Prevalence of Powassan Virus Seropositivity Among People with History of Lyme Disease and Non-Lyme Community Controls in the Northeastern United States.

Introduction: Lyme disease (LD) affects ∼476,000 people each year in the United States. Symptoms are variable and include rash and flu-like symptoms. Reasons for the wide variation in disease outcomes are unknown. Powassan virus (POWV) is a tick-borne flavivirus that causes disease ranging from asymptomatic infection to encephalitis, neurologic damage, and death. POWV and LD geographic case distributions overlap, with Ixodes species ticks as the common vectors. Clinical ramifications of coinfection or sequential infection are unknown. Objectives: This study's primary objective was to determine the prevalence of POWV-reactive antibodies in sera samples collected from previously studied cohorts of individuals with self-reported LD history residing in the Northeastern United States. As a secondary objective, we studied clinical differences between people with self-reported LD history and low versus high POWV antibody levels. Methods: We used an enzyme-linked immunosorbent assay (ELISA) to quantify IgG directed at the POWV envelope (E) protein domain III in 538 samples from individuals with self-reported LD history and 16 community controls. The samples were also tested with an ELISA assay to quantify IgG directed at the POWV NS1 protein. Results: The percentage of individuals with LD history and possible evidence of POWV exposure varied depending on the assay utilized. We found no significant difference in clinical symptoms between those with low or high POWV IgG levels in the in-house assay. Congruence of the EDIII and NS1 assays was low with only 12% of those positive in the in-house EDIII ELISA testing positive in the POWV NS1 ELISA. Conclusions: The results highlight the difficulty in flavivirus diagnostic testing, particularly in the retrospective detection of flavivirus exposure. The findings suggest that a prospective study with symptomatic patients using approved clinical testing is necessary to address the incidence and clinical implications of LD and POWV co-infection or sequential infection.

Neuropsychiatric Lyme Disease and Vagus Nerve Stimulation.

Lyme disease, the most common tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. While most patients with acute Lyme disease recover completely if treated with antibiotics shortly after the onset of infection, approximately 10-30% experience post-treatment symptoms and 5-10% have residual symptoms with functional impairment (post-treatment Lyme disease syndrome or PTLDS). These patients typically experience pain, cognitive problems, and/or fatigue. This narrative review provides a broad overview of Lyme disease, focusing on neuropsychiatric manifestations and persistent symptoms. While the etiology of persistent symptoms remains incompletely understood, potential explanations include persistent infection, altered neural activation, and immune dysregulation. Widely recognized is that new treatment options are needed for people who have symptoms that persist despite prior antibiotic therapy. After a brief discussion of treatment approaches, the article focuses on vagus nerve stimulation (VNS), a neuromodulation approach that is FDA-approved for depression, epilepsy, and headache syndromes and has been reported to be helpful for other diseases characterized by inflammation and neural dysregulation. Transcutaneous VNS stimulates the external branch of the vagus nerve, is minimally invasive, and is well-tolerated in other conditions with few side effects. If well-controlled double-blinded studies demonstrate that transcutaneous auricular VNS helps patients with chronic syndromes such as persistent symptoms after Lyme disease, taVNS will be a welcome addition to the treatment options for these patients.

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Disulfiram: Mechanisms, Applications, and Challenges.

Background: Since disulfiram's discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were "disulfiram" and "Antabuse". Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948-2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a "repurposed" agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.

Language Fluency Deficits in Post-treatment Lyme Disease Syndrome.

OBJECTIVE: Recent neurocognitive studies of patients with post-treatment Lyme disease syndrome (PTLDS) find consistent deficits in memory and processing speed. Language fluency deficits are observed as well but may be secondary to poor memory and slowing rather than an independent deficit. METHOD: This study performed a secondary analysis of data presented previously, including individuals with PTLDS and comparison samples of healthy volunteers (HC) and patients with major depressive disorder (MDD), to determine if language fluency deficits could be accounted for by poor performance in these other neurocognitive domains. RESULTS: Basic verbal abilities, memory, and processing speed were all significantly associated with fluency performance. MDD patients' fluency deficits relative to HC were accounted for by these covariates. However, PTLDS patients' poorer fluency performance relative to both other groups was not. CONCLUSIONS: Language fluency appears to be an independent area of neurocognitive deficit within the constellation of PTLDS symptoms.

