THE EFFECT OF EXERCISE ON MENTAL HEALTH: A FOCUS ON INFLAMMATORY MECHANISMS

A growing body of research suggests that neuropsychiatric disorders are closely associated with a background state of chronic, low-grade inflammation. This insight highlights that these disorders are not just localized to dysfunction within the brain, but also have a systemic aspect, which accounts for the frequent comorbid presentation of chronic inflammatory conditions and metabolic syndromes. It is possible that a treatment resistant subgroup of neuropsychiatric patients may benefit from treatment regimens that target their associated proinflammatory state. Lifestyle factors such as physical activity (PA) and exercise (i.e. structured PA) are known to influence mental health. In turn, mental disorders may limit health-seeking behaviors - a proposed “bidirectional relationship” that perpetuates psychopathology. PA is renowned for its positive physical, physiological and mental health benefits. Evidence now points to inflammatory pathways as a potential mechanism for PA in improving mental illness. Relevant pathways include modulation of immune-neuroendocrine and neurotransmitter systems, the production of tissue-derived immunological factors that alter the inflammatory milieu and neurotrophins that are critical mediators of neuroplasticity. In this paper, we will focus on the role of PA in positively improving mental health through potential modulation of chronic inflammation, which is often found in individuals with mental disorders. In a related paper by Edirappuli and colleagues (2020), we will focus on the role of nutrition (another significant lifestyle factor) on mental health. Thus, inflammation appears to be a central process underlying mental illness, which may be mitigated by lifestyle modifications. Lifestyle factors are advantageous as first-line interventions due to their cost efficacy, low side-effect profile, and both preventative and therapeutic attributes. By promoting these lifestyle modifications and addressing their limitations and barriers to their adoption, it is hoped that their preventative and remedial benefits may galvanize therapeutic progress for neuropsychiatric disorders

Évaluation de l’impact de la maladie de Kawasaki sur le développement neurocognitif

Essai présenté à la Faculté des arts et des sciences en vue de l’obtention du grade de Doctorat en psychologie (D.Psy.) option neuropsychologie cliniqueIntroduction : La maladie de Kawasaki (MK) est une vascularite immunitaire transitoire se manifestant majoritairement chez les enfants d’âge préscolaire. Différentes atteintes neurologiques ont été répertoriées en phase aigüe, la plus fréquente étant une irritabilité excessive associée à une inflammation du système nerveux central. Les conséquences potentielles de la MK sur le développement cognitif, comportemental et cérébral des enfants demeurent peu étudiées. Objectifs : Cette étude pilote vise à (1) décrire le profil neuropsychologique d’enfants d’âge scolaire primaire ayant eu la MK et (2) explorer les impacts sur des marqueurs électroencéphalographiques (EEG) associés à l’attention et à la maturation cérébrale. Méthode : Quinze enfants (âgés de 8.8±2.5 ans) ont été recrutés pour l’étude, en moyenne 4.9±2.7 ans après avoir eu la MK. Une évaluation des fonctions intellectuelles (Wechsler Intelligence Scale for Children – 5th Edition), de l’attention soutenue auditive (Test of Everyday Attention for Children) et de la mémoire épisodique verbale (California Verbal Learning Test for Children) a été effectuée. Les parents ont répondu à 4 questionnaires standardisés pour évaluer 1) le fonctionnement exécutif (Behavior Rating Inventory of Executive Function); 2) les problèmes internalisés et externalisés (Child Behavior Checklist); 3) les symptômes du Trouble déficitaire de l’attention avec hyperactivité (Conners-3) et 4) les symptômes du Trouble du spectre de l’autisme (Social Responsiveness Scale-2). La fréquence de participants présentant une performance cognitive plus faible (≤ 1 écart-type sous la moyenne normative) et/ou des difficultés comportementales potentielles (≥ 1 écart-type au-dessus de la moyenne normative) a été calculée. Le ratio thêta/bêta et le pic alpha ont été extraits du signal EEG de repos et comparés aux données de 32 enfants contrôles (8.9±2.1 ans). Un algorithme de réduction de dimensions a été utilisé sur la bande alpha pour détecter des tendances inter et intra-groupes. Résultats : Les fonctions intellectuelles et mnésiques des participants se sont avérées dans les normes. Toutefois, une proportion importante d’enfants a performé dans la moyenne faible ou dans la zone limite à la tâche attentionnelle (4/14; 29%). Les réponses parentales ont révélé des proportions considérables d’inattention (6/14; 43%), de difficultés en mémoire de travail (7/14; 50%) et d’hyperactivité-impulsivité (5/14; 36%). Alors qu’aucune différence au niveau du ratio thêta/bêta n’a été soulevée, le ratio d’amplitude du pic alpha du groupe clinique s’est avéré significativement plus faible que celui du groupe contrôle, montrant un pic atténué dans 4 des 6 régions étudiées (p<0.05 au Mann-Whitney). L’algorithme de réduction des paramètres de la bande alpha a révélé une séparation franche des participants MK en deux sous-groupes. Le sous-groupe ayant une bande alpha davantage atténuée comportait plus d’enfants ayant présenté de l’irritabilité en phase aigüe (8 vs 1; test exact de Fisher p = 0.023). Conclusions : Malgré des aptitudes cognitives globalement préservées, nos résultats suggèrent une association potentielle entre la MK et des difficultés attentionnelles ultérieures. Cette première étude en EEG fournit une indication préliminaire d’un pic alpha atténué après la MK, plus particulièrement chez les patients ayant présenté une irritabilité marquée en phase inflammatoire. Des études à plus grande échelle sont nécessaires afin de confirmer les présents résultats et de mieux caractériser la trajectoire développementale des patients

