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Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD’s mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD’s mechanism on fear extinction and learning of stress coping., Highlights • CBD reduces PTSD symptoms via the DRN and corticoraphe circuit. • Acute effects of CBD reduce DRN-amygdala excitatory signaling to lessen the activity disparity between amygdala and mPFC. • Chronic CBD officially resolves mPFC hypoactivity by facilitating 5-HT release from DRN to mPFC. • CBD-facilitated endocannabinoid signaling stabilizes DRN activity and restores mPFC inhibitory control. • Chronically administered CBD acts via the corticoraphe circuit to favor fear extinction over fear memory reconsolidation.

Highlights • Fatigue is a very frequent and disabling symptom in traumatic brain injury (TBI). • Effects of task-induced fatigue on resting-state functional connectivity (rsFC). • Striatal rsFC relates differently to subjective fatigue in TBI compared to controls. • Default mode network rsFC relates similar to subjective fatigue in TBI and controls., Background People with traumatic brain injury (TBI) often experience fatigue, but an understanding of the neural underpinnings of fatigue following TBI is still lacking. This study used resting-state functional magnetic resonance imaging (rs-fMRI) to examine associations between functional connectivity (FC) changes and task-induced changes in subjective fatigue in people with moderate-severe TBI. Methods Sixteen people with moderate-severe TBI and 17 matched healthy controls (HC) performed an adaptive N-back task (working memory task) to induce cognitive fatigue. Before and after the task they rated their state fatigue level and underwent rs-fMRI. Seed-to-voxel analyses with seeds in areas involved in cognitive fatigue, namely the striatum and default mode network (DMN) including, medial prefrontal cortex and posterior cingulate cortex, were performed. Results The adaptive N-back task was effective in inducing fatigue in both groups. Subjective task-induced fatigue was positively associated with FC between striatum and precuneus in people with TBI, while there was a negative association in HC. In contrast, subjective task-induced fatigue was negatively associated with FC between striatum and cerebellum in the TBI group, while there was no association in HC. Similar associations between task-induced subjective fatigue and DMN FC were found across the groups. Conclusions Our results suggest that the subjective experience of fatigue was linked to DMN connectivity in both groups and was differently associated with striatal connectivity in people with moderate-severe TBI compared to HC. Defining fatigue-induced neuronal network changes is pertinent to the development of treatments that target abnormal neuronal activity after TBI.

There has been a long history since human beings began to realize the existence of post-traumatic symptoms. Posttraumatic stress disorder (PTSD), a diagnostic category adopted in 1980 in the Diagnostic and Statistical Manual of Mental Disorders-Ⅲ, described typical clusters of psychiatric symptoms occurring after traumatic events. Abundant researches have helped deepen the understanding of PTSD in terms of epidemiological features, biological mechanisms, and treatment options. The prevalence of PTSD in general population ranged from 6.4% to 7.8% and was significantly higher among groups who underwent major public traumatic events. There has been a long way in the studies of animal models and genetic characteristics of PTSD. However, the high comorbidity with other stress-related psychiatric disorders and complexity in the pathogenesis of PTSD hindered the effort to find specific biological targets for PTSD. Neuroimage was widely used to elucidate the underlying neurophysiological mechanisms of PTSD. Functional MRI studies have showed that PTSD was linked to medial prefrontal cortex, anterior cingulate cortex and sub-cortical structures like amygdala and hippocampus, and to explore the functional connectivity among these brain areas which might reveal the possible neurobiological mechanism related to PTSD symptoms. For now, cognitive behavior therapy-based psychotherapy, including combination with adjunctive medication, showed evident treatment effects on PTSD. The emergence of more effective PTSD pharmacotherapies awaits novel biomarkers from further fundamental research. Several natural disasters and emergencies have inevitably increased the possibility of suffering from PTSD in the last two decades, making it critical to strengthen PTSD research in China. To boost PTSD study in China, the following suggestions might be helpful: (1) establishing a national psychological trauma recover project, and (2) exploring the mechanisms of PTSD with joint effort and strengthening the indigenized treatment of PTSD.

Background: Progressive neuronal death in monoaminergic nuclei and widespread accumulation of α-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Given that α-synuclein may be an early mediator of the pathological cascade that ultimately leads to neurodegeneration, decreased α-synuclein synthesis will abate neurotoxicity if delivered to the key affected neurons. Methods: We used a non-viral gene therapy based on a new indatraline-conjugated antisense oligonucleotide (IND-ASO) to disrupt the α-synuclein mRNA transcription selectively in monoamine neurons of a PD-like mouse model and elderly nonhuman primates. Molecular, cell biology, histological, neurochemical and behavioral assays were performed. Findings: Intracerebroventricular and intranasal IND-ASO administration for four weeks in a mouse model with AAV-mediated wild-type human α-synuclein overexpression in dopamine neurons prevented the synthesis and accumulation of α-synuclein in the connected brain regions, improving dopamine neurotransmission. Likewise, the four-week IND-ASO treatment led to decreased levels of endogenous α-synuclein protein in the midbrain monoamine nuclei of nonhuman primates, which are affected early in PD. Conclusions: : The inhibition of α-synuclein production in dopamine neurons and its accumulation in cortical/striatal projection areas may alleviate the early deficits of dopamine function, showing the high translational value of antisense oligonucleotides as a disease modifying therapy for PD and related synucleinopathies., Grants SAF2016-75797-R, RTC-2014-2812-1 and RTC-2015-3309-1, Ministry of Economy and Competitiveness (MINECO) and European Regional Development Fund (ERDF), UE; Grant ID 9238, Michael J. Fox Foundation; and Centres for Networked Biomedical Research on Mental Health (CIBERSAM), and on Neurodegenerative Diseases (CIBERNED).