Neuropsychiatric Symptoms and Tick-Borne Diseases.

In North America, Lyme disease (LD) is primarily caused by the spirochetal bacterium Borrelia burgdorferi, transmitted to humans by Ixodes species tick bites, at an estimated rate of 476,000 patients diagnosed per year. Acute LD often manifests with flu-like symptoms and an expanding rash known as erythema migrans (EM) and less often with neurologic, neuropsychiatric, arthritic, or cardiac features. Most acute cases of Lyme disease are effectively treated with antibiotics, but 10-20% of individuals may experience recurrent or persistent symptoms. This chapter focuses on the neuropsychiatric aspects of Lyme disease, as these are less widely recognized by physicians and often overlooked. Broader education about the potential complexity, severity, and diverse manifestations of tick-borne diseases is needed.

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course.

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 infection and autoimmune disorders, but they target different chemokines than those in COVID-19. Monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence Summary: Naturally arising anti-chemokine antibodies associate with favorable COVID-19 and predict lack of long COVID.

Persistent Symptoms, Lyme Disease, and Prior Trauma.

ABSTRACT: One prior study suggests that traumatic events before Lyme disease play an important role in symptom severity. We examined this hypothesis among 60 individuals with persistent symptoms after Lyme disease using validated measures of trauma history, mental and physical symptoms, and functional status. Analysis of variance with Tukey-Kramer multiple comparisons test revealed that a greater number of traumatic events were significantly associated with greater symptom severity on the scales of mood (stress, depression, and anxiety), cognition, multisystem symptom burden, and functional status (mental and physical), but not on measures of pain and fatigue. The effect sizes-meaningful but not large (0.17-0.29)-were mostly produced by comparison with individuals reporting multiple prior traumatic events, representing half of the posttreatment Lyme disease syndrome (PTLDS) group. In conclusion, although PTLDS may be exacerbated by past trauma, trauma plays a role in only a subgroup of PTLDS. Whether addressing prior trauma can improve outcomes in this subgroup requires study.

Differential Treatment Response Between Hypochondriasis With and Without Prominent Somatic Symptoms.

Background: Health anxiety may exist with or without prominent somatic symptoms, but the impact of somatic symptoms on treatment response is unclear. The study objective was to examine this question further as symptom burden may impact choice of type of treatment. Methods: This exploratory study used a unique database from a prior trial of 193 individuals with DSM-IV hypochondriasis who had been randomly assigned to either cognitive behavioral therapy, fluoxetine, combined therapy, or placebo. Two subgroups were newly defined-no/low somatic burden (n = 42) and prominent somatic burden (n = 151). Response was defined by ≥30% improvement in hypochondriasis. Results: Among high somatic hypochondriacal participants, compared to placebo, the odds of being a responder were significantly greater among those who received fluoxetine, either alone (OR = 4.46; 95% CI: 1.38, 14.41) or with cognitive behavioral therapy (OR = 3.56; 95% CI: 1.19, 10.68); the estimated odds were not significantly different for those receiving cognitive behavioral therapy alone (OR = 1.81; 95% CI: 0.59, 5.54). In contrast, among low somatic hypochondriacal participants, compared to placebo, the observed odds of being a responder were similar in magnitude and direction for those who received cognitive behavioral therapy, either alone (OR = 3.00; 95% CI: 0.38, 23.68) or in combination with fluoxetine (OR = 3.60; 95% CI: 0.62, 21.03), compared to the odds for those receiving fluoxetine alone (OR = 0.90; 95% CI: 0.14, 5.65). High somatic hypochondriacal individuals assigned to any fluoxetine group had significantly greater odds of being a responder than those who had not received fluoxetine (OR = 2.70; 95% CI: 1.33, 5.48). Low somatic hypochondriacal individuals assigned to any cognitive behavioral therapy group had significantly greater odds of being a responder than those who had not received cognitive behavioral therapy (OR = 8.03; 95% CI: 1.41, 45.67). Conclusion: These findings indicate that somatic symptom burden may be important in guiding treatment selection among individuals with marked health anxiety, as hypochondriacal individuals with high somatic burden responded more often to fluoxetine while those with low somatic burden responded more often to cognitive behavioral therapy. Systematic replication with larger studies is needed.

