Neural Representations of Unconditioned Stimuli in Basolateral Amygdala Mediate Innate and Learned Responses.

Stimuli that possess inherently rewarding or aversive qualities elicit emotional responses and also induce learning by imparting valence upon neutral sensory cues. Evidence has accumulated implicating the amygdala as a critical structure in mediating these processes. We have developed a genetic strategy to identify the representations of rewarding and aversive unconditioned stimuli (USs) in the basolateral amygdala (BLA) and have examined their role in innate and learned responses. Activation of an ensemble of US-responsive cells in the BLA elicits innate physiological and behavioral responses of different valence. Activation of this US ensemble can also reinforce appetitive and aversive learning when paired with differing neutral stimuli. Moreover, we establish that the activation of US-responsive cells in the BLA is necessary for the expression of a conditioned response. Neural representations of conditioned and unconditioned stimuli therefore ultimately connect to US-responsive cells in the BLA to elicit both innate and learned responses.

Reset of hippocampal-prefrontal circuitry facilitates learning.

The ability to rapidly adapt to novel situations is essential for survival, and this flexibility is impaired in many neuropsychiatric disorders1. Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Exposure to novelty recruits the hippocampus and medial prefrontal cortex (mPFC)2 and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. Here we show that novelty resets the neural circuits that link the ventral hippocampus (vHPC) and the mPFC, facilitating the ability to overcome an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4-12 Hz) oscillations and weakening existing vHPC-mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC-mPFC connectivity was strengthened, and mPFC neurons updated to encode the new rules. Without novelty, however, mice adhered to their established strategy. Blocking dopamine D1 receptors (D1Rs) or inhibiting novelty-tagged cells that express D1Rs in the vHPC prevented these behavioural and physiological effects of novelty. Furthermore, activation of D1Rs mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling subsequent learning-associated circuit plasticity.

Long-range neural synchrony in behavior.

Long-range synchrony between distant brain regions accompanies multiple forms of behavior. This review compares and contrasts the methods by which long-range synchrony is evaluated in both humans and model animals. Three examples of behaviorally relevant long-range synchrony are discussed in detail: gamma-frequency synchrony during visual perception, hippocampal-prefrontal synchrony during working memory, and prefrontal-amygdala synchrony during anxiety. Implications for circuit mechanism, translation, and clinical relevance are discussed.

Revisiting the seven pillars of RDoC.

BACKGROUND: In 2013, a few years after the launch of the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative, Cuthbert and Insel published a paper titled "Toward the future of psychiatric diagnosis: the seven pillars of RDoC." The RDoC project is a translational research effort to encourage new ways of studying psychopathology through a focus on disruptions in normal functions (such as reward learning or attention) that are defined jointly by observable behavior and neurobiological measures. The paper outlined the principles of the RDoC research framework, including emphases on research that acquires data from multiple measurement classes to foster integrative analyses, adopts dimensional approaches, and employs novel methods for ascertaining participants and identifying valid subgroups. DISCUSSION: To mark the first decade of the RDoC initiative, we revisit the seven pillars and highlight new research findings and updates to the framework that are related to each. This reappraisal emphasizes the flexible nature of the RDoC framework and its application in diverse areas of research, new findings related to the importance of developmental trajectories within and across neurobehavioral domains, and the value of computational approaches for clarifying complex multivariate relations among behavioral and neurobiological systems. CONCLUSION: The seven pillars of RDoC have provided a foundation that has helped to guide a surge of new studies that have examined neurobehavioral domains related to mental disorders, in the service of informing future psychiatric nosology. Building on this footing, future areas of emphasis for the RDoC project will include studying central-peripheral interactions, developing novel approaches to phenotyping for genomic studies, and identifying new targets for clinical trial research to facilitate progress in precision psychiatry.

Evaluating whole-genome expression differences in idiopathic and diabetic adhesive capsulitis.

