The PD-Ballet study: study protocol for a randomised controlled single-blind hybrid type 2 clinical trial evaluating the effects of ballet dancing on motor and non-motor symptoms in Parkinson's disease.

BACKGROUND: To date, beneficial effects of multimodal exercise programmes on Parkinson's disease (PD) have focused on motor symptoms and little attention has been paid to the potential effects of such programmes on the non-motor symptoms of PD, which are now universally known as one of the key drivers of quality of life and a key unmet need. We aim to explore clinical effectiveness of a ballet-based dance programme in addressing non-motor and motor symptoms of Parkinson's disease across all stages of progression. METHODS: A randomised, single-blind, controlled trial of 160 people with Parkinson's across all motor stages (Participants will be stratified into three groups of motor advancement: Hoehn and Yahr (HY) stages I and II being Mild Group, HY Stage III being Moderate Group and HY Stages IV and V being Severe Group) will be randomly allocated to either an intervention or a control group using an independent randomisation body. The primary outcome is an improvement in non-motor symptoms as measured by the Movement Disorders Society Non-Motor Scale (MDS-NMS). The intervention protocol consists of 12 one-weekly dance sessions led by English National Ballet. Each session is followed by a 'tea and biscuit' social time. Control group follows standard clinical pathway and joins the 'tea and biscuit' to control for any positive effects of social interactions. All participants are assessed at baseline, immediately after completion of the intervention and 3-6 months later to explore any potential longitudinal effects. DISCUSSION: To our knowledge, no adequately powered study has explored the effects of a dance-based intervention on non-motor symptoms of Parkinson's disease, assessing these on both holistic and granular levels. We also aim to stratify participants in accordance with their motor state as assessed by. HY staging to explore specific effects on the symptoms at the initial, moderate and complex stages of the disease. If successful, this trial provides first evidence on clinical effectiveness of a ballet-based dance intervention for symptoms of Parkinson's disease, assessed in a robust, rigorous manner. TRIAL REGISTRATION: NCT04719468.

Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the "long COVID." The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus-pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.

Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030.

Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort.

What can neuroimmunology teach us about the symptoms of long-COVID?

Long-Coronavirus Disease (Long-COVID) is becoming increasingly recognized due to the persistence of symptoms such as profound fatigue, neurocognitive difficulties, muscle pains and weaknesses and depression, which would last beyond 3-12 weeks following infection with SARS-CoV-2. These particular symptoms have been extensively observed and studied in the context of previous psychoneuroimmunology research. In this short commentary, we discuss how previous neuroimmunology studies could help us to better understand pathways behind the development of these prolonged symptoms. Various mechanisms, including viral neuroinvasion, glial cells activation, neurogenesis, oxidative stress have been shown to explain these symptoms in the context of other disorders. Previous neuroimmunology findings could represent helpful pointers for future research on long-COVID symptoms and suggest potential management strategies for patients suffering with long-COVID.

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1ß), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

Omega-3 fatty acids in the psychological and physiological resilience against COVID-19.

As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.

Why we do need a new gold open access journal called "Brain, behavior and immunity - Health".

This Editorial discusses the missions and scope of the new Gold Open Access journal "Brain, Behavior and Immunity (BBI) - Health" and how it complements the activity of the established BBI journal.

High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels.

