Corrigendum: Case Series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequalae of COVID (PASC).

[This corrects the article DOI: 10.3389/fmed.2023.1122529.].

Neuroplasticity of the extended amygdala in opioid withdrawal and prolonged opioid abstinence.

Opioid use disorder is characterized by excessive use of opioids, inability to control its use, a withdrawal syndrome upon discontinuation of opioids, and long-term likelihood of relapse. The behavioral stages of opioid addiction correspond with affective experiences that characterize the opponent process view of motivation. In this framework, active involvement is accompanied by positive affective experiences which gives rise to "reward craving," whereas the opponent process, abstinence, is associated with the negative affective experiences that produce "relief craving." Relief craving develops along with a hypersensitization to the negatively reinforcing aspects of withdrawal during abstinence from opioids. These negative affective experiences are hypothesized to stem from neuroadaptations to a network of affective processing called the "extended amygdala." This negative valence network includes the three core structures of the central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis (BNST), and the nucleus accumbens shell (NAc shell), in addition to major inputs from the basolateral amygdala (BLA). To better understand the major components of this system, we have reviewed their functions, inputs and outputs, along with the associated neural plasticity in animal models of opioid withdrawal. These models demonstrate the somatic, motivational, affective, and learning related models of opioid withdrawal and abstinence. Neuroadaptations in these stress and motivational systems are accompanied by negative affective and aversive experiences that commonly give rise to relapse. CeA neuroplasticity accounts for many of the aversive and fear-related effects of opioid withdrawal via glutamatergic plasticity and changes to corticotrophin-releasing factor (CRF)-containing neurons. Neuroadaptations in BNST pre-and post-synaptic GABA-containing neurons, as well as their noradrenergic modulation, may be responsible for a variety of aversive affective experiences and maladaptive behaviors. Opioid withdrawal yields a hypodopaminergic and amotivational state and results in neuroadaptive increases in excitability of the NAc shell, both of which are associated with increased vulnerability to relapse. Finally, BLA transmission to hippocampal and cortical regions impacts the perception of conditioned aversive effects of opioid withdrawal by higher executive systems. The prevention or reversal of these varied neuroadaptations in the extended amygdala during opioid withdrawal could lead to promising new interventions for this life-threatening condition.

Estrous cycle dependent expression of oxycodone conditioned reward in rats.

Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.

Disturbances in fear extinction learning after mild traumatic brain injury in mice are accompanied by alterations in dendritic plasticity in the medial prefrontal cortex and basolateral nucleus of the amygdala.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions.

Mitochondrial dysfunction in animal models of PTSD: Relationships between behavioral models, neural regions, and cellular maladaptation.

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal, stress responses, insomnia and other symptoms. This review of rodent models of PTSD examines trauma effects on fear-related learning, cognition, and avoidance, emotional and arousal behaviors and on mitochondrial dysfunction in relevant neural pathways. The review focuses on research that includes four elements: consensus PTSD rodent models, behavioral phenotyping, mitochondrial dysfunction within key neural regions. This approach allows for the integration of behavioral, neural and cellular findings in PTSD models. The PTSD models reviewed include fear conditioning, predator/social stress, chronic restraint stress, single prolonged stress, social isolation, chronic unpredictable stress and early life stress. These models produce a variety of PTSD-related behaviors that include associative and non-associative fear- and stress-related responses, hyperarousal, avoidance behaviors, cognitive disturbances, social withdrawal, compulsive behaviors, anhedonia-, anxiety- and depression-related behaviors. Neural regions included fear- and stress-related regions of the prefrontal cortex, hippocampal, amygdala, nucleus accumbens and hypothalamus. PTSD models produced mitochondrial dysfunction that includes dysregulation of oxidative phosphorylation and other metabolic pathways including ß-oxidation of fatty acids and the tricarboxylic acid pathway. These models generated neural reactive oxygen species that damage DNA, proteins, and lipids. Trauma models further altered mitochondrial structure and replication and affected neuroinflammatory responses, signal transduction and apoptosis. Antidepressant medications used for the treatment of PTSD reversed stress-induced changes in some PTSD-like behaviors and many elements of brain mitochondrial dysfunction. Future studies can develop PTSD models which are ecologically valid and result in a broader manifestation of PTSD-related behaviors as it is clinically defined. This review highlights mitochondrial mechanisms associated with PTSD-like behaviors that have been produced in an array of consensus PTSD models and identifies putative circuit-based targets for more effective treatment for this debilitating disorder.

Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC).

Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants' response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.

Translational approaches to influence sleep and arousal.

Sleep disorders are widespread in society and are prevalent in military personnel and in Veterans. Disturbances of sleep and arousal mechanisms are common in neuropsychiatric disorders such as schizophrenia, post-traumatic stress disorder, anxiety and affective disorders, traumatic brain injury, dementia, and substance use disorders. Sleep disturbances exacerbate suicidal ideation, a major concern for Veterans and in the general population. These disturbances impair quality of life, affect interpersonal relationships, reduce work productivity, exacerbate clinical features of other disorders, and impair recovery. Thus, approaches to improve sleep and modulate arousal are needed. Basic science research on the brain circuitry controlling sleep and arousal led to the recent approval of new drugs targeting the orexin/hypocretin and histamine systems, complementing existing drugs which affect GABAA receptors and monoaminergic systems. Non-invasive brain stimulation techniques to modulate sleep and arousal are safe and show potential but require further development to be widely applicable. Invasive viral vector and deep brain stimulation approaches are also in their infancy but may be used to modulate sleep and arousal in severe neurological and psychiatric conditions. Behavioral, pharmacological, non-invasive brain stimulation and cell-specific invasive approaches covered here suggest the potential to selectively influence arousal, sleep initiation, sleep maintenance or sleep-stage specific phenomena such as sleep spindles or slow wave activity. These manipulations can positively impact the treatment of a wide range of neurological and psychiatric disorders by promoting the restorative effects of sleep on memory consolidation, clearance of toxic metabolites, metabolism, and immune function and by decreasing hyperarousal.

Sleep-wake and arousal dysfunctions in post-traumatic stress disorder: Role of orexin systems.

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness.

Suppression and acceptance in unipolar depression: Short-term and long-term effects on emotional responding.

OBJECTIVES: Transdiagnostic treatments increasingly include emotion regulation training focused on use of emotional suppression and acceptance. Despite the frequent use of these treatments in depression, little is known about the effects of these strategies in this population. DESIGN: An experimental study. METHODS: Eighty Veterans with unipolar depression participated in a study examining effects of these strategies on emotional responding (subjective, behavioural, and physiological). Physiological measures included: heart rate (HR), respiration (Resp), skin conductance (SC), and corrugator electromyography. On Day 1, participants were randomised to one of three conditions (acceptance, suppression, or control) and underwent an autobiographical sad mood induction. On Day 2, participants underwent a similar mood induction one week later. RESULTS: The suppression group demonstrated reduced physiological reactivity (Resp and SC) on Day 1. However, the suppression group reported decreased positive affect on Day 2. CONCLUSIONS: Results support short-term effectiveness and longer term costs from suppression use among depressed individuals. Findings may inform application of transdiagnostic emotion regulation treatments and suggest suppression functions differently in depressed versus other clinical populations.

Highlighting gaps in spinal cord injury research in activity-based interventions for the upper extremity: A scoping review.

BACKGROUND: Upper extremity activity-based therapy for neurologic disorders employs high-intensity, high repetition functional training to exploit neuroplasticity and improve function. Research focused on high-intensity upper extremity activity-based therapy for persons with spinal cord injury (SCI) is limited. OBJECTIVE: To summarize high-intensity activity-based interventions used in neurological disorders for their current or potential application to SCI. METHODS: The scoping review included articles from MEDLINE, CINAHL, Cochrane CENTRAL, and OTSeeker with the criteria: non-invasive activity-based interventions delivered at least three times/week for two weeks, upper extremity functional outcomes, age 13 years or older, English language, and neurological disorders three months post onset/injury. RESULTS: The search yielded 172 studies. There were seven studies with SCI, all in adults. Activity-based interventions in SCI included task-specific training and gaming, with and without electrical stimulation, and a robotic exoskeleton. The other populations found in the review included studies in stroke, cerebral palsy, and multiple sclerosis. Thirty-four different interventions were reported in other populations. In comparison to the extensive stroke research, work in SCI was not found for high-intensity interventions using virtual reality, brain stimulation, rehabilitation devices, and applications to the home and telerehab settings. CONCLUSION: The results highlight critical gaps within upper extremity high-intensity activity-based research in SCI.

