µ Opioid Receptor Agonism for L-DOPA-Induced Dyskinesia in Parkinson's Disease.

Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA-induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid cotransmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by µ opioid receptor antagonists. Reports that both antagonists and agonists of the µ opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of nonspecific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID. After in vitro characterization of the functional activity at the µ opioid receptor, we selected prototypical agonists, antagonists, and partial agonists at the µ opioid receptor. We then showed that both oral and discrete intracerebral administration of a µ receptor agonist, but not of an antagonist as long thought, ameliorated LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned female macaque model of PD and LID. The results call for a reappraisal of opioid pharmacology in the basal ganglia as well as for the development of brain nucleus-targeted µ opioid receptor agonists.SIGNIFICANCE STATEMENT µ opioid receptors have long been considered as a viable target for alleviating the severity of L-DOPA-induced hyperkinetic side effects, induced by the chronic treatment of Parkinson's disease motor symptoms with L-DOPA. Conflicting results between experimental parkinsonism and Parkinson's disease patients, however, dampened the enthusiasm for the target. Here we reappraise the pharmacology and then demonstrate that both oral and discrete intracerebral administration of a µ receptor agonist, but not of an antagonist as long thought, ameliorates LIDs in the gold-standard bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease, calling for a reappraisal of the opioid pharmacology as well as for the development of brain nucleus-targeted µ receptor agonists.

Norepinephrine in the avian auditory cortex enhances developmental song learning.

Sensory learning during critical periods in development has lasting effects on behavior. Neuromodulators like dopamine and norepinephrine (NE) have been implicated in various forms of sensory learning, but little is known about their contribution to sensory learning during critical periods. Songbirds like the zebra finch communicate with each other using vocal signals (e.g., songs) that are learned during a critical period in development, and the first crucial step in song learning is memorizing the sound of an adult conspecific's (tutor's) song. Here, we analyzed the extent to which NE modulates the auditory learning of a tutor's song and the fidelity of song imitation. Specifically, we paired infusions of NE or vehicle into the caudomedial nidopallium (NCM) with brief epochs of song tutoring. We analyzed the effect of NE in juvenile zebra finches that had or had not previously been exposed to song. Regardless of previous exposure to song, juveniles that received NE infusions into NCM during song tutoring produced songs that were more acoustically similar to the tutor song and that incorporated more elements of the tutor song than juveniles with control infusions. These data support the notion that NE can regulate the formation of sensory memories that shape the development of vocal behaviors that are used throughout an organism's life.NEW & NOTEWORTHY Although norepinephrine (NE) has been implicated in various forms of sensory learning, little is known about its contribution to sensory learning during critical periods in development. We reveal that pairing infusions of NE into the avian secondary auditory cortex with brief epochs of song tutoring significantly enhances auditory learning during the critical period for vocal learning. These data highlight the lasting impact of NE on sensory systems, cognition, and behavior.

Perception-Action Integration Is Modulated by the Catecholaminergic System Depending on Learning Experience.

BACKGROUND: The process underlying the integration of perception and action is a focal topic in neuroscientific research and cognitive frameworks such as the theory of event coding have been developed to explain the mechanisms of perception-action integration. The neurobiological underpinnings are poorly understood. While it has been suggested that the catecholaminergic system may play a role, there are opposing predictions regarding the effects of catecholamines on perception-action integration. METHODS: Methylphenidate (MPH) is a compound commonly used to modulate the catecholaminergic system. In a double-blind, randomized crossover study design, we examined the effect of MPH (0.25 mg/kg) on perception-action integration using an established "event file coding" paradigm in a group of n = 45 healthy young adults. RESULTS: The data reveal that, compared with the placebo, MPH attenuates binding effects based on the established associations between stimuli and responses, provided participants are already familiar with the task. However, without prior task experience, MPH did not modulate performance compared with the placebo. CONCLUSIONS: Catecholamines and learning experience interactively modulate perception-action integration, especially when perception-action associations have to be reconfigured. The data suggest there is a gain control-based mechanism underlying the interactive effects of learning/task experience and catecholaminergic activity during perception-action integration.

The Effect of Platelet-Rich Plasma on the Intra-Articular Microenvironment in Knee Osteoarthritis.

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.

