COVID-19 pandemic impact on children and adolescents' mental health: Biological, environmental, and social factors

1. Introduction

The world has been changing at a dizzying speed since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), promoted a drastic and sudden change in the way we organize ourselves as social human beings. In March 2020, WHO declared that COVID-19 reached a pandemic status, putting the planet in a state of maximum alert and grew to dimensions that still cannot be measured today (World Health Organization (WHO), 2020a).

The literature has pointed out that older individuals are more susceptible to develop COVID-19, and those with major comorbidities such as diabetes, hypertension and obesity can be more affected and could potentially be at higher risk for severe illness and death. Although children apparently present a lower risk of developing the severe form of the disease as well as less hospital care and mechanical ventilation, they can develop a multisystemic inflammatory syndrome. Recently, some studies have pointed out that some children and adolescents infected with the newly discovered coronavirus developed skin lesions and a picture of Kawasaki syndrome. This unusual syndrome, initially identified in Japan (1967), is a vasculitis caused by a hyperinflammatory state.

Although youngsters appear to be less vulnerable to COVID-19, the side effects of the pandemic can be devastating. Children and adolescents may be highly exposed to biopsychosocial stressors generated by the pandemic and once population's containment measures to reduce virus spread are required, they could be potentially affected by the disruption in daily life routine as a result of social isolation and their unseasoned ability to conceive and comprehend the short- and long-term consequences of this outbreak.

Commonly, although children and adolescents have experienced a drastic routine disruption due to the closure of schools and the absence of outdoor activities, they may not be completely isolated. In most cases, parents are at home. In this case, some youngsters may not necessarily experience an evident feeling of loneliness, as they may compensate for this by spending more time with their family members and also increasing time spent with social media and the internet. However, this situation also brings up some concerns. It was already observed that children with parents diagnosed with some psychiatric disturbance are more susceptible to developing psychopathologies. In the context of the ongoing COVID-19 pandemic, most parents had to reorganize their lives to deal with working at home in addition to children's management. As a result, this sudden overload has been putting parents under extra stressful conditions, potentially increasing the risk of children face emotional and behavioral problems.

This particular moment we are facing is an unprecedented global situation with numerous idiosyncratic factors. People are being affected in multifaceted ways, having their physical, psychological and emotional well-being compromised, along with social and economic problems. The heterogeneity and plurality of biopsychosocial stressors bring a multifactorial approach to the COVID-19 pandemic, which leads to unpredictable consequences on the mental health of vulnerable populations such as children and adolescents.

Recently, a study has evaluated 1036 quarantined children and adolescents in China in an age range from 6 up to 15 years, of which 112, 196, and 68 presented depression, anxiety, and both, respectively. Another study demonstrated a high prevalence of psychological distress in quarantined children and adolescents due to the COVID-19 pandemic in India. These individuals have experienced helplessness (66.11%), worry (68.59%) and fear (61.98%), compared to non-quarantined children. Moreover, it was also reported in China that children and adolescents aged 3–18 years presented symptoms of inattention, clinging, worry and irritability during this pandemic.

Accordingly, in light of a large body of literature that unveiled several mechanisms behind the potential harms on brain development and/or behavioral outcomes result from different stressors during childhood and adolescence, we proposed herein a reflexive discussion addressing the following issues: (i) Stress and neuroinflammation; (ii) Social isolation and diet; (iii) Brain plasticity: social behavior; social inequalities, neglect and distress; playing and nature environment; and (iv) Public health and support, to shed light on points that should be considered by governments and health authorities to start a follow-up on the young population. It is the nature of human beings to be social and, despite the need for these restraint measures, it should be of great concern how this pandemic period can affect the young brain that is under development and it is more susceptible to stressors. Therefore, the search for strategies to mitigate a harmful long-term impact on it should be sought. These points will bring us information and guide us, in the future, if we have to face another situation like this COVID-19 pandemic.

