activity in response to processing painful stimuli for a large majority of cerebral white fibre tracts investigated. In contrast, white matter functional MRI activity in the fibromyalgia cohort was limited to the contralateral posterior and anterior limb of the internal capsule as well as the bilateral cerebral peduncles. Pain stimulation and appraisal of pain intensity also resulted in widespread time-locked functional MRI activity in grey matter, such as visual, somatomotor, fronto-parietal attention and frontal networks as well as in the insular cortex. We have shown that white matter functional MRI signal changes localized to thalamocortical projection fibres, which are attributed to sensory and motor neuronal processing, are related to the perception and appraisal of pain in both fibromyalgia patients and healthy controls. Our results suggest that functional MRI of white matter projection fibres provide additional information that goes beyond task-induced functional MRI responses in cerebral grey matter, with a potential to become clinically useful in the future.

AIM:To investigate the interaction between specialized motor networks and higher associative brain networks for motor performance in adolescents exposed to neonatal hypoxic-ischaemic encephalopathy (HIE). METHOD:In this prospective, population-based cohort study of children (n = 66) with neonatal HIE treated with therapeutic hypothermia, follow-up was performed at age 10 to 12 years with resting-state functional magnetic resonance imaging and assessment of motor performance with the Movement Assessment Battery for Children, Second Edition (MABC-2). Brain-behaviour analysis was performed using statistical enrichment analysis and was compared to a control group (n = 43) using the McNemar test. RESULTS:The final analysis included 35 children in the cohort with HIE (mean [SD] age at magnetic resonance imaging = 11 years 2 months [9 months]) and 21 children in the control cohort (10 years 2 months [8 months]). Motor performance (assessed with the MABC-2 total score and all subdomains) was reduced in the cohort with HIE compared to the controls and was significantly associated with several clusters of brain network connections. A significant group difference was found in the MABC-2 aiming and catching subdomain, which correlated with clusters of functional connectivity between the somatomotor and default mode networks in the cohort with HIE. INTERPRETATION:Motor impairment after therapeutic hypothermia-treated neonatal HIE is connected to alternative neural processing between motor and cognitive networks.

Evidence that the brain adapts its intrinsic rhythms to a task paradigm (entrainment) and that it actively anticipates up-coming tasks has mostly come from analysis of neurophysiological data. Here we show that these phenomena are present in fMRI motor task data as well. We represent brain activity as a series (time resolved) of complex weighted networks and introduce a novel phase clustering algorithm that divides the matrices into functionally meaningful communities with comparable phase content across time and subjects. We find brain-wide patterns of cross-subject synchronizations timed to the task paradigm. This pattern of entrainment features systematic negative deflections prior to task paradigm across many different brain regions. We interpret this pattern as a fMRI-equivalent to the Contingent Negative Variation (CNV) seen in neurophysiological data in anticipation of an up-coming task. A more pronounce version of the CNV-like signal is seen in task specific motor and somatosensory cortex prior to movement, potentially the fMRI-equivalent of the readiness potential (RP). Finally, we show that fMRI data, when represented as complex weighted matrices, full-fills the criteria of structural balance. ### Competing Interest Statement The authors have declared no competing interest.

Autism Spectrum Condition (ASC) is linked to altered local and global visual processing. Previous meta-analyses demonstrated brain activation differences across a broad range of visual tasks in ASC compared to non-autistic individuals, suggesting alterations in visual processing. However, a more specific understanding of brain mechanisms underlying detail-oriented visual attention is still lacking. To address this question, we conducted a systematic review and an activation likelihood estimation (ALE) meta-analysis on brain imaging studies assessing 252 individuals with ASC and 263 neurotypical controls (CON). We included tasks that either required focusing on details while ignoring global configurations (local visual processing) or vice versa (global visual processing). Using ALE, we performed between-group and within-group meta-analyses across 15 studies involving local and global visual tasks. We found greater activation in the right inferior occipital gyrus (Brodmann Area, BA 19) in ASC compared to CON in the between-group meta-analysis of local and global visual studies. In the within-group analysis, we identified two activation convergences in the thalamus and middle occipital gyrus (BA 19) in the ASC group, and one in the inferior parietal lobule (BA 40) in the CON group. In line with theories suggesting alterations in local and global visual processing in ASC, our results indicate that autistic individuals may rely more on the visual cortex for local/global visual processing, while non-autistic controls may rely more on parietal regions.

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in ∼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.

