Preliminary evidence of transcutaneous vagus nerve stimulation effects on sleep in veterans with post-traumatic stress disorder.

Sleep problems are common among veterans with post-traumatic stress disorder and closely associated with hyperarousal symptoms. Transcutaneous vagus nerve stimulation (tVNS) may have potential to improve sleep quality in veterans with PTSD through effects on brain systems relevant to hyperarousal and sleep-wake regulation. The current pilot study examines the effect of 1 h of tVNS administered at "lights out" on sleep architecture, microstructure, and autonomic activity. Thirteen veterans with PTSD completed two nights of laboratory-based polysomnography during which they received 1 h of either active tVNS (tragus) or sham stimulation (earlobe) at "lights out" with randomised order. Sleep staging and stability metrics were derived from polysomnography data. Autonomic activity during sleep was assessed using the Porges-Bohrer method for calculating respiratory sinus arrhythmia (RSAP-B ). Paired t-tests revealed a small decrease in the total sleep time (d = -0.31), increase in N3 sleep (d = 0.23), and a small-to-moderate decrease in REM sleep (d = -0.48) on nights of active tVNS relative to sham stimulation. tVNS was also associated with a moderate reduction in cyclic alternating pattern (CAP) rate (d = -0.65) and small-to-moderate increase in RSAP-B during NREM sleep. Greater NREM RSAP-B was associated with a reduced CAP rate and NREM alpha power. This pilot study provides preliminary evidence that tVNS may improve sleep depth and stability in veterans with PTSD, as well as increase parasympathetically mediated nocturnal autonomic activity. These results warrant continued investigation into tVNS as a potential tool for treating sleep disturbance in veterans with PTSD.

The Effects of Transcutaneous Vagus Nerve Stimulation on Functional Connectivity Within Semantic and Hippocampal Networks in Mild Cognitive Impairment.

Better treatments are needed to improve cognition and brain health in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Transcutaneous vagus nerve stimulation (tVNS) may impact brain networks relevant to AD through multiple mechanisms including, but not limited to, projection to the locus coeruleus, the brain's primary source of norepinephrine, and reduction in inflammation. Neuropathological data suggest that the locus coeruleus may be an early site of tau pathology in AD. Thus, tVNS may modify the activity of networks that are impaired and progressively deteriorate in patients with MCI and AD. Fifty patients with MCI (28 women) confirmed via diagnostic consensus conference prior to MRI (sources of info: Montreal Cognitive Assessment Test (MOCA), Clinical Dementia Rating scale (CDR), Functional Activities Questionnaire (FAQ), Hopkins Verbal Learning Test - Revised (HVLT-R) and medical record review) underwent resting state functional magnetic resonance imaging (fMRI) on a Siemens 3 T scanner during tVNS (left tragus, n = 25) or sham control conditions (left ear lobe, n = 25). During unilateral left tVNS, compared with ear lobe stimulation, patients with MCI showed alterations in functional connectivity between regions of the brain that are important in semantic and salience functions including regions of the temporal and parietal lobes. Furthermore, connectivity from hippocampi to several cortical and subcortical clusters of ROIs also demonstrated change with tVNS compared with ear lobe stimulation. In conclusion, tVNS modified the activity of brain networks in which disruption correlates with deterioration in AD. These findings suggest afferent target engagement of tVNS, which carries implications for the development of noninvasive therapeutic intervention in the MCI population.

The Association Between Peripheral Oxytocin Levels and Depressive Symptoms in People With HIV.

OBJECTIVE: Depression is common in people with HIV (PWH), yet little is known about the mechanisms contributing to depressive symptoms in PWH. Previous research across a range of populations has suggested a relationship between the neuropeptide oxytocin and depressive symptoms, with variable directionality. This article investigated the association between peripheral oxytocin levels and depressive symptoms in PWH. METHODS: Unextracted oxytocin serum concentrations were assayed in 79 PWH (44% female, mean age = 34.35 [8.5], mean body mass index = 25.69 [5.46], mean CD4 = 516.60 [271.15]) who also completed the Center for Epidemiologic Studies Depression Scale (CES-D). CES-D items were evaluated in an exploratory factor analysis (EFA), and the relationships between oxytocin, total CES-D score, and the resulting EFA factors were analyzed with multivariate linear regressions conducted in R. Multiple regression models were used to adjust for age, sex, body mass index, CD4, and education. RESULTS: Contrary to hypothesized, higher peripheral oxytocin levels were associated with higher CES-D total scores with a small-to-moderate effect size ( ß = 0.26, p = .009). Following Bonferroni correction, oxytocin was not significantly associated with any of the five factors identified from the EFA: depressed affect, positive affect, appetite, cognitive symptoms, or perceived failure ( p values > .042). Small effect sizes were found for the depressed affect ( ß = 0.22) and perceived failure ( ß = 0.21) factors ( p values > .042). CONCLUSIONS: In a sample of predominately Black or African American individuals with HIV, higher oxytocin was associated with higher total depressive symptoms. In addition, this relationship was slightly stronger than those of specific depressive symptoms. These findings warrant further study into the role of oxytocin in mood symptoms within PWH.

