Sex differences in the age-related decrease of spontaneous baroreflex function in healthy individuals.

The baroreflex is a powerful physiological mechanism for rapidly adjusting heart rate in response to changes in blood pressure. Spontaneous baroreflex sensitivity (BRS) has been shown to decrease with age. However, studies of sex differences in these age-related changes are rare. Here we investigated several markers of spontaneous baroreflex function in a large sample of healthy individuals. Cardiovascular signals were recorded in the supine position under carefully controlled resting conditions. After quality control, n = 980 subjects were divided into five age groups [age < 30 yr (n = 612), 30-39 yr (n = 140), 40-49 yr (n = 95), 50-59 yr (n = 61), and >60 yr (n = 72)]. Spontaneous baroreflex function was assessed in the time domain (bradycardic and tachycardic slope) and in the frequency domain in the low- and high-frequency band (LF-α, HF-α) applying the transfer function. General linear models showed a significant effect of factor age (P < 0.001) and an age × sex interaction effect (P < 0.05) on each indicator of the baroreflex function. Simple main effects showed a significantly higher BRS as indicated by tachycardic slope, LF-α and HF-α in middle-aged women compared with men (30-39 yr) and higher LF-α, bradycardic and tachycardic slope in men compared with women of the oldest age group (>60 yr). Changes in BRS over the lifespan suggest that baroreflex function declines more slowly but earlier in life in men than in women. Our findings could be linked to age-related changes in major sex hormone levels, suggesting significant implications for diverse cardiovascular outcomes and the implementation of targeted preventive strategies.NEW & NOTEWORTHY In this study, we demonstrate that the age-related decrease of spontaneous baroreflex sensitivity is different in men and women by analyzing resting state cardiovascular data of a large sample of healthy individuals.

Unconscious Activation of Negative Emotional Memories Increases Pain Unpleasantness.

OBJECTIVE: The influence of unconscious emotional processes on pain remains poorly understood. The present study tested whether cues to forgotten unpleasant images might amplify pain (i.e., in the absence of conscious recall). METHODS: Seventy-two healthy female adults (19 to 34 years) performed an adapted Think/No-think paradigm (T/NT) using 72 combinations of neutral face images (cues) paired with 36 neutral and 36 unpleasant images. After completion of the T/NT task, cues associated with forgotten neutral or unpleasant images were identified. Cues to either neutral or unpleasant images from the NT condition were then presented in randomized order while participants received intermediate-level thermal pain stimulation on the left hand. Ratings of both pain intensity and unpleasantness were acquired after each trial. RESULTS: Mean pain unpleasantness ratings were greater during presentation of cues to forgotten negative versus neutral images (5.52 [SD = 2.06] versus 5.23 [SD = 2.10]; p = .02). This pattern was also present when comparing cues to remembered negative versus neutral images (5.62 [SD = 1.94] versus 5.04 [SD = 1.90]; p < .001). Mean pain intensity ratings were higher for cues to negative versus neutral images when remembered (5.48 [SD = 1.79] versus 5.00 [SD = 1.69]; p < .001), but not when forgotten (5.27 [SD = 1.96] versus 5.16 [SD = 1.93]; p = .30). CONCLUSIONS: Using an adapted T/NT-Pain paradigm, this study demonstrated that cues to nonrecallable (but potentially unconsciously activated) negative emotional memories amplify pain unpleasantness, similar to known effects of conscious negative emotions.

Brains of endurance athletes differ in the association areas but not in the primary areas.

Regular participation in sports results in a series of physiological adaptations. However, little is known about the brain adaptations to physical activity. Here we aimed to investigate whether young endurance athletes and non-athletes differ in the gray and white matter of the brain and whether cardiorespiratory fitness (CRF) is associated with these differences. We assessed the CRF, volumes of the gray and white matter of the brain using structural magnetic resonance imaging (sMRI), and brain white matter connections using diffusion magnetic resonance imaging (dMRI) in 20 young male endurance athletes and 21 healthy non-athletes. While total brain volume was similar in both groups, the white matter volume was larger and the gray matter volume was smaller in the athletes compared to non-athletes. The reduction of gray matter was located in the association areas of the brain that are specialized in processing of sensory stimuli. In the microstructure analysis, significant group differences were found only in the association tracts, for example, the inferior occipito-frontal fascicle (IOFF) showing higher fractional anisotropy and lower radial diffusivity, indicating stronger myelination in this tract. Additionally, gray and white matter brain volumes, as well as association tracts correlated with CRF. No changes were observed in other brain areas or tracts. In summary, the brain signature of the endurance athlete is characterized by changes in the integration of sensory and motor information in the association areas.