Microglia are the predominant immune cells of the central nervous system (CNS) that exert key physiological roles required for maintaining CNS homeostasis, notably in response to chronic stress, as well as mediating synaptic plasticity, learning and memory. The repeated exposure to stress confers a higher risk of developing neurodegenerative diseases including sporadic Alzheimer's disease (AD). While microglia have been causally linked to amyloid beta (Aβ) accumulation, tau pathology, neurodegeneration, and synaptic loss in AD, they were also attributed beneficial roles, notably in the phagocytic elimination of Aβ. In this review, we discuss the interactions between chronic stress and AD pathology, overview the roles played by microglia in AD, especially focusing on chronic stress as an environmental risk factor modulating their function, and present recently-described microglial phenotypes associated with neuroprotection in AD. These microglial phenotypes observed under both chronic stress and AD pathology may provide novel opportunities for the development of better-targeted therapeutic interventions. Keywords: Microglia, Stress, Alzheimer's disease, Neurodegeneration, Neuroinflammation, Synaptic remodeling, Microglial phenotypes, Dark microglia

Highlights • Neonatal handling affects the developmental course of cannabinoid receptors in rat brain. • In adult handled rats, [3H]CP55,940 binding levels are reduced in CPu, NAc and BLA. • Dorsal hippocampal [3H]CP55,940 binding levels are reduced only in female handled rats. • Handling increases adolescent and decreases adult [3H]CP55,940 binding levels in mPFC., Neonatal handling is an experimental model of early life experience associated with resilience in later life challenges, altering the ability of animals to respond to stress. The endocannabinoid system of the brain modulates the neuroendocrine and behavioral effects of stress, while this system is also capable of being modulated by stress exposure itself. The present study has addressed the question of whether neonatal handling in rats could affect cannabinoid receptors, in an age- and sex-dependent manner, using in situ hybridization and receptor binding techniques. Different effects of neonatal handling were observed in adolescent and adult brain on CB1 receptor mRNA and [3H]CP55,940 binding levels, which in some cases were sexually dimorphic. Neonatal handling interfered in the developmental trajectories of CB1 receptor mRNA levels in striatum and amygdaloid nuclei, as well as of [3H]CP55,940 binding levels in almost all regions studied. Adult handled rats showed reduced [3H]CP55,940 binding levels in the prefrontal cortex, striatum, nucleus accumbens and basolateral amygdala, while binding levels in prefrontal cortex of adolescent handled rats were increased. Finally, handling resulted in decreases in female [3H]CP55,940 binding levels in the striatum, nucleus accumbens, CA3 and DG of dorsal hippocampus and basolateral amygdala. Our results suggest that a brief and repeated maternal separation during the neonatal period induces changes on cannabinoid receptors differently manifested between adolescence and adulthood, male and female brain, which could be correlated to their stress response.

Highlights • We developed a photoacoustic modality for direct imaging of Fos-expressing neuronal ensembles in Fos-LacZ transgenic rats. • X-gal product provided exogenous contrast for imaging of neuronal ensembles. • We detected Fos-expressing activated neuronal ensembles after either cocaine administration or a shock-tone pairing paradigm., Measuring neuroactivity underlying complex behaviors facilitates understanding the microcircuitry that supports these behaviors. We have developed a functional and molecular photoacoustic tomography (F/M-PAT) system which allows direct imaging of Fos-expressing neuronal ensembles in Fos-LacZ transgenic rats with a large field-of-view and high spatial resolution. F/M-PAT measures the beta-galactosidase catalyzed enzymatic product of exogenous chromophore X-gal within ensemble neurons. We used an ex vivo imaging method in the Wistar Fos-LacZ transgenic rat, to detect neuronal ensembles in medial prefrontal cortex (mPFC) following cocaine administration or a shock-tone paired stimulus. Robust and selective F/M-PAT signal was detected in mPFC neurons after both conditions (compare to naive controls) demonstrating successful and direct detection of Fos-expressing neuronal ensembles using this approach. The results of this study indicate that F/M-PAT can be used in conjunction with Fos-LacZ rats to monitor neuronal ensembles that underlie a range of behavioral processes, such as fear learning or addiction.