Effects of intracerebroventricularly administered opioid peptide antagonists on tissue glycogen levels in rats after exercise

Background/aim: Physical exercise is a state of physiological stress that requires adaptation of the organism to physical activity. Glycogen is an important and essential energy source for muscle contraction. Skeletal muscle and liver are two important glycogen stores, and the energy required to maintain exercise in rodents are provided by destruction of this glycogen depot. In this study, the effects of endogenous opioid peptide antagonism at the central nervous system level on tissue glycogen content after exhaustive exercise were investigated. Materials and methods: Rats had intracerebroventricularly (icv) received nonspecific opioid peptide receptor antagonist, naloxone (50 µg/10 µL in saline) and δ-opioid receptor-selective antagonist naltrindole (50 µg/10 µL in saline) and then exercised till exhaustion. After exhaustion, skeletal muscle, heart, and liver were excised immediately. Results: Both opioid peptide antagonists decreased glycogen levels in skeletal muscle. Although, in soleus muscle, this decrease was not statistically significant (p > 0.05), in gastrocnemius muscle, it was significant in the icv naloxone administered group compared with control (p < 0.05). Heart glycogen levels increased significantly in both naloxone and naltrindole groups compared to control and sham-operated groups (p < 0.05). Heart glycogen levels were higher in the naloxone group than naltrindole (p < 0.05). Liver glycogen levels were elevated significantly with icv naloxone administration compared with the control group (p < 0.05). Glycogen levels in the naloxone group was also significantly higher than the naltrindole group (p < 0.05). Conclusion: Our findings indicate that icv administered opioid peptide antagonists may play a role in glycogen metabolism in peripheral tissues such as skeletal muscle, heart, and liver.

Neuromodulatory Action of Picomolar Extracellular Aß42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory.

Failure of anti-amyloid-ß peptide (Aß) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Aß released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aß42 (oAß42) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAß42 induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAß42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Aß in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short- to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oAß42 These effects were present upon extracellular but not intracellular application of the peptide and involved α7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAß42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aß levels in the AD brains.SIGNIFICANCE STATEMENT High levels of oligomeric amyloid-ß42 (oAß42) induce synaptic dysfunction leading to memory impairment in Alzheimer's disease (AD). However, at picomolar concentrations, the peptide is needed to ensure long-term potentiation (LTP) and memory. Here, we show that extracellular 200 pm oAß42 concentrations increase neurotransmitter release, number of docked vesicles, postsynaptic density length, and expression of plasticity-related proteins leading to the conversion of early LTP into late LTP and of short-term memory into long-term memory. These effects require α7 nicotinic acetylcholine receptors and are mediated through the nitric oxide/cGMP/protein kinase G pathway. The knowledge of Aß function in the healthy brain might be useful to understand the causes leading to its increase and detrimental effect in AD.

Neuropeptide S Displays as a Key Neuromodulator in Olfactory Spatial Memory.

Neuropeptide S (NPS) is an endogenous peptide recently recognized to be presented in the brainstem and believed to play an important role in maintaining memory. The deletion of NPS or NPS receptor (NPSR) in mice shows a deficit in memory formation. Our recent studies have demonstrated that central administration of NPS facilitates olfactory function and ameliorates olfactory spatial memory impairment induced by muscarinic cholinergic receptor antagonist and N-methyl-D-aspartate receptor antagonist. However, it remains to be determined if endogenous NPS is an indispensable neuromodulator in the control of the olfactory spatial memory. In this study, we examined the effects of NPSR peptidergic antagonist [D-Val5]NPS (10 and 20 nmol, intracerebroventricular) and nonpeptidergic antagonist SHA 68 (10 and 50 mg/kg, intraperitoneal) on the olfactory spatial memory using computer-assisted 4-hole-board olfactory spatial memory test in mice. Furthermore, immunofluorescence was employed to identify the distributions of c-Fos and NPSR immunoreactive (-ir) neurons in olfactory system and hippocampal formation known to closely relate to the olfactory spatial memory. [D-Val5]NPS dosing at 20 nmol and SHA 68 dosing at 50 mg/kg significantly decreased the number of visits to the 2 odorants interchanged spatially, switched odorants, in recall trial, and simultaneously reduced the percentage of Fos-ir in NPSR-ir neurons, which were densely distributed in the anterior olfactory nucleus, piriform cortex, subiculum, presubiculum, and parasubiculum. These findings suggest that endogenous NPS is a key neuromodulator in olfactory spatial memory.

