Behavioral Effect of Chemogenetic Inhibition Is Directly Related to Receptor Transduction Levels in Rhesus Monkeys.

We used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male rhesus monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hSyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD-transduced cells using stereological analysis of mCherry-immunolabeled neurons. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared with monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.SIGNIFICANCE STATEMENT Cognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (designer receptor exclusively activated by designer drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine-N-oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.

Safety and Efficacy of Microfocused Ultrasound in Tightening of Lax Elbow Skin.

BACKGROUND: With the increased popularity of minimally invasive cosmetic treatments, this study evaluates the efficacy and safety of microfocused ultrasound with visualization (MFU-V) for tightening lax skin above the elbow. METHODS: Subjects were treated bilaterally above the elbows with MFU-V using transducers with different focal depths. Photographs were taken before treatment and at 90- and 180-day follow-ups. Masked observer ratings and physician and subject global aesthetic improvement scales (PGAIS and SGAIS) were completed at follow-ups. Safety, based on adverse event (AE) incidence, was assessed. RESULTS: Masked blinded assessment was completed at 90 days; 56% showed aesthetic improvement. Overall improvement in SGAIS was 83% and 81% at 90 and 180 days, respectively. The overall improvement in PGAIS was 94% at both 90 and 180 days. Patient satisfaction questionnaires showed that 83% noticed improvements in elbow characteristics at 90 days, with 81% still indicating improvement at 180 days. No serious AEs or treatment-related AEs were reported. CONCLUSION: This pilot study suggests that MFU-V is a safe and promising nonsurgical option for the treatment of skin laxity above the elbow. Based on the positive results of this study, a larger trial is warranted together with testing different treatment densities to optimize this noninvasive approach.