Pathological anxiety/chronic stress increases the risk of developing neuropsychiatric disorders, including depression and dementia. Chronic stress can cause amygdala hyperactivity and damage to PFC and hippocampal structures, thereby impairing emotion regulation. Pharmacological/non-pharmacological interventions can reverse the damage to PFC and hippocampal neurons. Studies have demonstrated that pathological anxiety and chronic stress can lead to structural degeneration and functional impairment of the hippocampus and prefrontal cortex, thereby increasing the risk of other psychiatric disorders (e.g., depression and dementia).
Anxiety is a feeling of uneasiness, nervousness, and worry about uncertain events, often experienced subjectively with physical signs such as sweating, shaking, dizziness, and rapid heartbeat. Occasional and transient anxiety is a necessary part of life, but when frequent or persistent, it can develop into a pathological disorder that interferes with work, school, and interpersonal activities. Anxiety, fear, and stress are somewhat similar, exist in association with each other, and have a common neuroendocrine structural basis.
1. anxiety places more emphasis on the feeling of events that have not yet occurred, or even necessarily occurred, and is often negative.
2, Fear is generally a reaction to a threat that has been confirmed to exist and is critical to survival. However, fear can also manifest as pathological, such as phobias
3, while stress is conceptualized as an adaptive response to a specific stimulus or demand, with more emphasis on changes in physiological state than on emotional changes. While stress itself is an adaptive response, chronic stress is pathological – and can cause significant damage to the immune, metabolic and cardiovascular systems.
Chronic stress can increase the risk of serious mental disorders such as depression, and has recently been found to be associated with the development of dementia. In both animal and human studies, stress has been observed to cause hyperactivity in the amygdala and damage to PFC and hippocampal structures, leading to impaired emotion regulation and cognitive function. It is evident that pathological anxiety/stress can cause damage to the brain, but this damage is reversible and can be reversed by pharmacological and non-pharmacological treatments.
1. Neurological basis of fear and anxiety
The perception of threatening signals in the environment produces autonomic arousal and emotions such as fear and anxiety – a process that is mediated through the ventral nervous system. This system includes the amygdala, insula, ventral striatum, hypothalamus, periaqueductal gray matter, ventral anterior cingulate cortex (ACC) and prefrontal cortex (PFC), especially the ventral medial PFC (mPFC) and orbitofrontal cortex. The amygdala is central in this loop and plays a crucial role in the formation and expression of fear, as well as being an important structure for emotional learning. The neurological process of fear and anxiety in brief is that the amygdala detects threat and generates fear and anxiety, while the medial prefrontal cortex and hippocampus inhibit the amygdala activity, and with the dynamic balance between the amygdala and the mPFC and hippocampus, the regulation of emotions is achieved.
2. Functional neuroanatomy of anxiety disorders
Anxiety disorders are characterized by the inability to regulate emotions in the face of threat. Possible causes are decreased thresholds, over-activation, and abnormal conduction functions in the amygdala and other limbic/subcortical areas. That is, patients with anxiety disorders have an overactive amygdala and hypoactive PFC and hippocampus in the face of threat.
Patients with anxiety disorders are more sensitive to negative information and threats in the environment, and this hypersensitivity to threats is the result of overactivation of the amygdala, as seen in panic disorder, social anxiety disorder (SAD), simple phobia, generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD). There is also evidence of impaired emotional learning, reduced mPFC activity, and diminished association of the amygdala with the mPFC in the above patients, suggesting diminished regulation of the amygdala and other brain regions of the central nervous system by the PFC. patients with GAD, panic disorder, PTSD, and social phobia disorder can generalize fear to neutral or benign stimuli due to an impaired ability to distinguish threat from safety.
In patients with PTSD, the hippocampus is reduced in size and function, making it difficult for patients to distinguish between threats, and so they experience a constant repetition of previously receding fears, and this “fear repertoire” is one of the pathogenesis of anxiety disorders.
3. Neurological basis of stress response
In acute stress, catecholamines are released to the periphery via the sympathetic-adrenal medullary system, while the release of the stress hormone cortisol increases via the central hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus stimulates the release of epinephrine and norepinephrine from the adrenal medulla, resulting in autonomic changes such as increased heart rate, increased blood pressure, increased respiration, and enhanced skin conductance, which together constitute the “fight/flight response”. Glucocorticoids in turn play an important role in the feedback inhibition of the stress response and are responsible for relieving the stress response after the stressor has withdrawn. The above processes, which are a dynamic balance of physiological factors, are carried out by the combined action of all organs and enable the individual to adapt well to environmental changes, which is called allostasis.
