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Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

Supplemental material, Supplemental_Data for Samidorphan mitigates olanzapine-induced weight gain and metabolic dysfunction in rats and non-human primates by Jacobi I Cunningham, David J Eyerman, Mark S Todtenkopf, Reginald L Dean, Daniel R Deaver, Connie Sanchez and Mark Namchuk in Journal of Psychopharmacology

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a popular drug of abuse with well-documented acute effects on serotonergic, dopaminergic, and cholinergic transmitter systems, as well as evidence of long-term disruption of serotoninergic systems in the rat brain. Recently, it was demonstrated that MDMA evokes a delayed and sustained increase in glutamate release in the hippocampus. The purpose of the present study was to determine the role of inflammatory mediators in the MDMA-induced increase in glutamate release, as well as the contribution of inflammatory pathways in the persistent neurochemical toxicity associated with repeated MDMA treatment. Treatment with the non-selective cyclooxygenase (COX) inhibitor ketoprofen and the COX-2 selective inhibitor nimesulide attenuated the increase in extracellular glutamate in the hippocampus evoked by repeated MDMA exposure (10 mg/kg, i.p., every 2 h); no attenuation was observed in rats treated with the COX-1 selective inhibitor piroxicam. Reverse dialysis of a major product of COX activity, prostaglandin E2, also resulted in a significant increase in extracellular glutamate in the hippocampus . Repeated exposure to MDMA diminished the number of parvalbumin-positive GABA interneurons in the dentate gyrus of the hippocampus, an effect that was attenuated by ketoprofen treatment. However, COX inhibition with ketoprofen did not prevent the long-term depletion of 5-HT in the hippocampus evoked by MDMA treatment. These data are supportive of the view that cyclooxygenase activity contributes to the mechanism underlying both the increased release of glutamate and decreased number of GABA interneurons in the rat hippocampus produced by repeated MDMA exposure.

3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress, including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. Whereas MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT.

Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA-induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 h for 4 injections) resulted in a 50–65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40–80% reduction in 5-HT transporter immunoreactivity (SERTir), and the reduction in SERTir also was completely attenuated in MDMA-preconditioned animals. Preconditioning with MDMA (10 mg/kg, ip) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not dopamine depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA-induced hyperthermia in rats previously exposed to MDMA contribute towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute towards neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT produced by subsequent MDMA administration. The mechanisms underlying preconditioning-induced neuroprotection for MDMA remain to be determined.

This study investigated whether trachea pressures during brass instrument play of laryngectomised patients are within the range of those measured during tracheoesophageal voicing, and whether application of an automatic speaking valve can 'free' both hands to play a brass instrument. Objective assessment of voicing and music playing parameters was carried out in 2 laryngectomised patients with a low-pressure indwelling voice-prosthesis able to play brass instruments (tenor horn and slide trombone): sound pressure levels in dB, maximum phonation time in seconds and trachea pressures in mmHg; videofluoroscopy, stroboscopy and digital high speed endoscopy to assess neoglottis vibration and opening. The dynamic range of the voice in the patients was 29 and 20 dB, and maximum phonation time was 22 and 19 sec, respectively; intratracheal pressures during voicing varied from 7 mmHg for the softest /a/ to 49 mmHg for the loudest /a/. For brass instrument play, the intratracheal pressures varied from 14 mmHg for the softest tone to 48 mmHg for the loudest tone. Imaging confirmed earlier findings that the neoglottis is closing and vibrating during voicing and remains 'open' without vibrations during music play, indicating good neoglottis control and innervation. From these objective measurements, we can conclude that trachea pressures during brass instrument play are within physiological ranges for tracheoesophageal voicing with a low-pressure indwelling voice-prosthesis. Furthermore, it was shown that application of a stable baseplate for retaining an automatic speaking valve and an additional customisable 'neck brace' makes bimanual play possible again.Lo scopo del presente studio è stato quello di valutare se le differenze pressorie misurate durante il suono di un ottone rientrano nel range di quelle ottenute durante la voce parlata tracheoesofagea nei pazienti laringectomizzati, e se l'applicazione di una valvola automatica può permettere di suonare uno strumento musicale senza l'utilizzo delle mani nella gestione della valvola. La valutazione obiettiva della voce e della musica suonata è stata effettuata in due pazienti laringectomizzati portatori di una protesi vocale a bassa pressione, capaci di suonare uno strumento musicale della categoria degli ottoni (corno e trombone) mediante la misurazione di: intensità sonora in dB, tempo massimo di fonazione in secondi, pressione endotracheale; videofluoroscopia, stroboscopia ed endoscopia digitale ad alta velocità sono state utilizzate per valutare l'apertura e la vibrazione della neoglottide. Il range dinamico della voce è stato da 29 e 20 dB, con un tempo di fonazione massimo rispettivamente di 22 e 19 secondi; la pressione intra-tracheale durante la fonazione è variata da 7 mmHg per le tonalità più basse /a/ a 49 per le più alte /a/. Durante l'utilizzo dello strumento musicale la pressione endotracheale è variata da 14 mmHg per le basse tonalità a 48 mmHg per le alte tonalità. L'imaging ha confermato che la neoglottide si chiude e vibra durante la fonazione, mentre rimane aperta senza vibrazioni durante l'utilizzo di uno strumento musicale, indicando che c'è un buon controllo della neoglottide e una buona innervazione. Tramite queste misurazioni obiettive possiamo concludere che le pressioni endotracheali durante l'utilizzo di strumenti musicali rispecchiano i range fisiologici della fonazione tracheoesofagea con ausilio di una protesi fonatoria a bassa pressione. Inoltre, è stato dimostrato che l'applicazione di uno "baseplate" stabile con una valvola fonatoria automatica e un sostegno per il collo personalizzato permette a questi pazienti di suonare tenendo libere entrambe le mani.

