PHYSICAL, EMOTIONAL, AND SOCIAL PAIN DURING COVID-19 PANDEMIC-
RELATED SOCIAL ISOLATION
Priscila Medeiros1,2*, Ana Carolina Medeiros1,2,8, Jade Pisssamiglio Cysne Coimbra3,
Lucas Emmanuel Teixeira4, Carlos José Salgado5, José Aparecido da Silva6, Norberto
Cysne Coimbra1,8, Renato Leonardo de Freitas2,7,8**
1Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto
Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São
2Laboratory of Neurosciences of Pain & Emotions and Multi-User Centre of Neuroelectrophysiology,
Department of Surgery and Anatomy, Ribeirão Preto Medical School of the University of São Paulo, Av.
Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
3Pontificial Catholic University of Campinas (PUC-Campinas), Prof. Dr. Euryclides de Jesus Zerbini Str.,
1516, Parque Rural Fazenda Santa Cândida, Campinas, 13087-571, São Paulo, Brazil.
4Institute of Motricity Sciences, Federal University of Alfenas (UNIFAL), Alfenas, MG, Brazil
5International School of Economics and Administrative Sciences, Universidad de La Sabana, Chia, Colombia.
6Laboratory of Psychophysics, Perception, Psychometrics, and Pain, Department of Psychology, Ribeirão
Preto School of Philosophy, Sciences and Literature of the University of São Paulo (FFCLRP-USP), Ribeirão
Preto, 14049-901, São Paulo, Brazil.
7Biomedical Sciences Institute, Federal University of Alfenas (UNIFAL-MG), Gabriel Monteiro da Silva Str.,
700, Alfenas, 37130-000, Minas Gerais, Brazil.
8Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Ribeirão Preto, 14050-220, São Paulo,
*Corresponding authors: Dra. Priscila de Medeiros and Prof. Dr. Renato Leonardo de Freitas
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology* and Laboratory of
Neurosciences of Pain and Emotions and Multiuser Centre of Neuroelectrophysiology, Department of Surgery
and Anatomy**, (FMRP-USP) Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
email@example.com or firstname.lastname@example.org and email@example.com
The recognition and management of the socio-emotional pain facing the COVID-19
pandemic refer to different, but interdependent, clues regarding cognitive and emotional
aspects of the pandemic threat, considering the need of social distancing as a prophylactic
procedure to avoid spreading the pathogen. The socio-emotional condition at the time of
outbreak subsidizes the (re)modulation of interactive neural circuits underlying the risk
assessment behaviour at physical, emotional, and social levels. Experiences of social
isolation, exclusion or affective loss are generally considered to be some of the most
“painful” things that people face. The threats of social disconnection are processed by some
of the same neural structures that process basic threats to survival. The lack of social
connection can be "painful" due to an overlap in the neural circuitry responsible for both
physical and emotional pain related to feelings of social rejection. Indeed, many of us go to
great lengths to avoid situations that may engender these experiences. Because of this, this
work focusses on times of pandemic, the somatization mentioned above seeks the
interconnection and/or interdependence between neural systems related to emotional and
cognitive processes, so that the person involved in that aversive social environment
becomes aware of himself, the others, and the threatening situation experienced to avoid
daily psychological and neuropsychiatric effects. Social distancing during the isolation
evokes the formation of social distress, raising the intensity of learned fear that people
acquire, consequently enhancing the emotional and social pain.
Key words: social distancing, social pain, emotional pain, neurosciences, COVID-19.
1.1 Victims of The Alienist
The discussion regarding the consequences of the social isolation on human being
health is not a novelty, considering that these factors have been studied since 1987 in
Brazil, that characterize the beginning of the Psychiatric Reform Movement (Brazilian
Health Ministery, 2018). Since the times of Brazil Empire, under the reign of Dom Pedro
II, there were asylum hospitals, in which people were submitted to long-lasting social
isolation due to mental diseases.