FG 7142: is this validated tool to study anxiety now forgotten?

We describe the first human experience with FG 7142, a drug which in a phase I study has caused severe anxiety attacks and which therefore could be a validated tool for further experimental studies of anxiety.

Graded Transmission without Action Potentials Sustains Rhythmic Activity in Some But Not All Modulators That Activate the Same Current.

Neurons in the central pattern-generating circuits in the crustacean stomatogastric ganglion (STG) release neurotransmitter both as a graded function of presynaptic membrane potential that persists in TTX and in response to action potentials. In the STG of the male crab Cancer borealis, the modulators oxotremorine, C. borealis tachykinin-related peptide Ia (CabTRP1a), red pigment concentrating hormone (RPCH), proctolin, TNRNFLRFamide, and crustacean cardioactive peptide (CCAP) produce and sustain robust pyloric rhythms by activating the same modulatory current (IMI), albeit on different subsets of pyloric network targets. The muscarinic agonist oxotremorine, and the peptides CabTRP1a and RPCH elicited rhythmic triphasic intracellular alternating fluctuations of activity in the presence of TTX. Intracellular waveforms of pyloric neurons in oxotremorine and CabTRP1a in TTX were similar to those in the intact rhythm, and phase relationships among neurons were conserved. Although cycle frequency was conserved in oxotremorine and TTX, it was altered in CabTRP1a in the presence of TTX. Both rhythms were primarily driven by the pacemaker kernel consisting of the Anterior Burster and Pyloric Dilator neurons. In contrast, in TTX the circuit remained silent in proctolin, TNRNFLRFamide, and CCAP. These experiments show that graded synaptic transmission in the absence of voltage-gated Na+ current is sufficient to sustain rhythmic motor activity in some, but not other, modulatory conditions, even when each modulator activates the same ionic current. This further demonstrates that similar rhythmic motor patterns can be produced by qualitatively different mechanisms, one that depends on the activity of voltage-gated Na+ channels, and one that can persist in their absence.SIGNIFICANCE STATEMENT The pyloric rhythm of the crab stomatogastric ganglion depends both on spike-mediated and graded synaptic transmission. We activate the pyloric rhythm with a wide variety of different neuromodulators, all of which converge on the same voltage-dependent inward current. Interestingly, when action potentials and spike-mediated transmission are blocked using TTX, we find that the muscarinic agonist oxotremorine and the neuropeptide CabTRP1a sustain rhythmic alternations and appropriate phases of activity in the absence of action potentials. In contrast, TTX blocks rhythmic activity in the presence of other modulators. This demonstrates fundamental differences in the burst-generation mechanisms in different modulators that would not be suspected on the basis of their cellular actions at the level of the targeted current.

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

Neuromodulation-dependent effect of gated high-frequency, LFMS-like electric field stimulation in mouse cortical slices.

Low-field magnetic stimulation (LFMS) is a gated high-frequency non-invasive brain stimulation method (500 Hz gated at 2 Hz) with a proposed antidepressant effect. However, it has remained unknown how such stimulation paradigms modulate neuronal network activity and how the induced changes depend on network state. Here we examined the immediate and outlasting effects of the gated high-frequency electric field associated with LFMS on the cortical activity as a function of neuromodulatory tone that defines network state. We used a sham-controlled study design to investigate effects of stimulation (20 min of 0.5 s trains of 500 Hz charge-balanced pulse stimulation patterned at 0.5 Hz) on neural activity in mouse medial prefrontal cortex in vitro. Bath application of cholinergic and noradrenergic agents enabled us to examine the stimulation effects as a function of neuromodulatory tone. The stimulation attenuated the increase in firing rate of layer V cortical neurons during the post-stimulation period in the presence of cholinergic activation. The same stimulation had no significant immediate or outlasting effect in the absence of exogenous neuromodulators or in the presence of noradrenergic activation. These results provide electrophysiological insights into the neuromodulatory-dependent effects of gated high-frequency stimulation. More broadly, our results are the first to provide a mechanistic demonstration of how behavioral states and arousal levels may modify the effects of non-invasive brain stimulation.

Nanocapsules for Programmed Neurotransmitter Release: Toward Artificial Extracellular Synaptic Vesicles.