Background Thirty-percent of patients with epilepsy are drug-resistant, and might benefit from effective noninvasive therapeutic interventions. Evidence is accumulating on the efficacy of autonomic biofeedback therapy using galvanic skin response (GSR; an index of sympathetic arousal) in treating epileptic seizures. This study aimed to extend previous controlled clinical trials of autonomic biofeedback therapy with a larger homogeneous sample of patients with temporal lobe epilepsy. In addition, we used neuroimaging to characterize neural mechanisms of change in seizure frequency following the therapy. Methods Forty patients with drug-resistant temporal lobe epilepsy (TLE) (age: 18 to 70 years old), on stable doses of anti-epileptic medication, were recruited into a controlled and parallel-group trial from three screening centers in the UK. Patients were allocated to either an active intervention group, who received therapy with GSR biofeedback, or a control group, who received treatment as usual. Allocation to the group was informed, in part, by whether patients could travel to attend repeated therapy sessions (non-randomized). Measurement of outcomes was undertaken by an assessor blinded to the patients' group membership. Resting-state functional and structural MRI data were acquired before and after one month of therapy in the therapy group, and before and after a one-month interval in the control group. The percentage change of seizure frequency was the primary outcome measure. The analysis employed an intention–to–treat principle. The secondary outcome was the change in default mode network (DMN) and limbic network functional connectivity tested for effects of therapy. The trial was registered with the National Institute for Health Research (NIHR) portfolio (ID 15967). Findings Data were acquired between May 2014 and October 2016. Twenty participants were assigned to each group. Two patients in the control group dropped out before the second scan, leaving 18 control participants. There was a significant difference in reduction of seizure frequency between the therapy and control groups (p 50%. Neuroimaging analysis revealed that post-therapy seizure reduction was linearly correlated with enhanced functional connectivity between right amygdala and both the orbitofrontal cortex (OFC) and frontal pole (FP). Interpretation Our clinical study provides evidence for autonomic biofeedback therapy as an effective and potent behavioral intervention for patients with drug-resistant epilepsy. This approach is non-pharmacological, non-invasive and seemingly side-effect free., Highlights • Autonomic biofeedback using GSR significantly reduced seizure frequencies in patients with drug resistant TLE. • The effect of GSR biofeedback in reducing seizures was mediated by increased fronto-limbic functional connectivity. • Autonomic biofeedback is a potent bio-behavioral therapy for patients with drug resistant epilepsy. Biofeedback training therapy is non-invasive and apparently side-effect free. The positive clinical findings of the current study carry significant translational implications for patients with epilepsy and for medical professionals. Beyond demonstrating the efficacy of autonomic biofeedback, our study provides fresh insight into neural mechanisms mediating the expression of seizures. We identified a key relationship wherein the strength of neural coupling between frontal cortex and right amygdala enhances the capacity to suppress seizures. The finding also implies that abnormal function of this network may promote the spread of seizures across the brain in a manner that is influenced by autonomic, and probably, emotional state.

Background Individuals with autism spectrum disorder (ASD) appear to have a unique awareness of their own body, which may be associated with difficulties of gestural interaction. In typically developing (TD) individuals, the perception of body parts is processed in various brain regions. For instance, activation of the lateral occipito-temporal cortex (LOTC) is known to depend on perspective (i.e., first- or third-person perspective) and identity (i.e., own vs. another person's body). In the present study, we examined how perspective and identity affect brain activation in individuals with ASD, and how perspective- and identity-dependent brain activation is associated with gestural imitation abilities. Methods Eighteen young adults with ASD and 18 TD individuals participated in an fMRI study in which the participants observed their own or another person's hands from the first- and third-person perspectives. We examined whether the brain activation associated with perspective and identity was altered in individuals with ASD. Furthermore, we identified the brain regions the activity of which correlated with gestural imitation difficulties in individuals with ASD. Results In the TD group, the left LOTC was more strongly activated by viewing a hand from the third-person perspective compared with the first-person perspective. This perspective effect in the left LOTC was significantly attenuated in the ASD group. We also observed significant group differences in the perspective effect in the medial prefrontal cortex (mPFC). Correlation analysis revealed that the perspective effect in the inferior parietal lobule (IPL) and cerebellum was associated with the gestural imitation ability in individuals with ASD. Conclusions Our study suggests that atypical visual self-body recognition in individuals with ASD is associated with an altered perspective effect in the LOTC and mPFC, which are thought to be involved in the physical and core selves, respectively. Furthermore, the gestural imitation difficulty in individuals with ASD might be associated with the altered activation in the IPL and cerebellum, but not in the LOTC. These findings shed light on common and divergent neural mechanisms underlying atypical visual self-body awareness and gestural interaction in ASD., Highlights • Own-body awareness and gestural skills are altered in autism spectrum disorder (ASD). • The lateral occipito-temporal cortex (LOTC) is key for body perspective and identity. • The perspective effects in the LOTC and medial prefrontal cortex are altered in ASD. • Inferior parietal lobule and cerebellum activity underlie imitation deficits in ASD. • Identity and perspective dysperception may alter the body-gesture interaction in ASD.

Locus of control (LOC) is an important personality trait. LOC over cognitive competency reflects an individual's perceived control of desired cognitive outcomes, which is critical for maintaining successful cognitive aging. It is important to understand the neural substrates of LOC over cognitive competency in older adults, especially for individuals at high risk of dementia. Here, we characterized a cohesive functional and structural connectivity profile underlying LOC among 55 older adults with amnestic mild cognitive impairment (aMCI), combining resting-state functional magnetic resonance imaging and diffusion tensor imaging. The results showed that both functional and structural connectivity between the medial prefrontal cortex and amygdala were significantly correlated with external LOC. The functional connectivity mediated the correlation between structural connectivity and external LOC. In addition, aging-associated neurodegeneration moderated the relationship between structural connectivity and external LOC, showing that the structural connectivity was positively correlated with external LOC in low, but not high neurodegeneration. Our results suggest a critical role of the functional amygdala-frontal network, which may serve as a bridge between its white matter tract and LOC over cognitive competency in groups at high risk for dementia., Highlights • Amygdala connectivity is associated with external locus of control (eLOC). • Functional connectivity mediates the relationship of structural connectivity and eLOC. • Neurodegeneration disrupts the relationship between structural connectivity and eLOC.