2. Stress and neuroinflammation

Stress is usually approached under medical or biological aspects. It causes physiological damages or psychological disturbances to an organism and is generated by external or internal adverse stimuli (Gunnar and Quevedo). The adequate body response to stress helps to preserve and achieve an allostasis condition (Gunnar and Quevedo,). However, uncontrolled or chronic responses to stress may have health harmful effects. There is already evidence of the multiple and negative psychological impacts of COVID-19 pandemic on children and adolescents quarantined populations (social isolation stressors), turning these individuals more susceptible to develop long-term psychiatric disorders. Although it is still under speculation the extent of the damages caused by the stressors of COVID-19 pandemic, it was recently proposed that dysregulated neuroendocrine-immune interactions can be behind psychiatric manifestations observed in quarantined people.

Under normal acute stress stimuli, the hypothalamic-pituitary-adrenal (HPA) axis activation leads to a release of glucocorticoids (e.g. cortisol) on the bloodstream that regulates the levels of pro- and anti-inflammatory molecules, which, in turn, also controls the secretion of these hormones by the HPA pathway, a mechanism of negative feedback that prevents an exacerbated inflammatory response. However, persistent and enhanced stressful events during early life (childhood and adolescence) can drive responses by the immune, endocrine and nervous systems mainly through a dysfunction of the HPA axis. Dahmen Juruena and alterations on inflammatory mediators levels in the brain, and/or systemically, predisposing these individuals to psychopathological conditions in adulthood (e.g. anxiety and depression). Moreover, the stress can be one of the possible triggers for neuroinflammation, a term used to designate an imbalance or exacerbation of the immune signaling in the brain that can lead to several disorders (e.g. aggressive, psychosis, depression, and anxiety disorders).

During infancy, early childhood or even in adolescence, the central nervous system (CNS) is in a vulnerable developmental window, in which the occurrence of any stressful challenges at the time of critical periods can trigger short- and long-term physiological, cognitive and behavioral damages. The main brain regions that respond to environmental stimuli (e.g. stress) are amygdala, hippocampus, and prefrontal cortex. The response occurs via an intricate network of hormonal, immune and neurotransmitter responses, which can, in turn, change the response patterns of glial cells and monoamines metabolism, leading to cell death and/or mental health disturbances.

Longitudinal studies have significantly correlated the presence of psychosocial stressors such as social isolation during childhood and adolescence with high levels of C-reactive protein (an inflammatory biomarker) later in life. Moreover, Danese also positively associated social isolation in childhood as a risk factor for depression in adult life. Since dysfunctional systemic inflammation has been extensively demonstrated to impair the neurodevelopmental processes and lead to cognitive and mood disturbances, it seems reasonable that inflammatory alterations in children exposed to the harmful effects of COVID-19 outbreak could lead to long-term physiological and psychological damages and should be a public health concern.

Another important concern comes from the impact of fear in children and adolescents. A recent study reported a high prevalence of fear in quarantined children and adolescents during COVID-19 pandemic, a feeling that was mainly associated with financial worries or concerns regarding being exposed to COVID-19 or having infected others (Saurabh and Ranjan). Moreover, it is not surprising that adolescence represents a stress-sensitive developmental window relative to fear regulation (Tottenham and Galvan). Indeed, there is evidence showing chronic stress have a great impact on amygdala-prefrontal cortex connectivity and activity, impairing, for instance, the extinction of fear memory (Tottenham and Galvan). These questions claim for further studies addressing the harmful fear effects on the developing brain in the context of the COVID-19 pandemic.

3. Social isolation and diet: From animals to humans

The chronic stress caused by social isolation conditions in mice is also associated with an increased motivation to consume palatable foods. In this context, studies using animal models suggest that intake of caloric foods can act as “comfort food” and would be an alternative to alleviate the negative effects of stress. Chronic high-fat diet, induced by social isolation stress, reduces anxiety- and depression-like behaviors in animal models and in humans. Moreover, it was rescued the memory impairment on the object recognition test as well as the changes in brain-derived neurotrophic factor levels caused by social isolation conditions in rats.