Dynamic changes in the central autonomic network of patients with anorexia nervosa.

Autonomic cardiac dysfunction is a common complication in patients with anorexia nervosa (AN). Despite its high prevalence, physicians often overlook this clinical condition, and little research has been dedicated so far. To probe the functional role of the neurocircuitry underpinning the poorly understood autonomic cardiac dysfunction, we examined dynamic functional differences in the central autonomic network (CAN) between 21 acute AN individuals and 24 age, sex and heart rate-matched healthy controls (HC). We assessed functional connectivity (FC) changes in CAN using seeds in the ventromedial prefrontal cortex, left and right anterior insular cortex, left and right amygdala and dorsal anterior cingulate cortex. The overall FC between the six investigated seeds is reduced in AN individuals compared to HC, although no changes were observed for single connections. Moreover, AN exhibited higher complexity in the FC time series of such CAN regions. Contrary to HC, we found that the degree of complexity between FC and heart rate (HR) series did not correlate in AN, suggesting a shift from central to peripheral control of the heart in AN individuals. Using dynamic FC analysis, we showed that the CAN transits across five functional states with no preference for any. Strikingly, at the state of weakest connectivity, the entropy significantly diverges between healthy and AN individuals, reaching its minimum and maximum values, respectively. Overall, our findings provide evidence that core regions of the CAN engaged in cardiac regulation are functionally affected in acute AN.

Testing visual self-misperception in anorexia nervosa using a symmetrical body size estimation paradigm.

OBJECTIVE: Individuals diagnosed with anorexia nervosa (AN) often report seeing themselves as overweight. While body size estimation tasks suggest that such individuals overestimate their body size, these tasks have failed to establish whether this misestimation stems from visual misperception. Misestimation might, instead, be due to response bias. We designed a paradigm to distinguish between visual and response bias contributions to body size misestimation: the symmetrical body size estimation (s-BSE) paradigm. METHOD: The s-BSE paradigm involves two tasks. In the conventional task, participants estimate the width of their photographed body by adjusting the size of a rectangle to match. In the transposed task, participants adjust the size of a photograph of their body to match the rectangle. If overestimation stems exclusively from visual misperception, then errors in each task would be equal and opposite. Using this paradigm, we compared the performance of women diagnosed with AN (n = 14) against women without any eating disorder (n = 40). RESULTS: In the conventional task, we replicated previous findings indicating that both women with AN and women without any eating disorder overestimate their body size. In the transposed task, neither group adjusted the bodies to be narrower than the rectangle. Participants with AN set their photographs to be significantly wider. DISCUSSION: While we replicated previous findings of body size overestimation amongst women with AN and those without any eating disorder, our results are inconsistent with the hypothesis that such overestimation stems exclusively from visual misperception and instead suggest a substantial response bias effect. PUBLIC SIGNIFICANCE: Women with anorexia nervosa overestimate their own body size. Research has not yet determined whether this overestimation stems from them seeing themselves as larger or other, non-visual factors. We employ a new method for distinguishing these possibilities and find that non-visual factors influence size estimates for women with and without anorexia nervosa. This method can help future research control for non-perceptual influences on participant responses.

Neural mechanisms of pain processing differ between endurance athletes and nonathletes: A functional connectivity magnetic resonance imaging study.