These psychiatric hospitals were known by isolation of insanity from the rest of
mentally healthy people putting together patients considered non-suitable for the social
relationship. According to Saraceno (1999), the Asylum is a variable independent of the
socioeconomic conditions of the country in which it is situated, consisting of a place for
resetting the exchange of social skills”.
In the Asylums, people were hospitalized during several years, sometimes until their
decrease, as reported by Maurício Lougon´s experiences (Lougon M 2006) during the de-
institutionalization of Juliano Moreira Colony, from 1982 to 1985, highlighting the
hospitalization of 2600 patients, in their majority elderly, who lived years of their lives
suffering several kinds of abandon, violence and social isolation.
The psychologic consequences coming from that long-lasting hospitalization in
Asylums such as Juliano Moreira Colony are the following: (a) a lack of autonomy of
patients regarding the choice of medical treatment and forced familiar exclusion; (b) the
limitation of the physical spaces and social experiences in the society, highlighting that the
psychiatric hospital becomes the residence of the patient with mental disease. In this case,
the life of the patient is limited to the psychiatric hospital activities, searching a meaning
for their lives and daily routine, but facing the emotional pain caused by the absence of
their parents and actual home (Salles and Barros I 2013).
The Psychiatric Reform Movement accomplished in the last decades could offer
better medical care and more attention to the mental health of these patients who have lived
for years under bad sanitary conditions, socially isolated. New approaches were established,
such as Therapeutical Houses, Psychosocial Care Centers; Homecoming Program,
Acquaintanceship and Cultural Centers, and Mental Health Clinic, that allowed the
development of the autonomy feeling regarding the own life of the patient, healthy social
relationship and mental health, the opportunity of working, and better living conditions
(Salles and Barros 2013).
Interestingly, like illustrated in The Alienist (Assis 1998), the new world context of
the COVID-19 pandemic, people considered healthy were suddenly obligated to socially
isolate themselves inside their homes, or even in places far from their familiar homes, due
to their work beside potentially infected people. The social isolation caused by COVID-19
pandemic threatening also caused a forced poor affective behaviour during absences in
traditional social events, such as funeral, weddings, and anniversaries, in addition to
isolation from parents infected by COVID-19 pathogen (Danzmann et al. 2020).
The social isolation caused by COVID-19-related quarantine may cause severy
post-traumatic stress disorder, not only by pandemic fear, but also by unemployment, loss
of parents without mourning, and by the riks of traumatic familiar experience, such as
those regarding the isolation with a potential aggressor in the same environment, coexisting
daily with a non-escapable threatening situation, similarly to the patients with mental
diseases forgotten inside the Asylums in the past.
The health professionals aiming at to avoid additional psychological damages must
carefully manage possible stigmatization of both infected and healed people, in addition to
people submitted to aggressive social interactions inside their homes, chronic stress, fear,
sadness, helplessness, and jitters, causing increased serum levels of cortisol and
consequently immunological system impairment and susceptibility to other diseases and
also COVID-19 re-infection.
1.2 Impact on health caused by social isolation
The COVID-19 pandemic is a global public health. Due to high transmissibility and
the lack of a vaccine capable of immunizing the population, restrictive measures such as
social isolation are implemented and encouraged (Zhai et al., 2020). The question is based
on the perspective that while the social impacts of isolation meet public health benefits,
psychological and neuropsychiatric problems can be triggered (Wang et al. 2017). As a
result, social isolation may be reflected as a risk factor equivalent to the harmful effects
caused by smoking and obesity (Holt-Lunstad et al. 2010) as reduced well-being,
depression (Heikkinen and Kauppinen 2004), cognitive decline (Wilson et al. 2007), pain
(Aslund et al. 2010; Karayannis et al. 2019) and mortality (Patterson and Veenstra 2010;
Steptoe et al. 2013). This trigger may be more problematic in older people, due to
decreasing economic and social resources, functional limitations, the death of relatives and
spouses, and changes in family structures and mobility (Administration on Aging, 2013).