Social isolation stress can induce an increased food intake and weight gain both in animal models and in humans, and can be associated with increased hypothalamic production of neuropeptide. Indeed, neuropeptide Y is involved with appetite control and insulin resistance in the brain. Accordingly, the relationship between a stressful environment and the consequent increase in the search for such types of food early in life may be one of the reasons for an increase in obesity among children and young people. In addition to obesity, access to both high-fat diets during development and social isolation can lead to structural synaptic changes, impacting cognitive processes in adult life such as learning and memory in rodents as well as in humans.

Furthermore, it has been shown that a short period of social isolation during adolescence is able to induce long-term effects on dopaminergic pathways in rats. However, a high-fat diet has controversial results on the dopaminergic pathways due, in part, to different dietary lipid compositions. While administering a high- fat diet composed of saturated fatty acids leads to perturbations in mesolimbic dopaminergic signaling, a diet composed of unsaturated fatty acid does not.

A possible relationship between social isolation stress during childhood and access to high-fat diets may involve the activation of the HPA axis. In this sense, the leptin released by this type of diet can reduce the activation of the HPA axis and inhibit the hypothalamic neuropeptide Y synthesis and release triggered by stress, minimizing the effects of social isolation. However, the way, the duration and the localization in the brain of the effects of how caloric food intake acts to counteract stress effects in the brain deserve further investigation. In addition, the intake of highly caloric foods and the exposure to a social stressor can also affect the composition of the intestinal microbiota Deshpande leading to changes in the brain, since metabolic products of the intestinal microbiota can influence brain functions (and vice versa) during development and adult life.

Evidently, we must be careful when extrapolating data from animal models to human conditions, since protocols of social isolation stress with animals mismatch the circumstances produced by the COVID-19 lockdown. Yet, studies with animal models are useful when trying to understand certain molecular mechanisms behind the observed behavioral changes in humans. In addition, we want to highlight that the nutritional status during neurodevelopment is critical to children and adolescents' proper development. It is also important to adequate nutrition and to enhance the immune system in order to provide effective protection against possible diseases, including COVID-19, and to guarantee the rapid recovery from the disease. As social isolation is capable of changing our relationship with food, the importance of social ties for an adequate diet becomes more evident during this period of quarantine.

4. Brain plasticity

4.1. Social behavior

Humans are inherently social and since early in development they have the ability to become apt cooperators with a strong motivation to communicate with other individuals. Evolutionarily, the formation of social bonds was fundamental to both human survival and to guarantee a healthy cognitive, emotional, endocrine and immune development. In fact, staying close to significant others is essential to create and maintain social bonds in humans. In normal circumstances (i.e. in the absence of threats), spatial distancing is unnatural for us. This is more pronounced during threatening contexts, like this COVID-19 pandemic, where our affiliative tendencies and the desire to seek physical contact become even stronger. In the same vein, a recent paper showed that people can crave social cues just like they crave food.

From this perspective, the adolescence period is considered a time of deep learning about the social environment when several key aspects of social cognition continue to develop, including the comprehension of other people's emotions, intentions, and beliefs. It is a time of psychosocial changes between childhood and adulthood, and a period of heightened sensitivity to social contexts during which adolescents spend more time with peers. In fact, for most teenagers, school is one of the most important social environments and one in which peers increasingly affect adolescents' self-concept, well-being and behavior.

Unfortunately, many adolescents during the COVID-19 pandemic are unable to attend schools which culminated in limited interaction with peers, imposing a gap on their social network that has been tentatively supplied by virtual interaction. It was shown by Crone and Konijn that the use of social media by adolescents builds not only the connection among peers, but also their brain connectivity. However, a recent study showed that school routines are important coping mechanisms specifically for young people with mental health issues. Furthermore, it was shown that periods without school are also associated with decreased physical activity; increased screen time, irregular sleep patterns, and less appropriate diets in children and adolescents.

