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Die geringe Kontrollierbarkeit repetitiver Schmerzattacken ist eine der bedeutendsten Ursachen für die eingeschränkte Lebensqualität chronischer Schmerzpatienten. Der Effekt des Kontrollerlebens auf den subjektiven Schmerz, sowie die zugrundeliegenden neuronalen Mechanismen, sind bei Schmerzpatienten noch nicht umfänglich bekannt und wurden bislang hauptsächlich bei gesunden Kontrollprobanden untersucht. In diesem Vortrag soll die neuronale Modulation experimenteller Schmerzreize durch Kontrollerleben bei Patientinnen mit Fibromyalgie (FM) und gesunden Probandinnen vorgestellt werden. Mittels funktioneller Magnetresonanztomographie (fMRT) wurden die neuronalen Korrelate selbst zu beendender Hitzereize mit physikalisch in Intensität und Dauer identischen, jedoch external kontrollierten Hitzereizen, verglichen. Im Gegensatz zur Kontrollgruppe, konnten die Patientinnen mit FM nicht die in die Schmerzmodulation involvierten Hirnregionen, wie den rechten ventrolateralen prefrontal Cortex (VLPFC), den dorsolateralen prefrontal Cortex (DLPFC) und den dorsalen anterioren cingulären Cortex (dACC), aktivierten. Extern kontrollierte Hitzereize aktivierten bei der Kontrollgruppe den orbitofrontalen Cortex, während die Patientinnen mit FM Strukturen, die in die Emotionsverarbeitung involviert sind (Amygdala, parahippocampal Gyrus), aktivierten. Weiterhin zeigten Patientinnen mit FM bei selbstkontrollierten Hitzereizen eine gestörte funktionelle Konnektivität des VLPFC, DLPFC und dACC mit somatosensorischen und schmerzinhibitorischen Arealen. Außerdem wurde ein reduziertes Volumen der grauen Substanz im DLPFC und dACC bei FM gefunden. Die beschriebenen funktionellen und strukturellen Veränderungen weisen auf eine dysfunktionale neuronale Schmerzmodulation durch erlebte Kontrolle bei FM hin. Diese extensiven funktionellen und strukturellen Veränderungen in relevanten sensorischen, limbischen und assoziativen Hirnarealen könnten über Behandlungen wie TMS, Neurofeedback oder Verhaltenstrainings adressiert werden.

Abstract Lower neighborhood socioeconomic status (nSES) is associated with poorer cognitive function; underlying neural correlates are unknown. Cross-sectional associations of nSES (six census-derived measures of income, education, and occupation) and gray matter volume (GMV) of eight memory-related regions (hippocampus, middle frontal gyrus, amygdala, insula, parahippocampal gyrus, anterior, middle, and posterior cingulum) were examined in 264 community-dwelling older adults (mean age=83, 56.82% female, 39.02% black). In linear mixed effects models adjusted for total brain atrophy and accounting for geographic clustering, higher nSES was associated with greater GMV of the left hippocampus, left posterior cingulum, and bilateral insula, middle frontal, and parahippocampal gyri. nSES remained associated with GMV of the right insula (β= -32.26, p=0.026, 95%CI: -60.66, -3.86) after adjusting for individual level age, gender, race, income, and education. The nSES and cognitive function association may not be due to gray matter volume differences; other behavioral and biological mediators should be explored.

Non-invasive assessment of human neurotransmitter function is a highly valuable tool in clinical research. Despite the current interest in task-based pharmacological MRI (phMRI) for the assessment of neural correlates of serotonin (5-HT) function, testaretest reliability of this technique has not yet been established. Using a placebo-controlled crossover design, we aimed to examine the repeatability of task-related phMRI with a single dose of oral citalopram in twelve healthy female subjects. Since we were interested in the drug's effect on neural correlates of 5-HT related cognitive processes, a sensorimotor and an emotional face processing paradigm were used. For both paradigms, we found no significant effects of the oral citalopram challenge on task-positive brain activity with whole-brain analysis. With ROI-based analysis, there was a small effect of the challenge related to emotional processing in the amygdala, but this effect could not be reproduced between sessions. We did however find reproducible effects of the challenge on task-negative BOLD-responses, particularly in the medial frontal cortex and paracingulate gyrus. In conclusion, our data shows that a single oral dose of citalopram does not reliably affect emotional processing and sensorimotor activity, but does influence task-negative processes in the frontal cortex. This latter finding validates previous studies indicating a role for 5-HT in suppression of the task-negative network during goal-directed behavior.

