Widening the scope of intensive treatment for PTSD in the military health system.

Recent trends have exacerbated existing problems accessing mental health care for military service members. To address these problems, lawmakers and military leaders have been busy introducing new legislation and changing policies in order to improve access. While these initiatives are critical for long-term change, military service members need solutions that can help them now. Although it may not be a panacea, intensive outpatient treatments may be part of the solution for the MHS, especially when considering posttraumatic stress disorder (PTSD). This commentary begins by describing the history of intensive treatments in the military health system, which has been largely offered as intensive outpatient treatments (IOPs). Next, it describes a decade of research on intensive treatments for PTSD, which has included a diverse array of IOP formats as well as stand-alone, massed treatments. Lastly, this commentary recommends that lawmakers and military leaders expand their notion of intensive outpatient treatments to include both programs and stand-alone, massed treatments. By doing so, the MHS could have more options for service members and commands as they search for workable treatment options.

Surface electromyographic frequency characteristics of the quadriceps differ between continuous high- and low-torque isometric knee extension to momentary failure.

Surface EMG (sEMG) has been used to compare loading conditions during exercise. Studies often explore mean/median frequencies. This potentially misses more nuanced electrophysiological differences between exercise tasks. Therefore, wavelet-based analysis was used to evaluate electrophysiological characteristics in the sEMG signal of the quadriceps under both higher- and lower-torque (70 % and 30 % of MVC, respectively) isometric knee extension performed to momentary failure. Ten recreationally active adult males with previous resistance training experience were recruited. Using a within-session, repeated-measures, randomised crossover design, participants performed isometric knee extension whilst sEMG was collected from the vastus medialis (VM), rectus femoris (RF) and vastus lateralis (VL). Mean signal frequency showed similar characteristics in each condition at momentary failure. However, individual wavelets revealed different frequency component changes between the conditions. All frequency components increased during the low-torque condition. But low-frequency components increased, and high-frequency components decreased, in intensity throughout the high-torque condition. This resulted in convergence of the low-torque and high-torque trial wavelet characteristics towards the end of the low-torque trial. Our results demonstrate a convergence of myoelectric signal properties between low- and high-torque efforts with fatigue via divergent signal adaptations. Further work should disentangle factors influencing frequency characteristics during exercise tasks.

Transport between im/mobile fractions shapes the speed and profile of cargo distribution in neurons.

Neuronal function requires continuous distribution of ion channels and other proteins throughout large cell morphologies. Protein distribution is complicated by immobilization of freely diffusing subunits such as on lipid rafts or in postsynaptic densities. Here, we infer rates of immobilization for the voltage-gated potassium channel Kv4.2. Fluorescence recovery after photobleaching quantifies protein diffusion kinetics, typically reported as a recovery rate and mobile fraction. We show that, implicit in the fluorescence recovery, are rates of particle transfer between mobile and immobile fractions (im/mobilization). We performed photobleaching of fluorescein-tagged ion channel Kv4.2-sGFP2 in over 450 dendrites of rat hippocampal cells. Using mass-action models, we infer rates of Kv4.2-sGFP2 im/mobilization. Using a realistic neuron morphology, we show how these rates shape the speed and profile of subunit distribution. The experimental protocol and model inference introduced here is widely applicable to other cargo and experimental systems.

R-type voltage-gated Ca2+ channels mediate A-type K+ current regulation of synaptic input in hippocampal dendrites.