Research shows that social isolation and loneliness have an impact on health.
However, it is interesting to mention that different dimensions (objective or subjective) are
investigated in this construct of social isolation (Cornwell and Waite 2009; Valtorta et al.
2016). Objective social isolation is the physical separation, the absence, or inability to
interact with other people. Tools that address participation in groups, social activities and
events, frequency of interaction, and the social network are investigated (Cornwell and
Waite 2009; Coyle and Dugan 2012; Valtorta et al. 2016). On the other hand, subjective
social isolation is characterized by self-perceptions and quality of the relationships between
a given person with members of his/her social networks, as well as perceived integration
and involvement in social networks (Valtorta et al. 2016).
Coyle and Dugan (2012) also showed that both loneliness and objective social
isolation were significantly related to the presence of a mental health problem. Then, both
objective and subjective isolations are correlated but are not the same constructor (Shankar
et al. 2013). That phenomenon is possible to show when people have experienced objective
social isolation but they can feel subjectively isolated or not (Coyle and Dugan 2012).
1.3 Social isolation and pain
Studies suggest that social relationships have an important role in pain. Individuals
with larger self-reported social group size showed higher pain tolerance (Johnson and
Dunbar 2016). Experimentally-induced social exclusion and perceived social support
respectively increase and reduce the severity of acute experimental pain (Brown et al. 2003;
Eisenberger et al. 2006; Master et al. 2009). Inversely, poor relationships and self-imposed
isolation over time have been correlated with chronic pain (Smith and Osborn 2007;
Hormonal stress responses and anxiety are evoked by social isolation when
happening in the early life of adult rodents and social support can play a role as a buffer
against stress (DeVries et al. 2003). Moreover, there is evidence that social distress
potentiated the sensitivity to physical pain (Aslund et al. 2010). Eisenberger and
collaborators (2006) also showed that socially excluded individuals displayed lower pain
thresholds to unpleasant heat stimuli. Correlation between rheumatoid arthritis and low
levels of social support experienced higher levels of pain intensity at the subsequent three
and five years (Evers et al. 2003). In addition, chronic musculoskeletal pain has an
association with perceived social support and pain interference (Ferreira-Valente et al.
Biopsychosocial factors are also frequently regarded as significant factors that can
increase the risk of poor prognosis of low back pain, but the “social” component in the
biopsychosocial model has received little attention. Perceived social isolation is prevalent
in patients with low back pain of any duration (Hawthorne et al. 2013) and this can be a
crucial but under-investigated prognostic factor for that condition. The point prevalence of
patients who perceive at least some social isolation is 43% when they have low back pain,
being 24% higher than in the general population (Hawthorne et al. 2013).
The recurrent pain episodes have also been associated with a lack of understanding
about endometriosis symptoms and with the resignation of women during social isolation
(Mellado et al. 2016). Considering that, inflammatory and immunologic factors are
modified during endometriosis, and social isolation may also change it. The social isolation
can interfere on endometriosis via these factors (Cacioppo et al. 2011).
The sequelae of perceived social isolation associated with chronic pain include
maladaptive responses, work loss and financial security, being anxious with others,
experiencing loss of traditional family roles, losing care and concern for others, sexual
dysfunction, depression, anxiety and realizing that others do not understand the life lived
with low back pain (Bowman 1994; Schwartz and Slater 1991).
Depressive symptoms are an important factor to consider when interpreting the link
between social and physical health. Individuals with low back pain and higher levels of
baseline depression experienced a slower recovery process (Melloh, Elfering, Stanton, et al.
2013). Individuals with depressive symptoms and acute and subacute episodes of low back
pain (LBP) were more likely to have persistent pain in a 6-month follow-up (Melloh,
Elfering, Käser, et al. 2013).