Recent Progress in Lyme Disease and Remaining Challenges.

Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.

Lyme Borreliosis and Associations With Mental Disorders and Suicidal Behavior: A Nationwide Danish Cohort Study.

OBJECTIVE: Lyme borreliosis is a tick-borne infectious disease that may confer an increased risk of mental disorders, but previous studies have been hampered by methodological limitations, including small sample sizes. The authors used a nationwide retrospective cohort study design to examine rates of mental disorders following Lyme borreliosis. METHODS: Using Denmark's National Patient Register and the Psychiatric Central Research Register, and including all persons living in Denmark from 1994 through 2016 (N=6,945,837), the authors assessed the risk of mental disorders and suicidal behaviors among all individuals diagnosed with Lyme borreliosis in inpatient and outpatient hospital contacts (N=12,156). Incidence rate ratios (IRRs) were calculated by Poisson regression analyses. RESULTS: Individuals with Lyme borreliosis had higher rates of any mental disorder (IRR=1.28, 95% CI=1.20, 1.37), of affective disorders (IRR=1.42, 95% CI=1.27, 1.59), of suicide attempts (IRR=2.01, 95% CI=1.58, 2.55), and of death by suicide (IRR=1.75, 95% CI=1.18, 2.58) compared with those without Lyme borreliosis. The 6-month interval after diagnosis was associated with the highest rate of any mental disorder (IRR=1.96, 95% CI=1.53, 2.52), and the first 3 years after diagnosis was associated with the highest rate of suicide (IRR=2.41, 95% CI=1.25, 4.62). Having more than one episode of Lyme borreliosis was associated with increased incidence rate ratios for mental disorders, affective disorders, and suicide attempts, but not for death by suicide. CONCLUSIONS: Individuals diagnosed with Lyme borreliosis in the hospital setting had an increased risk of mental disorders, affective disorders, suicide attempts, and suicide. Although the absolute population risk is low, clinicians should be aware of potential psychiatric sequelae of this global disease.

Detecting Borrelia Spirochetes: A Case Study With Validation Among Autopsy Specimens.

The complex etiology of neurodegenerative disease has prompted studies on multiple mechanisms including genetic predisposition, brain biochemistry, immunological responses, and microbial insult. In particular, Lyme disease is often associated with neurocognitive impairment with variable manifestations between patients. We sought to develop methods to reliably detect Borrelia burgdorferi, the spirochete bacteria responsible for Lyme disease, in autopsy specimens of patients with a history of neurocognitive disease. In this report, we describe the use of multiple molecular detection techniques for this pathogen and its application to a case study of a Lyme disease patient. The patient had a history of Lyme disease, was treated with antibiotics, and years later developed chronic symptoms including dementia. The patient's pathology and clinical case description was consistent with Lewy body dementia. B. burgdorferi was identified by PCR in several CNS tissues and by immunofluorescent staining in the spinal cord. These studies offer proof of the principle that persistent infection with the Lyme disease spirochete may have lingering consequences on the CNS.

Borrelia miyamotoi Serology in a Clinical Population With Persistent Symptoms and Suspected Tick-Borne Illness.

Eighty-two patients seeking consultation for long-term sequalae after suspected tick-borne illness were consecutively tested for Borrelia miyamotoi antibodies using a recombinant glycerophosphodiester phosphodiesterase (GlpQ) enzyme immunoassay. Twenty-one of the 82 patients (26%) tested positive on the GlpQ IgG ELISA. Nearly all of the patients (98%) had no prior B. miyamotoi testing, indicating that clinicians rarely test for this emerging tick-borne pathogen. Compared to patients who solely tested positive for Lyme disease antibodies, patients with B. miyamotoi antibodies presented with significantly more sleepiness and pain. A prospective study is needed to ascertain the relationship between the presence of B. miyamotoi antibodies and persistent symptoms.

Religion and Psychiatry in the Age of Neuroscience.