Speech therapy aiming at improving voice quality and speech intelligibility is often hampered by the lack of knowledge of the underlying deficits. One way to help speech therapists treating patients would be to supply synthetic benchmarks for pathological speech. These can be used to train therapists and evaluate and interpret automatic speech recognizers used for diagnosing pathological speech. Moreover, synthetic pathological speech can also be used to make expected therapy aims audible before treatment. In a listening experiment testing perceived intelligibility, three types of manipulations of tracheoesophageal speech were evaluated by experienced speech therapists. It was found that modeling the intensity contour of the voice source signal improved speech quality over plain analysis-synthesis. Replacing the voicing source with fully synthetic source periods decreased the perceived intelligibility markedly. Making the source fully periodic with a regular pitch had no effect on perceived intelligibility. Low quality speech benefitted more from manipulations, or deteriorated less, than high quality speech.

Objectives/Hypothesis: To assess device life of the new Provox Vega 22.5 and 20 Fr prostheses, to establish whether the optimized airflow characteristics of these devices materialize in better voice characteristics in comparison to Provox2, and to assess the feasibility of voice prosthesis replacement with the new Smart Inserter. Study Design: Prospective clinical phase II study. Methods: Prospective clinical phase II study including two patient cohorts (Provox Vega 22.5 Fr: N = 33; Provox Vega 20 Fr: N = 26). Device-life assessment, subjective data collection with study-specific structured questionnaires, perceptual analysis (Comparative Mean Opinion Score), and objective voice analysis (standard Dutch text, maximum phonation time, and dynamic range). Results: Device life of both prostheses appears comparable to Provox2. Several voice characteristics were better in Vega 22.5, which coincides well with patients' preference. Voicing with Vega 20 appears comparable to Provox2. Use of Smart Inserter showed a short learning curve, and was considered an improvement by the clinicians. Conclusions: The new Provox Vega 22.5 and 20 Fr prostheses have a device life comparable to Provox2, whereas voicing is better than (with the 22.5Fr version) or comparable (with the 20 Fr version) to Provox2. The Smart Inserter, after a short learning curve, turns out to be a further improvement of the anterograde replacement of these indwelling devices.

Voicing of 46 tracheoesophageal male speakers was analyzed acoustically with diverse parameters, such as the harmonics-to-noise-ratio, maximum phonation time, dynamic range, f0 and amplitude perturbation. The results revealed significant age effects in the amount of jitter and spectral tilt in sustained /a/-vowels, with decreasing steadiness and increasing vocal effort for older speakers. Voicing in speakers with prostheses of 6 mm or shorter was compared to voicing in speakers with prostheses of 10 mm or longer. Speakers with longer prostheses showed significantly less jitter and deviation in intensity. In general, the measurements indicated a better voicing quality and more vocal effort. The speakers’ own ratings of their voice coincided with differences in the acoustic measurements of the sustained /a/ in terms of jitter and periodicity (breaks). Perceived fatigue was reflected in the duration of a read-aloud sentence and by the dB-distance between the speaker’s comfortable and loudest phonation level.

To judge the influence of speaker background on the quality of five long vowels and diphthongs /oU/, /eI/, /Au/, /EI/, and /2y/ in Standard Dutch, the spectra of these vowel realizations in spontaneous speech were measured for 70 subjects, and analyzed with regard to the subjects’ regions of education and residence, their level of education and occupation, as well as their sex and age. Our preliminary analyses indicated that high educated speakers lowered (higher F1, articulated more open) the long vowels and diphthongs and diphthongized them stronger than low educated speakers. There seemed to be effects of age but more data were needed to specify these. The new data show that besides the level of education or occupation, the factor ’age group’ has a major effect on the variations in speech production. The vowel attributes ’onset’ and ’degree of diphthongization’ were affected variably by speaker background data. Speakers of the older generation hardly differed in their realization behavior, contrary to the younger and middle aged speakers. The higher educated displayed systematic age patterns, the lower educated did not. A slight effect of region of residence was found for the females from the north peripheral residence region, who had higher onsets for /oU/. An effect of sex was found within the youngest age group, where higher educated males differed from higher educated females by their stronger diphthongization of /eI/ and /oU/. The vowel variations that were related to age reflected several pronunciation changes in progress.