A Potential Prognostic Gene Signature Associated with p53-Dependent NTRK1 Activation and Increased Survival of Neuroblastoma Patients.

Neuroblastoma is the most common extracranial solid tumour in children, comprising close to 10% of childhood cancer-related deaths. We have demonstrated that activation of NTRK1 by TP53 repression of PTPN6 expression is significantly associated with favourable survival in neuroblastoma. The molecular mechanisms by which this activation elicits cell molecular changes need to be determined. This is critical to identify dependable biomarkers for the early detection and prognosis of tumours, and for the development of personalised treatment. In this investigation we have identified and validated a gene signature for the prognosis of neuroblastoma using genes differentially expressed upon activation of the NTRK1-PTPN6-TP53 module. A random survival forest model was used to construct a gene signature, which was then assessed across validation datasets using Kaplan-Meier analysis and ROC curves. The analysis demonstrated that high BASP1, CD9, DLG2, FNBP1, FRMD3, IL11RA, ISGF10, IQCE, KCNQ3, and TOX2, and low BSG/CD147, CCDC125, GABRB3, GNB2L1/RACK1 HAPLN4, HEBP2, and HSD17B12 expression was significantly associated with favourable patient event-free survival (EFS). The gene signature was associated with favourable tumour histology and NTRK1-PTPN6-TP53 module activation. Importantly, all genes were significantly associated with favourable EFS in an independent manner. Six of the signature genes, BSG/CD147, GNB2L1/RACK1, TXNDC5, FNPB1, B3GAT1, and IGSF10, play a role in cell differentiation. Our findings strongly suggest that the identified gene signature is a potential prognostic biomarker and therapeutic target for neuroblastoma patients and that it is associated with neuroblastoma cell differentiation through the activation of the NTRK1-PTPN6-TP53 module.

Phosphatidylethanol Detects Occult Heavy Alcohol Use in Patients With Acute and Chronic Pancreatitis.

Given the paucity of interventions to treat pancreatitis, it is imperative to identify and intervene upon modifiable risk factors such as heavy alcohol use. Current trends indicate a concerning increase in alcohol misuse and alcohol-related disease since the onset of the coronavirus disease-2019 pandemic.1 The incidence of pancreatitis associated with alcohol misuse has increased by approximately 3% annually from 1961 to 2016.2 Alcohol recidivism may be the most important risk factor for pancreatitis recurrence and development of chronic pancreatitis in the United States.3 Early identification of alcohol misuse as a modifiable risk factor is paramount to mitigating pancreatitis-related morbidity. However, blood ethanol and urine ethyl glucuronide levels may be low in symptomatic individuals because they clear rapidly and patients may abstain from drinking in the days before their clinical presentation. Patient self-report may underestimate the quantity of alcohol intake and falsely reassure the provider that this is not a contributing factor to the presentation.4.

Binding of GTP to BifA is required for the production of Pel-dependent biofilms in Pseudomonas aeruginosa.