In recent decades, an evolving conversation among religion, psychiatry, and neuroscience has been taking place, transforming how we conceptualize religion and how that conceptualization affects its relation to psychiatry. In this article, we review several dimensions of the dialogue, beginning with its history and the phenomenology of religious experience. We then turn to neuroscientific studies to see how they explain religious experience, and we follow that with two related areas: the benefits of religious beliefs and practices, and the evolutionary foundation of those benefits. A final section addresses neuroscientific and evolutionary accounts of the transcendent, that is, what these fields make of the claim that religious experience connects to a transcendent reality. We conclude with a brief summary, along with the unresolved questions we have encountered.

Anti-lysoganglioside and other anti-neuronal autoantibodies in post-treatment Lyme Disease and Erythema Migrans after repeat infection.

BACKGROUND: Molecular mimicry targeting neural tissue has been reported after Borrelia burgdorferi(Bb) infection. Herein, we investigate whether antineuronal autoantibodies are increased and whether antibody-mediated signaling of neuronal cells is elevated in a cohort of symptomatic adults with a history of Lyme Disease (LD). METHODS: Participants (n â€‹= â€‹179) included 24 with recent Erythema Migrans (EM) without prior LD, 8 with recent EM and prior LD (EM â€‹+ â€‹prior LD), 119 with persistent post-treatment LD symptoms (PTLS), and 28 seronegative endemic controls with no prior LD history. Antineuronal immunoglobulin G (IgG) titers were measured by standard ELISA and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was identified in serum. RESULTS: EM â€‹+ â€‹prior LD cases had higher antibody titers than controls for anti-lysoganglioside GM1 (p â€‹= â€‹0.002), anti-tubulin (p â€‹= â€‹0.03), and anti-D1R (p â€‹= â€‹0.02), as well as higher expression in the functional antibody-mediated CaMKII Assay (p â€‹= â€‹0.03). The EM cases with no prior history showed no significant differences on any measures. The PTLS cases demonstrated significantly higher titers (p â€‹= â€‹0.01) than controls on anti-lysoganglioside GM1, but not for the other measures. CONCLUSION: The finding of elevated anti-neuronal autoantibodies in our small sample of those with a prior history of Lyme disease but not in those without prior Lyme disease, if replicated in a larger sample, suggests an immune priming effect of repeated infection; the CaMKII activation suggests that antineuronal antibodies have functional significance. The elevation of anti-lysoganglioside antibodies among those with PTLS is of particular interest given the established role of anti-ganglioside antibodies in peripheral and central neurologic diseases. Future prospective studies can determine whether these autoantibodies emerge after Bb infection and whether their emergence coincides with persistent neurologic or neuropsychiatric symptoms.

When it hurts even more: The neural dynamics of pain and interpersonal emotions.

OBJECTIVE: Chronic pain is highly prevalent among patients with mood, anxiety, personality, and somatic symptom disorders; and patients with chronic pain often suffer from persistent interpersonal distress. However, the neural mechanisms underlying this phenomenon and its possible role in the etiology of chronic pain are not yet understood. Based on our Developmental Theory of Centralized/Somatoform Pain, and prior research suggesting the existence of a shared neural system subserving interpersonal emotions and pain, we aimed to identify the neural basis for modulation of pain by feelings of interpersonal rejection and the role of the early interpersonal environment in development of this shared neural system. METHODS: During fMRI scanning, 22 healthy participants received moderately painful thermal stimuli in 3 interpersonal contexts: Acceptance, Rejection, and Reacceptance (modified Cyberball paradigm). Early interpersonal environment was assessed using the Parental Bonding Instrument. RESULTS: Interpersonal context modulated activity in pain neural systems during rejection and during accepting interactions with previously rejecting others. Moreover, the subjective perception of rejection, even when rejection was not occurring, correlated positively with reported pain severity and neural activity in the insula. The magnitude of neural modulation in pain circuits by feelings of rejection was associated with the quality of early interpersonal experience with caregivers. CONCLUSIONS: Results suggest that interpersonal emotions play an important role in the development and functioning of the pain system, supporting our Developmental Theory of predisposition to chronic centralized pain. These findings have direct implications for clinical practice, including the importance of treating interpersonal distress to alleviate pain.