Pain perception and the ability to modulate arising pain vary tremendously between individuals. It has been shown that endurance athletes possess higher pain tolerance thresholds and a greater effect of conditioned pain modulation than nonathletes, both indicating a more efficient system of endogenous pain inhibition. The aim of the present study was to focus on the neural mechanisms of pain processing in endurance athletes that have not been investigated yet. Therefore, we analyzed the pain processing of 18 male athletes and 19 healthy male nonathletes using functional magnetic resonance imaging. We found lower pain ratings in endurance athletes compared to nonathletes to physically identical painful stimulation. Furthermore, brain activations of athletes versus nonathletes during painful heat stimulation revealed reduced activation in several brain regions that are typically activated by nociceptive stimulation. This included the thalamus, primary and secondary somatosensory cortex, insula, anterior cingulate cortex, midcingulate cortex, dorsolateral prefrontal cortex, and brain stem (BS). Functional connectivity analyses revealed stronger network during painful heat stimulation in athletes between the analyzed brain regions except for connections with the BS that showed reduced functional connectivity in athletes. Post hoc correlation analyses revealed associations of the subject's fitness level and the brain activation strengths, subject's fitness level and functional connectivity, and brain activation strengths and functional connectivity. Together, our results demonstrate for the first time that endurance athletes do not only differ in behavioral variables compared to nonathletes, but also in the neural processing of pain elicited by noxious heat.

Interrelations between dopamine and serotonin producing sites and regions of the default mode network.

Recent functional magnetic resonance imaging (fMRI) studies showed that blood oxygenation level-dependent (BOLD) signal fluctuations in the default mode network (DMN) are functionally tightly connected to those in monoaminergic nuclei, producing dopamine (DA), and serotonin (5-HT) transmitters, in the midbrain/brainstem. We combined accelerated fMRI acquisition with spectral Granger causality and coherence analysis to investigate causal relationships between these areas. Both methods independently lead to similar results and confirm the existence of a top-down information flow in the resting-state condition, where activity in core DMN areas influences activity in the neuromodulatory centers producing DA/5-HT. We found that latencies range from milliseconds to seconds with high inter-subject variability, likely attributable to the resting condition. Our novel findings provide new insights into the functional organization of the human brain.

Microstructural alterations in medial forebrain bundle are associated with interindividual pain sensitivity.

The perception of pain to noxious stimuli, also known as pain sensitivity, varies among individuals. The comprised brain structures and their white matter pathways are complex and elusive. Here, we aimed to investigate whether variation of microstructure of the medial forebrain bundle (MFB), a tract connecting the basal forebrain with the brain stem, is associated with interindividual pain sensitivity. We assessed interindividual pain sensitivity as a rating of pain intensity to heat stimuli (45, 47, and 48.9°C) in 38 healthy men (age: 27.05 ± 5.7 years). We also reconstructed the MFB using multitensor tractography from diffusion magnetic resonance imaging (dMRI) and calculated free-water corrected dMRI measures of fractional anisotropy (FAt ), radial diffusivity (RDt ), and axial diffusivity (ADt ). Lower ratings of interindividual pain intensity correlated with higher FAt and lower RDt of the MFB. As changes in FAt and RDt may reflect abnormalities in myelination, the results might be interpreted as that a lower pain rating is associated with higher degree of myelination of the MFB and could represent an inhibitory pathway of pain. Our results suggest that alteration of microstructure in the MFB contributes to the interindividual variation of pain perception.

Estimating Resting HRV during fMRI: A Comparison between Laboratory and Scanner Environment.

Heart rate variability (HRV) is regularly assessed in neuroimaging studies as an indicator of autonomic, emotional or cognitive processes. In this study, we investigated the influence of a loud and cramped environment during magnetic resonance imaging (MRI) on resting HRV measures. We compared recordings during functional MRI sessions with recordings in our autonomic laboratory (LAB) in 101 healthy subjects. In the LAB, we recorded an electrocardiogram (ECG) and a photoplethysmogram (PPG) over 15 min. During resting state functional MRI, we acquired a PPG for 15 min. We assessed anxiety levels before the scanning in each subject. In 27 participants, we performed follow-up sessions to investigate a possible effect of habituation. We found a high intra-class correlation ranging between 0.775 and 0.996, indicating high consistency across conditions. We observed no systematic influence of the MRI environment on any HRV index when PPG signals were analyzed. However, SDNN and RMSSD were significantly higher when extracted from the PPG compared to the ECG. Although we found a significant correlation of anxiety and the decrease in HRV from LAB to MRI, a familiarization session did not change the HRV outcome. Our results suggest that psychological factors are less influential on the HRV outcome during MRI than the methodological choice of the cardiac signal to analyze.

Functional consequences of acute tryptophan depletion on raphe nuclei connectivity and network organization in healthy women.

