A Quality Improvement Curriculum for Psychiatry Residents.

Introduction: Quality improvement (QI) is an increasingly important aspect of health care and residency education. There is relatively little research describing QI curricula for residents in psychiatry. Although QI curricula have been published in MedEdPORTAL, the current resource represents the first such curriculum specific to psychiatry residents. This resource aims to present a QI curriculum for psychiatry residents. Methods: The University of Wisconsin psychiatry residency program implemented a QI curriculum for our PGY 3 psychiatry residents in 2010. The initial version of the curriculum has undergone marked changes over the ensuing years, reflecting feedback received from learners and faculty instructors, as well as ongoing review of the literature, to ascertain best practices in this area of medical education. Steps taken have included faculty training, development of evaluation forms, and implementation of elements to increase accountability for successful, sustainable project development. Results: During the 8 completed years of this curriculum, 77 PGY 3 psychiatry residents have completed it. The Quality Improvement Knowledge Application Tool adapted for psychiatry was completed by PGY 3 residents in advance of and upon completion of the curriculum for the first 2 years of the curriculum; results demonstrated a significant improvement in scores as a measurement of QI knowledge and skills. Thirty-one of 32 resident teams (97%) have implemented a QI project. Discussion: Our QI curriculum for PGY 3 psychiatry residents has been successful in equipping residents with QI knowledge and having them implement QI projects.

Psychiatrists' use of electronic communication and social media and a proposed framework for future guidelines.

BACKGROUND: Recent and ongoing advances in information technology present opportunities and challenges in the practice of medicine. Among all medical subspecialties, psychiatry is uniquely suited to help guide the medical profession's response to the ethical, legal, and therapeutic challenges--especially with respect to boundaries--posed by the rapid proliferation of social media in medicine. Ironically, while limited guidelines exist for other branches of medicine, guidelines for the responsible use of social media and information technology in psychiatry are lacking. OBJECTIVE: To collect data about patterns of use of electronic communications and social media among practicing psychiatrists and to establish a conceptual framework for developing professional guidelines. METHODS: A structured survey was developed to assess the use of email, texting, and social media among the active membership of the Group for the Advancement of Psychiatry (GAP) to gain insight into current practices across a spectrum of the field and to identify areas of concern not addressed in existing guidelines. This survey was distributed by mail and at an annual meeting of the GAP and a descriptive statistical analysis was conducted with SPSS. RESULTS: Of the 212 members, 178 responded (84% response rate). The majority of respondents (58%) reported that they rarely or never evaluated their online presence, while 35% reported that they had at some time searched for information online about patients. Only 20% posted content about themselves online and few of these restricted that information. Approximately 25% used email to communicate with patients, and very few obtained written consent to do so. CONCLUSION: Discipline-specific guidelines for psychiatrists' interactions with social media and electronic communications are needed. Informed by the survey described here, a review of the literature, and consensus opinion, a framework for developing such a set of guidelines is proposed. The model integrates four key areas: treatment frame, patient privacy, medico-legal concerns, and professionalism. This conceptual model, applicable to many psychiatric settings, including clinical practice, residency training, and continuing medical education, will be helpful in developing discipline-wide guidelines for psychiatry and can be applied to a decision-making process by individual psychiatrists in day-to-day practice.

Health care reform and integrated care: a golden opportunity for preventive psychiatry.

The Affordable Care Act (ACA) includes provisions to shift the U.S. health care system to address achieving wellness rather than just treating illness. In this Open Forum, the Prevention Committee of the Group for the Advancement of Psychiatry describes opportunities created by the ACA for improving prevention of mental illnesses and promotion of mental health. These include improved coverage of preventive services, models to integrate primary and behavioral health care, and establishment of the National Prevention, Health Promotion, and Public Health Council, which has developed a National Prevention Strategy. The authors describe the important role that psychiatrists can play in advancing prevention of mental illnesses, in particular by working to incorporate prevention strategies in integrated care initiatives and by collaborating with primary care providers to screen for risk factors and promote mental and emotional well-being.

Functional connectivity in slow-wave sleep: identification of synchronous cortical activity during wakefulness and sleep using time series analysis of electroencephalographic data.