Nanocapsules present a promising platform for delivering chemicals and biomolecules to a site of action in a living organism. Because the biological action of the encapsulated molecules is blocked until they are released from the nanocapsules, the encapsulation structure enables triggering of the topical and timely action of the molecules at the target site. A similar mechanism seems promising for the spatiotemporal control of signal transduction triggered by the release of signal molecules in neuronal, metabolic, and immune systems. From this perspective, nanocapsules can be regarded as practical tools to apply signal molecules such as neurotransmitters to intervene in signal transduction. However, spatiotemporal control of the payload release from nanocapsules persists as a key technical issue. Stimulus-responsive nanocapsules that release payloads in response to external input of physical stimuli are promising platforms to enable programmed payload release. These programmable nanocapsules encapsulating neurotransmitters are expected to lead to new insights and perspectives related to artificial extracellular synaptic vesicles that might provide an experimental and therapeutic strategy for neuromodulation and nervous system disorders.

Effect of Brexpiprazole on Agitation and Hostility in Patients With Schizophrenia: Post Hoc Analysis of Short- and Long-Term Studies.

BACKGROUND: Managing agitation and hostility represents a significant treatment challenge in schizophrenia. The aim of this analysis was to evaluate the short- and long-term efficacy of brexpiprazole for reducing agitation and hostility in schizophrenia. METHODS: This was a post hoc analysis of data from two 6-week, randomized, double-blind, placebo-controlled studies (ClinicalTrials.gov identifiers, NCT01396421 and NCT01393613) and a 52-week, open-label, extension study (NCT01397786). In the short-term studies, 1094 patients received placebo, 2 mg/d of brexpiprazole, or 4 mg/d of brexpiprazole; 346 brexpiprazole-treated patients rolled over into the long-term study and received 1 to 4 mg/d of brexpiprazole. Agitation was assessed using the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), and hostility was assessed using the PANSS hostility item (P7). RESULTS: Brexpiprazole improved PANSS-EC score over 6 weeks, with least squares mean differences versus placebo of -0.69 (95% confidence limits, -1.28, -0.11) for 2 mg/d (P = 0.020) and -1.11 (-1.70, -0.53) for 4 mg/d (P = 0.0002). In the subgroup with hostility at baseline (P7 score ≥3; 50.8% of the randomized sample), least squares mean differences versus placebo at week 6 on the PANSS-EC were -0.63 (-1.54, 0.28) for 2 mg/d (P = 0.18) and -1.03 (-1.92, -0.14) for 4 mg/d (P = 0.024), and on P7 (adjusted for positive symptoms) were -0.27 (-0.53, -0.01) for 2 mg/d (P = 0.038) and -0.34 (-0.59, -0.09) for 4 mg/d (P = 0.0080). The improvements were maintained over 58 weeks. Adverse events were generally comparable between treatment groups over 6 weeks; the incidence of akathisia among patients with hostility was 5.9% with placebo, 5.2% with 2 mg/d, and 8.6% with 4 mg/d. CONCLUSIONS: Brexpiprazole has the potential to be an efficacious and well-tolerated treatment for agitation and hostility among patients with schizophrenia.

Providing Optimal Rejuvenation to the Periocular Area Using Botulinum Toxin A Neuromodulators and Hyaluronic Acid Dermal Fillers.

The periorbital area is the first area of the face to show signs of aging. To provide safe and natural looking rejuvenation of the delicate eyelids, and supporting structures, an advanced understanding of anatomy, ideal facial proportions, and the most effective methods for rejuvenation is discussed. Periocular rejuvenation is particularly challenging due to the intricate and delicate anatomy of the periocular area. To ensure safe and successful outcomes, it is crucial that injectors use a global approach when providing treatments and that they consider soft tissue, vasculature, and bone structure of the periocular region before administering treatments for aesthetic rejuvenation. Neuromodulators, specifically botulinum toxin A (BoNT-A), and hyaluronic acid (HA) dermal fillers are 2 nonsurgical treatments frequently used to address signs of aging in the periocular area. The objective of this article is to review different BoNT-A and HA filler treatments and discuss how these treatments can be used for optimal rejuvenation of the periocular area.

Acute Effects of Methylphenidate, Modafinil, and MDMA on Negative Emotion Processing.

