Increased plasminogen activator inhibitor-1 (PAI-1) and its associations with metabolic risk in healthy young adults with early life stress.

OBJECTIVES: We aimed to characterize the interplay between early life stress (ELS), metabolic syndrome (MetS), and plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of the fibrinolytic system implicated in cardiometabolic diseases. We also examined the understudied intersection of ELS, physical activity and PAI-1. METHODS: Healthy young adults ages 18-40 (N=200; 68% female) were recruited from the community. Participants with ELS (N=118) experienced childhood maltreatment, and the majority (n=92) also experienced childhood parental loss. Control participants (N=82) had no history of childhood maltreatment or parental loss. Participants had no current cardiometabolic or thrombotic conditions. Fasting plasma samples were assessed for markers of metabolic risk and total PAI-1 using the Bio-Plex Pro Human Diabetes Panel (Bio-Rad Laboratories). A composite metabolic risk z-score (MetS risk) was computed from the mean standardized z-scores of waist-to-height ratio, systolic and diastolic blood pressure, triglycerides, total cholesterol, LDL and HLD cholesterol, fasting plasma glucose, and hemoglobin A1c. RESULTS: We found that a history of ELS was linked to both higher PAI-1 levels and a higher MetS risk score. ELS was associated with a higher MetS Z-score in adulthood via increased circulating PAI-1 levels (Average Causal Mediation Effect [ACME]= 0.07, p = 0.036). ELS was also linked to increased PAI-1 levels via greater MetS z-scores (ACME = 0.02, p < 0.001). There was a significant interaction effect of ELS and exercise on PAI-1 levels (p = 0.03), such that engaging in higher levels of daily exercise was linked to lower PAI-1 levels in individuals with ELS. CONCLUSION: Healthy young adults with ELS have elevated PAI-1 levels and metabolic risk scores. Among individuals with ELS, exercise is linked to lower PAI-1 levels, suggesting a potential direction for early intervention.

Corrigendum: Mechanical affective touch therapy for anxiety disorders: Feasibility, clinical outcomes, and electroencephalography biomarkers from an open-label trial.

[This corrects the article DOI: 10.3389/fpsyt.2022.877574.].

Mechanical Affective Touch Therapy for Anxiety Disorders: Feasibility, Clinical Outcomes, and Electroencephalography Biomarkers From an Open-Label Trial.

Background: Most external peripheral nerve stimulation devices designed to alter mood states use electrical energy, but mechanical stimulation for activation of somatosensory pathways may be harnessed for potential therapeutic neuromodulation. A novel investigational device for Mechanical Affective Touch Therapy (MATT) was created to stimulate C-tactile fibers through gentle vibrations delivered by piezoelectric actuators on the bilateral mastoid processes. Methods: 22 adults with anxiety disorders and at least moderate anxiety symptom severity enrolled in an open-label pilot trial that involved MATT self-administration using a simple headset at home at least twice per day for 4 weeks. Resting EEG data were acquired before and after a baseline MATT session and again before the final MATT session. Self-report measures of mood and anxiety were collected at baseline, week 2, and week 4, while interoception was assessed pre- and post-treatment. Results: Anxiety and depressive symptoms improved significantly from baseline to endpoint, and mindfulness was enhanced. EEG metrics confirmed an association between acute MATT stimulation and oscillatory power in alpha and theta bands; symptom changes correlated with changes in some metrics. Conclusion: Open-label data suggest MATT is a promising non-invasive therapeutic approach to anxiety disorders that warrants further development.

Mechanical Affective Touch Therapy for Anxiety Disorders: Effects on Resting State Functional Connectivity.

OBJECTIVES: Mechanical Affective Touch Therapy (MATT) is a safe, novel form of noninvasive peripheral nerve stimulation. Although mechanical stimulation activates nerves, we know little about its impact on psychiatric symptoms and their underlying cortical mechanisms. We examined the effects of open-label MATT on resting state functional connectivity (RSFC) and its relationship with anxiety and affective symptomatology (clinical results in separate report). MATERIALS AND METHODS: A total of 22 adults with an Axis I anxiety disorder were recruited from the community. After two initial sessions assisted by research staff, participants self-administered 20-minute sessions of MATT at home at least twice daily for four weeks. Self-report measures of mood and anxiety severity were collected at baseline, two weeks, and four weeks. Resting state functional magnetic resonance imaging was collected before the initial MATT session (n = 20), immediately after the first session (n = 18), and following four weeks of MATT (n = 14). Seed-based whole-brain functional connectivity analyses identified brain connectivity patterns correlated with responsiveness to MATT. Seeds were based on Neurosynth meta-analytic maps for "anxiety" and "pain" given MATT's hypothesized role in anxiety symptom amelioration and potential mechanism of action through C-tactile afferents, which play an important role in detecting pain and its affective components. Connectivity results were corrected for multiple comparisons (voxel p < 0.005, cluster p-FDR < 0.05). RESULTS: Baseline RSFC is predictive of symptom improvement with chronic MATT. Acute increases in insula connectivity were observed between mid-cingulate cortex and postcentral motor regions following the first MATT session. Chronic MATT was associated with increased connectivity between pain and anxiety regions of interest (ROIs) and posterior default mode network (DMN) regions involved in memory and self-reflection; the connectivity changes correlated with decreases in stress and depression symptoms. CONCLUSIONS: MATT is associated with alterations in RSFC in the DMN of anxiety disorder patients both acutely and after long-term administration, and baseline RSFC is predictive of post-treatment symptom improvement.

Frequency-modulated up-chirps produce larger evoked responses than down-chirps in the big brown bat auditory brainstem.

In many mammals, upward-sweeping frequency-modulated (FM) sounds (up-chirps) evoke larger auditory brainstem responses than downward-sweeping sounds (down-chirps). To determine if similar effects occur in FM echolocating bats, auditory evoked responses (AERs) in big brown bats in response to up-chirps and down-chirps at different chirp durations and levels were recorded. Even though down-chirps are the biologically relevant stimulus for big brown bats, up-chirps typically evoked larger peaks in the AER, but with some exceptions at the shortest chirp durations. The up-chirp duration that produced the largest AERs and the greatest differences between up-chirps and down-chirps varied between individual bats and stimulus levels. Cross-covariance analyses using the entire AER waveform confirmed that amplitudes were typically larger to up-chirps than down-chirps at supra-threshold levels, with optimal durations around 0.5-1 ms. Changes in response latencies with stimulus levels were consistent with previous estimates of amplitude-latency trading. Latencies tended to decrease with increasing up-chirp duration and increase with increasing down-chirp duration. The effects of chirp direction on AER waveforms are generally consistent with those seen in other mammals but with small differences in response patterns that may reflect specializations for FM echolocation.