The General Symptom Questionnaire-30 (GSQ-30): A Brief Measure of Multi-System Symptom Burden in Lyme Disease.

Introduction: The multi-system symptoms accompanying acute and post-treatment Lyme disease syndrome pose a challenge for time-limited assessment. The General Symptom Questionnaire (GSQ-30) was developed to fill the need for a brief patient-reported measure of multi-system symptom burden. In this study we assess the psychometric properties and sensitivity to change of the GSQ-30. Materials and Methods: 342 adult participants comprised 4 diagnostic groups: Lyme disease (post-treatment Lyme disease syndrome, n = 124; erythema migrans, n = 94); depression, n = 36; traumatic brain injury, n = 51; healthy, n = 37. Participants were recruited from clinical research facilities in Massachusetts, Maryland, and New York. Validation measures for the GSQ-30 included the Patient Health Questionnaire-4 for depression and anxiety, visual analog scales for fatigue and pain, the Sheehan Disability Scale for functional impairment, and one global health question. To assess sensitivity to change, 53 patients with erythema migrans completed the GSQ-30 before treatment and 6 months after 3 weeks of treatment with doxycycline. Results: The GSQ-30 demonstrated excellent internal consistency (Cronbach α = 0.95). The factor structure reflects four core domains: pain/fatigue, neuropsychiatric, neurologic, and viral-like symptoms. Symptom burden was significantly associated with depression (r s = 0.60), anxiety (r s = 0.55), pain (r s = 0.75), fatigue (r s = 0.77), functional impairment (r s = 0.79), and general health (r s = -0.58). The GSQ-30 detected significant change in symptom burden before and after antibiotic therapy; this change correlated with change in functional impairment. The GSQ-30 total score significantly differed for erythema migrans vs. three other groups (post-treatment Lyme disease syndrome, depression, healthy controls). The GSQ-30 total scores for traumatic brain injury and depression were not significantly different from post-treatment Lyme disease syndrome. Conclusions and Relevance: The GSQ-30 is a valid and reliable instrument to assess symptom burden among patients with acute and post-treatment Lyme disease syndrome and is sensitive in the detection of change after treatment among patients with erythema migrans. The GSQ-30 should prove useful in clinical and research settings to assess multi-system symptom burden and to monitor change over time. The GSQ-30 may also prove useful in future precision medicine studies as a clinical measure to correlate with disease-relevant biomarkers.

Neurocognition in Post-Treatment Lyme Disease and Major Depressive Disorder.

OBJECTIVE: Neurocognitive dysfunction in patients with residual or emergent symptoms after treatment for Lyme Disease is often attributed to comorbid depression. In this study, patients with Post-Treatment Lyme Disease Syndrome (PTLDS) were compared to patients with Major Depressive Disorder (MDD), as well as healthy comparison subjects (HC), on neurocognitive measures administered through the same laboratory, to determine if patterns of performance were similar. METHODS: Two analyses were conducted. First, performance on the Wechsler Adult Intelligence Scale (WAIS-III) and on subtests from the Wechsler Memory Scale (WMS-III) was compared among the groups. Second, comparable subgroups of PTLDS and MDD patients with at least one low WMS-III score were compared on an additional set of measures assessing motor function, psychomotor performance, attention, memory, working memory, and language fluency, to determine if the overall profile of performance was similar in the two subgroups. RESULTS: In the first analysis, PTLDS patients performed more poorly than both MDD and HC on tasks assessing verbal abilities, working memory, and paragraph learning. Processing speed in the two patient groups, however, was equally reduced. In the second analysis, MDD patients with low WMS-III exhibited concomitantly greater difficulties in psychomotor speed and attention, while low-WMS-III PTLDS patients exhibited greater difficulties in language fluency. CONCLUSIONS: MDD and PTLDS can be confused neuropsychologically because both exhibit similar levels of psychomotor slowing. However, problems on memory-related tasks, though mild, are more pronounced in PTLDS. PTLDS patients with poorer memory also exhibit poorer language fluency, and less deficit in processing speed and attention compared to MDD.