The social touch is essential to develop cognition, emotions, attachment and relationships. In addition, it also contributes to the physiological regulation of the body's responses to acute stressors as well as other short-term challenges. Gallace and Spence reviewed the importance of the social touch to human development under different aspects. It was discussed that, even when virtual relationships are established, they cannot cater to physical needs which are essential to improvement of interpersonal connections that contribute to the global development of the individual. In the context of quarantine, the questions to the discussion we bring here are if this “virtual contact” will be enough to social behavior constructions and if it will change the course of brain development. Could social isolation stress and adversities that were installed during the pandemic result in a poor relational experience and affect the brains under development? What will be the effects of this long-term switch to “virtual contact” on human interactions? It is also important to highlight that the impact of COVID-19 is not uniform across adolescents, considering families with medium to high-income resources being able to provide adolescents with additional opportunities to interact with peers through technology, while other families cannot.

In addition, it should be considered that adolescence is also characterized by multiple biological changes that include a cascade of hormonal and physical changes, leading to a substantial development of the brain, burst of activity dynamically strengthening and weakening connections among key brain regions in response to environmental input. Therefore, the developmental transition between childhood and adulthood brains circuits involves maturation in frontal cortical neural systems and in social and affective circuitry that occurs in response to social experiences (e.g. relationships and interactions that a person experiences with others, including that from the same age), socioeconomic status and culture.

However, this benefit of increased plasticity also renders vulnerability to stressors and to mental health issues. In fact, adolescence is the peak age of onset for the most common psychiatric disorder such as attention-deficit/hyperactivity disorder (ADHD), anxiety, mood and schizophrenia, and it is also a time of high risk for substance abuse and suicidal behavior. The peak onset of mental illness during the teenage years could be explained by the surges of sex hormones and neurobiological changes that target specific brain regions as well as cell populations. During development, the CNS undergoes an intense process of formation and maintenance of synaptic connections until adulthood. Environmental factors constantly act in this process, influencing the formation of individual cognitive and emotional aspects.

The pandemic situation that we have plunged into showed multiples outspread on the individual's mental health. However, how will it affect adolescents' brains in adulthood, especially those key regions associated with action-emotion regulation (e.g. impulsive behavior), empathy, and decision-making skills? In pandemic times, there is a pressing need to mitigate the impact the young population is subjected to, particularly the more vulnerable ones who suffer from social inequalities in which families with low income cannot face education, remote learning and virtual contact with peers and family members.

4.2. Social inequalities, neglect and distress

The pandemic has been widening and exposing the social inequality in every country affected by the economic shutdown, especially in underdeveloped countries. Social isolation also brought elevated levels of domestic violence, including childhood maltreatment or neglect as a result of parenthood insecurities and inabilities. Parenting during the pandemic is an additional challenge to deal with remote learning, home office working, and endless house chores. Children at home represent high costs from feeding to internet access. Moreover, the internet often has to be shared with all family members. To those who live in a low-income situation or a crowded house, this is even harder to manage. Adding to this scenario, children who have special needs, those who have had a previous COVID-19 diagnosis, or were already under treatment for any condition are more vulnerable.

During childhood, adverse experiences such as trauma can induce long-term impacts on brain development as well as promote mental and behavioral disturbances through neurochemical and physiological imbalance related to neuroimmunoendocrine regulatory mechanisms. Copeland followed children of different age groups for 22 years and pointed out that the outcome of trauma during childhood results in much more than a mental health issue and it became a public health issue. Moreover, it was shown by that childhood trauma can trigger mental disorders, including addiction in adulthood. Therefore, it is necessary to look at this subject very carefully, in the way people is managing the COVID-19 pandemic stress. We need to guarantee that children and adolescents, as well as their families, receive the proper psychological help to support their mental health. If an emotional neglect already exists, this will most likely be intensified by the work overload that parents and/or caregivers are subjected to, as well as by social inequalities, that may be related to the economic crash and the employment discharges around the world. The sum of the trauma effects can be devastating, and the damage might not be detected only in a few years after-pandemic.

4.3. Playing and nature environment

In the last few years, there has been a growing number of works demonstrating that a direct contact with nature is associated with great health benefits. Among the suggested mechanisms by which stimuli from nature can impact on individual well-being and mental health include regulation of blood pressure, regulation of the immune system, reduction of pro-inflammatory cytokines after walks in a forest (outside urbanized areas), regulation of autonomous activity (through the reduction of sympathetic activity opposed to an increase in the parasympathetic activity), and a deep feeling of relaxation and concentration.