No studies have examined the relationship between endogenous polyunsaturated fatty acids (PUFAs) levels and treatment response to PUFAs. We conducted a 12-week, double-blind, placebo-controlled trial comparing the effects of high-dose eicosapentaenoic acid (EPA, 1.2 g) and placebo on cognitive function (continuous performance test) in n = 92 youth (age 6-18-years-old) with Attention Deficit Hyperactivity Disorder (ADHD). Blood erythrocytes PUFAs were measured before and after treatment, to examine the effects of baseline endogenous EPA levels on treatment response and the effects of EPA treatment on PUFAs levels. Secondary measures included other ADHD symptoms, emotional symptoms, and levels of plasma high-sensitivity c-reactive protein (hs-CRP) and brain-derived neurotrophic factor (BDNF). Overall, EPA group improved more than placebo group on focused attention (variability, Effect size (ES) = 0.38, p = 0.041); moreover, within youth with the lowest baseline endogenous EPA levels, EPA group improved more than placebo group in another measure of focused attention (hit reaction time, HRT, ES = 0.89, p = 0.015) and in vigilance (HRT interstimulus interval changes, HRTISIC, ES = 0.83, p = 0.036). Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. EPA increased blood erythrocytes EPA by 1.6-fold but not DHA levels, and did not affect hs-CRP and BDNF plasma levels. In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.

International Society for Nutritional Psychiatry Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder.

Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.

Effectiveness of depression interventions for people living with HIV in Sub-Saharan Africa: A systematic review & meta-analysis of psychological & immunological outcomes.

This meta-analytic review evaluated the effectiveness of depression interventions on the psychological and immunological outcomes of people living with HIV in sub-Saharan Africa. 14 studies, yielding 932 participants were eligible. A random-effects models indicated that depression interventions were followed by large reductions in depression scores (effect size = 1.86, 95% CI = 1.71, 2.01, p < 0.01). No significant effect on immune outcome was observed, however there was a trend toward immune improvement of medium effect size (effect size on CD4 count and/or viral suppression = 0.57, 95% CI = -0.06, 1.20, p = 0.08). Pharmacological interventions appeared to have a significantly larger improvement in depression scores than psychological interventions. The greatest improvement in immune status was demonstrated in psychological treatments which incorporated a component to enhance HIV medication adherence, however these results did not reach significance. Small sample sizes and highly heterogeneous analysis necessitate caution in interpretation. The results of this meta-analysis should thus be treated as preliminary evidence and used to encourage further studies of immunopsychiatry in HIV in sub-Saharan Africa.

Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder: a Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies.

The role of omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) in the pathogenesis and treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD) is unclear. A systematic review followed by meta-analysis was conducted on: (1) randomized controlled trials (RCTs) assessing the effects of n-3 PUFAs on clinical symptoms and cognition in children and adolescent with ADHD; and (2) case-control studies assessing the levels of n-3 PUFAs in blood and buccal tissues of children and adolescents with ADHD. In seven RCTs, totalling n=534 randomized youth with ADHD, n-3 PUFAs supplementation improves ADHD clinical symptom scores (g=0.38, p<0.0001); and in three RCTs, totalling n=214 randomized youth with ADHD, n-3 PUFAs supplementation improves cognitive measures associated with attention (g=1.09, p=0.001). Moreover, children and adolescents with ADHD have lower levels of DHA (seven studies, n=412, g=-0.76, p=0.0002), EPA (seven studies, n=468, g=-0.38, p=0.0008), and total n-3 PUFAs (six studies, n=396, g=-0.58, p=0.0001). In summary, there is evidence that n-3 PUFAs supplementation monotherapy improves clinical symptoms and cognitive performances in children and adolescents with ADHD, and that these youth have a deficiency in n-3 PUFAs levels. Our findings provide further support to the rationale for using n-3 PUFAs as a treatment option for ADHD.

Rescue of IL-1ß-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants.

Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) ß, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3days and further differentiate for 7days in the presence of IL-1ß (10ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10µM) or docosahexaenoic acid (DHA, 10µM). Co-incubation with each of these compounds reversed the IL-1ß-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1ß-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1ß-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1ß, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.

Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation.

Studies over the last 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are two of the most consistent biological findings in major depression and are often associated: but the molecular and clinical mechanisms underlying these abnormalities are still unclear. These findings are particularly enigmatic, especially considering the accepted notion that high levels of cortisol have an anti-inflammatory action, and therefore the coexistence of inflammation and hypercortisolemia in the same diagnostic group appears counter-intuitive. To celebrate the 2015 Anna-Monika Foundation Award to our laboratory, this review will discuss our own 20 years of research on the clinical and molecular evidence underlying the increased inflammation in depression, especially in the context of a hyperactive HPA axis, and discuss its implications for the pathogenesis and treatment of this disorder.