The Pel exopolysaccharide is one of the most mechanistically conserved and phylogenetically diverse bacterial biofilm matrix determinants. Pel is a major contributor to the structural integrity of Pseudomonas aeruginosa biofilms, and its biosynthesis is regulated by the binding of cyclic-3',5'-dimeric guanosine monophosphate (c-di-GMP) to the PelD receptor. c-di-GMP is synthesized from two molecules of guanosine triphosphate (GTP) by diguanylate cyclases with GGDEF domains and degraded by phosphodiesterases with EAL or HD-GYP domains. As the P. aeruginosa genome encodes 43 c-di-GMP metabolic enzymes, one way signaling specificity can be achieved is through direct interaction between specific enzyme-receptor pairs. Here, we show that the inner membrane hybrid GGDEF-EAL enzyme, BifA, directly interacts with PelD via its cytoplasmic HAMP, GGDEF, and EAL domains. Despite having no catalytic function, the degenerate active site motif of the BifA GGDEF domain (GGDQF) has retained the ability to bind GTP with micromolar affinity. Mutations that abolish GTP binding result in increased biofilm formation but stable global c-di-GMP levels. Our data suggest that BifA forms a dimer in solution and that GTP binding induces conformational changes in dimeric BifA that enhance the BifA-PelD interaction and stimulate its phosphodiesterase activity, thus reducing c-di-GMP levels and downregulating Pel biosynthesis. Structural comparisons between the dimeric AlphaFold2 model of BifA and the structures of other hybrid GGDEF-EAL proteins suggest that the regulation of BifA by GTP may occur through a novel mechanism.IMPORTANCEc-di-GMP is the most common cyclic dinucleotide used by bacteria to regulate phenotypes such as motility, biofilm formation, virulence factor production, cell cycle progression, and cell differentiation. While the identification and initial characterization of c-di-GMP metabolic enzymes are well established, our understanding of how these enzymes are regulated to provide signaling specificity remains understudied. Here we demonstrate that the inactive GGDEF domain of BifA binds GTP and regulates the adjacent phosphodiesterase EAL domain, ultimately downregulating Pel-dependent P. aeruginosa biofilm formation through an interaction with PelD. This discovery adds to the growing body of literature regarding how hybrid GGDEF-EAL enzymes are regulated and provides additional precedence for studying how direct interactions between c-di-GMP metabolic enzymes and effectors result in signaling specificity.

Hybrid-delivered community psychoeducation for people aged 50 and older: A mixed-method evaluation and lesson learned.

Introduction: Hybrid training mode comprising in-person and teleconferencing sessions is effective and sustainable, yet no standardized principles guide its development for older people. This study aimed to develop a set of principles for hybrid-mode psychoeducation for older people from the experiences of middle-aged and older people in two folds: (1) examining the effects of hybrid-mode community psychoeducation and (2) identifying features that could enhance participants' experience. Methods: We delivered 12-hour Older Person Mental Health First Aid and 3-hour late-life depression training to adults aged 50 and older in in-person and hybrid modes. Hybrid group participants received technology-related support, including in-advance training and on-site support. All participants completed assessments on depression literacy, depression stigma, meaning in life, social support, depressive symptoms, and anxiety pre-and post-intervention and evaluated the program in open-ended questions. Results: A total of 471 in-person and 346 hybrid group participants completed the psychoeducation and post-assessment (80.4 % female, mean age = 64.73 years, SD = 7.29). Linear mixed models revealed improvements in depression literacy, depression stigma, meaning in life, social support, and anxiety (B = -1.43 to 0.13, all p < .001), with no significant difference between in-person and hybrid groups. Thematic analysis of open-ended questions identified three themes: (1) informational content with case studies, (2) hardcopy course handouts, and (3) interactive learning environment. Discussion/conclusion: Hybrid-mode and in-person psychoeducation had comparable benefits on middle-aged and older people. The TORCH principles, an acronym for Technology provision, On-site technical support, Rehearsal, Connection with group members, and Hardcopy notes, was derived from practice wisdom and qualitative findings to support older people in online learning.

Full-face snorkel masks increase the incidence of hypoxaemia and hypercapnia during simulated snorkelling compared to conventional snorkels.

Introduction: Air flow in full-face snorkel masks (FFSMs) should be unidirectional to prevent rebreathing of exhaled air. This study evaluated rebreathing and its consequences when using FFSMs compared to a conventional snorkel. Methods: In a dry environment 20 participants wore three types of snorkel equipment in random order: Subea Easybreath FFSM; QingSong 180-degree panoramic FFSM; and a Beuchat Spy conventional snorkel (with nose clip), in three conditions: rest in a chair; light; and moderate intensity exercise on a cycle ergometer. Peripheral oxygen saturation, partial pressure of carbon dioxide (PCO2) and oxygen (PO2) in the end tidal gas and FFSM eye-pockets, respiratory rate, minute ventilation, were measured continuously. Experiments were discontinued if oxygen saturation dropped below 85%, or if end-tidal CO2 exceeded 7.0 kPa. Results: Experimental runs with the FFSMs had to be discontinued more often after exceeding 7.0 kPa end-tidal CO2 compared to a conventional snorkel e.g., 18/40 (45%) versus 4/20 (20%) during light intensity exercise, and 9/22 (41%) versus 3/16 (19%) during moderate intensity exercise. Thirteen participants exhibited peripheral oxygen saturations below 95% (nine using FFSMs and four using the conventional snorkel) and five fell below 90% (four using FFSMs and one using the conventional snorkel). The PCO2 and PO2 in the eye-pockets of the FFSMs fluctuated and were significantly higher and lower respectively than in inspired gas, which indicated rebreathing in all FFSM wearers. Conclusions: Use of FFSMs may result in rebreathing due to non-unidirectional flow, leading to hypercapnia and hypoxaemia.