The subthreshold voltage-gated transient K+ current (IA) carried by pore-forming Kv4.2 subunits regulates the propagation of synaptic input, dendritic excitability, and synaptic plasticity in CA1 pyramidal neuron dendrites of the hippocampus. We report that the Ca2+ channel subunit Cav2.3 regulates IA in this cell type. We initially identified Cav2.3 as a Kv4.2-interacting protein in a proteomic screen and we confirmed Cav2.3-Kv4.2 complex association using multiple techniques. Functionally, Cav2.3 Ca2+-entry increases Kv4.2-mediated whole-cell current due to an increase in Kv4.2 surface expression. Using pharmacology and Cav2.3 knockout mice, we show that Cav2.3 regulates the dendritic gradient of IA. Furthermore, the loss of Cav2.3 function leads to the enhancement of AMPA receptor-mediated synaptic currents and NMDA receptor-mediated spine Ca2+ influx. These results propose that Cav2.3 and Kv4.2 are integral constituents of an ion channel complex that affects synaptic function in the hippocampus.

Evaluation of outcomes for military mental health partial hospitalization program.

In the military health system, there has been a growing demand for mental health services over the last two decades. Partial hospitalization programs fill a critical niche between outpatient and inpatient services. The present study evaluated immediate and long-term outcomes of a military mental health partial hospitalization program at a large military treatment facility. This study collected retrospective data of active duty patients who completed a 6-day partial hospitalization program within a 2-year period. Results showed that the majority of participants were young, male, and junior enlisted service members endorsing suicidal ideation as well as adjustment/stressor- and depressive-related psychiatric symptoms. Immediately after treatment, participants showed a significant reduction in psychiatric symptoms and dysfunction after treatment. In the long-term, most participants engaged in mental health services post-discharge, though engagement with services decreased over time. In addition, career-impacting medical recommendations were made for over half of participants with almost three-quarters of these recommendations made before or during enrollment in the program. This study expanded the limited evidence base for military mental health partial hospitalization programs. In addition, this study offered data on the frequency of career-impacting medical recommendations made for patients engaged in care at this level of acuity.

Paradoxical relationships between active transport and global protein distributions in neurons.

Neural function depends on continual synthesis and targeted trafficking of intracellular components, including ion channel proteins. Many kinds of ion channels are trafficked over long distances to specific cellular compartments. This raises the question of whether cargo is directed with high specificity during transit or whether cargo is distributed widely and sequestered at specific sites. We addressed this question by experimentally measuring transport and expression densities of Kv4.2, a voltage-gated transient potassium channel that exhibits a specific dendritic expression that increases with distance from the soma and little or no functional expression in axons. In over 500 h of quantitative live imaging, we found substantially higher densities of actively transported Kv4.2 subunits in axons as opposed to dendrites. This paradoxical relationship between functional expression and traffic density supports a model-commonly known as the sushi belt model-in which trafficking specificity is relatively low and active sequestration occurs in compartments where cargo is expressed. In further support of this model, we find that kinetics of active transport differs qualitatively between axons and dendrites, with axons exhibiting strong superdiffusivity, whereas dendritic transport resembles a weakly directed random walk, promoting mixing and opportunity for sequestration. Finally, we use our data to constrain a compartmental reaction-diffusion model that can recapitulate the known Kv4.2 density profile. Together, our results show how nontrivial expression patterns can be maintained over long distances with a relatively simple trafficking mechanism and how the hallmarks of a global trafficking mechanism can be revealed in the kinetics and density of cargo.

Cardiovascular outcomes after percutaneous coronary intervention on bifurcation lesions with moderate to severe coronary calcium: A single-center registry study.