Successes and challenges of implementing an integrative medicine practice in an allopathic medical center.

Patient demand for integrative medicine is increasing, and presents a service opportunity for health care systems. Implementing integrative medicine in an allopathic health care setting poses unique challenges. Addressing organizational culture, finances, patient experience/physical space, and credentialing issues can help ensure success.

Opioid-induced structural and functional plasticity of medium-spiny neurons in the nucleus accumbens.

Opioid Use Disorder (OUD) is a chronic relapsing clinical condition with tremendous morbidity and mortality that frequently persists, despite treatment, due to an individual's underlying psychological, neurobiological, and genetic vulnerabilities. Evidence suggests that these vulnerabilities may have neurochemical, cellular, and molecular bases. Key neuroplastic events within the mesocorticolimbic system that emerge through chronic exposure to opioids may have a determinative influence on behavioral symptoms associated with OUD. In particular, structural and functional alterations in the dendritic spines of medium spiny neurons (MSNs) within the nucleus accumbens (NAc) and its dopaminergic projections from the ventral tegmental area (VTA) are believed to facilitate these behavioral sequelae. Additionally, glutamatergic neurons from the prefrontal cortex, the basolateral amygdala, the hippocampus, and the thalamus project to these same MSNs, providing an enriched target for synaptic plasticity. Here, we review literature related to neuroadaptations in NAc MSNs from dopaminergic and glutamatergic pathways in OUD. We also describe new findings related to transcriptional, epigenetic, and molecular mechanisms in MSN plasticity in the different stages of OUD.

Defining a New Leadership Model to Stay Relevant in Healthcare.

Because the healthcare landscape is in a state of extreme disruption, the ability to adapt is essential for organizations and their leadership teams. Players outside the sector, changing workforce and patient demographics, new technologies, cost pressures, and other influences are challenging hospital and health systems' abilities to perform as expected.Amid this ambiguity, a lack of urgency is preventing organizations from adjusting to a business environment in flux. Never has it been more important for leaders to show courage, learn, and guide their organizations to the front lines of innovation. In today's world, being a learning organization-one in which leaders and team members lean together into change, rather than back away-is crucial to remaining relevant. To quote philosopher Eric Hoffer, "In times of change, learners inherit the earth while the learned find themselves beautifully equipped to deal with a world that no longer exists."At Virginia Mason, a health system based in Seattle, Washington, our management methodology-the Virginia Mason Production System-allows the organization to be a nimble responder to change. It also empowers individuals across the enterprise, regardless of job or title, to assume hands-on roles in accomplishing our collective vision to transform healthcare. This "we culture" shines a bright light on improvement opportunities and provides the framework needed for collaborative, interdisciplinary efforts to develop solutions.

Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms.

OBJECTIVE: This retrospective study examined whether changes in patient pre- and post-treatment symptoms correlated with changes in anti-neuronal autoantibody titers and the neuronal cell stimulation assay in the Cunningham Panel in patients with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). METHODS: In an analysis of all tests consecutively performed in Moleculera Labs' clinical laboratory from April 22, 2013 to December 31, 2016, we identified 206 patients who were prescribed at least one panel prior to and following treatment, and who met the PANDAS/PANS diagnostic criteria. Patient follow-up was performed to collect symptoms and treatment or medical intervention. Of the 206 patients, 58 met the inclusion criteria of providing informed consent/assent and documented pre- and post-treatment symptoms. Clinician and parent-reported symptoms after treatment or medical intervention were categorized as "Improved/Resolved" (n = 34) or "Not-Improved/Worsened" (n = 24). These were analyzed for any association between changes in clinical status and changes in Cunningham panel test results. Clinical assay performance was also evaluated for reproducibility and reliability. RESULTS: Comparison of pre- and post-treatment status revealed that the Cunningham Panel results correlated with changes in patient's neuropsychiatric symptoms. Based upon the change in the number of positive tests, the overall accuracy was 86%, the sensitivity and specificity were 88% and 83% respectively, and the Area Under the Curve (AUC) was 93.4%. When evaluated by changes in autoantibody levels, we observed an overall accuracy of 90%, a sensitivity of 88%, a specificity of 92% and an AUC of 95.7%. Assay reproducibility for the calcium/calmodulin-dependent protein kinase II (CaMKII) revealed a correlation coefficient of 0.90 (p < 1.67 × 10-6) and the ELISA assays demonstrated test-retest reproducibility comparable with other ELISA assays. CONCLUSION: This study revealed a strong positive association between changes in neuropsychiatric symptoms and changes in the level of anti-neuronal antibodies and antibody-mediated CaMKII human neuronal cell activation. These results suggest there may be clinical utility in monitoring autoantibody levels and stimulatory activity against these five neuronal antigen targets as an aid in the diagnosis and treatment of infection-triggered autoimmune neuropsychiatric disorders. Future prospective studies should examine the feasibility of predicting antimicrobial and immunotherapy responses with the Cunningham Panel.