How adults understand what young children say.

Children's early speech often bears little resemblance to that of adults, and yet parents and other caregivers are able to interpret that speech and react accordingly. Here we investigate how adult listeners' inferences reflect sophisticated beliefs about what children are trying to communicate, as well as how children are likely to pronounce words. Using a Bayesian framework for modelling spoken word recognition, we find that computational models can replicate adult interpretations of children's speech only when they include strong, context-specific prior expectations about the messages that children will want to communicate. This points to a critical role of adult cognitive processes in supporting early communication and reveals how children can actively prompt adults to take actions on their behalf even when they have only a nascent understanding of the adult language. We discuss the wide-ranging implications of the powerful listening capabilities of adults for theories of first language acquisition.

A systematic review of electroencephalography in acute cerebral hypoxia: clinical and diving implications.

Introduction: Hypoxia can cause central nervous system dysfunction and injury. Hypoxia is a particular risk during rebreather diving. Given its subtle symptom profile and its catastrophic consequences there is a need for reliable hypoxia monitoring. Electroencephalography (EEG) is being investigated as a real time monitor for multiple diving problems related to inspired gas, including hypoxia. Methods: A systematic literature search identified articles investigating the relationship between EEG changes and acute cerebral hypoxia in healthy adults. Quality of clinical evidence was assessed using the Newcastle-Ottawa scale. Results: Eighty-one studies were included for analysis. Only one study investigated divers. Twelve studies described quantitative EEG spectral power differences. Moderate hypoxia tended to result in increased alpha activity. With severe hypoxia, alpha activity decreased whilst delta and theta activities increased. However, since studies that utilised cognitive testing during the hypoxic exposure more frequently reported opposite results it appears cognitive processing might mask hypoxic EEG changes. Other analysis techniques (evoked potentials and electrical equivalents of dipole signals), demonstrated sustained regulation of autonomic responses despite worsening hypoxia. Other studies utilised quantitative EEG analysis techniques, (Bispectral index [BISTM], approximate entropy and Lempel-Ziv complexity). No change was reported in BISTM value, whilst an increase in approximate entropy and Lempel-Ziv complexity occurred with worsening hypoxia. Conclusions: Electroencephalographic frequency patterns change in response to acute cerebral hypoxia. There is paucity of literature on the relationship between quantitative EEG analysis techniques and cerebral hypoxia. Because of the conflicting results in EEG power frequency analysis, future research needs to quantitatively define a hypoxia-EEG response curve, and how it is altered by concurrent cognitive task loading.

Magnetic resonance imaging parameters on lacrimal gland in thyroid eye disease: a systematic review and meta-analysis.