BACKGROUND: Diabetic patients have a greater incidence of adhesive capsulitis (AC) and a more protracted disease course than patients with idiopathic AC. The purpose of this study was to compare gene expression differences between AC with diabetes mellitus and AC without diabetes mellitus. METHODS: Shoulder capsule samples were prospectively obtained from diabetic or nondiabetic patients who presented with shoulder dysfunction and underwent arthroscopy (N = 16). Shoulder samples of AC with and without diabetes (n = 8) were compared with normal shoulder samples with and without diabetes as the control group (n = 8). Shoulder capsule samples were subjected to whole-transcriptome RNA sequencing, and differential expression was analyzed with EdgeR. Only genes with a false discovery rate < 5% were included for further functional enrichment analysis. RESULTS: The sample population had a mean age of 47 years (range, 24-62 years), and the mean hemoglobin A1c level for nondiabetic and diabetic patients was 5.18% and 8.71%, respectively. RNA-sequencing analysis revealed that 66 genes were differentially expressed between diabetic patients and nondiabetic patients with AC whereas only 3 genes were differentially expressed when control patients with and without diabetes were compared. Furthermore, 286 genes were differentially expressed in idiopathic AC patients, and 61 genes were differentially expressed in diabetic AC patients. On gene clustering analysis, idiopathic AC was enriched with multiple structural and muscle-related pathways, such as muscle filament sliding, whereas diabetic AC included a greater number of hormonal and inflammatory signaling pathways, such as cellular response to corticotropin-releasing factor. CONCLUSIONS: Whole-transcriptome expression profiles demonstrate a fundamentally different underlying pathophysiology when comparing diabetic AC with idiopathic AC, suggesting that these conditions are distinct clinical entities. The new genes expressed explain the differences in the disease course and suggest new therapeutic targets that may lead to different treatment paradigms in these 2 subsets.

Priorities in stress research: a view from the U.S. National Institute of Mental Health.

The mission of the National Institute of Mental Health is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. In consultation with a broad range of experts, the NIMH has identified a set of priorities for stress biology research aimed squarely at creating the basic and clinical knowledge bases for reducing and alleviating mental health burden across the lifespan. Here, we discuss these priority areas in stress biology research, which include: understanding the heterogeneity of stressors and outcomes; refining and expanding the experimental systems used to study stress and its effects; embracing and exploiting the complexity of the stress response; and prioritizing translational studies that seek to test mechanistic hypotheses in human beings. We emphasize the challenge of establishing mechanistic links across levels of analysis to explain how and when specific and diverse stressors lead to enduring changes in neural systems and produce lasting functional deficits in mental health relevant behaviors. An improved understanding of mechanisms underlying stress responses and the functional consequences of stress can and will speed translation from basic research to predictive markers of risk and to improved, personalized interventions for mental illness.

The NIH BRAIN Initiative: Advancing neurotechnologies, integrating disciplines.

In 2014, the National Institutes of Health (NIH) began funding an ambitious research program, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, with the singular focus of advancing our understanding of brain circuits though development and application of breakthrough neurotechnologies. As we approach the halfway mark of this 10-year effort aimed at revolutionizing our understanding of information processing in the human brain, it is timely to review the progress and the future trajectory of BRAIN Initiative research.

Hippocampal-prefrontal input supports spatial encoding in working memory.

Spatial working memory, the caching of behaviourally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. Although the prefrontal cortex and hippocampus are known to contribute jointly to successful spatial working memory, the anatomical pathway and temporal window for the interaction of these structures critical to spatial working memory has not yet been established. Here we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues in mice. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.

Comparison of Magnetic Resonance Imaging and Ultrasound Evaluations of Zone II Partial Flexor Tendon Lacerations: A Cadaveric Study.

