Unveiling the Neuroscientific Underpinnings of Mood and Anxiety Disorders

Abstract

Depression and anxiety are two of the most prevalent mental health disorders worldwide, affecting millions of individuals across various age groups, and social categories. While the origins of these disorders are complex and multifaceted, recent advancements in Neuroscience provide valuable insights into the underlying mechanisms that contribute to the development and maintenance of mood and anxiety disorders. This review delves into the intricate interplay of neurobiological factors involved in these mental disorders, shedding light on the neural pathways, neurotransmitters, and structural/functional circuit changes that contribute to their manifestations. A special focus is given on new and upcoming insights in Neuroscience that emerge from a deeper understanding of the complex interplay of biological and environmental factors that takes place at a multi-scale level, from genes to behaviors.

Keywords: Affect Regulation; Interoception; Emotions; Biomarkers; Homeostasis

Introduction

Recently, it was estimated that 970 million people worldwide are living with a mental health disorder [1]. Among these people, the World Health Organization estimates that affective disorders are the most serious form of mental disorder in the world [2]. Mood and anxiety disorders are categories of mental health conditions that involve disturbances in a person's emotional and psychological well-being. These disorders impact an individual's mood, emotions, thoughts, and behaviors, often leading to significant distress and impairment in daily functioning [3]. This family of illnesses encompasses a range of specific disorders, each characterized by distinct symptoms and diagnostic criteria [4]. For instance, mood disorders, also known as affective disorders, involve persistent changes in mood or emotional states that go beyond typical fluctuations. The primary mood disorders include Major Depressive Disorder (MDD) characterized by persistent feelings of sadness, emptiness, or hopelessness, along with a loss of interest or pleasure in activities that were once enjoyable. Other symptoms accompanying the disease may include changes in appetite and sleep patterns, fatigue, difficulty concentrating, and thoughts of death or suicide. But mood disorders also encompass bipolar disorder that involves cycles of depressive episodes and periods of mania or hypomania [5]. In this case, depressive episodes resemble those in major depressive disorder, while manic or hypomanic episodes involve elevated mood, increased energy, impulsivity, and sometimes exaltation [6].

On the other hand, anxiety disorders are marked by excessive and persistent feelings of fear, worry, or apprehension that can interfere with an individual's daily life. Common anxiety disorders include six different symptoms:

• Generalized Anxiety Disorder (GAD): GAD involves chronic and excessive worry about a variety of everyday concerns, even when there is no immediate threat. Physical symptoms like restlessness, muscle tension, fatigue, and irritability are often present.

• Panic Disorder: People with panic disorder experience sudden and intense episodes of fear known as panic attacks. These attacks are accompanied by physical symptoms like rapid heartbeat, sweating, trembling, and a sense of impending doom.

• Social Anxiety Disorder (Social Phobia): This disorder is characterized by an intense fear of social situations and interactions due to the fear of being judged or embarrassed. Individuals may go to great lengths to avoid such situations.

• Specific Phobias: These phobias involve an irrational fear of a particular object or situation, such as heights, spiders, or flying. The fear is excessive and often leads to avoidance behavior.

• Obsessive-Compulsive Disorder (OCD): OCD is marked by intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions) performed to alleviate the distress caused by these thoughts. Common obsessions include fears of contamination or harm.

• Post-Traumatic Stress Disorder (PTSD): PTSD occurs following exposure to a traumatic event. It involves symptoms such as intrusive memories, nightmares, flashbacks, avoidance of reminders, and heightened arousal.

Mood and anxiety disorders are prevalent and can have a profound impact on an individual's quality of life. They often co-occur or share similar underlying mechanisms [7]. In Western countries during the 20th century, public awareness and policy towards mental illnesses have improved, notably by greater social acceptance of the disease, but simultaneously raising greater expectation for discovering of new effective therapeutics. Treatment against these disorders typically involves medication [8], but since most existing drugs are not fully effective [9,10], they are more often combined with psychotherapy such as cognitive-behavioral therapy for instance [11]. Yet, despite all efforts, the reported benefits from quality somatic and/or psychological treatments remain rather small [12]. The general lack of an actionable understanding of disease pathophysiology together with the scarcity of reliable biomarkers also limits clinical interventions. Early intervention and a comprehensive approach that considers together biological and psychological factors are essential for future effective management and better success in recovery. Let us now describe where interactions between biological and psychological factors take place.

Neural Pathways and Related Brain Regions

Traditionally, the common ‘biological’ foresight of psychiatric illness has highlighted cellular and molecular mechanisms that were considered to be putative therapeutic targets. However, the numerous advances in Neuroscience and rapid technological progresses, have challenged this traditional concept leading to a new emerging vision that considers the need of combining multi-scale approaches (overlapping cell types, circuits and brain areas) with a multi-space dimension where environmental cues interplay with internal state, for comprehensive understanding and treatment of mental disorders. Only then will it be possible to unify the patient's symptoms with the panel of disorders affecting this patient.