BACKGROUND: Both target vessel calcification and target vessel bifurcation are associated with worse outcomes following percutaneous coronary intervention (PCI). Whether these entities in combination interact to influence outcomes after PCI of complex coronary disease is not known. OBJECTIVES: This study evaluated the association of target vessel bifurcation and target vessel calcification, alone and in combination, with adverse events following PCI. METHODS: Registry data from 21,165 patients who underwent PCI with drug-eluting stents (DES) between January 2009 and December 2017 were analyzed. Patients were divided into four groups according to the presence or absence of target vessel bifurcation and presence of none/mild or moderate/severe target vessel calcification on angiography. Associations between lesion groups and 1 year major adverse cardiac events (MACE) were examined using Cox regression analysis. RESULTS: At 1 year, unadjusted rates of MACE, death, myocardial infarction (MI), as well as stent thrombosis were highest in the group with both bifurcation lesion and moderate/severe calcification. After adjusting for confounders such as age, renal disease, and smoking, hazard ratios for MACE were 1.14 (95%CI 0.99-1.33) for bifurcation with none/mild calcification, 1.21 (95%CI 1.06-1.38) for no bifurcation and moderate/severe calcification, and 1.37 (95%CI 1.14-1.64) for bifurcation and moderate severe calcification, compared to patients with no bifurcation and none/mild calcification. CONCLUSIONS: The presence of a bifurcating target vessel with moderate/severe calcification is associated with a higher risk of adverse outcomes than either attribute alone. New approaches are needed to improve outcomes in this subset of patients with complex coronary artery disease.

Management of calcified coronary artery bifurcation lesions.

Calcified coronary artery bifurcation lesions (CBL) remain a challenge for the interventional cardiologist. Evidence regarding treatment of CBL is minimal. Optimal plaque modification is the most important step prior to stent deployment. Provisional stenting is the preferred strategy for most bifurcation lesions. However, two-stent strategy should be considered for BL with compromised large SB (>2.5 mm) supplying a large territory, >70% SB stenosis and lesions more than 5 mm long. In this contemporary review article, we present a simplified approach to treating CBL and demonstrate the approach to specific case examples using our newly developed mobile application, BifurcAID.

Emotion regulation flexibility and disordered eating.

Research suggests that individuals with eating disorders use more putatively maladaptive emotion regulation strategies and fewer putatively adaptive strategies. However, there is growing theoretical and empirical support for the notion that the efficacy of emotion regulation strategies varies across situations. Thus, successful emotion regulation is characterized by the ability to flexibly choose between emotion regulation strategies in order to fit one's situational needs. Despite growing support for this conceptualization of successful emotion regulation, no research has investigated it in relation to disordered eating. Using the emotion regulation choice paradigm, this study investigated the association between emotion regulation flexibility and disordered eating. Women (N = 50) completed self-report questionnaires and a laboratory-based emotion regulation choice task to assess emotion regulation flexibility. Results indicated that lower emotion regulation flexibility was associated with more frequent purging and excessive exercise. Emotion regulation flexibility was not significantly associated with binge eating or overall eating disorder psychopathology. These findings suggest that individuals who engage in unhealthy compensatory behaviors exhibit reduced emotion regulation flexibility. If replicated in clinical samples, treatment for eating disorders characterized by compensatory behaviors may benefit from incorporating additional strategies to help people utilize emotion regulation strategies in a flexible, situationally appropriate manner.

Monitoring processes in extended emotion regulation.

The extended process model of emotion regulation (ER) posits that dynamic ER processes monitor and adjust the implementation of ER strategies over time. When an initial ER strategy is ineffective, monitoring processes allow one to flexibly switch to a new, possibly more effective strategy. The present study employed a novel experimental task to explore these dynamic ER processes. Sixty-eight adult female participants each completed 40 trials. In each trial, participants first were assigned to use either distraction or reappraisal for the either low- or high-intensity negative image presented. Then, they were presented with a choice between continuing to use the assigned strategy or switching strategies before viewing the negative image again. Results showed that the combinations of ER strategies and image intensities generated different affect states for the choice context. The magnitude of intermediate negative affect was positively associated with a greater probability of choosing to switch strategies. Finally, for higher intermediate negative affect, negative affect was lower after choosing to switch strategies. For lower intermediate negative affect, negative affect remained low regardless of continuing or switching strategies. These findings support the extended process model and contribute to a growing body of empirical support for dynamic models of ER.

Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses. The absence of FMRP leads to neuronal and circuit-level hyperexcitability that is thought to arise from the aberrant expression and activity of voltage-gated ion channels, although the identification and characterization of these ion channels have been limited. Here, we show that FMRP binds the mRNA of the R-type voltage-gated calcium channel Cav2.3 in mouse brain synaptoneurosomes and represses Cav2.3 translation under basal conditions. Consequently, in hippocampal neurons from male and female FMRP KO mice, we find enhanced Cav2.3 protein expression by western blotting and abnormally large R currents in whole-cell voltage-clamp recordings. In agreement with previous studies showing that FMRP couples Group I metabotropic glutamate receptor (GpI mGluR) signaling to protein translation, we find that GpI mGluR stimulation results in increased Cav2.3 translation and R current in hippocampal neurons which is disrupted in FMRP KO mice. Thus, FMRP serves as a key translational regulator of Cav2.3 expression under basal conditions and in response to GpI mGluR stimulation. Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies.SIGNIFICANCE STATEMENT Patients with fragile X syndrome (FXS) exhibit signs of neuronal and circuit hyperexcitability, including anxiety and hyperactive behavior, attention deficit disorder, and seizures. FXS is caused by the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein, and the neuronal hyperexcitability observed in the absence of FMRP likely results from its ability to regulate the expression and activity of voltage-gated ion channels. Here we find that FMRP serves as a key translational regulator of the voltage-gated calcium channel Cav2.3 under basal conditions and following activity. Cav2.3 impacts cellular excitability and calcium signaling, and the alterations in channel translation and expression observed in the absence of FMRP could contribute to the neuronal hyperactivity that underlies FXS.

A novel bungarotoxin binding site-tagged construct reveals MAPK-dependent Kv4.2 trafficking.

Kv4.2 voltage-gated K+ channel subunits, the primary source of the somatodendritic A-type K+ current in CA1 pyramidal neurons of the hippocampus, play important roles in regulating dendritic excitability and plasticity. To better study the trafficking and subcellular distribution of Kv4.2, we created and characterized a novel Kv4.2 construct encoding a bungarotoxin binding site in the extracellular S3-S4 linker region of the α-subunit. When expressed, this construct can be visualized in living cells after staining with rhodamine-conjugated bungarotoxin. We validated the utility of this construct by visualizing the spontaneous internalization and insertion of Kv4.2 in HEK 293T cells. We further report that Kv4.2 colocalized with several endosome markers in HEK 293T cells. In addition, Kv4.2 internalization is significantly impaired by mitogen-activated protein kinase (MAPK) inhibitors in transfected primary hippocampal neurons. Therefore, this newly developed BBS-Kv4.2 construct provides a novel and powerful tool for studying surface Kv4.2 channel localization and trafficking.

AKAP79/150 recruits the transcription factor NFAT to regulate signaling to the nucleus by neuronal L-type Ca2+ channels.

In neurons, regulation of activity-dependent transcription by the nuclear factor of activated T-cells (NFAT) depends upon Ca2+ influx through voltage-gated L-type calcium channels (LTCC) and NFAT translocation to the nucleus following its dephosphorylation by the Ca2+-dependent phosphatase calcineurin (CaN). CaN is recruited to the channel by A-kinase anchoring protein (AKAP) 79/150, which binds to the LTCC C-terminus via a modified leucine-zipper (LZ) interaction. Here we sought to gain new insights into how LTCCs and signaling to NFAT are regulated by this LZ interaction. RNA interference-mediated knockdown of endogenous AKAP150 and replacement with human AKAP79 lacking its C-terminal LZ domain resulted in loss of depolarization-stimulated NFAT signaling in rat hippocampal neurons. However, the LZ mutation had little impact on the AKAP-LTCC interaction or LTCC function, as measured by Förster resonance energy transfer, Ca2+ imaging, and electrophysiological recordings. AKAP79 and NFAT coimmunoprecipitated when coexpressed in heterologous cells, and the LZ mutation disrupted this association. Critically, measurements of NFAT mobility in neurons employing fluorescence recovery after photobleaching and fluorescence correlation spectroscopy provided further evidence for an AKAP79 LZ interaction with NFAT. These findings suggest that the AKAP79/150 LZ motif functions to recruit NFAT to the LTCC signaling complex to promote its activation by AKAP-anchored calcineurin.