Sleep is a behavioral state ideal for studying functional connectivity because it minimizes many sources of between-subject variability that confound waking analyses. This is particularly important for potential connectivity studies in mental illness where cognitive ability, internal milieu and active psychotic symptoms can vary widely across subjects. We, therefore, sought to adapt techniques applied to magnetoencephalography for use in high-density electroencephalography (EEG), the gold-standard in brain-recording methods during sleep. Autoregressive integrative moving average modeling was used to reduce spurious correlations between recording sites (electrodes) in order to identify functional networks. We hypothesized that identified network characteristics would be similar to those found with magnetoencephalography, and would demonstrate sleep stage-related differences in a control population. We analysed 60-s segments of low-artifact data from seven healthy human subjects during wakefulness and sleep. EEG analysis of eyes-closed wakefulness revealed widespread nearest-neighbor positive synchronous interactions, similar to magnetoencephalography, though less consistent across subjects. Rapid eye movement sleep demonstrated positive synchronous interactions akin to wakefulness but weaker. Slow-wave sleep (SWS), instead, showed strong positive interactions in a large left fronto-temporal-parietal cluster markedly more consistent across subjects. Comparison of connectivity from early SWS to SWS from a later sleep cycle indicated sleep-related reduction in connectivity in this region. The consistency of functional connectivity during SWS within and across subjects suggests this may be a promising technique for comparing functional connectivity between mental illness and health.

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders.

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimer's disease, schizophrenia, Sjögren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Synchronous dynamic brain networks revealed by magnetoencephalography.

We visualized synchronous dynamic brain networks by using prewhitened (stationary) magnetoencephalography signals. Data were acquired from 248 axial gradiometers while 10 subjects fixated on a spot of light for 45 s. After fitting an autoregressive integrative moving average model and taking the residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) between the i and j sensors were calculated, providing estimates of the strength and sign (positive and negative) of direct synchronous coupling between neuronal populations at a 1-ms temporal resolution. Overall, 51.4% of PCC(ij)(0) were positive, and 48.6% were negative. Positive PCC(ij)(0) occurred more frequently at shorter intersensor distances and were 72% stronger than negative ones, on the average. On the basis of the estimated PCC(ij)(0), dynamic neural networks were constructed (one per subject) that showed distinct features, including several local interactions. These features were robust across subjects and could serve as a blueprint for evaluating dynamic brain function.

Dipole analysis of magnetoencephalographic data during continuous shape copying.

High density, whole head magnetoencephalography (MEG) was used to study ten healthy human subjects (five females and five males) participating in a continuous shape-copying task. The task was performed with eyes open and fixated. The three-part task began with 45 s of fixation on a blue dot, after which the dot turned red, and a pentagon was presented around it. Subjects continued to fixate on the red dot for 45 s, after which it turned green. The green dot instructed subjects to begin copying the shape continuously for 45 s, without visual feedback, using a joystick mounted at arm's length. Data were collected at 1,017.25 Hz with a 248 sensor axial-gradiometer system. After cardiac artifact subtraction (Leuthold 2003), each corner was identified, and 1 s epochs (centered on each corner) were averaged and filtered from 1 to 44 Hz. Grand average flux maps demonstrated dipolar distributions identifying the most relevant sensors. With these sensors, which were located over flux extrema (Valaki et al. 2004), dipole models were used for source localization within subjects. Consistent dipole locations included the left motor cortex, bilateral parietal, frontal and temporal regions, and the occipital cortex. These results indicate that MEG source-localization may be derived from a limited number of trials of continuous data, and that visual cortex activity may be consistently present during continuous motor activity despite the absence of novel visual stimulation and eye-movements.

Magnetoencephalographic signals predict movement trajectory in space.

Brain-machine interface (BMI) efforts have been focused on using either invasive implanted electrodes or training-extensive conscious manipulation of brain rhythms to control prosthetic devices. Here we demonstrate an excellent prediction of movement trajectory by real-time magnetoencephalography (MEG). Ten human subjects copied a pentagon for 45 s using an X-Y joystick while MEG signals were being recorded from 248 sensors. A linear summation of weighted contributions of the MEG signals yielded a predicted movement trajectory of high congruence to the actual trajectory (median correlation coefficient: r=0.91 and 0.97 for unsmoothed and smoothed predictions, respectively). This congruence was robust since it remained high in cross-validation analyses (based on the first half of data to predict the second half; median correlation coefficient: r=0.76 and 0.85 for unsmoothed and smoothed predictions, respectively).

Time series analysis of magnetoencephalographic data during copying.