OBJECTIVES: Surgical intervention for zone II high-grade partial flexor tendon lacerations is often required when more than half of the tendon width is torn. Reliable noninvasive tests are critical for optimizing clinical decision making. Our team previously investigated the use of ultrasound (US) for identification of high-grade zone II flexor digitorum profundus lacerations. In this study, we compared magnetic resonance imaging (MRI) to US for the evaluation of high-grade partial flexor tendon lacerations in cadaveric specimens. METHODS: Dissection of 32 digits in 8 fresh-frozen upper extremity cadaveric specimens was performed. The flexor digitorum profundus tendons were randomized into 3 groups: intact, low-grade laceration, and high-grade laceration. A dynamic US examination was performed by a blinded musculoskeletal radiologist. The same specimens underwent hand coil MRI, which was read by the same blinded radiologist. Magnetic resonance imaging test performance metrics were calculated and compared to those computed for the US evaluation. RESULTS: For US evaluation of high-grade lacerations, the sensitivity and specificity were 0.5 and 1.0, with positive likelihood ratio (LR+) and negative likelihood ratio (LR-) values of ∞ and 0.50, respectively. The sensitivity and specificity for MRI evaluation were 0.2 and 1.0, with LR+ and LR- values of ∞ and 0.80. CONCLUSIONS: Both US and MRI are adequate at determining the presence of a high-grade laceration. Magnetic resonance imaging was more specific than US in identification of high-grade partial flexor tendon lacerations. Although less specific, US is a reasonable and less-expensive alternative to MRI when evaluating for clinically significant high-grade partial flexor tendon lacerations.

Fiber-coupled vapor cell for a portable Rydberg atom-based radio frequency electric field sensor.

We demonstrate a movable, Rydberg atom-based radio frequency (RF) electric (E) field probe. The technique is based on electromagnetically induced transparency and Autler-Townes splitting. Two fibers attached to a 10 mm cubic Cs133 vapor cell are used to couple counter-propagating probe and control lasers through the cell. This all-dielectric fiber-coupled sensor can be moved from the optics table to locations more suitable for RF (gigahertz to sub-terahertz) E-field measurements and calibrations.

Ultrasonographic Evaluation of Zone II Partial Flexor Tendon Lacerations of the Fingers: A Cadaveric Study.

OBJECTIVES: Accurate assessment of zone II partial flexor tendon lacerations in the finger is clinically important. Surgical repair is recommended for lacerations of greater than 50% to 60%. Our goal was to evaluate ultrasonographic test characteristics and accuracy in identifying partial flexor tendon lacerations in a cadaveric model. METHODS: From fresh-frozen above-elbow human cadaveric specimens, 32 flexor digitorum profundus tendons were randomly selected to remain intact or receive low- or high-grade lacerations involving 10% to 40% and 60% to 90% of the radioulnar width within Verdan Zone II, respectively. Static and dynamic ultrasonography using a linear array 14-MHz transducer was performed by a blinded musculoskeletal radiologist. Sensitivities, specificities, and other standard test performance metrics were calculated. Actual and measured percentages of tendon laceration were compared by the paired t test. RESULTS: After randomization, 24 tendons were lacerated (12 low- and 12 high-grade), whereas 8 remained intact. The sensitivity and specificity in detecting the presence versus absence of a partial laceration were 0.54 and 0.75, respectively, with positive and negative likelihood ratio values of 2.17 and 0.61. For low-grade lacerations, the sensitivity and specificity were 0.25 and 0.85, compared to 0.83 and 0.85 for high-grade lacerations. Ultrasonography underestimated the percentage of tendon involvement by a mean of 18.1% for the study population as a whole (95% confidence interval, 9.0% to 27.2%; P < .001) but accurately determined the extent for correctly diagnosed high-grade lacerations (-6.7%; 95% confidence interval, -18.7% to 5.2%; P = .22). CONCLUSIONS: Ultrasonography was useful in identifying and characterizing clinically relevant high-grade zone II partial flexor digitorum profundus lacerations in a cadaveric model.

Contact efflorescence as a pathway for crystallization of atmospherically relevant particles.