During acute stress, amygdala action can cause increased levels of dopamine and norepinephrine in the PFC, which in turn activates blue spot norepinephrinergic neurons. In animal experiments, the use of dopamine or epinephrine agonists induces activation of PFC function, which increases the release of catecholamines in the PFC and can result in impaired functioning mainly in working memory. Catecholamine levels are further increased due to glucocorticoid inhibition of glial transport proteins and their effects on hypothalamus and nearby brain regions containing glucocorticoid receptors, including the PFC, amygdala and hippocampus. Subsequently, glucocorticoid-sensitive hippocampal neurons provide negative feedback regulation of the HPA axis to achieve termination of the stress response. Thus, the hippocampus and mPFC, together with the amygdala, regulate emotions and achieve the regulation of the stress response under a glucocorticoid-mediated feedback mechanism.
4. The effects of pathological anxiety and chronic stress on the brain
Frequent and chronic stress exposure can lead to impairment of the neuroendocrine system and, over time, other related physiological systems, such as immune, metabolic, and cardiovascular functions, increasing the risk of developing diseases, including cardiovascular disease, diabetes, metabolic syndrome, and neuropsychiatric disorders.
It has been recently reported that women who experience significant psychological stress in midlife have an increased risk of developing Alzheimer’s disease 20 years later; anxiety symptoms can increase the risk of developing Alzheimer’s disease in older adults up to 2.5 times. In animal models, stress levels of glucocorticoids were found to cause amyloid production and tau protein accumulation.
Although previous studies have not found an association between anxiety and Alzheimer’s disease, recent neuroimaging data show that older adults with amnestic mild cognitive impairment (aMCI, a prodromal symptom of Alzheimer’s disease) have an increased risk of developing Alzheimer’s disease when their anxiety is severe, with a risk ratio of 1.33 for anxiety, and mild, moderate, and severe anxiety causing an increased risk of Alzheimer’s disease of 33%, 78%, and 135%, respectively. 78%, and 135%, respectively. Also, the severity of anxiety in older adults with aMCI was positively correlated with the degree of atrophy of the internal olfactory cortex and medial temporal lobe.
5. Hippocampal damage
It has been found that chronic and prolonged excitation of the HPA axis and the secondary increase in glucocorticoid secretion can cause damage to hippocampal structures in both humans and animals, leading to hippocampal atrophy and reduced hippocampal neuron formation. Similar results have been observed in human studies, where hippocampal atrophy and HPA dysregulation have been found in patients with psychiatric disorders (including depression and PTSD). Transgenic mice with abnormal hippocampal neuron function can exhibit impaired associative learning and generalization of fear and anxiety.
Hippocampal neurons enhance individuals’ ability to predict and judge unknown events in dangerous situations, thereby reducing anxiety and fear, which explains the presence of both cognitive dysfunction and mood disorders such as anxiety and depression in individuals with Alzheimer’s disease. It has been suggested that regenerative repair of hippocampal neurons may serve as one of the targets of antidepressant action. Chronic fluoxetine exposure induces enhanced expression of myelin-related genes in hippocampal tissue, and this expression level has been shown to be negatively correlated with anxiety-like behavior in mice tests.
6. Prefrontal cortex damage
In rodent experiments, chronic stress was found to cause structural and functional degeneration of part of the PFC in mice, i.e., damage to dendritic spines of some PFC pyramidal cells, leading to impaired working memory. Consistent results were also obtained in other animal experiments. The reduction of PFC dendritic spines under chronic stress was accompanied by an increase in dendritic spines in amygdala neurons, further exacerbating the imbalance between amygdala and PFC function.
In human studies, exposure to negative events has been found to be associated with reduced PFC gray matter volume. Chronic stress has also been associated with reduced PFC connectivity and decreased modulation of the amygdala. 3-year follow-up trials have found that patients with remitted depression have less volume reduction in the hippocampus, anterior cingulate gyrus, dorsomedial and dorsolateral prefrontal cortex compared to patients without remission. Studies and the literature have shown that stress-induced impairment of the PFC can lead to psychiatric disorders, including depression and PTSD, but whether the same mechanisms are present in dementia is unknown and further research is needed to find out.