In animals, the social isolation altered the neurochemical systems such as enhanced
presynaptic dopaminergic function in the nucleus accumbens and the prefrontal cortex, a
decrease in presynaptic serotonergic function, and an imbalance in dopamine and 5-
hydroxytryptamine (5-HT) in the frontal cortex (Crespi et al. 1992; Fone et al. 1996; Jones
et al. 1992). Animals that were isolated during the infancy display a long-lasting effect on
acute heat pain sensitivity, disturbing primarily the C-fiber-related pain pathways,
suggesting a selective disruption in the ascendingantero-lateral spinal-thalamic pathways
(Tuboly et al. 2009). Moreover, the housing conditions are an important factor evoking
modifications in pain perception in animals, and it was also showed that isolation of
juvenile animals caused significant changes in pain sensitivity, which might be due to
changes mainly in the number and activity of µ-opioid receptors (Defeudis et al. 1976; Van
Den Berg et al. 1999).
1.4 Multiple faces of pain pathways: from nociception to pain perception
According to the International Association for the Study of Pain (IASP), nociception
is referred as “activity that occurs in the nervous system in response to a noxious stimulus,”
whereas pain is “an unpleasant sensory and emotional experience associated with, or
resembling that associated with, actual or potential tissue damage” (Raja et al., 2020).
Nociception thus includes the mechanisms by which noxious stimuli are detected by the
peripheral nervous system, encoded, transferred, and unconsciously treated by the central
nervous system structures.
Sensitization of sensitive fibers, including nociceptive fibers, is the common
denominator after injury or inflammation, which results in the release of chemical
mediators from different cells. The released chemical mediators act by directly activating
the nociceptors or even sensitizing them (Julius 2001; Kandel 2014).
Chemical mediators can activate or sensitize nociceptors, which are free nerve
endings of pseudo-unipolar neurons dendrites, whose cell bodies are found in the ganglia of
the dorsal root of the spinal nerve and trigeminal nerve sensory ganglion that process these
traumatic or inflammatory stimuli (Kandel 2014; Millan 1999) Messlinger, 1997. The
axons of these pseudo-unipolar neurons, called primary afferent fibers, carry nociceptive
information to the central nervous system.
Three types of receptors for free nerve endings are associated with two types of
primary afferent nerve fibers. Considering a functional criterion, they are: (a)
mechanosensitive nociceptors with Aδ low myelinated and medium diameter fibers, with
conduction speeds of 5 to 30 m/s; (b) mechanothermal nociceptors with Aδ fibers, and (c)
polymodal nociceptors with not myelinated C fibers of small diameter with a conduction
speed of about 1 m/s, which respond to thermal, mechanical and chemical stimuli (Julius
2001; Millan 1999) (Figure 1).
Figure 1: Pain pathways from nociception to sensory discriminative perception and emotion
pain (Source authorship).
The nociceptive stimulus recruits peripheral nociceptors that carry the nociceptive
signal to the first somatosensory neuron located in the dorsal root ganglion of the spinal
nerve, which connects with the second-order neuron located in the dorsal horn of the spinal
cord. It is precisely situated on II, III, and V Rexed’s laminae, of the dorsal horn of the
spinal cord, in which the primary afferent neuron makes the first synapse with the second
neuron (Figure 1). The second neuron sends axons that will form the neoespinotalamic and
paleoespinotalamic tracts, after crossing the median plane of the spinal cord and sends
afferent ascending projections to the great supraspinal centres, such as the reticular
formation, the limbic system, the posterolateral ventral nuclei (neo-spinal-tract nucleus) and
intralaminar (paleoespinotalamic tract) of the dorsal thalamus (Marshand, 2012) (Figure 1).
The trigeminal component of the anterolateral system has its first neuron in Gasser's
semilunar ganglion, which establishes synapses in the spinal nucleus of the trigeminal
nerve, where the second-order neurons of the pathway are located, whose axons cross the
midline and comprise the trigeminal lemniscus, which goes to the posteromedial ventral
nucleus of the dorsal thalamus. From the dorsal thalamus, through the corona radiata, the
third-order neurons connect with the somesthesic cortex, where they spread
somatotopically (Marshand, 2012).