The intricate interplay between various brain cell types, neural circuits and brain regions plays a pivotal role in the etiology of depression and anxiety. The dysfunctioning might originate across multiple brain areas, circuits and/or cell types as described below. Yet, the most concerned brain areas include the amygdala, prefrontal cortex, hippocampus, and anterior cingulate cortex that are key players in the emotional processing, and thus in initiating these mental disorders [13]. Overactivity of the amygdala, responsible for processing threat-related stimuli, has been linked to heightened anxiety responses. Conversely, alterations in the prefrontal cortex's functioning disrupt emotion regulation, potentially leading to depressive symptoms [7].

During periods of mood or anxiety disorders, the brain affects many systems of the organism to increase survival and ensure homeostasis. Experimental research has revealed the complex network of neurons, neurotransmitters, and hormonal signals by which the brain send command to the whole body to adaptively respond to perceived threats or stressors. But the brain-body communication is not unidirectional starting from the brain and ending to the body. The actual processes are much more intricate and involve a bidirectional pathway with a route from the body to the brain as well, as initially conceptualized a century ago by Lange and James [14]. According to the existence of such feedback loop, a natural response to stress or perceived threats by the body would be detected by the brain. The existence of such bottom-up pathway named interoception, i.e., the continuous perception by the brain of internal body signals, was recently demonstrated experimentally by showing how a worried body communicates to the brain, and how this communication in turn, controls emotional behaviors [15]. This study demonstrates the power of interoception in triggering or alleviating anxiety according to the nature of the internal signals perceive by the brain. To achieve this effect, interoception send cues first to the brainstem and then to the posterior insular cortex known to trigger anxiety-related behaviors [15]. Collectively, the recent studies bring insights into the notion of the embodied brain and raise new questions and open up new areas for research and clinical treatment which, in order to act on the brain, decide first to influence the body.

Neurotransmitter Imbalance

Our understanding of the neurobiology of mood and anxiety disorders was greatly exacerbated by the serendipitous discovery of the antidepressant effects of some drugs that were not initially designed to enhance the levels embodied brain of brain monoamines [16]. Since then, the neurotransmitter systems of serotonin, dopamine, and norepinephrine have been implicated in depression and anxiety. For instance, a link between lowered serotonin's level and depression was first suggested by the English psychiatrist Alec Coppen in the late 1960s [17] and then widely publicized with the advent of the Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants [reviewed in 18]. However, one should keep in mind that the idea that depression results from abnormalities in brain level of serotonin (the so-called serotonin hypothesis), though very influential has been questioned more recently [18,19]. Dopamine dysregulation contributes to anhedonia, a reduced ability to experience pleasure, and implicates dysfunction within the corticostriatal circuits, a core feature of depression [20], while norepinephrine irregularities underlie the hyperarousal seen in anxiety disorders [reviewed in 21]. GABA, the brain's primary inhibitory neurotransmitter in mature neural circuits, also plays a significant role as its imbalance can lead to heightened anxiety responses [22].

A new and emerging approaches to treatment in mood and anxiety disorders rely on the use of rapidly (within few hours sometimes) acting therapeutics, that either encompass anesthetics (e.g., ketamine, esketamine, nitrous oxide, positive allosteric modulation of GABA_A receptor), hallucinogens (e.g., Psilocybin, LSD or MDMA) or immunotherapeutics (e.g., anti-inflammatory properties including inhibitors of cyclo-oxygenase 2, minocycline, omega 3 fatty acids and cytokine-targeted t brain-sensitive herapies) [13]. When not administrated artificially, a major site for production of brain-sensitive molecules is the gastrointestinal tract in which dietary components are chemically transformed by the microbiota and gut-derived metabolites. Then, these compounds are disseminated to all organs, including the brain [23]. At least in rodents, the gut microbiota has been clearly described to impact various behaviors [24], but the gut microbiome seems also capable to act on human brain functioning [25], where it modulates neurotransmitter production [26,27]. According to the current state of evidence-based knowledge, let us describe now how mood and anxiety disorders, considered as a dysbalanced dynamic system involving genetic, epigenetic, environmental and stress vulnerabilities, initiate a cascade of neurobiological events that lead to functional and structural plasticity, for better or worse.

Neuroplasticity and Structural Changes

Functional and structural plasticity (collectively known as neuroplasticity) are concepts related to the brain's ability to adapt and reorganize in response to experiences and environmental factors. More precisely, functional plasticity refers to the brain's ability to reconfiguring its neural circuits to compensate for damage or changes in function. This feature can be implicated in the pathophysiology of mood and anxiety disorders since it might involve the strengthening or weakening of existing connections between neurons or between neurons and non-neuronal brain cells. In line with this, one of the most intriguing questions nowadays consists in deciphering whether mood and anxiety-related behaviors rely on common or distinct neural circuits and if peculiar neural activity patterns could predict future behavior and/or vulnerability to mood and anxiety disorders.