It has been proposed that pain competes with other attention-demanding stimuli for cognitive resources, and many chronic pain patients display significant attention and mental flexibility deficits. These alterations may result from disruptions in the functioning of the default mode network (DMN) which plays a critical role in attention, memory, prospection and self-processing, and recent investigations have found alterations in DMN function in multiple chronic pain conditions. Whilst it has been proposed that these DMN alterations are a characteristic of pain that is chronic in nature, we recently reported altered oscillatory activity in the DMN during an acute, 5 minute noxious stimulus in healthy control subjects. We therefore hypothesize that altered DMN activity patterns will not be restricted to those in chronic pain but instead will also occur in healthy individuals during tonic noxious stimuli. We used functional magnetic resonance imaging to measure resting state infra-slow oscillatory activity and functional connectivity in patients with chronic orofacial pain at rest and in healthy controls during a 20-minute tonic pain stimulus. We found decreases in oscillatory activity in key regions of the DMN in patients with chronic pain, as well as in healthy controls during tonic pain in addition to changes in functional connectivity between the posterior cingulate cortex and areas of the DMN in both groups. The results show that similar alterations in DMN function occur in healthy individuals during acute noxious stimuli as well as in individuals with chronic pain. These DMN changes may reflect the presence of pain per se and may underlie alterations in attentional processes that occur in the presence of pain., Highlights • Default mode network dynamics were measured in chronic and acute pain. • Altered infra-slow activity and connectivity occurred in chronic and acute pain. • Default mode network changes characterize pain per se.

Graphical abstract, Highlights • Activation of mesolimbic dopamine system underlies exercise-induced hypoalgesia. • Interaction between mesolimbic system and hypothalamus determines physical activity. • Changing the lifestyle inactive to active may attenuate and prevent chronic pain., Physical exercise has been established as a low-cost, safe, and effective way to manage chronic intractable pain. We investigated the underlying mechanisms of exercise-induced hypoalgesia (EIH) using a mouse model of neuropathic pain (NPP). Epigenetic changes in activated microglia and maintained GABA synthesis in the spinal dorsal horn may contribute to EIH. Voluntary exercise (VE), a strong reward for animals, also induced EIH, which may be due in part to the activation of dopamine (DA) neurons in the ventral tegmental area (VTA). VE increases the expression of pCREB in dopaminergic neurons in the VTA, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. We demonstrated that neurons in the laterodorsal tegmental and pedunculopontine tegmental nuclei, a major input source of rewarding stimuli to the VTA, were activated by exercise. Chronic pain is at least partly attributed to sedentary and inactive lifestyle as indicated by the Fear-avoidance model. Therefore, chronic pain could be recognized as a lifestyle-related disease. Physical activity/inactivity may be determined by genetic/epigenetic and neural factors encoded in our brain. The hypothalamus and reward system is closely related in the axis of food intake, energy metabolism and physical activity. Understanding the interactions between the mesolimbic DA system and the hypothalamus that sense and regulate energy balance is thus of significant importance. For example, proopiomelanocortin neurons and melanocortin 4 receptors may play a role in connecting these two systems. Therefore, in a certain sense, chronic pain and obesity may share common behavioral and neural pathology, i.e. physical inactivity, as a result of inactivation of the mesolimbic DA system. Exercise and increasing physical activity in daily life may be important in treating and preventing chronic pain, a life-style related disease.

Highlights • Attention and stimulus selection deficits in Gdi1-null Intellectual Disability model. • Behavioral deficits correlated with fronto-striatal system dysfunction. • A major role for glutamatergic activity in fronto-striatal circuitry dysfunction. • Correlation between reported patient’s cognitive deficits and present findings., RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients.

Highlights • Fractionating insight into objects aids its neuroanatomical exploration in dementia. • Distinctive neural correlates seem to underpin different insight objects in FTD. • Altered insight into disease/health condition mostly involves right frontal areas. • Altered insight into social cognition implicates frontal, temporal and limbic areas. • Frontal, medial temporal and parietal areas underpin insight into memory problems., Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

Highlights • Subarachnoid hemorrhage patients show a reduced sensitivity to negative feedback, depicted by diminished amplitude of the feedback-related negativity (FRN). • A delayed increase of theta oscillatory activity (4–8 Hz) was found for the patient group in presence of monetary losses compared to the healthy control group. • No significant differences between groups were found at positive feedback event-related (ERP) components, such as the feedback P300 (FB-P3), neither on the time-frequency domain (beta-gamma band −25–35). • Damage to medial prefrontal cortex (mPFC) regions might be altering the performance monitoring mechanisms associated to feedback processing and belief updating, resulting in altered day-to-day decision-making functioning., Patients with subarachnoid hemorrhage (SAH) secondary to anterior communicating artery (AComA) aneurysm rupture often experience deficits in executive functioning and decision-making. Effective decision-making is based on the subjects’ ability to adjust their performance based on feedback processing, ascribing either positive or negative value to the actions performed reinforcing the most adaptive behavior in an appropriate temporal framework. A crucial brain structure associated to feedback processing is the medial prefrontal cortex (mPFC), a brain region frequently damaged after AComA aneurysm rupture. In the present study, we recorded electrophysiological responses (event-related potentials (ERPs') and oscillatory activity (time frequency analysis) during a gambling task in a series of 15 SAH patients. Previous studies have identified a feedback related negativity (FRN) component associated with an increase on frontal medial theta power in response to negative feedback or monetary losses, which is thought to reflect the degree of negative prediction error. Our findings show a decreased FRN component in response to negative feedback and a delayed increase of theta oscillatory activity in the SAH patient group when compared to the healthy controls, indicating a reduced sensitivity to negative feedback processing and an effortful signaling of cognitive control and monitoring processes lengthened in time, respectively. These results provide us with novel neurophysiological markers regarding feedback processing and performance monitoring patterns in SAH patients, illustrating a dysfunctional reinforcement learning system probably contributing to the maladaptive day-to-day functioning in these patients.