Polyunsaturated fatty acids levels and initial presentation of somatic symptoms induced by interferon-alpha therapy in patients with chronic hepatitis C viral infection.

OBJECTIVES: Somatic symptoms are common in depressive disorder and are similar to sickness behaviors due to inflammatory activation after cytokine administration. Omega-3 polyunsaturated fatty acids (PUFAs) are natural anti-inflammatory agents and may reduce inflammation-induced behavioral changes. The aim of this study was to investigate the role of PUFAs on the development of somatic symptoms and depression in patients of hepatitis C virus infection (HCV) receiving interferon-alpha therapy (IFN-α) in a prospective manner. METHODS: In this 24-week, prospective cohort study, 43 patients with chronic HCV ongoing IFN-α therapy were assessed with the mini-international neuropsychiatric interview for major depressive episodes and neurotoxicity rating scale (NRS) for somatic symptoms. RESULTS: One-third later developed IFN-α-induced depression (depression (DEP) group). As compared to subjects without depression, DEP group had higher NRS scores (P < 0.001), lower eicosapentaenoic acid (EPA) levels (P = 0.038) at week 2. Somatic symptoms, regardless of painful/non-painful characteristics, had positive association with arachidonic acid (P < 0.05), and negative association with EPA (P < 0.05). CONCLUSION: This study implies that early intervention with omega-3 PUFAs might be a promising strategy to prevent depression and somatic symptoms in patients receiving cytokine therapy.

Does Diet Matter? The Use of Polyunsaturated Fatty Acids (PUFAs) and Other Dietary Supplements in Inflammation-Associated Depression.

An increasingly pertinent issue in psychiatry in recent years is that of the limitations of conventional antidepressants, which are not effective in a large number of patients with major depressive disorder (MDD). Coupled with emerging hypotheses about the role of inflammation in depression, it would appear that it is time to look for alternative treatments for these symptoms.This review will examine an emerging area in psychiatry, that of dietary supplements and the diet in general to treat depressive symptoms, and inflammation in depression. In particular, polyunsaturated fatty acids (PUFAs), probiotics and folic acid are three supplements that demonstrate the ability to target inflammation and other underlying systems in depression. While there is a definite need for more research in all these supplements to determine true efficacy, dosage and target populations, they can be used as mono- or adjunctive therapies to good effect, and show superior safety profiles when compared with more traditional alternatives.

Major depressive disorder.

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Neurodevelopmental outcome for offspring of women treated for antenatal depression: a systematic review.

The aim of this systematic review is to appraise existing literature on the effects of treatments for antenatal depression on the neurodevelopment outcomes of the offspring. We conducted a systematic review of the literature to identify studies on different kinds of treatments for antenatal depression (antidepressants and alternative therapies) and their effects on infants' neurodevelopment. After reading the title, abstract, or full text and applying exclusion criteria, a total of 22 papers were selected. Nineteen papers studied the effects of antidepressant drugs, one on docosahexanoic acid (DHA) (fish oil capsules) and two on massage therapy; however, no studies used a randomized controlled design, and in most studies, the control group comprise healthy women not exposed to depression. Comparisons between newborns exposed to antidepressants in utero with those not exposed showed significant differences in a wide range of neurobehavioral outcomes, although in many cases, these symptoms were transient. Two studies found a slight delay in psychomotor development, and one study found a delay in mental development. Alternative therapies may have some benefits on neurodevelopmental outcomes. Our review suggests that antidepressant treatment may be associated with some neurodevelopmental changes, but we cannot exclude that some of these effects may be due to depression per se.

Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial.

BACKGROUND: Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression. METHODS: We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis. RESULTS: Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels. CONCLUSIONS: EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.