We used standard time series modeling to analyze magnetoencephalographic (MEG) data acquired during three tasks. Each task lasted 45 s, for a total data acquisition period of 135 s. Ten healthy human subjects fixated their eyes on a central blue point for 45 s (fixation only, "F" task). Then a pentagon (visual template) appeared surrounding the fixation point which simultaneously became red (fixation + template, "FT" task). After 45 s, the fixation point changed to green, which was the "go" signal for the subjects to begin continuously copying the pentagon for 45 s using a joystick and without visual feedback of their movement trajectory (fixation + template + copying, "FTC" task). MEG data were acquired continuously from 248 axial gradiometers at a sampling rate of 1017.25 Hz. After removal of cardiac artifacts and rejection of records with eyeblink artifacts, a Box-Jenkins autoregressive integrative moving average (ARIMA) analysis was applied to the unsmoothed, unaveraged MEG time series for model identification and estimation within 25 time lags (approximately 25 ms). We found that an ARIMA model of 25th order autoregressive, first order differencing, and first order moving average (p=25, d=1, q=1) adequately modeled the series and yielded residuals practically stationary with respect to their mean, variance, and autocorrelation structure. These "prewhitened" residuals were then used for assessing pairwise associations between series using crosscorrelation analysis with +/-25 time lags (approximately +/-25 ms). The cross-correlograms thus obtained revealed rich and consistent patterns of interactions between series with respect to positive and/or negative correlations. The overall prevalence of these patterns was very similar in the three tasks used, and, for particular sensor pairs, they tended to be preserved across tasks.

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors.

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.

Vagal modulation of bradykinin-induced mechanical hyperalgesia in the female rat.

In male rats, activity in subdiaphragmatic vagal afferents modulates nociception via an adrenal medulla-dependent mechanism. Because both the vagus and adrenal medullae are sexually dimorphic, we evaluated vagotomy-induced changes in mechanical nociceptive threshold and inflammatory hyperalgesia in female rats and compared them to those previously reported in male rats. We have found that (1) mechanical nociceptive threshold is lower in female rats than in male rats, perhaps because of tonic release of adrenal medullary factors in female rats; (2) mechanical nociceptive threshold in female rats is influenced to a lesser degree by activity in the subdiaphragmatic vagus; (3) vagotomy-induced enhancement of bradykinin hyperalgesia is greater in female rats; (4) in female rats, in contrast to male rats, celiac plus celiac accessory branch vagotomy failed to fully account for the enhancement of bradykinin hyperalgesia in complete subdiaphragmatic vagotomy; and (5) in female rats, in contrast to male rats, adrenal medullectomy plus subdiaphragmatic vagotomy only partially (approximately 30%) reversed the effect of vagotomy on bradykinin hyperalgesia. These findings demonstrate sexual dimorphism in the modulation of both mechanical nociceptive threshold and bradykinin-induced hyperalgesia by activity in subdiaphragmatic vagal afferents as well as the adrenal medulla.

Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat.

Vagal afferent activity modulates mechanical nociceptive threshold and inflammatory mediator-induced hyperalgesia, effects that are mediated by the adrenal medulla. To evaluate the role of epinephrine, the major hormone released from the adrenal medulla, the beta2-adrenergic receptor antagonist ICI 118,551 was chronically administered to vagotomized rats and epinephrine to normal rats. In vagotomized rats, chronic administration of ICI 118,551 markedly attenuated vagotomy-induced enhancement of bradykinin hyperalgesia but had no effect on nociceptive threshold. In normal rats, chronic epinephrine had the opposite effect, enhancing bradykinin hyperalgesia. Like vagotomy-, epinephrine-induced enhancement of hyperalgesia developed slowly, taking 14 days to reach its peak. Vagotomy induced a chronic elevation in plasma concentrations of epinephrine. We suggest that ongoing activity in vagal afferents inhibits the release of epinephrine from the adrenal medulla. Chronically elevated levels of epinephrine, occurring after vagotomy, desensitize peripheral beta2-adrenergic receptors and lead to enhancement of bradykinin hyperalgesia. The ability of prolonged elevated plasma levels of epinephrine to sensitize bradykinin receptors could contribute to chronic generalized pain syndromes.

Cortical systems associated with covert music rehearsal.

Musical representation and overt music production are necessarily complex cognitive phenomena. While overt musical performance may be observed and studied, the act of performance itself necessarily skews results toward the importance of primary sensorimotor and auditory cortices. However, imagined musical performance (IMP) represents a complex behavioral task involving components suited to exploring the physiological underpinnings of musical cognition in music performance without the sensorimotor and auditory confounds of overt performance. We mapped the blood oxygenation level-dependent fMRI activation response associated with IMP in experienced musicians independent of the piece imagined. IMP consistently activated supplementary motor and premotor areas, right superior parietal lobule, right inferior frontal gyrus, bilateral mid-frontal gyri, and bilateral lateral cerebellum in contrast with rest, in a manner distinct from fingertapping versus rest and passive listening to the same piece versus rest. These data implicate an associative network independent of primary sensorimotor and auditory activity, likely representing the cortical elements most intimately linked to music production.

Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat.

Bradykinin-induced mechanical hyperalgesia is sympathetically dependent and B(2)-type bradykinin receptor-mediated in the rat; however, a sympathetically independent component of bradykinin hyperalgesia is shown after subdiaphragmatic vagotomy. We evaluated the mechanism of this bradykinin-induced sympathetic-independent mechanical hyperalgesia. The dose-response curve for bradykinin mechanical hyperalgesia in sympathectomized plus vagotomized rats was similar in magnitude to that for sympathetically dependent bradykinin hyperalgesia in normal rats. Although bradykinin mechanical hyperalgesia was mediated by the B(2)-type bradykinin receptors after sympathectomy plus vagotomy, it had a much more rapid latency to onset. This hyperalgesia was significantly attenuated by inhibition of protein kinase A but not protein kinase C, similar to the hyperalgesia produced by prostaglandin E(2), an agent that directly sensitizes primary afferent nociceptors. However, unlike prostaglandin E(2)-induced mechanical hyperalgesia in normal rats, after sympathectomy plus vagotomy, bradykinin-induced hyperalgesia was not attenuated by inhibition of nitric oxide synthesis. Peripheral administration of a mu opioid agonist, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin, significantly attenuated bradykinin mechanical hyperalgesia after sympathectomy plus vagotomy. These data suggest that after sympathectomy plus subdiaphragmatic vagotomy, bradykinin acts directly on primary afferents to produce mechanical hyperalgesia via a novel protein kinase A-dependent signaling mechanism.

The loss of Smad3 results in a lower rate of bone formation and osteopenia through dysregulation of osteoblast differentiation and apoptosis.

Smad3 is a well-characterized intracellular effector of the transforming growth factor beta (TGF-beta) signaling pathway and was implicated recently in the potentiation of vitamin D receptor (VDR)-mediated signaling. Given that both TGF-beta and vitamin D are important regulators of bone remodeling, it is expected that Smad3 plays an integral role in normal maintenance of bone. However, the exact mechanisms by which Smad3 functions in bone remodeling are unknown. Here, we show that mice with targeted deletion of Smad3 are osteopenic with less cortical and cancellous bone compared with wild-type littermates. Decreases in bone mineral density (BMD) in Smad3 null mice reflect the inability of osteoblasts to balance osteoclast activity, although osteoclast numbers are normal and vitamin D mediated serum calcium homeostasis is maintained. The osteopenia of Smad3 null mice is attributed to a decreased rate of bone formation associated with increased osteocyte number and apoptosis. These findings are supported by studies with isolated primary osteoblasts that show TGF-beta can no longer inhibit the differentiation of osteoblasts in the absence of Smad3; yet, TGF-beta-stimulated proliferation remains intact. Together these data support a model that a loss of Smad3 increases the osteocyte fate of the osteoblast and decreases the duration of osteoblast function by shortening lifespan, ultimately resulting in osteopenia.

The role of Smad3 in mediating mouse hepatic stellate cell activation.

Transforming growth factor beta (TGF-beta) is the most potent profibrogenic mediator in liver fibrosis. Although Smad proteins have been identified as intracellular mediators in the TGF-beta signaling pathway, the function of individual Smad proteins remains poorly understood. The aim of this study was to explore the contribution of Smad3 in mediating TGF-beta responses in a model of acute liver injury in vivo and in culture-activated hepatic stellate cells (HSCs). Wild-type, Smad3 heterozygous or Smad3 homozygous knockout mice were treated with a single intragastric administration of CCl(4). After 72 hours, the induction of hepatic collagen alpha1(I) and alpha2(I) messenger RNA (mRNA) levels in Smad3 knockout mice was only 42% and 64%, respectively, of the levels induced in wild-type mice. However, smooth muscle alpha-actin (alpha-SMA) was expressed at a slightly higher level in livers from knockout mice compared with wild-type mice. In culture-activated HSCs from Smad3 knockout mice, collagen alpha1(I) mRNA was 73% of wild-type HSCs, but alpha-SMA expression was the same. HSCs from knockout mice showed a higher proliferation rate than wild-type HSCs. Smad3-deficient HSCs did not form TGF-beta1-induced Smad-containing DNA-binding complexes. In conclusion, (1) maximal expression of collagen type I in activated HSCs requires Smad3 in vivo and in culture; (2) Smad3 is not necessary for HSC activation as assessed by alpha-SMA expression; (3) Smad3 is necessary for inhibition of proliferation of HSCs, which might be TGF-beta-dependent; and (4) Smad3 is required for TGF-beta1-mediated Smad-containing DNA-binding complex formation in cultured HSCs.

Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene.

B-lymphocyte activation and proliferation induced by the B-cell receptor (BCR) signals are important steps in the initiation of humoral immune responses. How the BCR signals are translated by nuclear transcription factors into cell cycle progression is poorly understood. Id3 is an immediate-early gene responding to growth and mitogenic signals in many cell types including B cells. The primary function of the Id3 protein has been defined as that of inhibitor of basic-helix-loop-helix (bHLH) transcription factors. The interaction between Id3 and bHLH proteins, many of which are essential for cellular differentiation, has been proposed as a key regulatory event leading to cellular proliferation instead of differentiation. To further investigate the role of Id3 in tissue and embryo development and the mechanism of Id3-mediated growth regulation, we generated and analyzed Id3-deficient mice. While these mice display no overt abnormality in tissue and embryo development, their humoral immunity is compromised. The amounts of immunoglobulins produced in Id3-deficient mice immunized with a T-cell-dependent antigen and a type 2 T-cell-independent antigen are attenuated and severely impaired, respectively. Further analysis of lymphocytes isolated from Id3-deficient mice reveals a B-cell defect in their proliferation response to BCR cross-linking but not to lipopolysaccharide or a combination of BCR cross-linking and interleukin-4. Analyses of cultured lymphocytes also suggest involvement of Id3 in cytokine production in T cells and isotype switching in B cells. Finally, the proliferation defect in Id3-deficient B cells can be rescued by ectopic expression of Id1, a homologue of Id3. Taken together, these results define a necessary and specific role for Id3 in mediating signals from BCR to cell cycle progression during humoral immune responses.

Smads bind directly to the Jun family of AP-1 transcription factors.

Smad3 and Smad4 are sequence-specific DNA-binding factors that bind to their consensus DNA-binding sites in response to transforming growth factor beta (TGFbeta) and activate transcription. Recent evidence implicates Smad3 and Smad4 in the transcriptional activation of consensus AP-1 DNA-binding sites that do not interact with Smads directly. Here, we report that Smad3 and Smad4 can physically interact with AP-1 family members. In vitro binding studies demonstrate that both Smad3 and Smad4 bind all three Jun family members: JunB, cJun, and JunD. The Smad interacting region of JunB maps to a C-terminal 20-amino acid sequence that is partially conserved in cJun and JunD. We show that Smad3 and Smad4 also associate with an endogenous form of cJun that is rapidly phosphorylated in response to TGFbeta. Providing evidence for the importance of this interaction between Smad and Jun proteins, we demonstrate that Smad3 is required for the activation of concatamerized AP-1 sites in a reporter construct that has previously been characterized as unable to bind Smad proteins directly. Together, these data suggest that TGFbeta-mediated transcriptional activation through AP-1 sites may involve a regulated interaction between Smads and AP-1 transcription factors.

Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction.

The Smads are a family of nine related proteins which function as signaling intermediates for the transforming growth factor beta (TGF-beta) superfamily of ligands. To discern the in vivo functions of one of these Smads, Smad3, we generated mice harboring a targeted disruption of this gene. Smad3 null mice, although smaller than wild-type littermates, are viable, survive to adulthood, and exhibit an early phenotype of forelimb malformation. To study the cellular functions of Smad3, we generated Smad3 null mouse embryonic fibroblasts (MEFs) and dermal fibroblasts. We demonstrate that null MEFs have lost the ability to form Smad-containing DNA binding complexes and are unable to induce transcription from the TGF-beta-responsive promoter construct, p3TP-lux. Using the primary dermal fibroblasts, we also demonstrate that Smad3 is integral for induction of endogenous plasminogen activator inhibitor 1. We subsequently demonstrate that Smad3 null MEFs are partially resistant to TGF-beta's antiproliferative effect, thus firmly establishing a role for Smad3 in TGF-beta-mediated growth inhibition. We next examined cells in which Smad3 is most highly expressed, specifically cells of immune origin. Although no specific developmental defect was detected in the immune system of the Smad3 null mice, a functional defect was observed in the ability of TGF-beta to inhibit the proliferation of splenocytes activated by specific stimuli. In addition, primary splenocytes display defects in TGF-beta-mediated repression of cytokine production. These data, taken together, establish a role for Smad3 in mediating the antiproliferative effects of TGF-beta and implicate Smad3 as a potential effector for TGF-beta in modulating immune system function.