Chronic stress, a known trigger for these disorders, can lead to structural changes in the hippocampus and prefrontal cortex, including reduced volume and dendritic branching. Conversely, neurotrophic factors like BDNF (brain-derived neurotrophic factor) promote neural growth and resilience, with decreased levels contributing to mood disorders [28]. Research into understanding the mechanisms involved in disrupting the neuroplasticity, leading to altered neural circuitry and emotional dysregulation and their relationships to mood and anxiety disorders is ongoing and holds promise for the development of more effective and personalized treatments.

Hormonal Factors

The Hypothalamic-Pituitary-Adrenal (HPA) axis and its release of cortisol are intimately connected to the stress response and subsequent development of depression and anxiety [29]. Prolonged exposure to stressors can dysregulate the HPA axis, leading to excessive cortisol release, which, in turn, influences neurotransmitter systems, reduces the degree of adult neurogenesis in the dentate gyrus of the hippocampus [30], and contributes to the persistent mood disturbances seen in these disorders. The dysregulation of the HPA axis leads to glucocorticoid hypersecretion and alterations in its negative feedback loop [31]. Since the glucocorticoid immunomodulatory effects are widespread, complex, and multifaceted, they target nearly all cell types and functions of immune systems [32]. In the context of chronic stress and depression, the pro-inflammatory effects of glucocorticoids may surpass their anti-inflammatory effects [33]. Today, mounting clinical and preclinical evidence support the assumption that the main players in brain immunity, as well as blood-borne inflammatory cues, play major role in the pathophysiological cascade leading to mood disorders [34].

Genetic and Epigenetic Influences

Emerging research suggests that genetic and epigenetic factors contribute significantly to an individual's susceptibility to depression and anxiety [35]. As described above, mood and anxiety disorders result from a complex interplay of genetic and environmental factors. Genetic factors contribute to a person's susceptibility to developing a mood disorder, while epigenetic factors refer to changes in gene expression in response to environmental influences, but that do not involve alterations to the underlying DNA sequence. Certain gene variants related to neurotransmitter metabolism, stress response, and neural plasticity have been associated with increased vulnerability [36,37]. Epigenetic changes can affect how genes related to mood regulation are turned ‘on’ or ‘off’, potentially leading to long-lasting effects on brain function. Chronic stress or trauma, for instance, may induce epigenetic changes that disrupt the balance of mood-related neurotransmitters and increase the risk of mood disorders [38]. Interestingly, epigenetic factors also provide a potential bridge between genetic predisposition and environmental influences. A subject with a genetic vulnerability to a mood disorder might be more likely to develop the disorder if they experience epigenetic changes triggered by stressful life events [39]. Therefore, understanding the interactions between genetic and epigenetic factors is critical for gaining new insights into the underlying mechanisms of mood and anxiety disorders. It can guide the development of treatment approaches that target specific genetic and epigenetic vulnerabilities, thus opening a new era of personalized treatment for mood and anxiety disorders. However, the field of epigenetics and its role in mental disorders is still evolving, and more research is needed to fully comprehend these intricate relationships.

Conclusions

Mood and anxiety disorders are the very expression of the human condition, as philosophy teaches us. Are they resulting from a ‘sad passion’ in the ethical way of Spinoza? The product of a concept in the way of Kierkegaard with his notion of ‘anguish’? Or just the expression of an existentialist symptom following Sartre's ideas expressed in ‘Nausea’? The elucidation of the neuroscientific underpinnings of depression and anxiety disorders has provided a deeper understanding of the complex interplay between neural circuits, neurotransmitters, structural/functional changes, hormones, and genetic/epigenetic influences. While this review provides a rather limited overview, it is crucial to note that these mental disorders are inherently multifactorial, and individual variability in their manifestations persists. The insights gleaned from Neuroscience not only enhance our comprehension of these disorders but also pave the way for the development of more targeted and effective interventions, offering hope for improved treatment strategies and a brighter future for those who suffer from such disabling conditions.

In essence, mood and anxiety disorders are multifaceted and result from the intricate interaction of external stressors and internal vulnerabilities. The combination of genetic predisposition, biological processes such as adult neurogenesis [40], cognitive patterns, and environmental influences all contribute to an individual's risk of developing these disorders. Recognizing and addressing both external and internal factors is crucial for effective prevention, diagnosis, and treatment of mood and anxiety disorders. After all, let us not forget that Sisyphus never showed signs of the anxiety event thought Hades punished him by forcing him to roll an immense boulder up a hill only for it to roll back down every time… It is reassuring to know that some of us do not always fall victim into illness, or that they can easily overcome the handicap, even when hope is so faint.

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