Previous research on central nervous serotonin (5-HT) function provided evidence for a substantial involvement of 5-HT in the regulation of brain circuitries associated with cognitive and affective processing. The underlying neural networks comprise core subcortical/cortical regions such as amygdala and medial prefrontal cortex, which are assumed to be modulated amongst others by 5-HT. Beside the use of antidepressants, acute tryptophan depletion (ATD) is a widely accepted technique to manipulate of 5-HT synthesis and its respective metabolites in humans by means of a dietary and non-pharmacological tool. We used a double-blind, randomized, cross-over design with two experimental challenge conditions, i.e. ATD and tryptophan (TRP) supplementation (TRYP+) serving as a control. The aim was to perturb 5-HT synthesis and to detect its impact on brain functional connectivity (FC) of the upper serotonergic raphe nuclei, the amygdala and the ventromedial prefrontal cortex as well as on network organization using resting state fMRI. 30 healthy adult female participants (age: M â€‹= â€‹24.5 â€‹± â€‹4.4 â€‹yrs) were included in the final analysis. ATD resulted in a 90% decrease of TRP in the serum relative to baseline. Compared to TRYP â€‹+ â€‹for the ATD condition a significantly lower FC of the raphe nucleus to the frontopolar cortex was detected, as well as greater functional coupling between the right amygdala and the ventromedial prefrontal cortex. FC of the raphe nucleus correlated significantly with the magnitude of TRP changes for both challenge conditions (ATD & TRYP+). Network-based statistical analysis using time series from 260 independent anatomical ROIs revealed significantly greater FC after ATD compared to TRYP+ in several brain regions being part of the default-mode (DMN) and the executive-control networks (ECN), but also of salience or visual networks. Finally, we observed an impact of ATD on the rich-club organization in terms of decreased rich-club coefficients compared to TRYP+. In summary we could confirm previous findings that the putative decrease in brain 5-HT synthesis via ATD significantly alters FC of the raphe nuclei as well as of specific subcortical/cortical regions involved in affective, but also in cognitive processes. Moreover, an ATD-effect on the so-called rich-club organization of some nodes with the high degree was demonstrated. This may indicate effects of brain 5-HT on the integration of information flow from several brain networks.

[Implementation of exercise therapy in daily clinical practice in psychiatric clinics in Germany]. / Angebot und Inanspruchnahme von Sporttherapie in psychiatrischen Kliniken in Deutschland.

Exercise therapy has proven to be effective in the treatment of multiple mental illnesses. As mental disorders result in tremendous costs for the healthcare system as well as a huge burden for the affected individuals, improving treatment strategies according to latest scientific evidence should be of highest priority. In 2016 a first study provided indications that only a minority of patients are treated with exercise therapy during their stay in hospital. Hence, the aim of this study was to assess the actual extent of exercise therapy usage in psychiatric inpatients in Germany, thereby giving a scientific foundation to the call for a better standard of care. To achieve this, a retrospective analysis was performed on pre-existing data from 2693 patients who were treated in 1 of 4 participating university hospitals. Only 23% of these patients participated in exercise therapy with a mean training duration of 36 min per week. Patients with the diagnosis of schizophrenia or patients with multiple comorbidities were even less likely to participate in exercise therapy. With these findings it becomes evident that the healthcare situation concerning exercise therapy is insufficient. Solid evidence for the effectiveness of exercise therapy, the current treatment guidelines as well as the positive side effects, especially when compared to side effects of pharmacotherapy (i.e. weight gain) should motivate healthcare officials to make an effort to improve this situation.

The relationship between heart rate and functional connectivity of brain regions involved in autonomic control.