It is important to emphasize that the second neuron can connect with different nuclei
of the brain stem, including the periaqueductal gray matter (PAG) and the nucleus raphe
magnum (NRMg), which are areas involved in the endogenous downward modulation of
pain system. The primary (S1) and secondary (S2) somatosensory cortexes, which receive
afferents from the dorsal thalamus, are involved in the quality of the sensory perception of
pain, which includes location, duration, and intensity of pain. Tertiary neurons also project
to limbic structures, including the anterior region of the cingulate gyrus cortex (Cg1) and
the insula, which are involved with the affective and emotional components of pain
(Marshand, 2012), as well as the hypothalamic nuclei, parabrachial area and amygdaloid
complex (Hammond 1989). These connections emphasize that the pain is more than the
activation of sensory components. The anterior cingulated cortex also sends glutamatergic
inputs to the posterior hypothalamic nucleus, modulating the perception of painful stimuli
in a threatening situation (Falconi-Sobrinho et al. 2017).
1.5 Emotional aspects of pain
According to IASP, about one in five people suffer from chronic pain worldwide.
The effects on quality of life are devastating. A study published in 2006, analyzed 126
patients with chronic pain and found that the group had several affective and cognitive
impairments, such as insomnia (60%), difficulty to concentrate (36%), depression (33%),
and anxiety (27%). Even the professional life of the affected people seems to be affected:
52% of the participants had losses at work due to pain (Breivik et al. 2006).
Over the past few decades, the influence of anxiety on pain perception has been
extensively investigated. Anxiety is accepted as one of the determining psychological
factors in the subjective experience of pain (Tang and Gibson 2005). Asmundson and
collaborators (1996) pointed out the existence of a link between anxiety disorder and pain,
demonstrating that the prevalence of anxiety is higher in people who suffer from chronic
pain. Furthermore, chronic pain and anxiety disorders coexist in 45% of chronic pain
patients screening positive for an anxiety disorder (Asmundson and Katz, 2009).
Knaster and collaborators (2012) showed that the diagnosis of anxiety disorder
precedes the onset of pain in more than 75% of individuals. Similarly, Shaw and
collaborators (2010) identified that patients who suffered from low back pain were 2.45
times more likely to develop chronic low back pain when they were diagnosed with a
generalized anxiety disorder.
There is a high association of comorbidity between anxiety and chronic pain, and
some researchers postulate that this type of pain may be an expression of chronic post-
traumatic stress disorder (Grande et al., 2004; Otis et al. 2003). There are functional and
metabolic similarities between NP and post-traumatic stress disorder, with mPFC playing a
key role in the integration between that comorbid (Feldman 2004, Liberizon and Phan,
2003). There are reports in the literature showing in both human patients and laboratory
animals, that the presence of chronic pain causes changes in functional reorganizations in
cortical and subcortical structures, including mPFC (Apkarian et al. 2009; Baliki et al.
2006; Medeiros et al. 2019a,b, 2020a,b; Metz et al. 2009), dorsal thalamus (Apkarian et al.
2004), amygdaloid complex (Han et al. 2005; Ji et al. 2010), and anterior cingulate cortex
(ACC) (Li et al. 2010).
Considering the pain pathways. The nociceptive stimuli case action potentials that
get through of the anterolateral system and the neospinothalamic tract in the most important
spinal-thalamic tract reaching the primary somatosensory cortex, through the specific
thalamus-cortical system and is involved in the physical sensation of pain (Lumley et al.
2011). The affective experiences of pain-related connexions reach supraspinal brain
structures through the paleospinothalamic tract, which recruits the periaqueductal gray
matter, amygdaloid complex, parabrachial area, hypothalamus and insula (Lumley et al.