Posteromedial cortex (PMC) is a highly segregated and dynamic core, which appears to play a critical role in internally/externally directed cognitive processes, including conscious awareness. Nevertheless, neuroimaging studies on acquired disorders of consciousness, have traditionally explored PMC as a homogenous and indivisible structure. We suggest that a fine-grained description of intrinsic PMC topology during coma, could expand our understanding about how this cortical hub contributes to consciousness generation and maintain, and could permit the identification of specific markers related to brain injury mechanism and useful for neurological prognostication. To explore this, we used a recently developed voxel-based unbiased approach, named functional connectivity density (CD). We compared 27 comatose patients (15 traumatic and 12 anoxic), to 14 age-matched healthy controls. The patients' outcome was assessed 3 months later using Coma Recovery Scale-Revised (CRS-R). A complex pattern of decreased and increased connections was observed, suggesting a network imbalance between internal/external processing systems, within PMC during coma. The number of PMC voxels with hypo-CD positive correlation showed a significant negative association with the CRS-R score, notwithstanding aetiology. Traumatic injury specifically appeared to be associated with a greater prevalence of hyper-connected (negative correlation) voxels, which was inversely associated with patient neurological outcome. A logistic regression model using the number of hypo-CD positive and hyper-CD negative correlations, accurately permitted patient's outcome prediction (AUC = 0.906, 95%IC = 0.795–1). These points might reflect adaptive plasticity mechanism and pave the way for innovative prognosis and therapeutics methods., Highlights • A twofold pattern of decreased and increased connections within PMC was observed during coma. • The number of PMC voxels with decreased positive connections, was significantly associated with patient's outcome. • Greater prevalence of hyperconnected PMC voxels in traumatic brain injury was correlated to outcome in this subgroup.

Attention and executive dysfunction are features of Lewy body dementia (LBD) but their neuroanatomical basis is poorly understood. To investigate underlying dysfunctional attention-executive network (EXEC) interactions, we examined functional connectivity (FC) in 30 patients with LBD, 20 patients with Alzheimer's disease (AD), and 21 healthy controls during an event-related functional magnetic resonance imaging (fMRI) experiment. Participants performed a modified Attention Network Test (ANT), where they were instructed to press a button in response to the majority direction of arrows, which were either all pointing in the same direction or with one pointing in the opposite direction. Network activations during both target conditions and a baseline condition (no target) were derived by (ICA) Independent Component Analysis, and interactions between these networks were examined using the beta series correlations approach. Our study revealed that FC of ventral and dorsal attention networks DAN was reduced in LBD during all conditions, although most prominently during incongruent trials. These alterations in connectivity might be driven by a failure of engagement of ventral attention networks, and consequent over-reliance on the DAN. In contrast, when comparing AD patients with the other groups, we found hyperconnectivity between the posterior part of the default mode network (DMN) and the DAN in all conditions, particularly during incongruent trials. This might be attributable to either a compensatory effect to overcome DMN dysfunction, or be arising as a result of a disturbed transition of the DMN from rest to task. Our results demonstrate that dementia syndromes can be characterized both by hyper- and hypoconnectivity of distinct brain networks, depending on the interplay between task demand and available cognitive resources. However these are dependent upon the underlying pathology, which needs to be taken into account when developing specific cognitive therapies for LBD as compared to Alzheimer's.

Dysfunction in corticolimbic circuits that mediate the extinction of learned fear responses is thought to underlie the perseveration of fear in stress-related psychopathologies, including post-traumatic stress disorder. Chronic stress produces dendritic hypertrophy in basolateral amygdala (BLA) and dendritic hypotrophy in medial prefrontal cortex, whereas acute stress leads to hypotrophy in both BLA and prelimbic cortex. Additionally, both chronic and acute stress impair extinction retrieval. Here, we examined the effects of a single elevated platform stress on extinction learning and dendritic morphology in infralimbic cortex, a region considered to be critical for extinction. Acute stress produced resistance to extinction, as well as dendritic retraction in infralimbic cortex. Spine density on apical and basilar terminal branches was unaffected by stress. However, animals that underwent conditioning and extinction had decreased spine density on apical terminal branches. Thus, whereas dendritic morphology in infralimbic cortex appears to be particularly sensitive to stress, changes in spines may more sensitively reflect learning. Further, in stressed rats that underwent conditioning and extinction, the level of extinction learning was correlated with spine densities, in that rats with poorer extinction retrieval had more immature spines and fewer thin spines than rats with better extinction retrieval, suggesting that stress may have impaired learning-related spine plasticity. These results may have implications for understanding the role of medial prefrontal cortex in learning deficits associated with stress-related pathologies.