The peripheral autonomic nervous system (ANS) adjusts the heart rate (HR) to intrinsic and extrinsic demands. It is controlled by a group of functionally connected brain regions assembling the so-called central autonomic network (CAN). More specifically, forebrain cortical regions, limbic and brainstem structures within the CAN have been identified as important components of circuits involved in HR regulation. The present study aimed to investigate whether functional connectivity (FC) between these regions varies in subjects with different heart rates. Thus, 84 healthy subjects were separated according to their HR in slow, medium and fast. We observed a direct association between HR and FC in CAN regions, where stronger FC was related to slower HR. This relationship, however, is non-linear, follows an exponential course and is not restricted to CAN areas only. The network-based analysis (NBS) using time series from 262 independent anatomical ROIs revealed significantly increased functional connectivity in subjects with slow HR compared to subjects with fast HR mainly in regions being part of the salience network, but also of the default-mode network. We additionally simulated the effect of aliasing on the functional connectivity using several TRs and heart rates to exclude the possibility that FC differences might be due to different aliasing effects in the data. The result of the simulation indicated that aliasing cannot explain our findings. Thus, present results imply a functionally meaningful coupling between FC and HR that need to be accounted for in future studies. Moreover, given the established link between HR and emotional, cognitive and social processes, present findings may also be considered to explain individual differences in brain activation or connectivity when using corresponding paradigms in the MR scanner to investigate such processes.

Activation of brainstem and midbrain nuclei during cognitive control in medicated patients with schizophrenia.

Evidence suggests that cognitive control functions as well as the underlying brain network, anchored by the prefrontal cortex (PFC) and the dorsal anterior cingulate cortex (dACC), are dysfunctional in schizophrenia. Catecholamine producing midbrain and brainstem nuclei are densely connected with the PFC and dACC and exert profound contributions to cognitive control processes. Dysfunctions within the underlying neurotransmitter systems are considered to play a central role in the occurrence of various symptoms of schizophrenia. We sought to investigate the putatively abnormal activation pattern of the dopaminergic midbrain nuclei, that is, ventral tegmental area (VTA) and substantia nigra as well as that of the noradrenergic locus coeruleus (LC) in patients with schizophrenia during cognitive control. A total of 28 medicated patients and 27 healthy controls were investigated with the manual version of the Stroop task using event-related fMRI. The main finding was a reduced BOLD activation in the VTA during both Stroop task conditions in patients in comparison to controls, which correlated significantly with the degree of negative symptoms. We further detected a comparable LC activation in in patients and healthy controls. However, in controls LC activation was significantly correlated with the Stroop interference time, which was not observed in patients. The finding of reduced VTA activation in schizophrenia patients lends further support to the assumed dysfunction of the DA system in schizophrenia. In addition, despite comparable LC activation, the nonsignificant correlation with the Stroop interference time might indicate altered LC functioning in schizophrenia and, thus, needs further investigations.

Altered Causal Coupling Pathways within the Central-Autonomic-Network in Patients Suffering from Schizophrenia.

The multivariate analysis of coupling pathways within physiological (sub)systems focusing on identifying healthy and diseased conditions. In this study, we investigated a part of the central-autonomic-network (CAN) in 17 patients suffering from schizophrenia (SZO) compared to 17 age-gender matched healthy controls (CON) applying linear and nonlinear causal coupling approaches (normalized short time partial directed coherence, multivariate transfer entropy). Therefore, from all subjects continuous heart rate (successive beat-to-beat intervals, BBI), synchronized maximum successive systolic blood pressure amplitudes (SYS), synchronized calibrated respiratory inductive plethysmography signal (respiratory frequency, RESP), and the power PEEG of frontal EEG activity were investigated for 15 min under resting conditions. The CAN revealed a bidirectional coupling structure, with central driving towards blood pressure (SYS), and respiratory driving towards PEEG. The central-cardiac, central-vascular, and central-respiratory couplings are more dominated by linear regulatory mechanisms than nonlinear ones. The CAN showed significantly weaker nonlinear central-cardiovascular and central-cardiorespiratory coupling pathways, and significantly stronger linear central influence on the vascular system, and on the other hand significantly stronger linear respiratory and cardiac influences on central activity in SZO compared to CON, and thus, providing better understanding of the interrelationship of central and autonomic regulatory mechanisms in schizophrenia might be useful as a biomarker of this disease.

Impact of the heart rate on the shape of the cardiac response function.