A review of cytokine-based pathophysiology of Long COVID symptoms

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with "brain fog," arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS

A review of cytokine-based pathophysiology of Long COVID symptoms

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production. In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines. There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS

Low-grade inflammation and cognitive functioning-emotion recognition, reinforcement learning, and attention

The research in this thesis investigated low-grade inflammation as a factor in cognitive function, focussing on three cognitive domains: social cognition, motivated behaviour, and attention and psychomotor processes. Vaccination-induced acute low-grade inflammation reduced emotion recognition and perceived loneliness predicted the magnitude of the inflammatory response to this induction. The effects of acute low-grade inflammation on emotion recognition were replicated in age- and BMI-related chronic low-grade inflammation. Next, acute inflammation affected selective aspects of motivated learning (e.g., rate of learning, flexibility). These results were again partly replicated in chronic inflammation. Finally, older age and high BMI were both associated with psychomotor slowing, and inflammation appeared to be a mediator. Behavioural responses to the Attention Network Task appeared unaffected by both acute and chronic low-grade inflammation. However, EEG analysis demonstrated that acute low-grade inflammation affected the underlying neurophysiological process that underpins attentional alerting functions, as evident by greater cue-induced suppression of alpha power. This result suggests greater deployment of mental effort to maintain adequate performance. While prior research has mostly focussed on inflammation as a possible determinant of psychopathology, the present results indicate that low-grade inflammation in the absence of illness likewise impact cognitive function, suggesting also relevance for every-day cognitive functioning

Alcohol as a catalyst for hiv-associated neuroinflammation and tbi-induced iron toxicity