Inadequate knowledge of the phase state of atmospheric particles represents a source of uncertainty in global climate and air quality models. Hygroscopic aqueous inorganic particles are often assumed to remain liquid throughout their atmospheric lifetime or only (re)crystallize at low relative humidity (RH) due to the kinetic limitations of efflorescence (salt crystal nucleation and growth from an aqueous solution). Here we present experimental observations of a previously unexplored heterogeneous nucleation pathway that we have termed "contact efflorescence," which describes efflorescence initiated by an externally located solid particle coming into contact with the surface of a metastable aqueous microdroplet. This study demonstrates that upon a single collision, contact efflorescence is a pathway for crystallization of atmospherically relevant aqueous particles at high ambient RH (≤80%). Soluble inorganic crystalline particles were used as contact nuclei to induce efflorescence of aqueous ammonium sulfate [(NH4)2SO4], sodium chloride (NaCl), and ammonium nitrate (NH4NO3), with efflorescence being observed in several cases close to their deliquescence RH values (80%, 75%, and 62%, respectively). To our knowledge, these observations represent the highest reported efflorescence RH values for microdroplets of these salts. These results are particularly important for considering the phase state of NH4NO3, where the contact efflorescence RH (∼20-60%) is in stark contrast to the observation that NH4NO3 microdroplets do not homogeneously effloresce, even when exposed to extremely arid conditions (<1% RH). Considering the occurrence of particle collisions in the atmosphere (i.e., coagulation), these observations of contact efflorescence challenge many assumptions made about the phase state of inorganic aerosol.

Trends in MD/PhD Graduates Entering Psychiatry: Assessing the Physician-Scientist Pipeline.

OBJECTIVE: The goal of this study was to identify trends in MD/PhD graduates entering psychiatry, to compare these trends with other specialties, and to review strategies for enhancing the physician-scientist pipeline. METHODS: Data on 226,588 medical students graduating from Liaison Committee on Medical Education accredited programs between 1999 and 2012 (6626 MD/PhDs) were used to evaluate the number, percentage, and proportion of MD/PhDs entering psychiatry in comparison with other specialties (neurology, neurosurgery, internal medicine, family medicine, and radiation oncology). Linear regression and multiple linear regression determined whether these values increased over time and varied by sex. RESULTS: Over 14 years, an average of 18 MD/PhDs (range 13-29) enrolled in psychiatry each year. The number of MD/PhDs going into psychiatry significantly increased, although these gains were modest (less than one additional MD/PhD per year). The proportion of students entering psychiatry who were MD/PhDs varied between 2.9 and 5.9 per 100 residents, with no significant change over time. There was also no change in the percentage of MD/PhDs entering psychiatry from among all MD/PhD graduates. The rate of increase in the number of MD/PhDs going into psychiatry did not differ significantly from other specialties except for family medicine, which is decreasing. The rate of MD/PhDs going into psychiatry was higher for women, suggesting closure of the sex gap in 17 years. CONCLUSIONS: Despite the increase in the number of MD/PhDs entering psychiatry, these numbers remain low. Expanding the cohort of physician-scientists dedicated to translational research in psychiatry will require a multipronged approach.

Higher-Order Sensory Cortex Drives Basolateral Amygdala Activity during the Recall of Remote, but Not Recently Learned Fearful Memories.