Nature exposure can also reduce stress during early childhood in comparison to the ones that did not have much access to similar outside stimuli. Children highly exposed to nature also present great health and physical development (development and refinement of locomotor skills, for example), improved self-control (reduces inappropriate in-class behaviors), better communication and social development (more complex language), besides proper cognitive development (multi-sensorial stimuli that raise curiosity and creativity).

Sunlight exposures have also positive effects on human health. Suitable sunlight exposure is essential for vitamin D synthesis, which is involved in several physiological functions. However, insufficient sunlight exposure along with a low status of vitamin D may be responsible for critical public health issues and neuropsychiatric disturbances such as cardiovascular diseases, metabolic syndrome, hypertension, multiple sclerosis, asthma, type 1 diabetes, autism, Alzheimer's disease, schizophrenia and depression. Accordingly, it was demonstrated that adults with depression exposed to low sunlight showed a decrease in interleukin-6 (IL-6) serum levels, a pro-inflammatory cytokine, when compared to adults with depression who were exposed to high sunlight, which supports the well described benefits of proper sunlight exposition. Also, there was already observed that increased serum levels of IL-6 during childhood have been associated with a greater risk of developing depression and psychosis in young adulthood. Therefore, we can comprehend the importance of appropriate sunlight exposure, mainly during childhood, regarding mental health conditions since this prolonged lockdown period may be potentially limiting youngsters to have a proper sunlight exposition.

Unfortunately, because of quarantine, children are not allowed to play in outdoor areas and explore unstructured play. This means that we are switching from the “play-outside mode” to the “play-indoor mode”, which includes spending more time on the screen. The negative impact of media and technology use was analyzed in children (aged 4–8), preteens (9–12), and teenagers (13–18). It seems that increasing the screen time use correlates positively with unhealthy eating, lack of physical exercise, more total ill-being as well as attention and physical problems. A meta-analysis review showed a negative correlation between the amount of screen use and language development in younger children. However, if exposed to better quality content with an educational bias, the use of screens can be beneficial for children's language in an age-dependent manner.

It is undeniable that we might have prejudice on their development, including on their mental health, but the results from this switch on our modi operandi will be known in years, not now. A follow up from these children will determine if we had or not an impact on brain organization and changes in social behavior as a consequence of the pandemic.

5. Public health and support

In face of this pandemic scenario, children and adolescents are exposed to stressful situations such as fear of contracting the disease, frustration, boredom, information overload, family financial loss, and drastic changes in daily activity patterns, which make clear the multifaceted threats of COVID-19. All these issues collaborate for future unpredictable damages that could impact not only the own children's health, but also the health systems. For instance, Sprang and Silman (2013) showed a higher incidence of post-traumatic stress disorder symptoms in quarantined children than those who were not quarantined (Sprang and Silman, 2013), evidencing just one aspect of how a pandemic situation may impact on a vulnerable population.

The government and public health authorities need to consider the impact of this unusual situation on children and adolescents by implementing mitigating measures and making investments available to reduce the damages. Notwithstanding this, as the impact on the individual's health is multifactorial, the launched resources and efforts to mitigate these damages must include health authorities, government, communities, organizations, schools, and family members. Some resources currently discussed in the literature address (i) making available a proper online environment for students to develop scholar activities (e.g. create suitable online platforms), (ii) providing motivational videos which can help to improve the daily lifestyle (e.g. how to have a balanced diet, practice exercises at home, and regulate the sleep), (iii) providing access to adequate information (e.g. how to adopt correct hygiene practices) and (iv) providing access to psychological professional support. Furthermore, social support is widely understood as the presence of positive relationships that create a feeling of belonging, stimulate trust, and encourage self-care. In this case, despite the external essential support, the internal support in the family context is fundamental. Parenting has been often described as the best resource to reduce adverse impacts on children's social-emotional and behavioral development. In these circumstances, whenever parents are able to stay close, to care, to love, to play, and to have conversations with their children, it is easier to perceive indicators of psychological issues and, then, interfere appropriately. On the other hand, and complementarily, parents should be able to receive psychological, financial and logistic support provided by their government.