There is limited understanding about how heart rate (HR) influences the blood-oxygen level dependent (BOLD) signal. While the mechanism by which respiration induces fluctuation in the BOLD signal is relatively well understood, the mechanisms regarding the HR remains unclear. The application of canonical cardiac response function (CRF), or subject-specific CRF, is an effective method for creating nuisance regressors, which can be used to remove cardiac-induced fluctuations in the BOLD signal. However, the relationship between physiological parameters and the characteristics of the CRF has not been systematically investigated. In the present investigation, we studied the relationship between the variations in mean HR and the shape of the cardiac response function in 84 healthy subjects with a wide range of HR lying between 47 and 97 beats per minute (bpm). Three groups (n = 28) were created based on the subject's mean HR. We demonstrated that the HR plays an important role in determining the shape of the CRFs. We also observed that the canonical CRF explains more variance in subjects with a slow HR, than in subjects exhibiting faster HR. We found that the amount of explained variance significantly increased in each group when a group-specific CRF was used. In a further analysis, we found two forms of a CRF, which explain a considerable amount of variance in subjects with a mean HR below and above 68 bpm. The shape of the CRF in subjects below 68 bpm is characterized by a shape similar to the canonical CRF, while in subjects with a HR above 68 bpm a well-defined second maximum was identified around 17 s. Thus, in the present study, we provide evidence for the necessity to use mean HR-based CRFs, rather than one canonical CRF, in order to optimally describe the interaction between BOLD and HR signal in subjects with varying heart rates.

Functional connectivity and network analysis of midbrain and brainstem nuclei.

There is limited understanding of how monoamine-producing nuclei within midbrain and brainstem contribute to the formation and functional dynamics of brain networks across the human neocortex. We used resting state fMRI in 154 healthy participants to elucidate patterns of functional connectivity and network organization between cortical/subcortical regions and midbrain/brainstem nuclei. By means of univariate functional connectivity and graph-based analysis, we show that dopaminergic midbrain centers and the serotonergic dorsal raphe nucleus (DRN) are functionally integrated with the default mode network (DMN), whereas the remaining serotonergic raphe nuclei and the noradrenergic locus coeruleus are functionally integrated with the executive-control network (ECN). The majority of midbrain/brainstem nuclei show a high level of connectedness to other network modules classifying these nuclei as "connector" hubs. The additionally applied probabilistic independent component analysis (PICA) broadly corresponded with the results of the GT analysis, describing similar functionally-relevant cortical networks. Since monoaminergic neurotransmission is essential to neocortical function, and represents an important target for pharmacotherapy, our novel findings contribute to a comprehensive understanding of the functional organization of the human brain.

Differential involvement of brainstem noradrenergic and midbrain dopaminergic nuclei in cognitive control.

Several lines of evidence suggest that the lateral prefrontal cortex (PFC), the dorsal anterior cingulate cortex (dACC), the parietal cortex, and the thalamus are central cortical nodes in a network underlying cognitive control. However, the role of catecholamine producing midbrain and brainstem structures has rarely been addressed by functional magnetic resonance imaging (fMRI). We hypothesized differential activation patterns in the ventral tegmental area (VTA)/substantia nigra (SN) and locus coeruleus (LC) with respect to the degree of cognitive control during a Stroop task in healthy subjects. Forty-five healthy subjects were investigated by the manual version of the Stroop task in an event-related fMRI design. We observed significant BOLD activation of both the SN/VTA and LC during the Stroop interference condition (incongruent vs. congruent condition). LC, but not SN/VTA activation significantly correlated with the Stroop interference. Interestingly, a significant linear decrease in BOLD activation during the incongruent condition during the experiment was mainly observed in the fronto-cingulo-striatal network, but not in SN/VTA and LC. Using psychophysiological (PPI) analyses, a significant functional connectivity during cognitive control was observed between SN/VTA and the nigrostriatal/mesolimbic dopaminergic system. For the LC, distinct functional connectivity pattern was observed mainly to the dorsolateral and ventrolateral PFC. Both regions revealed significant functional connectivity to the dACC, parietal and occipital regions. Thus, we demonstrate for the first time that functional activation patterns in the SN/VTA and the LC are modulated by different demands of cognitive control. In addition, these nuclei exhibit distinguishable functional connectivity patterns to cortical brain networks. Hum Brain Mapp 37:2305-2318, 2016. © 2016 Wiley Periodicals, Inc.

A data-driven approach to mapping cortical and subcortical intrinsic functional connectivity along the longitudinal hippocampal axis.