BACKGROUND: Thyroid eye disease is an extrathyroidal manifestation of Graves' disease and is associated with dry eye disease. This is the first systematic review and meta-analysis to evaluate the role of magnetic resonance imaging lacrimal gland parameters in thyroid eye disease diagnosis, activity grading, and therapeutic responses prediction. METHODS: Up to 23 August, 2022, 504 studies from PubMed and Cochrane Library were analyzed. After removing duplicates and imposing selection criteria, nine eligible studies were included. Risk of bias assessment was done. Meta-analyses were performed using random-effect model if heterogeneity was significant. Otherwise, fixed-effect model was used. Main outcome measures include seven structural magnetic resonance imaging parameters (lacrimal gland herniation, maximum axial area, maximum coronal area, maximum axial length, maximum coronal length, maximum axial width, maximum coronal width), and three functional magnetic resonance imaging parameters (diffusion tensor imaging-fractional anisotropy, diffusion tensor imaging-apparent diffusion coefficient or mean diffusivity, diffusion-weighted imaging-apparent diffusion coefficient). RESULTS: Thyroid eye disease showed larger maximum axial area, maximum coronal area, maximum axial length, maximum axial width, maximum coronal width, diffusion tensor imaging-apparent diffusion coefficient/ mean diffusivity, and lower diffusion tensor imaging-fractional anisotropy than controls. Active thyroid eye disease showed larger lacrimal gland herniation, maximum coronal area, diffusion-weighted imaging-apparent diffusion coefficient than inactive. Lacrimal gland dimensional (maximum axial area, maximum coronal area, maximum axial length, maximum axial width, maximum coronal width) and functional parameters (diffusion tensor imaging-apparent diffusion coefficient, diffusion tensor imaging-apparent diffusion coefficient) could be used for diagnosing thyroid eye disease; lacrimal gland herniation, maximum coronal area, and diffusion-weighted imaging-apparent diffusion coefficient for differentiating active from inactive thyroid eye disease; diffusion tensor imaging parameters (diffusion tensor imaging-fractional anisotropy, diffusion tensor imaging-mean diffusivity) and lacrimal gland herniation for helping grading and therapeutic responses prediction respectively. CONCLUSIONS: Magnetic resonance imaging lacrimal gland parameters can detect active thyroid eye disease and differentiate thyroid eye disease from controls. Maximum coronal area is the most effective indicator for thyroid eye disease diagnosis and activity grading. There are inconclusive results showing whether structural or functional lacrimal gland parameters have diagnostic superiority. Future studies are warranted to determine the use of magnetic resonance imaging lacrimal gland parameters in thyroid eye disease.

Testing the Effects of a Multicomponent Frailty Management Program for Community-Dwelling Older Adults in Singapore: A Feasibility Study.

Frailty in later life is often associated with functional declines and reduced quality of life. A multicomponent frailty management program (mFMP) is lacking in Singapore. This study aimed to determine the feasibility and effects of an mFMP in reducing frailty and increasing participation among frail community-living older adults. Pre- and postassessments at three time points were conducted to compare the differences in body functions between the mFMP (experimental group [EG]) and a fitness program (control group [CG]). Recruitment, dropouts, and fall data were collected. Weekly field notes and semistructured interviews postintervention were thematically analyzed. Sixteen out of 23 participants (EG: eight; CG: eight) completed the 12-week interventions with reduced frailty immediately postintervention. At 3-month postintervention, 10 participants (EG: five; CG: five) being followed up had a sustained level of frailty (p < .05). The EG and CG reported zero and two falls, respectively. The mFMP demonstrated its feasibility and exhibited a trend to facilitate personal behavioral changes postintervention.

Understanding and preference toward DOs and OMT before and after an osteopathic principles and practice fellow lecture series.