Activity-based Rehabilitation Interventions of the Neurologically Impaired Upper Extremity: Description of a Scoping Review Protocol.

Introduction: A scoping review provides a means to synthesize and present a large body of literature on a broad topic, such as methods for various upper extremity activity-based therapy (ABT) interventions. Objectives: To describe our scoping review protocol to evaluate peer-reviewed articles focused on ABT interventions for individuals with neurologically impaired upper extremities. Methods: At Jefferson College of Health Professions and Sidney Kimmel Medical College at Jefferson, Philadelphia, the authors will follow this protocol to conduct a scoping review by establishing a research question and conducting a search of bibliographic databases to identify relevant studies. Using specific inclusion and exclusion criteria, abstracts will be screened and full-text articles will be reviewed for inclusion in charting, summarizing, and reporting results of appropriate studies. Conclusion: This protocol will guide the scoping review process to develop a framework for establishing a noninvasive ABT intervention informed by evidence for individuals with neurologically impaired upper extremities.

Transforming concepts in patient safety: a progress report.

In 2009, the National Patient Safety Foundation's Lucian Leape Institute (LLI) published a paper identifying five areas of healthcare that require system-level attention and action to advance patient safety.The authors argued that to truly transform the safety of healthcare, there was a need to address medical education reform; care integration; restoring joy and meaning in work and ensuring the safety of the healthcare workforce; consumer engagement in healthcare and transparency across the continuum of care. In the ensuing years, the LLI convened a series of expert roundtables to address each concept, look at obstacles to implementation, assess potential for improvement, identify potential implementation partners and issue recommendations for action. Reports of these activities were published between 2010 and 2015. While all five areas have seen encouraging developments, multiple challenges remain. In this paper, the current members of the LLI (now based at the Institute for Healthcare Improvement) assess progress made in the USA since 2009 and identify ongoing challenges.

Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder.

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation. Interestingly, both TBI and PTSD can be produced by overlapping pathophysiological changes that disrupt neural connections termed the "connectome." The neural disruptions shared by PTSD and TBI and the comorbid condition include asymmetrical white matter tract abnormalities and gray matter changes in the basolateral amygdala, hippocampus, and prefrontal cortex. These neural circuitry dysfunctions result in behavioral changes that include executive function and memory impairments, fear retention, fear extinction deficiencies, and other disturbances. Pathophysiological etiologies can be identified using experimental models of TBI, such as fluid percussion or blast injuries, and for PTSD, using models of fear conditioning, retention, and extinction. In both TBI and PTSD, there are discernible signs of neuroinflammation, excitotoxicity, and oxidative damage. These disturbances produce neuronal death and degeneration, axonal injury, and dendritic spine dysregulation and changes in neuronal morphology. In laboratory studies, various forms of pharmacological or psychological treatments are capable of reversing these detrimental processes and promoting axonal repair, dendritic remodeling, and neurocircuitry reorganization, resulting in behavioral and cognitive functional enhancements. Based on these mechanisms, novel neurorestorative therapeutics using anti-inflammatory, antioxidant, and anticonvulsant agents may promote better outcomes for comorbid TBI and PTSD.