The hippocampus (HPC) is functionally heterogeneous along the longitudinal anterior-posterior axis. In rodent models, gene expression maps define at least three discrete longitudinal subregions, which also differ in function, and in anatomical connectivity with the rest of the brain. In humans, equivalent HPC subregions are less well defined, resulting in a lack of consensus in neuroimaging approaches that limits translational study. This study determined whether a data-driven analysis, namely independent component analysis (ICA), could reproducibly define human HPC subregions, and map their respective intrinsic functional connectivity (iFC) with the rest of the brain. Specifically, we performed ICA of resting-state fMRI activity spatially restricted within the HPC, to determine the configuration and reproducibility of functional HPC components. Using dual regression, we then performed multivariate analysis of iFC between resulting HPC components and the whole brain, including detailed connectivity with the hypothalamus, a functionally important connection not yet characterized in human. We found hippocampal ICA resulted in highly reproducible longitudinally discrete components, with greater functional heterogeneity in the anterior HPC, consistent with animal models. Anterior hippocampal components shared iFC with the amygdala, nucleus accumbens, medial prefrontal cortex, posterior cingulate cortex, midline thalamus, and periventricular hypothalamus, whereas posterior hippocampal components shared iFC with the anterior cingulate cortex, retrosplenial cortex, and mammillary bodies. We show that spatially masked hippocampal ICA with dual regression reproducibly identifies functional subregions in the human HPC, and maps their respective brain intrinsic connectivity. Hum Brain Mapp 37:462-476, 2016. © 2015 Wiley Periodicals, Inc.

Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation.

The pain mediator prostaglandin E2 (PGE2) sensitizes nociceptive pathways through EP2 and EP4 receptors, which are coupled to Gs proteins and increase cAMP. However, PGE2 also activates EP3 receptors, and the major signaling pathway of the EP3 receptor splice variants uses inhibition of cAMP synthesis via Gi proteins. This opposite effect raises the intriguing question of whether the Gi-protein-coupled EP3 receptor may counteract the EP2 and EP4 receptor-mediated pronociceptive effects of PGE2. We found extensive localization of the EP3 receptor in primary sensory neurons and the spinal cord. The selective activation of the EP3 receptor at these sites did not sensitize nociceptive neurons in healthy animals. In contrast, it produced profound analgesia and reduced responses of peripheral and spinal nociceptive neurons to noxious stimuli but only when the joint was inflamed. In isolated dorsal root ganglion neurons, EP3 receptor activation counteracted the sensitizing effect of PGE2, and stimulation of excitatory EP receptors promoted the expression of membrane-associated inhibitory EP3 receptor. We propose, therefore, that the EP3 receptor provides endogenous pain control and that selective activation of EP3 receptors may be a unique approach to reverse inflammatory pain. Importantly, we identified the EP3 receptor in the joint nerves of patients with painful osteoarthritis.

The neural basis of the abnormal self-referential processing and its impact on cognitive control in depressed patients.

Persistent pondering over negative self-related thoughts is a central feature of depressive psychopathology. In this study, we sought to investigate the neural correlates of abnormal negative self-referential processing (SRP) in patients with Major Depressive Disorder and its impact on subsequent cognitive control-related neuronal activation. We hypothesized aberrant activation dynamics during the period of negative and neutral SRP in the rostral anterior cingulate cortex (rACC) and in the amygdala in patients with major depressive disorder. Additionally, we assumed abnormal activation in the fronto-cingulate network during Stroop task execution. 19 depressed patients and 20 healthy controls participated in the study. Using an event-related functional magnetic resonance imaging (fMRI) design, negative, positive and neutral self-referential statements were displayed for 6.5 s and followed by incongruent or congruent Stroop conditions. The data were analyzed with SPM8. In contrast to controls, patients exhibited no significant valence-dependent rACC activation differences during SRP. A novel finding was the significant activation of the amygdala and the reward-processing network during presentation of neutral self-referential stimuli relative to baseline and to affective stimuli in patients. The fMRI analysis of the Stroop task revealed a reduced BOLD activation in the right fronto-parietal network of patients in the incongruent condition after negative SRP only. Thus, the inflexible activation in the rACC may correspond to the inability of depressed patients to shift their attention away from negative self-related stimuli. The accompanying negative affect and task-irrelevant emotional processing may compete for neuronal resources with cognitive control processes and lead thereby to deficient cognitive performance associated with decreased fronto-parietal activation.