CONTEXT: One of the two major pathways to become a physician in the United States is the Doctor of Osteopathic Medicine (DO) degree. A major distinctive feature is often perceived as the addition of manual training in osteopathic manipulative treatment (OMT) in the DO education. However, the profession also has a distinct philosophy imbedded in the curriculum of all osteopathic medical schools. Many medical schools offer professional degrees with graduates who may choose to continue their education in medicine, such as the Master of Science in Biomedical Sciences (MSBS). At our institution, there is no formal exposure to the differences between osteopathic and allopathic medicine in the MSBS curriculum, and most of this understanding is gained through out-of-classroom conversations. During the SARS-CoV-2 pandemic, virtual learning prohibited the usual gathering and discourse that occurs when students are learning on campus. OBJECTIVES: The objective of this study is to create a curriculum in the form of a seminar series to assist premedical students in making an informed choice about which profession is the best fit for their own education and to gain an appreciation for osteopathic medicine. This appreciation could also aid in the future collaboration of premedical students with osteopathic providers, recommendations to patients, and potentially their own medical care. Questionnaires were utilized to determine if our osteopathic seminar series was effective at changing the preferences and understanding of MSBS students. We also sought to determine the effectiveness of virtual vs. in-person delivery of our curriculum. METHODS: A seminar series with pre-established objectives was developed and presented to MSBS students at an osteopathic institution during the Fall of 2020 and 2021. The 2020 seminar was delivered through a virtual conference platform, and the 2021 seminar was delivered in-person. An eight question pre-and postquestionnaire was given to participants to evaluate their preferences and understanding. Internal validity and differences between delivery formats were assessed. RESULTS: Both seminar series produced equally effective, significant changes in the preferences and perceptions of osteopathic medicine in both virtual and in-person delivery formats. Differences in pre-vs. post understanding across both seminar series were not consistently significant and were smaller than those observed in preferences and perceptions. Positive changes included an increased willingness to see a DO and to recommend a loved one see a DO as their personal physician. Preference changes between the in-person vs. virtual delivery platforms did not show significant differences; however, understanding did show some inconsistent differences. CONCLUSIONS: This study demonstrates the utility of a virtual or in-person seminar to improve the preferences and perceptions of the osteopathic profession in MSBS students. The seminar series was successful in its goal of offering formal exposure to the osteopathic profession. The improved preferences and perceptions will have potential substantial benefits to the field of osteopathic medicine in the future. Further research is warranted to determine the most effective way to increase understanding of the osteopathic profession.

Acute bilateral parotid swelling upon laryngeal mask airway insertion: A case report.

We describe a case of bilateral parotid swelling developing shortly after laryngeal mask airway insertion. Spontaneous resolution occurred within 12 h postoperatively This unusual phenomenon has been termed 'anaesthesia mumps' or 'acute sialadenosis'. Its exact relationship to anaesthesia remains unknown. It arises in a variety of patients and surgeries, making its pathogenesis difficult to determine. Its presentation can be confused with acute angioedema, but, unlike the latter, it is benign and not normally associated with airway compromise. Diagnosis is a process of exclusion, but careful airway assessment is an important component of this. Strategies to aid diagnosis and management are described.

High-performance multiplex drug-gated CAR circuits.

Chimeric antigen receptor (CAR) T cells can revolutionize cancer medicine. However, overactivation, lack of tumor-specific surface markers, and antigen escape have hampered CAR T cell development. A multi-antigen targeting CAR system regulated by clinically approved pharmaceutical agents is needed. Here, we present VIPER CARs (versatile protease regulatable CARs), a collection of inducible ON and OFF switch CAR circuits engineered with a viral protease domain. We established their controllability using FDA-approved antiviral protease inhibitors in a xenograft tumor and a cytokine release syndrome mouse model. Furthermore, we benchmarked VIPER CARs against other drug-gated systems and demonstrated best-in-class performance. We showed their orthogonality in vivo using the ON VIPER CAR and OFF lenalidomide-CAR systems. Finally, we engineered several VIPER CAR circuits by combining various CAR technologies. Our multiplexed, drug-gated CAR circuits represent the next progression in CAR design capable of advanced logic and regulation for enhancing the safety of CAR T cell therapy.

Uncovering the Locus of Object-Context-Based Modulations in Depth Processing Using Repetitive Transcranial Magnetic Stimulation.

Neural responses of dorsal visual area V7 and lateral occipital complex (LOC) have been shown to correlate with changes in behavioral metrics of depth sensitivity observed as a function of object context, although it is unclear as to whether the behavioral manifestation results from an alteration of early depth-specific responses in V7 or arises as a result of alterations of object-level representations at LOC that subsequently feed back to affect disparity readouts in dorsal cortex. Here, we used online transcranial magnetic stimulation (TMS) to examine the roles of these two areas in giving rise to context-disparity interactions. Stimuli were disparity-defined geometric objects rendered as random-dot stereograms, presented in geometrically plausible and implausible variations. Observers' sensitivity to depth (depth discrimination) or object identity (plausibility discrimination) was indexed while receiving repetitive TMS at one of the two sites of interest (V7, LOC) along with a control site (Cz). TMS over LOC produced results no different from TMS over baseline Cz (and prior no-TMS behavioral work). That is, depth sensitivity was higher for implausible versus plausible objects. Strikingly, TMS over V7 abolished differences in depth sensitivity for implausible versus plausible objects. V7 serves as a key locus in bringing stereosensitivity changes because of object context, perhaps by reweighing stereoscopic data en route to informing object-motoric interactions.