Background: Stimulants such as methylphenidate and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of methylphenidate and modafinil on negative emotions in healthy subjects have been partially missing. The aim of this study was to compare the acute effects of methylphenidate and modafinil on the neural correlates of fearful face processing using 3,4-methylenedioxymethamphetamine as a positive control. Methods: Using a double-blind, within-subject, placebo-controlled, cross-over design, 60 mg methylphenidate, 600 mg modafinil, and 125 mg 3,4-methylenedioxymethamphetamine were administrated to 22 healthy subjects while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings. Results: Relative to placebo, modafinil, but not methylphenidate or 3,4-methylenedioxymethamphetamine, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not methylphenidate also increased amygdala responses to fearful faces compared with 3,4-methylenedioxymethamphetamine. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration. Conclusions: Despite the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.

A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy.

INTRODUCTION: Radical prostatectomy (RP) is associated with erectile dysfunction, largely mediated through cavernous nerve injury. There are robust pre-clinical data supporting a potential role for neuromodulatory agents in this patient population. This study assessed tacrolimus in improving erectile function recovery rates after RP (ClinicalTrials.gov number, NCT00106392). AIM: To define the utility of oral tacrolimus in improving erectile function recovery after nerve sparing radical prostatectomy. METHODS: A randomized, double-blind trial compared tacrolimus 2-3 mg daily and placebo in men undergoing RP. Patients had localized prostate cancer and excellent baseline erectile function, underwent bilateral nerve-sparing RP, and were followed up for at least 18 months after RP. Patients received study drug for 27 weeks and completed the International Index of Erectile Function erectile function domain (EFD) questionnaire at baseline and serially after surgery. MAIN OUTCOME MEASURES: International Index of Erectile Function erectile function domain score. RESULTS: Data were available for 124 patients (59 tacrolimus, 65 placebo); mean age was 54.6 ± 6.2 years. No patient experienced permanent creatinine or potassium elevation. At baseline, mean EFD scores were 28.6 ± 2.1 (tacrolimus group) and 29 ± 1.5 (placebo group). By week 5, mean EFD scores had dropped to 8 ± 9.4 (tacrolimus) and 9 ± 10.7 (placebo). At 18 months, mean EFD scores were 16.0 ± 11.3 (tacrolimus) and 20.2 ± 9.0 (placebo) (P = .09). Tacrolimus failed to meet significance (hazard ratio = 0.83; P = .50), with no difference in: (i) percentage of patients achieving normal spontaneous erectile function (EFD score ≥24), (ii) time to normalization of EFD score (≥24), (iii) percentage of patients capable of intercourse in response to phosphieserase type 5 inhibitor (PDE5i), and (iv) time to achieve response to PDE5i. CLINICAL IMPLICATIONS: Despite positive animal data, oral tacrolimus as used in this trial failed to improve erectile function after nerve sparing radical prostatectomy. STRENGTHS & LIMITATIONS: The study is limited by a high attrition rate. The strengths include a randomized, placebo controlled design, extensive patient monitoring, use of medication diaries and a validated instrument as the primary outcome measure. CONCLUSION: Despite supportive animal data, tacrolimus used in this fashion in the RP population failed to demonstrate any superiority over placebo. Mulhall JP, Klein EA, Slawin K, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Utility of Tacrolimus (FK506) for the Prevention of Erectile Dysfunction Following Bilateral Nerve-Sparing Radical Prostatectomy. J Sex Med 2018;15:1293-1299.

ERß-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid.

Multiple sclerosis (MS), an autoimmune disease of the CNS, is mediated by autoreactive Th cells. A previous study showed that the neurosteroid dehydroepiandrosterone (DHEA), when administered preclinically, could suppress progression of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). However, the effects of DHEA on human or murine pathogenic immune cells, such as Th17, were unknown. In addition, effects of this neurosteroid on symptomatic disease, as well as the receptors involved, had not been investigated. In this study, we show that DHEA suppressed peripheral responses from patients with MS and reversed established paralysis and CNS inflammation in four different EAE models, including the 2D2 TCR-transgenic mouse model. DHEA directly inhibited human and murine Th17 cells, inducing IL-10-producing regulatory T cells. Administration of DHEA in symptomatic mice induced regulatory CD4(+) T cells that were suppressive in an IL-10-dependent manner. Expression of the estrogen receptor ß by CD4(+) T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-ß1 as well as aryl hydrocarbon receptor activation was necessary for the expansion of IL-10-producing T cells by DHEA. Thus, our studies demonstrate that compounds that inhibit pathogenic Th17 responses and expand functional regulatory cells could serve as therapeutic agents for autoimmune diseases, such as MS.