The amygdala is composed of multiple nuclei with unique functions and connections in the limbic system and to the rest of the brain. However, standard in vivo neuroimaging tools to automatically delineate the amygdala into its multiple nuclei are still rare. By scanning postmortem specimens at high resolution (100–150µm) at 7T field strength (n = 10), we were able to visualize and label nine amygdala nuclei (anterior amygdaloid, cortico-amygdaloid transition area; basal, lateral, accessory basal, central, cortical medial, paralaminar nuclei). We created an atlas from these labels using a recently developed atlas building algorithm based on Bayesian inference. This atlas, which will be released as part of FreeSurfer, can be used to automatically segment nine amygdala nuclei from a standard resolution structural MR image. We applied this atlas to two publicly available datasets (ADNI and ABIDE) with standard resolution T1 data, used individual volumetric data of the amygdala nuclei as the measure and found that our atlas i) discriminates between Alzheimer's disease participants and age-matched control participants with 84% accuracy (AUC=0.915), and ii) discriminates between individuals with autism and age-, sex- and IQ-matched neurotypically developed control participants with 59.5% accuracy (AUC=0.59). For both datasets, the new ex vivo atlas significantly outperformed (all p < .05) estimations of the whole amygdala derived from the segmentation in FreeSurfer 5.1 (ADNI: 75%, ABIDE: 54% accuracy), as well as classification based on whole amygdala volume (using the sum of all amygdala nuclei volumes; ADNI: 81%, ABIDE: 55% accuracy). This new atlas and the segmentation tools that utilize it will provide neuroimaging researchers with the ability to explore the function and connectivity of the human amygdala nuclei with unprecedented detail in healthy adults as well as those with neurodevelopmental and neurodegenerative disorders. •We visualized 9 nuclei boundaries (anterior amygdaloid area, cortico-amygdaloid transition area; basal, lateral, accessory basal, central, cortical medial, paralaminar nuclei) using ultra-high-resolution ex vivo imaging.•Nuclei were consistent across cases and raters.•We built a segmentation atlas of the amygdala nuclei, which will be distributed with FreeSurfer.•Atlas was applied to 2 datasets and showed higher discriminability of Alzheimer's & autism than previously possible.•The atlas will provide neuroimaging researchers with the ability to test nucleus function with greater spatial specificity.

The amygdala is a major structure that orchestrates defensive reactions to environmental threats and is implicated in hypervigilance and symptoms of heightened arousal in posttraumatic stress disorder (PTSD). The basolateral and centromedial amygdala (CMA) complexes are functionally heterogeneous, with distinct roles in learning and expressing fear behaviors. PTSD differences in amygdala-complex function and functional connectivity with cortical and subcortical structures remain unclear. Recent military veterans with PTSD (n=20) and matched trauma-exposed controls (n=22) underwent a resting-state fMRI scan to measure task-free synchronous blood-oxygen level dependent activity. Whole-brain voxel-wise functional connectivity of basolateral and CMA seeds was compared between groups. The PTSD group had stronger functional connectivity of the basolateral amygdala (BLA) complex with the pregenual anterior cingulate cortex (ACC), dorsomedial prefrontal cortex, and dorsal ACC than the trauma-exposed control group (p<0.05; corrected). The trauma-exposed control group had stronger functional connectivity of the BLA complex with the left inferior frontal gyrus than the PTSD group (p<0.05; corrected). The CMA complex lacked connectivity differences between groups. We found PTSD modulates BLA complex connectivity with prefrontal cortical targets implicated in cognitive control of emotional information, which are central to explanations of core PTSD symptoms. PTSD differences in resting-state connectivity of BLA complex could be biasing processes in target regions that support behaviors central to prevailing laboratory models of PTSD such as associative fear learning. Further research is needed to investigate how differences in functional connectivity of amygdala complexes affect target regions that govern behavior, cognition, and affect in PTSD.

The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ + neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ − neurons in CEl. Electrical silencing of PKC-δ + neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called CEl off units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing. The neural circuitry of fear The central amygdala, composed mainly of GABAergic inhibitory neurons, is the part of the brain that processes Pavlovian conditioned fear. Two groups reporting in this issue of Nature use different yet complementary experimental approaches to arrive at similar conclusions about the functional architecture that underlies the conditioned fear response. They find that two microcircuits are involved, one required for fear acquisition and the other for conditioned fear responses. Haubensak et al . use genetically based functional manipulations to identify a subpopulation of GABAergic neurons that has a key role in gating learned fear. Ciocchi et al . use a combination of in vivo electrophysiological, optogenetic and pharmacological approaches in mice to identify three functionally distinct types of neurons that are embedded in a highly organized local disinhibitory network. The central amygdala relies on inhibitory circuitry to encode fear memories, but how this information is acquired and expressed in these connections is unknown. Two new papers use a combination of cutting-edge technologies to reveal two distinct microcircuits within the central amygdala, one required for fear acquisition and the other critical for conditioned fear responses. Understanding this architecture provides a strong link between activity in a specific circuit and particular behavioural consequences.

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.

The ability to help and care for others fosters social cohesiveness and is vital to the physical and emotional well-being of social species, including humans 1 – 3 . Affiliative social touch, such as allogrooming (grooming behaviour directed towards another individual), is a major type of prosocial behaviour that provides comfort to others 1 – 6 . Affiliative touch serves to establish and strengthen social bonds between animals and can help to console distressed conspecifics. However, the neural circuits that promote prosocial affiliative touch have remained unclear. Here we show that mice exhibit affiliative allogrooming behaviour towards distressed partners, providing a consoling effect. The increase in allogrooming occurs in response to different types of stressors and can be elicited by olfactory cues from distressed individuals. Using microendoscopic calcium imaging, we find that neural activity in the medial amygdala (MeA) responds differentially to naive and distressed conspecifics and encodes allogrooming behaviour. Through intersectional functional manipulations, we establish a direct causal role of the MeA in controlling affiliative allogrooming and identify a select, tachykinin-expressing subpopulation of MeA GABAergic (γ-aminobutyric-acid-expressing) neurons that promote this behaviour through their projections to the medial preoptic area. Together, our study demonstrates that mice display prosocial comforting behaviour and reveals a neural circuit mechanism that underlies the encoding and control of affiliative touch during prosocial interactions. Neurons in the medial amygdala regulate prosocial comforting behaviour towards distressed social partners in mice.

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase 1 , 2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain–spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention. Neuronal activities in the central amygdala and paraventricular nucleus are transmitted via the splenic nerve to increase plasma cell formation after immunization, and this process can be behaviourally enhanced in mice.