Induction of Activity-Dependent Plasticity at Auditory Nerve Synapses.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

BACKGROUND: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life. METHODS: Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected. RESULTS: Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P = .007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P = .001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema. CONCLUSIONS: Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed.

Induction of synapse formation by de novo neurotransmitter synthesis.

A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.

Treatment of Spider Phobia Using Repeated Exposures and Adjunctive Repetitive Transcranial Magnetic Stimulation: A Proof-of-Concept Study.

Background: Specific phobias represent the largest category of anxiety disorders. Previous work demonstrated that stimulating the ventromedial prefrontal cortex (vmPFC) with repetitive Transcranial Magnetic Stimulation (rTMS) may improve response to exposure therapy for acrophobia. Objective: To examine feasibility of accelerating extinction learning in subjects with spider phobia using intermittent Theta Burst Stimulation (iTBS) rTMS of vmPFC. Methods: In total, 17 subjects with spider phobia determined by spider phobia questionnaires [Spider Phobia Questionnaire (SPQ) and Fear of Spiders questionnaire (FSQ)] underwent ratings of fear of spiders as well as behavioral and skin conductance data during a behavioral avoidance test (BAT). Subjects then received a sequential protocol of in vivo spider exposure followed by iTBS for three sessions administered to either active or control treatment sites (vmPFC [n = 8] or vertex [n = 9], respectively), followed 1 week later by repetition of questionnaires and BAT. Results: All subjects improved significantly regardless of group across both questionnaires (FSQ η2 = 0.43, p = 0.004; SPQ η2 = 0.39, p = 0.008) and skin conductance levels during BAT (Wald χ2 = 30.9, p < 0.001). Subjects in the vmPFC group tolerated lower treatment intensity than in the control group, and there was a significant correlation between treatment intensity, BAT subjective distress improvement, and physiologic measures (all ρ > 0.5). Conclusion: This proof-of-concept study provides preliminary evidence that a sequential exposure and iTBS over vmPFC is feasible and may have rTMS intensity-dependent effects on treatment outcomes, providing evidence for future areas of study in the use of rTMS for phobias.

Time Course of Activity-Dependent Changes in Auditory Nerve Synapses Reveals Multiple Underlying Cellular Mechanisms.

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within 2 d of noise exposure through a decrease in the probability of vesicle release (Pr). This was followed by a gradual increase in EPSC amplitude through a larger pool of releasable vesicles (N). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude through a decrease in N, which was followed by an increase in EPSC amplitude and synaptic depression through an increase in Pr After returning to normal sound levels, synaptic depression recovered to control levels within 1-2 d. However, repeated exposure to noise for as little as 8 h/d caused synaptic changes after 7 d, suggesting recovery did not fully offset changes. Thus, there appear to be three activity-dependent mechanisms in auditory nerve synapses-bidirectional changes in Pr in 1-2 d, slower bidirectional changes in N through synaptic growth or retraction, and rapid downregulation of N with low activity. The dynamic changes indicate that multiple mechanisms are present to fine-tune synaptic fidelity across different acoustic conditions in a simple relay.SIGNIFICANCE STATEMENT Hearing impairments can arise from exposure to noise or conductive hearing loss. This appears to result from changes in the brain, but the mechanisms are not well understood. We study this issue by studying the synapses made by auditory nerve fibers called endbulbs of Held. These synapses undergo bidirectional changes in size and release probability of neurotransmitter in response to increased or decreased activity. Here, we made a close examination of how quickly these synaptic characteristics change, which indicates there are at least three cellular mechanisms underlying changes. Furthermore, repeated exposure to brief periods of noise can produce cumulative effects. These changes could significantly affect hearing, especially because they occur at the start of the central auditory pathway.