Prospective Cohort Study Investigating Changes in Body Image, Quality of Life, and Self-Esteem Following Minimally Invasive Cosmetic Procedures.

BACKGROUND: Minimally invasive cosmetic injectable procedures are increasingly common. However, a few studies have investigated changes in psychosocial functioning following these treatments. OBJECTIVE: To assess changes in body image, quality of life, and self-esteem following cosmetic injectable treatment with soft tissue fillers and neuromodulators. METHODS: Open, prospective study of 75 patients undergoing cosmetic injectable procedures for facial aging to evaluate changes in psychosocial functioning within 6 weeks of treatment. Outcome measures included the Derriford appearance scale (DAS-24), body image quality of life inventory (BIQLI), and the Rosenberg self-esteem scale. RESULTS: Body image dissatisfaction, as assessed by the DAS-24, improved significantly 6 weeks after the treatment. Body image quality of life, as assessed by the BIQLI, improved, but the change did not reach statistical significance. Self-esteem was unchanged after the treatment. CONCLUSION: Minimally invasive cosmetic injectable procedures were associated with reductions in body image dissatisfaction. Future research, using recently developed cosmetic surgery-specific instruments, may provide further insight into the psychosocial benefits of minimally invasive procedures.

Noninvasive Targeted Transcranial Neuromodulation via Focused Ultrasound Gated Drug Release from Nanoemulsions.

Targeted, noninvasive neuromodulation of the brain of an otherwise awake subject could revolutionize both basic and clinical neuroscience. Toward this goal, we have developed nanoparticles that allow noninvasive uncaging of a neuromodulatory drug, in this case the small molecule anesthetic propofol, upon the application of focused ultrasound. These nanoparticles are composed of biodegradable and biocompatible constituents and are activated using sonication parameters that are readily achievable by current clinical transcranial focused ultrasound systems. These particles are potent enough that their activation can silence seizures in an acute rat seizure model. Notably, there is no evidence of brain parenchymal damage or blood-brain barrier opening with their use. Further development of these particles promises noninvasive, focal, and image-guided clinical neuromodulation along a variety of pharmacological axes.

Preoperative Use of Neuromodulators to Optimize Surgical Outcomes in Upper Blepharoplasty and Brow Lift.

BACKGROUND: Upper eyelid dermatochalasis often triggers frontalis hyperactivity in an effort to elevate the upper lids away from the visual axis. Similarly, prior neuromodulator treatment of the brow depressors may cause false elevation of the brows, diminishing the extent of preoperative brow ptosis or dermatochalasis. Studies have quantified postoperative brow ptosis and recurrent dermatochalasis following upper blepharoplasty, but a methodology to predict the postoperative brow position remains to be elucidated. OBJECTIVES: The authors present our comprehensive perioperative protocol utilizing neuromodulators to optimize results of upper blepharoplasty and brow lift. METHODS: In patients presenting with upper lid dermatochalasis and frontalis hyperactivity, who request upper blepharoplasty, the authors apply a neuromodulator treatment protocol. Patients with prior neuromodulator treatment of brow depressors wait four months after the last treatment to allow for product attrition. Two weeks prior to surgery, the authors treat the frontalis with 15 to 20 units of Botox Cosmetic. RESULTS: From 2002 to 2016, the authors treated 521 patients (458 women, 63 men) with frontalis hyperactivity who presented for periorbital rejuvenation. This method has led to neither excessive resection of upper eyelid skin tissue nor lagophthalmos. Preoperatively, the authors have unveiled upper eyelid ptosis in 39 patients (31 women, 8 men) and brow ptosis in 131 patients (97 women, 34 men). CONCLUSIONS: Brow position and frontalis hyperactivity should be taken into consideration during preoperative evaluation for upper blepharoplasty and brow lift. Routine preoperative treatment of the hyperactive frontalis with neuromodulator, along with attrition of prior neuromodulator in the brow depressors, reveals the true anatomic brow position to optimize surgical planning.