Highlights • IL-6 has been associated with poorer facial emotion recognition. • fMRI was performed during a faces task and IL-6 measured from blood samples. • IL-6 predicted increased neural response during facial emotion recognition., Background Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. Methods Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. Results Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p

The locus coeruleus (LC) is a critical node in the stress response, and its activation has been shown to promote hypervigilance and anxiety-like behavior. This noradrenergic nucleus has historically been considered homogeneous with highly divergent neurons that operate en masse to collectively affect central nervous system function and behavioral state. However, in recent years, LC has been identified as a heterogeneous structure whose neurons innervate discrete terminal fields and contribute to distinct aspects of behavior. We have previously shown that in late adolescent male rats, an acute traumatic stressor, simultaneous physical restraint and exposure to predator odor, preferentially induces c-Fos expression in a subset of dorsal LC neurons and persistently increases anxiety-like behavior. To investigate how these neurons respond to and contribute to the behavioral response to stress, we used a combination of retrograde tracing, whole-cell patch clamp electrophysiology, and chemogenetics. Here we show that LC neurons innervating the central nucleus of the amygdala (CeA) and medial prefrontal cortex (mPFC) undergo distinct electrophysiological changes in response to stressor exposure and have opposing roles in mediating anxiety-like behavior. While neurons innervating CeA become more excitable in response to stress and promote anxiety-like behavior, those innervating mPFC become less excitable and appear to promote exploration. These findings show that LC neurons innervating distinct terminal fields have unique physiological responses to particular stimuli. Furthermore, these observations advance the understanding of the LC as a complex and heterogeneous structure whose neurons maintain unique roles in various forms of behavior., Highlights • Locus coeruleus-central amygdala projections are hyperactive one week after stress. • Locus coeruleus-prefrontal cortex projections are hypoactive one week after stress. • Chemogenetic manipulation of each pathway distinctly affects anxiety-like behavior.

Graphical abstract, Highlights • Humans, monkey and rats all show evidence of synaptic pruning during adolescence. • Studies in rats also indicate that neurons are pruned in the prefrontal cortex. • Puberty plays an important role in pruning, especially in female rats. • Many adolescent cellular changes are not deducible from changes in cortical size., The human cortex, particularly the prefrontal cortex, decreases in volume during adolescence which indicates considerable pruning. There is consistent evidence from human, monkey and rat tissue that synapses, dendritic spines and dendrites are pruned during this time. However, our work with a rat model of adolescence shows that other cellular components are remodeling at this time as well. Neurons are also pruned and we have found that in female rats, puberty is a key signal for this process. Other critical developmental events occur that are not detectable in gross size changes including the growth of dopaminergic inputs. The changes in the inhibitory GABAergic system, especially the parvalbumin-expressing neuronal subtype, are an essential part of the maturation of the prefrontal cortex. This involves the formation of perineuronal nets around parvalbumin interneurons that allow mature fast spiking. We have found a large increase in perineuronal nets from early adolescence to adulthood in both sexes. We also have seen a temporary pause in this increase at the time of puberty in females. These complicated events cannot be deduced from MRI. The cellular reorganization that is indicated by size changes in the human cortex during adolescence can be informed by work from rodent models.

Ketamine is an uncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist. It induces effects in healthy individuals that mimic symptoms associated with schizophrenia. We sought to root these experiences in altered brain function, specifically aberrant resting state functional connectivity (rsfMRI). In the present study, we acquired rsfMRI data under ketamine and placebo in a between-subjects design and analyzed seed-based measures of rsfMRI using large-scale networks, dorsolateral prefrontal cortex (DLPFC) and sub-nuclei of the thalamus. We found ketamine-induced alterations in rsfMRI connectivity similar to those seen in patients with schizophrenia, some changes that may be more comparable to early stages of schizophrenia, and other connectivity signatures seen in patients that ketamine did not recreate. We do not find any circuits from our regions of interest that correlates with positive symptoms of schizophrenia in our sample, although we find that DLPFC connectivity with ACC does correlate with a mood measure. These results provide support for ketamine's use as a model of certain biomarkers of schizophrenia, particularly for early or at-risk patients., Highlights • Ketamine altered connectivity in default mode network, thalamus and DLPFC at rest. • Similar patterns of altered connectivity are seen with ketamine as in psychotic patients. • Mood symptoms correlated with DLPFC connectivity with ACC and frontal orbital cortex.

Highlights • Connectivity analyses complemented with a metric exploring switching in brain activity. • Lower insula-salience connectivity predicts insufficient antidepressant response. • This same insula region is activated less when switching from task to a rest. • This could be a potential biomarkers for predicting future antidepressant response., Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response.