A polybasic motif in alternatively spliced KChIP2 isoforms prevents Ca2+ regulation of Kv4 channels.

The Kv4 family of A-type voltage-gated K+ channels regulates the excitability in hippocampal pyramidal neuron dendrites and are key determinants of dendritic integration, spike timing-dependent plasticity, long-term potentiation, and learning. Kv4.2 channel expression is down-regulated following hippocampal seizures and in epilepsy, suggesting A-type currents as therapeutic targets. In addition to pore-forming Kv4 subunits, modulatory auxiliary subunits called K+ channel-interacting proteins (KChIPs) modulate Kv4 expression and activity and are required to recapitulate native hippocampal A-type currents in heterologous expression systems. KChIP mRNAs contain multiple start sites and alternative exons that generate considerable N-terminal variation and functional diversity in shaping Kv4 currents. As members of the EF-hand domain-containing neuronal Ca2+ sensor protein family, KChIP auxiliary proteins may convey Ca2+ sensitivity upon Kv4 channels; however, to what degree intracellular Ca2+ regulates KChIP-Kv4.2 complexes is unclear. To answer this question, we expressed KChIP2 with Kv4.2 in HEK293T cells, and, with whole-cell patch-clamp electrophysiology, measured an ∼1.5-fold increase in Kv4.2 current density in the presence of elevated intracellular Ca2+ Intriguingly, the Ca2+ regulation of Kv4 current was specific to KChIP2b and KChIP2c splice isoforms that lack a putative polybasic domain that is present in longer KChIP2a1 and KChIP2a isoforms. Site-directed acidification of the basic residues within the polybasic motif of KChIP2a1 rescued Ca2+-mediated regulation of Kv4 current density. These results support divergent Ca2+ regulation of Kv4 channels mediated by alternative splicing of KChIP2 isoforms. They suggest that distinct KChIP-Kv4 interactions may differentially control excitability and function of hippocampal dendrites.

Thera-prov: a pilot study of improv used to treat anxiety and depression.

Background: Improvisational theater exercises (improv) are used in various settings to improve mental health and medical outcomes. However, there is little documented evidence of the effectiveness of these interventions.Aims: We developed a short-term, group intervention that used improv exercises in a therapeutic manner to treat psychiatric patients.Methods: We evaluated the feasibility, acceptability and five clinical outcomes (depressive symptoms, anxious symptoms, self-esteem, perfectionism and satisfaction with social roles) of this intervention in an outpatient setting. Participants were 32 patients with symptoms of anxiety and depression and who had variable exposure to psychiatric treatment.Results: In paired samples t-tests, participants demonstrated reduced symptoms of anxiety (t(31) = 4.67, p < 0.001) and depression (t(31) = 3.78, p = 0.001), and improved self-esteem (t(31)= -3.31, p = 0.002) following the intervention. There was a trend towards reduction of perfectionism (t(31) = 1.77, p = 0.087), but no substantial change in rated satisfaction with social roles. Effect sizes were medium for reduction in symptoms of depression and anxiety.Conclusions: The results of this study indicate that a brief intervention based on improv exercises may provide a strong and efficient treatment for patients with anxiety and depression.

DPP6 Loss Impacts Hippocampal Synaptic Development and Induces Behavioral Impairments in Recognition, Learning and Memory.