Alcohol has long been considered an exacerbator of diseases, disorders, and injuries as well as many of the accompanying symptoms. As an alternative approach, this dissertation explores alcohol as a catalyst for two different human disease conditions, human immunodeficiency virus (HIV)-associated neuroinflammation and traumatic brain injury (TBI)-induced iron toxicity. In HIV-1 infection, this dissertation presents a novel anti-viral drug, called Drug-S, for a possible inhibition and treatment of HIV-1 disease progression. The first aim explores the influence of alcohol with HIV-associated neuroinflammation on macrophage migration across an in vitro model of the blood brain barrier. There is a gap in knowledge on the effects of low dose alcohol under HIV-associated injury in people living with HIV-1 who have achieved viral suppression. The model, consisting of a quad-cultivation of neuroimmune cells including endothelial, astrocyte, macrophage, and neuron cells, is challenged with low dose (10 mM) alcohol and the viral protein trans-activator of transcription (TAT). It was then observed for changes to barrier integrity and neuronal injury upon macrophage migration. Results show that combined alcohol and viral injuries significantly increases migration even under the clinically lowest concentrations of alcohol. The cause of enhanced macrophage migration and related neurotoxicity is implicated to alcohol-induced nitric oxide production by endothelial cells and TAT\u27s chemoattractant properties. The second aim analyzes a compound called Drug-S as a possible therapeutic for inhibiting HIV-1 replication and HIV-1 disease progression. Although the combination of highly active antiretroviral therapy can remarkably control HIV-1, it is not a cure. Current therapy is unable to eliminate persistent HIV-1 contained in latent reservoirs in the central nervous system and to prevent rebound viral replication and resurgence when treatment is withdrawn. Treating HIV-1 infected macrophage with Drug-S shows inhibition of infection and persistence at a low concentration without causing any toxicity to neuroimmune cells. Results suggest that Drug-S may have a direct effect on viral structure, prevent rebounding of HIV-1 infection, and arrest progression into acquired immunodeficiency syndrome. The third aim explores the role of low level of alcohol use in TBI-induced hemolytic iron management. As hemorrhage is a major component of TBI, the accumulated red blood cells in the tissue layers undergo hemolysis and release free iron into the central nervous system. As a secondary stressor, prior alcohol consumption can increase iron aggregation and alter its management. The effects of alcohol on TBI- induced iron toxicity is explored in an in vivo model of chronic alcohol exposure subjected to fluid percussion injury. Results show that alcohol increases the iron overload and alters iron management following injury by changing the expression profile of the iron regulatory proteins lipocalin 2, heme oxygenase 1, ferritin light chain, and hemosiderin. Accompanying these results, it was also found that microglia can similarly play a significant role in iron management by phagocytosing red blood cells and retaining iron. Overall, the results of this dissertation demonstrate the pervasive impact of alcohol use in neuropathophysiology arising from HIV protein TAT toxicity or TBI-induced iron toxicity. In addition, the newly discovered DrugS can be an effective antiviral drug for a possible HIV/AIDS disease prevention and progression

Selective effects of acute low-grade inflammation on human visual attention

Illness is often accompanied by perceived cognitive sluggishness, a symptom that may stem from immune system activation. The current study used electroencephalography (EEG) to assess how inflammation affected three different distinct attentional processes: alerting, orienting and executive control. In a double-blinded placebo-controlled within-subjects design (20 healthy males, mean age = 24.5, SD = 3.4), Salmonella typhoid vaccination (0.025 mg; Typhim Vi, Sanofi Pasteur) was used to induce transient mild inflammation, while a saline injection served as a placebo-control. Participants completed the Attention Network Test with concurrent EEG recorded 6 h post-injection. Analyses focused on behavioral task performance and on modulation of oscillatory EEG activity in the alpha band (9–12 Hz) for alerting as well as orienting attention and frontal theta band (4–8 Hz) for executive control. Vaccination induced mild systemic inflammation, as assessed by interleukin-6 (IL-6) levels. While no behavioral task performance differences between the inflammation and placebo condition were evident, inflammation caused significant alterations to task-related brain activity. Specifically, inflammation produced greater cue-induced suppression of alpha power in the alerting aspect of attention and individual variation in the inflammatory response was significantly correlated with the degree of alpha power suppression. Notably, inflammation did not affect orienting (i.e., alpha lateralization) or executive control (i.e., frontal theta activity). These results reveal a unique neurophysiological sensitivity to acute mild inflammation of the neural network that underpins attentional alerting functions. Observed in the absence of performance decrements, these novel findings suggest that acute inflammation requires individuals to exert greater cognitive effort when preparing for a task in order to maintain adequate behavioral performance