PURPOSE:The aim of this study was to explore patients' experience of participation in the treatment decision of proton beam therapy versus conventional radiotherapy. BACKGROUND:Proton beam therapy (PBT) has become a treatment option for some cancer patients receiving radiotherapy. The decision to give PBT instead of conventional radiotherapy (CRT) needs to be carefully planned together with the patient to ensure that the degree of participation is based on individuals' preferences. There is a knowledge gap of successful approaches to support patients' participation in the decision-making process, which is particularly important when it comes to the situation of having to choose between two treatment options such as PBT and CRT, with similar expected outcomes. METHOD:We conducted a secondary analysis of qualitative data collected from interviews with patients who received PBT for their brain tumor. Transcribed verbatims from interviews with 22 patients were analyzed regarding experiences of participation in the decision-making process leading to PBT. FINDINGS:Participants experienced their participation in the decision-making process to a varying degree, and with individual preferences. Four themes emerged from data: to be a voice that matters, to get control over what will happen, being in the hand of doctors' choice, and feeling selected for treatment. CONCLUSION:A decision for treatment with PBT can be experienced as a privilege but can also cause stress as it might entail practical issues affecting everyday life in a considerable way. For the patient to have confidence in the decision-making process, patients' preferences, expectations, and experiences must be included by the healthcare team. Including the patient in the healthcare team as an equal partner by confirming the person enables and facilitates for patients' voice to be heard and reckoned with. Person-centered care building on a partnership between patients and healthcare professionals should provide the right basis for the decision-making process.

BackgroundLong-term pain is a common health problem that results in disability for patients of all ages, leading to an enormous economic burden. Over 20% of the population suffer from long-term pain. Unfortunately, there are no clinical tests that predicts who will develop long-term pain. The overall aim is to predict future pain incidence based on brain function, pain behavior, health status, and genetic variability.MethodPrePain utilizes a superstruct design, which involves recruiting participants from ongoing research projects. Eligible individuals for participation in PrePain were over 18 years old and free from long-term pain. During the baseline visit, participants provide pain and health-related questionnaires, undergo structural and functional MRI scans, and provide a saliva sample for DNA extraction. Individual baseline measures are then routinely followed- up via national registries.ResultWe present quality-assessed data from over 300 participants. The average age was 34 years, and most participants were women (75%). Participants rated their pain sensitivity above average and reported low avoidance. Catastrophizing thoughts during painful episodes were rated as moderate. Assessments of (f)MRI data indicated generally good image quality. In this first follow-up, we found that 45 participants had a pain-related diagnoses.ConclusionResults indicate that a superstruct design is feasible for collecting a large number of high-quality data. The incidence of long-term pain indicates that a sufficient number of participants have been recruited to complete the prediction analyses. PrePain is a unique prospective pain database with a fair prognosis to determine risk factors of long-term pain.

Previous studies have shown that a re-organization of the brain's functional connectome expressed in terms of network integration and segregation may play a pivotal role for brain function. However, it has been proven diffi-cult to fully capture both processes independently in a single methodological framework. In this study, by starting from pair-wise assessments of instantaneous phase synchronization and community membership, we assemble spatiotemporally flexible networks that reflect changes in integration/segregation that occur at a spectrum of spatial as well as temporal scales. This is achieved by iteratively assembling smaller networks into larger units under the constraint that the smaller units should be internally integrated, i.e. belong to the same community. The assembled subnetworks can be partly overlapping and differ in size across time. Our results show that sub-network integration and segregation occur simultaneously in the brain. During task performance, global changes in synchronization between networks arise that are tied to the underlying temporal design of the experiment. We show that a hallmark property of the dynamics of the brain's functional connectome is a presence of quasi-periodic patterns of network activation and deactivation, which during task performance becomes intertwined with the underlying temporal structure of the experimental paradigm. Additionally, we show that the degree of network integration throughout a n-back working memory task is correlated to performance.