Highlights • First MEG study of neural underpinnings of theory of mind differences in autism. • Children with autism show decreased LTPJ activity from 300 to 375 and 425 to 500 ms. • Children with autism also show increased RIFG activity from 325 to 375 ms. • Co-incident lower LTPJ and higher RIFG activity implies compensatory use of RIFG. • Executive functions may augment impaired theory of mind in autism., The social impairments observed in children with autism spectrum disorder are thought to arise in part from deficits in theory of mind, the ability to understand other people’s thoughts and feelings. To determine the temporal-spatial dynamics of brain activity underlying these atypical theory-of-mind processes, we used magnetoencephalography to characterize the sequence of functional brain patterns (i.e. when and where) related to theory-of-mind reasoning in 19 high-functioning children with autism compared to 22 age- and sex-matched typically-developing children aged 8–12 during a false-belief (theory-of-mind) task. While task performance did not differ between the two groups, children with autism showed reduced activation in the left temporoparietal junction between 300–375 and 425–500 ms, as well as increased activation in the right inferior frontal gyrus from 325 to 375 ms compared to controls. The overlap in decreased temporoparietal junction activity and increased right inferior frontal gyrus activation from 325 to 375 ms suggests that in children with autism, the right inferior frontal gyrus may compensate for deficits in the temporoparietal junction, a neural theory-of-mind network hub. As the right inferior frontal gyrus is involved in inhibitory control, this finding suggests that children with autism rely on executive functions to bolster their false-belief understanding.

Highlights • 1 mg/kg LPS i.p. injection robustly suppresses theta frequency in hippocampus. • LPS administration augments delta frequency in hippocampus but not mPFC. • LPS injection triggers hippocampal spike-wave discharges., The early electrophysiological phenomena linked to systemic inflammation are largely underexplored. We developed here local field analyses to detect prodromal oscillatory abnormalities. We identified early band-specific patterns in local field potential recorded from freely-moving rats injected intraperitoneally with lipopolysaccharide (LPS, 1 mg/kg). Theta frequency was significantly reduced and this effect was not related to the decreased locomotion of the animal. Furthermore, LPS-induced alterations show a region-specific response when compared between the hippocampal region and medial prefrontal cortex. Delta mean frequency increased in the hippocampal region but not in the prefrontal cortex. We explored also the hypothesis that systemic inflammation increases the propensity of abnormally synchronized brain activity. Our data indicate that the LPS-evoked alteration of delta and theta frequency parameters reflects the formation of abnormal synchronization in similar frequency ranges. The onset of abnormal brain activity was indicated by spike-wave discharges in the range of 1–10 Hz with three main frequency domains. Importantly, the occurrence of spike-wave discharges was observed in the hippocampus but not in the cortex. In summary, the hippocampal theta rhythm is an accurate indicator of the oscillatory changes evoked by LPS application. The findings offer clear patterns of altered brain function that will facilitate mechanistic investigations of brain dysfunction and delirium occurring during sepsis.

There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral (‘rACC': Cg1 and Cg3 (prelimbic area)) and caudal (‘cACC’: Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. Systemic administration of d-amphetamine (3 mg/kg, i.p.) caused a transient increase in extracellular dopamine in the rACC, but an apparent increase in the cACC of the same animals was less clearly defined. Local infusion of d-amphetamine increased dopamine efflux in the rACC, only. Glutamate efflux in the rACC was increased by local infusion of dopamine (5–50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine increased glutamate efflux and only in the cACC. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC. This article is part of the Special Issue entitled ‘CNS Stimulants’., Highlights • Dopamine and glutamate efflux in two anterior cingulate subregions were compared. • Responses to d-amphetamine depended on subregion and route of drug administration. • These findings could help explain the disparate roles of the two subregions.

An imbalance between neuronal excitation and inhibition represents a core feature in multiple neuropsychiatry disorders, necessitating the development of novel strategies to calibrate the excitatory–inhibitory balance of therapeutics. Here we identify a natural compound quercetin that reduces prefrontal cortical GABAergic transmission and alleviates the hyperactivity induced by glutamatergic N-methyl-d-aspartate receptor antagonist MK-801. Quercetin markedly reduced the GABA-activated currents in a noncompetitive manner in cultured cortical neurons, and moderately inhibited spontaneous and electrically-evoked GABAergic inhibitory postsynaptic current in mouse prefrontal cortical slices. Notably, systemic and prefrontal-specific delivery of quercetin reduced basal locomotor activity in addition to alleviated the MK-801-induced hyperactivity. The effects of quercetin were not exclusively dependent on α5-subunit-containing A type GABA receptors (GABAARs), as viral-mediated, region-specific genetic knockdown of the α5-subunit in prefrontal cortex improved the MK-801-evoked psychotic symptom but reserved the pharmacological responsivity to quercetin. Both interventions together completely normalized the locomotor activity. Together, quercetin as a negative allosteric GABAAR modulator exerted antipsychotic activity, facilitating further therapeutic development for the excitatory–inhibitory imbalance disorders.

Highlights • Sex hormones and genomic factors underpin sex dimorphism in VTA structure and function. • Environmental stressors differentially impact male and female VTA dopaminergic systems. • Sex diversity in VTA has relevance for sex bias in dopaminergic dysfunction., The knowledge that diverse populations of dopaminergic neurons within the ventral tegmental area (VTA) can be distinguished in terms of their molecular, electrophysiological and functional properties, as well as their differential projections to cortical and subcortical regions has significance for key brain functions, such as the regulation of motivation, working memory and sensorimotor control. Almost without exception, this understanding has evolved from landmark studies performed in the male sex. However, converging evidence from both clinical and pre-clinical studies illustrates that the structure and functioning of the VTA dopaminergic systems are intrinsically different in males and females. This may be driven by sex differences in the hormonal environment during adulthood (‘activational’ effects) and development (perinatal and/or pubertal ‘organizational’ effects), as well as genetic factors, especially the SRY gene on the Y chromosome in males, which is expressed in a sub-population of adult midbrain dopaminergic neurons. Stress and stress hormones, especially glucocorticoids, are important factors which interact with the VTA dopaminergic systems in order to achieve behavioral adaptation and enable the individual to cope with environmental change. Here, also, there is male/female diversity not only during adulthood, but also in early life when neurobiological programing by stress or glucocorticoid exposure differentially impacts dopaminergic developmental trajectories in male and female brains. This may have enduring consequences for individual resilience or susceptibility to pathophysiological change induced by stressors in later life, with potential translational significance for sex bias commonly found in disorders involving dysfunction of the mesocorticolimbic dopaminergic systems. These findings highlight the urgent need for a better understanding of the sexual dimorphism in the VTA if we are to improve strategies for the prevention and treatment of debilitating conditions which differentially affect men and women in their prevalence and nature, including schizophrenia, attention/deficit hyperactivity disorder, autism spectrum disorders, anxiety, depression and addiction.