Novel tip-loaded dissolving and implantable microneedle array patches for sustained release of finasteride.

Finasteride (FND) is a competitive inhibitor of 5α-reductase, an enzyme involved in benign prostatic hyperplasia (BPH) and androgenic alopecia. FND is administered in oral, often lifelong treatments, increasing the pill burden of polymedicated patients. Microneedle array patches (MAPs) are minimally invasive devices that painlessly pierce the outermost layers of the skin, forming slowly-dissolving drug depots in the dermis, which can release drugs over weeks or months, making this platform an attractive, patient-friendly option for long-term treatments. This work describes the development of long-acting dissolving and implantable PLGA MAPs aimed for systemic release of FND for at least two weeks. Mechanically strong tip-loaded MAPs with pyramidal geometry were obtained using micromoulding methodology. In vitro studies revealed that the dissolving and implantable MAPs were able to release the drug for over 7 and 14 days, respectively. Skin deposition experiments in Franz cells demonstrated that after 24 h, dissolving and implantable MAPs were able to deposit 629.00 ± 214.54 µg and 1861.64 ± 383.30 µg of FND in the skin, respectively. On the other hand, transdermal permeation studies showed that both formulations produced a slow release of the drug to the receptor compartment of the Franz cells, with dissolving and implantable MAPs releasing 90.43 ± 6.20 µg and 27.80 ± 3.94 µg of FND after 24 h. The formulations described here could be an alternative to current oral treatments, having the potential to deliver the drug for extended periods, simplifying the treatment of BPH and androgenic alopecia.

Hyperarousal symptoms and decreased right hemispheric frontolimbic white matter integrity predict poorer sleep quality in combat-exposed veterans.

OBJECTIVE: Disrupted sleep is common following combat deployment. Contributors to risk include posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI); however, the mechanisms linking PTSD, mTBI, and sleep are unclear. Both PTSD and mTBI affect frontolimbic white matter tracts, such as the uncinate fasciculus. The current study examined the relationship between PTSD symptom presentation, lateralized uncinate fasciculus integrity, and sleep quality. METHOD: Participants include 42 combat veterans with and without PTSD and mTBI. Freesurfer and Tracula were used to establish specific white matter ROI integrity via 3-T MRI. The Pittsburgh Sleep Quality Index and PTSD Checklist were used to assess sleep quality and PTSD symptoms. RESULTS: Decreased fractional anisotropy in the right uncinate fasciculus (ß = -1.11, SE = 0.47, p < .05) and increased hyperarousal symptom severity (ß = 3.50, SE = 0.86, p < .001) were associated with poorer sleep quality. CONCLUSION: Both right uncinate integrity and hyperarousal symptom severity are associated withsleep quality in combat veterans. The right uncinate is a key regulator of limbic behavior and sympathetic nervous system reactivity, a core component of hyperarousal. Damage to this pathway may be one mechanism by which mTBI and/or PTSD could create vulnerability for sleep problems following combat deployment.

Posttraumatic Stress Disorder Subsequent to Apparent Mild Traumatic Brain Injury.

Posttraumatic stress disorder (PTSD) is prevalent among veterans with a history of traumatic brain injury (TBI); however, the relationship between TBI and PTSD is not well understood. We present the case of a 31-year-old male veteran with PTSD who reported TBI before entering the military. The reported injury appeared to be mild: He was struck on the head by a baseball, losing consciousness for ∼10 seconds. Years later, he developed severe PTSD after combat exposure. He was not receiving clinical services for these issues but was encountered in the context of a research study. We conducted cognitive, autonomic, and MRI assessments to assess brain function, structure, and neurophysiology. Next, we compared amygdala volume, uncinate fasciculus diffusion, functional connectivity, facial affect recognition, and baroreceptor coherence with those of a control group of combat veterans (n = 23). Our veteran's MRI revealed a large right medial-orbital prefrontal lesion with surrounding atrophy, which the study neuroradiologist interpreted as likely caused by traumatic injury. Comparison with controls indicated disrupted structural and functional connectivity of prefrontal-limbic structures and impaired emotional, cognitive, and autonomic responses. Detection of this injury before combat would have been unlikely in a clinical context because our veteran had reported a phenomenologically mild injury, and PTSD is a simple explanation for substance abuse, sleep impairment, and psychosocial distress. However, it may be that right prefrontal-limbic disruption imparted vulnerability for the development of PTSD and exacerbated our veteran's emotional response to, and recovery from, PTSD.