Men with metastatic castration-resistant prostate cancer (mCRPC) have an incurable disease and along with prolonging life, symptom management is one of the main goals in treatment of these men. Most of these men have bone metastases and a high frequency report pain. However, to be able to achieve an effective pain management, and to evaluate effects of treatments on pain in a real-world situation, not only knowledge of frequency is important. Today there are no studies describing different dimensions of pain, such as severity and distress, in men with mCRPC starting life-prolonging treatments in a real-world situation. The aim was to describe the multidimensional aspects of pain from the perspective of frequency, severity and distress, and analgesic use in men with mCRPC, starting a first-line life-prolonging treatment. Data was taken from a prospective study (n=143) where 72 men with mCRPC starting their first-line of life-prolonging treatment and reported pain were included. Three dimensions of pain (frequency, severity and distress) were measured using the Memorial System Assessment Scale (MSAS) and the use of analgesics was collected from medical records. Of the 72 men who reported pain on the MSAS, 63.9% (n=46) used analgesics while 36.1% (n=26) did not. Of the men using analgesics, 55.8 % reported pain “frequently” or “almost constantly” and among the men not using analgesics, 44.0% reported that they had pain “frequently” or “almost constantly”. Of those using analgesics, 27.5% reported severe or very severe pain, while none of the men not using analgesics reported very severe pain, and 19% reported severe pain. Of the men using analgesics 51% reported quite a bit/very much distress in contrast to 38% of the men not using analgesics. Pain management was not sufficient for more than half of the men, even for those receiving analgesics. Men with mCRPC starting life-prolonging treatment may benefit from a structured multidimensional assessment. When the disease has progressed to a mCRPC phase, an early integrated palliative approach with thorough symptom management may be essential in order to obtain the best possible quality of life.

Recent translational work has shown that fibromyalgia might be an autoimmune condition with pathogenic mechanisms mediated by a peripheral, pain-inducing action of immunoglobulin G (IgG) antibodies binding to satellite glia cells (SGC) in the dorsal root ganglia. A first clinical assessment of the postulated autoimmunity showed that fibromyalgia subjects (FMS) had elevated levels of antibodies against SGC (termed anti-SGC IgG) compared to healthy controls and that anti-SGC IgG were associated with a more severe disease status. The overarching aim of the current study was to determine whether the role of anti-SGC IgG in driving pain is exclusively through peripheral mechanisms, as indirectly shown so far, or could be attributed also to central mechanisms. To this end, we wanted to first confirm, in a larger cohort of FMS, the relation between anti-SGC IgG and pain-related clinical measures. Secondly, we explored the associations of these autoantibodies with brain metabolite concentrations (assessed via magnetic resonance spectroscopy, MRS) and pressure-evoked cerebral pain processing (assessed via functional magnetic resonance imaging, fMRI) in FMS. Proton MRS was performed in the thalamus and rostral anterior cingulate cortex (rACC) of FMS and concentrations of a wide spectrum of metabolites were assessed. During fMRI, FMS received individually calibrated painful pressure stimuli corresponding to low and high pain intensities. Our results confirmed a positive correlation between anti-SGC IgG and clinical measures assessing condition severity. Additionally, FMS with high anti-SGC IgG levels had higher pain intensity and a worse disease status than FMS with low anti-SGC IgG levels. Further, anti-SGC IgG levels negatively correlated with metabolites such as scyllo-inositol in thalamus and rACC as well as with total choline and macromolecule 12 in thalamus, thus linking anti-SGC IgG levels to the concentration of metabolites in the brain of FMS. However, anti-SGC IgG levels in FMS were not associated with the sensitivity to pressure pain or the cerebral processing of evoked pressure pain. Taken together, our results suggest that anti-SGC IgG might be clinically relevant for spontaneous, non-evoked pain. Our current and previous translational and clinical findings could provide a rationale to try new antibody-related treatments in FMS.

BACKGROUND:The ProtonCare Study Group (PCSG) was formed with the purpose to develop and implement a framework for evaluation of proton beam therapy (PBT) and the related care at a novel clinic (Skandionkliniken), based on patient reported data.METHOD:A logic model framework was used to describe the process of development and implementation of a structured plan for evaluation of PBT for all diagnoses based on patient reported data. After the mission for the project was determined, meetings with networks and stakeholders were facilitated by PCSG to identify assumptions, resources, challenges, activities, outputs, outcomes, and outcome indicators.RESULT:This paper presents the challenges and accomplishments PCSG made so far. We describe required resources, activities, and accomplished results. The long-term outcomes that were outlined as a result of the process are two; 1) Improved knowledge about health outcomes of patients that are considered for PBT and 2) The findings will serve as a base for clinical decisions when patients are referred for PBT.CONCLUSION:Using the logical model framework proved useful in planning and managing the ProtonCare project. As a result, the work of PCSG has so far resulted in long-lasting outcomes that creates a base for future evaluation of patients' perspective in radiotherapy treatment in general and in PBT especially. Our experiences can be useful for other research groups facing similar challenges. Continuing research on patients´ perspective is a central part in ongoing and future research. Collaboration, cooperation, and coordination between research groups/networks from different disciplines are a significant part of the work aiming to determine the more precise role of PBT in future treatment options.