Although all resources cited above seem to have great and real applicability, most of them, unfortunately, may be effective only for a portion of the children and adolescents' population. The sad and contrasting reality is that we live in a world with a broad social inequality and neglect in children's care (e.g. domestic violence. In this context, some questions are still to be properly addressed such as (i) how to deal with the reality wherein quarantined children are suffering from more domestic violence? And what will be the extent of the psychological damages in these individuals in the future? (ii) How to offer educational online support for children that live in rural or suburban areas where there is no or limited access to the internet or even technological devices? (iii) How motivational resources can work for children whose family members have lost their income source and are living in extreme poverty, and (iv) how to prevent these individuals from the risk of infection when their houses stay in areas with poor sanitary conditions and are neglected by the government? All these concerns make part of a major problem of social inequality present in the current world and have been aggravated with this pandemic situation.

To properly address these two faces of reality, we call attention of governments and authorities to also carefully look for this younger population that is particularly more vulnerable to develop a severe mental illness, considering their hard-living conditions. Moreover, further efforts must be launched to provide suitable care and protection for them. In this context, some strategies have been already implemented such as the development of a public documental material on how to prevent violence during the social isolation period. It has been developed by WHO in association with other organizations (World Health Organization (WHO), 2020c). The proper financial support for families that have lost their income sources must be implemented by government policies in order to reduce a worsening of health conditions in a population that already is severely impaired by social inequalities.

6. Discussion

Previous works demonstrated the importance of quarantine and social isolation to contain the spread of the virus and the overload of health systems. However, the impact of this long-lasting social isolation on children and adolescents is still not properly addressed. Moreover, we draw attention not only to the multifaceted and heterogeneous feature of this pandemic which adds new issues and challenges to the population, but also to the fact that this COVID-19 outbreak may heighten pre-existing difficulties and problems in people lives, reaching the broad spectrum of the biopsychosocial framework. Herein, we brought elements for a more comprehensive discussion around the neurobiology changes triggered by the stress caused by the different facets of COVID-19 outbreak (Fig. 1). We shed light on the effects of stress on the HPA axis and the possibility of triggering psychiatric disorders such as anxiety and depression, for example. We discussed neuroinflammation, diets, brain plasticity, social behavior and public health and support making an alert to a long-term public health issue and the need for prolonged governmental support (Fig. 1).

As discussed throughout the above topics, changes in daily routine particularly harm children and adolescents, and this could, in turn, become a critical public health problem in the future. Moreover, we emphasize that youngsters can experience not only short- but also long-term consequences of COVID-19 stressors, as they present individual responses. The opening of cities and the uncontrolled re-establishment of some daily activities led to peaks of new cases, which also generates waves of expectations and frustration especially among youngsters who do not know how to deal with this.

It is our obligation to emphasize the notorious urgency of psychological monitoring of quarantined children and adolescents, for an expected long period, especially for those who suffer domestic abuse, which grows in the same proportion to unemployment, financial bankruptcy and social inequalities. Moreover, we cannot forget the ones who lost their family members to COVID-19 or are separated from their parents or caregivers for safety reasons, and also those who already had a disorder and cannot receive proper health treatment. The withdrawal from social life, daily activities, as attending to school, combined with fear, anxiety and the feeling of the unpredictable, increase the risks for this group to develop psychiatric disorders in the future, even those who do not have such histories. Besides, children whose parents are under high stressful conditions at home due to pandemic also have a higher risk of developing psychiatric disorders.

Health authorities and government have to treat this as a public health issue, and not as something whose outcome is short-lived. However, more investment to research is needed to evaluate the impact of COVID-19 pandemic stressors on youngsters developing brains, so we can prevent or mitigate mental health outcomes by offering support and/or proper treatment. We reinforce the need to follow up these children, adolescents and also their families and caregivers in order to develop strategies that will be able to mitigate, in a long term, the COVID-19 pandemic effects.

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