Childhood maltreatment is a major risk factor for psychopathology associated with interpersonal problems in adulthood, but the etiological pathways involved are still unclear. The authors propose that childhood maltreatment confers risk for dysfunctional behavior in social interactions by altering interpersonal distance preference and the processing of social touch.Methods: Ninety-two medication-free adults (64 of them female) with low, medium, and high levels of childhood maltreatment were tested with an interpersonal distance paradigm and subsequently underwent a social touch functional MRI task during which they rated the perceived comfort of slow touch (C-tactile [CT] optimal speed; 5 cm/s) and fast touch (non-CT-optimal speed; 20 cm/s).Results: Participants with high childhood maltreatment levels preferred a larger interpersonal distance and experienced fast touch as less comforting compared with participants with no or moderate childhood maltreatment experiences. On the neural See related features: Editorial by Dr. Teicher (p. 4) and CME course (p. 97)

Social transmission of fear is not restricted to visual or auditory cues, but extends to the phylogenetically more ancient olfactory domain. Anxious individuals exhibit heightened sensitivity towards chemosensory stress signals in sweat; however, it is still unknown whether endogenous neuromodulators such as the peptide hormone oxytocin (OXT) influence the chemosensory communication of stress. Here, we investigated whether OXT selectively diminishes behavioral and neural responses to social chemosensory stress cues utilizing a randomized, double-blind, placebo (PLC)-controlled, within-subject functional MRI study design. Axillary sweat was obtained from 30 healthy male donors undergoing the Trier Social Stress Test (stress) and bicycle ergometer training (sport). Subsequently, 58 healthy participants (30 females) completed a forced-choice emotional face recognition task with stimuli of varying intensities (neutral to fearful) while they were exposed to both sweat stimuli and a non-social control odor following intranasal OXT or PLC administration, respectively. OXT diminished stress-induced recognition accuracy and response time biases towards fear. On the neural level, OXT reduced stress-evoked responses in the amygdala in both sexes, the anterior cingulate cortex (ACC) in females, and the hippocampus in males. Furthermore, OXT reinstated the functional connectivity between the ACC and the fusiform face area that was disrupted by stress odors under PLC. Our findings reveal a new role for OXT signaling in the modulation of chemosensory communication of stress in humans. Mechanistically, this effect appears to be rooted in a downregulation of stress-induced limbic activations and concomitant strengthening of top-down control descending from the ACC to the fusiform face area.

ObjectivesCervical noninvasive vagus nerve stimulation (nVNS) emerged as an adjunctive neuromodulation approach for primary headache disorders with limited responsiveness to pharmacologic and behavioral treatment. This narrative review evaluates the safety and efficacy of invasive and noninvasive peripheral nerve stimulation of the cervical branch of the vagal nerve (afferent properties) for primary headache disorders (episodic/chronic migraine [EM/CM] and cluster headache [ECH/CCH]) and provides a brief summary of the preclinical data on the possible mechanism of action of cervical vagus nerve stimulation (VNS) and trigemino-nociceptive head pain transmission.Materials and methodsA systematic search of published data was performed in PubMed for randomized controlled trials (RCTs) and prospective cohort clinical studies assessing the efficacy/safety and cost-effectiveness of cervical VNS in primary headache disorders and related preclinical studies.ResultsThree RCTs were identified for ECH/CCH (ACT-1, ACT-2 and PREVA), one RCT for migraine (EVENT) and several prospective cohort studies and retrospective analyses for both headache disorders. In ACT-1, a significantly higher response rate, a higher pain-free rate and a decrease in mean attack duration were found in nVNS-treated ECH/CCH patients compared to sham stimulation. ACT-2 confirmed these findings (e.g., significantly higher pain-free attacks, pain severity decline and increased responder-rate [defined as ≥50% reduction]). The PREVA study demonstrated the superiority of adjunctive nVNS to standard care alone and observed a significantly higher attack reduction (p=0.02) and responder rate (defined as ≥50% reduction). For CM, the EVENT study assessed a significantly higher frequency of decline in the open-label phase. Mostly transient mild/moderate adverse events were recorded, and no severe device-related adverse events occurred.ConclusionCervical nVNS represents a novel, safe and efficient adjunctive treatment option for primary headache disorders. In particular, preliminary observations suggest enhanced nVNS responsiveness in favor of episodic subtypes (EM and ECH). However, preclinical studies are urgently warranted to dissect the mechanism of action.

Accumulating evidence suggests that childhood maltreatment (CM) confers risk for psychopathology later in life by inducing hypervigilance to social threat cues such as fearful faces. However, it remains unclear whether the modulatory impact of CM extents to the olfactory domain of social communication in humans. To address this question, we examined whether CM modulates the neural processing of chemosensory threat signals in sweat and whether CM affects the stress-reducing effects of oxytocin (OXT) in this context. In a randomized, double-blind within-subject functional MRI study design, 58 healthy participants (30 females) received intranasal OXT (40 IU) or placebo (PLC) and completed a forced-choice emotion recognition task with faces of varying emotion intensities (neutral to fearful) while exposed to sweat stimuli and a non-social control odor. Axillary sweat samples were collected from 30 healthy male donors undergoing an acute psychosocial stressor (stress) and ergometer training (sport) as control in a prestudy. CM was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). The final fMRI analysis included 50 healthy participants (26 females). Regression analysis showed a stress-specific association of CTQ scores with amygdala hyperreactivity, hippocampal deactivation, and increased functional connectivity between the amygdala and the hippocampus, medial orbitofrontal cortex, and the anterior cingulate cortex (ACC) under PLC. Furthermore, we observed a positive association of CTQ scores and the dampening effects of OXT on stress-related amygdala responses. Our findings suggest that CM may induce hypervigilance to chemosensory threat cues in a healthy sample due to inefficient frontolimbic inhibition of amygdala activation. Future studies should investigate whether increased recruitment of the intralimbic amygdala-hippocampus complex reflects a compensatory mechanism that prevents the development of psychopathology in those who have experienced CM. Furthermore, the results reveal that the stress-specific effects of OXT in the olfactory domain are more pronounced in participants with increasing levels of CM exposure.