Although brain plasticity in the form of gray matter increases and decreases has been observed in chronic pain, factors determining the patterns of directionality are largely unknown. Here we tested the hypothesis that fibromyalgia interacts with age to produce distinct patterns of gray matter differences, specifically increases in younger and decreases in older patients, when compared to age-matched healthy controls. The relative contribution of pain duration was also investigated. Regional gray matter was measured in younger (n=14, mean age 43, range 29–49) and older (n=14; mean age 55, range 51–60) female fibromyalgia patients and matched controls using voxel-based morphometry and cortical thickness analysis of T1-weighted magnetic resonance images. To examine their functional significance, gray matter differences were compared with experimental pain sensitivity. Diffusion-tensor imaging was used to assess whether white matter changed in parallel with gray matter, and resting-state fMRI was acquired to examine whether pain-related gray matter changes are associated with altered functional connectivity. Older patients showed exclusively decreased gray matter, accompanied by compromised white matter integrity. In contrast, younger patients showed exclusively gray matter increases, namely in the basal ganglia and insula, which were independent of pain duration. Associated white matter changes in younger patients were compatible with gray matter hypertrophy. In both age groups, structural brain alterations were associated with experimental pain sensitivity, which was increased in older patients but normal in younger patients. Whereas more pronounced gray matter decreases in the posterior cingulate cortex were related to increased experimental pain sensitivity in older patients, insular gray matter increases in younger patients correlated with lower pain sensitivity, possibly indicating the recruitment of endogenous pain modulatory mechanisms. This is supported by the finding that the insula in younger patients showed functional decoupling from an important pain-processing region, the dorsal anterior cingulate cortex. These results suggest that brain structure and function shift from being adaptive in younger to being maladaptive in older patients, which might have important treatment implications.

Highlights • Reversal learning impaired after dorsomedial striatal dopamine depletion. • No evidence of set-formation after excitotoxic subthalamic nucleus lesions. • No impairments observed after both lesions together., Patients with Parkinson’s disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat. In a single session, rats performed the intradimensional/extradimensional (ID/ED) test of attentional set-shifting. This comprises a series of seven, two-choice discriminations, including acquisitions of novel discriminations in which the relevant stimulus is either in the currently attended dimension (ID) or the currently unattended dimension (ED shift) and reversals (REVs) following each acquisition stage. Bilateral lesions were made by injection of 6-hydroxydopamine (6-OHDA) into the DMS, resulting in a selective impairment in reversal learning. Large bilateral ibotenic acid lesions centered on the STN resulted in an increase in trials to criterion in the initial stages, but learning rate improved within the session. There was no evidence of a ‘cost’ of set-shifting – the ED stage was completed in fewer trials than the ID stage – and neither was there a cost of reversal learning. Strikingly, combined lesions of both regions did not resemble the effects of either lesion alone and resulted in no apparent deficits.

Impairments in executive function and cognitive control are a common feature of neuropsychiatric and neurodegenerative disorders. A promising behavioral paradigm for elucidating the neural mechanisms of executive function is extradimensional/intradimensional (ED/ID) shifting, which places demands on executive function by requiring the adjustment of behavioral responses based on affective or attentional information. To augment the understanding of the brain systems required for these aspects of executive function, we examined the induction of Fos protein in rats tested in the ED/ID paradigm. We found increased Fos-like immunoreactivity (Fos-LI) in several cortical areas, including medial and orbital frontal cortex (OFC), in rats performing affective or attentional shifts relative to rats performing control discriminations. However, increased Fos-LI was also present in rats that performed a yoked number of additional control discrimination trials, without affective or attentional shifting. These observations suggest that cortical networks required for affective and attentional shifting are also activated during comparable discrimination tasks that do not require shifting, consistent with a role for these networks in monitoring ongoing behavior even in situations in which adaptation to changing behavioral demands is not required.

Objective To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous μ-opioid neurotransmission. Background CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. Methods We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the μ-opioid receptor availability and the clinical data. Results μOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower μOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower μOR BPND values indicate either a decrease in μOR concentration or an increase in endogenous μ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in μOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value, Graphical abstract Unlabelled Image, Highlights • Increased endogenous μ-opioid neurotransmission in limbic system of chronic migraineurs • Right amygdala opioid dysfunction is 71% explained by attack frequency, severity and sensitivity. • Amygdala dysfunction links cognitive-emotional brain mechanisms to migraine suffering.