Negative experiences are quickly learned and long remembered. Key unresolved issues in the field of emotional memory include identifying the loci and dynamics of memory storage and retrieval. The present study examined neural activity in the higher-order auditory cortex Te2 and basolateral amygdala (BLA) and their crosstalk during the recall of recent and remote fear memories. To this end, we obtained local field potentials and multiunit activity recordings in Te2 and BLA of rats that underwent recall at 24 h and 30 d after the association of an acoustic conditioned (CS, tone) and an aversive unconditioned stimulus (US, electric shock). Here we show that, during the recall of remote auditory threat memories in rats, the activity of the Te2 and BLA is highly synchronized in the theta frequency range. This functional connectivity stems from memory consolidation processes because it is present during remote, but not recent, memory retrieval. Moreover, the observed increase in synchrony is cue and region specific. A preponderant Te2-to-BLA directionality characterizes this dialogue, and the percentage of time Te2 theta leads the BLA during remote memory recall correlates with a faster latency to freeze to the auditory conditioned stimulus. The blockade of this information transfer via Te2 inhibition with muscimol prevents any retrieval-evoked neuronal activity in the BLA and animals are unable to retrieve remote memories. We conclude that memories stored in higher-order sensory cortices drive BLA activity when distinguishing between learned threatening and neutral stimuli. SIGNIFICANCE STATEMENT: How and where in the brain do we store the affective/motivational significance of sensory stimuli acquired through life experiences? Scientists have long investigated how "limbic" structures, such as the amygdala, process affective stimuli. Here we show that retrieval of well-established threat memories requires the functional interplay between higher-order components of the auditory cortex and the amygdala via synchrony in the theta range. This functional connectivity is a result of memory consolidation processes and is characterized by a predominant cortical to amygdala direction of information transfer. This connectivity is predictive of the animals' ability to recognize auditory stimuli as aversive. In the absence of this necessary cortical activity, the amygdala is unable to distinguish between frightening and neutral stimuli.

Patient- and Disease-Specific Factors Associated With Operative Management of de Quervain Tendinopathy.

PURPOSE: It remains unclear which factors, patient- or disease-specific, are associated with electing to undergo operative management for de Quervain tendinopathy. Our null hypothesis was that no patient- or disease-specific factors would be associated with the choice of surgical treatment of de Quervain tendinopathy. METHODS: We performed a retrospective review of consecutive patients diagnosed with de Quervain tendinopathy over 3 years by 1 of 3 fellowship-trained hand surgeons at an urban academic institution. Descriptive statistics were calculated for patient baseline and disease-specific characteristics. Cohorts were compared using bivariate analysis for all collected variables. Binary logistic regression with backward stepwise term selection was performed including independent predictors identified by bivariate analysis. RESULTS: A total of 200 patients were identified for inclusion. Bivariate analysis revealed that surgically treated patients were significantly more likely to have Medicaid insurance, psychiatric illness history, and disabled work status. Regression analysis revealed an association between surgical treatment and 2 of the factors evaluated: Medicaid insurance status and psychiatric illness history. CONCLUSIONS: Psychiatric illness and Medicaid insurance status are associated with undergoing surgical release of the first dorsal compartment. These findings support the use of a biopsychosocial framework when treating patients with de Quervain tendinopathy. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

P2 porous titanium implants improve tendon healing in an acute rat supraspinatus repair model.

BACKGROUND: Current techniques in rotator cuff repair often lack structural integrity. P2 porous titanium-coated constructs (DJO Surgical, Austin, TX, USA) promote osseointegration and soft tissue ingrowth. This study examined the ability of this material to improve the structural integrity of supraspinatus tendon repair in a rat model. We hypothesized that P2 implants placed at the tendon-to-bone interface would improve mechanical and histologic measures of supraspinatus healing. METHODS: Forty rats underwent supraspinatus repairs with P2 implants in 1 shoulder and standard repair in the other. Rats were humanely killed at time 0 (n = 3), 2 weeks (n = 8), 4 weeks (n = 15), and 12 weeks (n = 14). Tendon-to-bone composite specimens were harvested and evaluated mechanically and histologically. RESULTS: Tendon cross-sectional area was decreased in the P2 implant group at 4 weeks, percentage of relaxation was increased at 2 weeks, elastic modulus was increased at 4 weeks, and maximum load and maximum stress were both increased at 2 and 4 weeks. Histologic analysis revealed no foreign body reactions within or around the P2 implant, and healthy viable bone was visible within the P2 implant. CONCLUSION: The results support our hypothesis, specifically in early healing, in this randomized controlled animal study. These data support the use of P2 porous titanium implants to improve tendon-to-bone healing.

Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia.

Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia. In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered. However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component, animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16)A(+/-) mice, which model a microdeletion on human chromosome 22 (22q11.2) that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A(+/-) mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A(+/-) mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.