DPP6 is well known as an auxiliary subunit of Kv4-containing, A-type K+ channels which regulate dendritic excitability in hippocampal CA1 pyramidal neurons. We have recently reported, however, a novel role for DPP6 in regulating dendritic filopodia formation and stability, affecting synaptic development and function. These results are notable considering recent clinical findings associating DPP6 with neurodevelopmental and intellectual disorders. Here we assessed the behavioral consequences of DPP6 loss. We found that DPP6 knockout (DPP6-KO) mice are impaired in hippocampus-dependent learning and memory. Results from the Morris water maze and T-maze tasks showed that DPP6-KO mice exhibit slower learning and reduced memory performance. DPP6 mouse brain weight is reduced throughout development compared with WT, and in vitro imaging results indicated that DPP6 loss affects synaptic structure and motility. Taken together, these results show impaired synaptic development along with spatial learning and memory deficiencies in DPP6-KO mice.

Dynamic processes in emotion regulation choice.

Because emotion regulation (ER) processes operate over time, they potentially change the context in which subsequent ER processes occur. To test this proposal, fifty-two healthy participants completed the ER choice task. Thirty standardized low- and high-intensity negative images were used to generate different emotional contexts in which participants selected between distraction or reappraisal strategies to decrease the intensity of their negative emotion. Participants then implemented their selected strategy and rated their negative emotion. Using a dynamic perspective, we examined as predictors of ER strategy choice, in addition to current stimulus intensity, several contextual factors from the immediately preceding trial: preceding stimulus intensity and strategy choice, and the intensity of negative affect following the previous strategy implementation and thus preceding the current trial. Results replicated earlier findings that participants are more likely to choose distraction for high-intensity images. Extending earlier findings, selecting reappraisal in the preceding trial and greater negative affect preceding the current trial were associated with lower odds of choosing distraction. The lack of significant interactions among the current and preceding trial factors suggests that these effects on ER choice were direct and not through moderating the effect of current stimulus intensity. These findings support dynamic theories of ER.

Structure-based prediction of transcription factor binding specificity using an integrative energy function.

UNLABELLED: Transcription factors (TFs) regulate gene expression through binding to specific target DNA sites. Accurate annotation of transcription factor binding sites (TFBSs) at genome scale represents an essential step toward our understanding of gene regulation networks. In this article, we present a structure-based method for computational prediction of TFBSs using a novel, integrative energy (IE) function. The new energy function combines a multibody (MB) knowledge-based potential and two atomic energy terms (hydrogen bond and π interaction) that might not be accurately captured by the knowledge-based potential owing to the mean force nature and low count problem. We applied the new energy function to the TFBS prediction using a non-redundant dataset that consists of TFs from 12 different families. Our results show that the new IE function improves the prediction accuracy over the knowledge-based, statistical potentials, especially for homeodomain TFs, the second largest TF family in mammals. CONTACT: jguo4@uncc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

AKAP-anchored PKA maintains neuronal L-type calcium channel activity and NFAT transcriptional signaling.

L-type voltage-gated Ca2+ channels (LTCC) couple neuronal excitation to gene transcription. LTCC activity is elevated by the cyclic AMP (cAMP)-dependent protein kinase (PKA) and depressed by the Ca2+-dependent phosphatase calcineurin (CaN), and both enzymes are localized to the channel by A-kinase anchoring protein 79/150 (AKAP79/150). AKAP79/150 anchoring of CaN also promotes LTCC activation of transcription through dephosphorylation of the nuclear factor of activated T cells (NFAT). We report here that the basal activity of AKAP79/150-anchored PKA maintains neuronal LTCC coupling to CaN-NFAT signaling by preserving LTCC phosphorylation in opposition to anchored CaN. Genetic disruption of AKAP-PKA anchoring promoted redistribution of the kinase out of postsynaptic dendritic spines, profound decreases in LTCC phosphorylation and Ca2+ influx, and impaired NFAT movement to the nucleus and activation of transcription. Thus, LTCC-NFAT transcriptional signaling in neurons requires precise organization and balancing of PKA and CaN activities in the channel nanoenvironment, which is only made possible by AKAP79/150 scaffolding.