2011; Vogt et al. 1993, Hammond, 1989)
Information from these both pathways comes together in the ACC and insular
cortexes. Thus, it is the combination of nociceptive and affective inputs to these areas—
elicited by the same stimulus—that influences interoceptive homeostasis (Craig 2003) and
response prioritization (Lumley et al. 2011; Price 2000a). Hence, both types of information
about pain contribute to our subjective experience and, ultimately, our response to it. It is
from this theory that we seek to establish the anatomical links between emotions and pain
Several areas are consistently activated in PET and fMRI studies when pain is
involved. The second somatosensory (S2) and insular cerebral regions, as well as the ACC,
are the cortical areas most consistently activated during the experience of pain (Cauda et al.
2012; Peyron et al. 2000). The thalamus is often activated as well, as an intermediate
diencephalic relé regarding the somatosensory ascending neural pathways. These areas
reflect activation of the anterolateral system, especially where the spinal –thalamic tracts
converge on the insula and ACC. Meta-analytic connectivity modelling was utilized to
identify areas that were active across multiple types of stimuli, as well as attentional,
emotional, and reward tasks (Cauda et al. 2012) (Figure 1).
The insula, dorsal ACC, and thalamus were again consistently activated. The neural
activity in these structures reflects both external inputs of pain and internal reflection on
pain, much in line with Melzack and Casey’s two-stage theory of pain described previously
in brief (Melzack and Casey 1968). The ACC appears to be particularly important in the
affective interpretation of pain. Some investigation dissociated the circuitry involved in
emotional and attentional modulation of pain and showed that the ACC was the largest
modulator of mood and influenced pain unpleasantness, but not pain intensity. Attentional
modulation associated with pain intensity was not as robust but activated the anterior
insular cortex (Villemure and Bushnell 2009).
The ACC likely acts as a mediator between cognition and emotion, with
connections to the limbic system structures (Falconi-Sobrinho et al. 2017) and prefrontal
cortex (PFC), as well as to somatosensory areas (Stevens et al. 2011). Because the ACC is
so closely linked with affective processing and it is consistently activated during the
experience of pain, the ACC likely plays a role in affective regulation during the experience
of pain (Zugaib et al. 2014; Zugaib and Menescal-de-Oliveira 2017). Both emotional and
physical pain elicit activity in these common areas, and conditions that affect one system
(e.g., drugs, neural plasticity) may affect the function of the other-ultimately altering the
experience of pain.
1.6 Neurobiological aspects of social pain
Due to this close link, emotional pain appears to mimic certain aspects of physical
pain in terms of brain activity and pain perception. For example, social rejection elicits
similar activation in the same areas as physical pain, and greater sensitivity to physical or
social pain is associated with greater sensitivity to physical pain. Social organization is not
an exclusive characteristic of human beings; social ties are essential for the well-being and
survival of mammals (Baumeister and Leary 1995).
The impossibility of self-care after birth and during a postnatal period, mammals
need the support of a caregiver. Then, this longe period could have organized a "system of
social ties". This system, in turn, could use parts of the physical pain system to "alert" us
when we have lost a social bond. Considering that the distance from a caregiver is a threat
to survival. Feeling "hurt, anguished" with this separation leads the threatened person to
develop adaptive strategies to avoid distance (Panksepp 1998).
Social ties are important for survival. Thus, using a social attachment system
together with the physical pain system will capture attention and alert us to real or potential
damage in social relationships (Panksepp 1998). In this sense, social isolation, like what we
are living in, can cause unpleasant experiences, described as pain and recruits at least part
of the same neurobiological substrates that underlie experiences of physical pain. Multiple
ascending pathways carry physical pain information to supraspinal structures, adding
aspects of autonomic system activation, escape, motor orientation, arousal, and fear (Price
2000b). The integration between somatosensory inputs and cognitive aspects also seems to
happen in posterior parietal cortical areas (Friedman et al. 1986).
Nociceptive information pathways that integrate structures such as insular cortex
and amygdaloid complex converge at the level of the ACC, a mechanism by which somatic
perceptual and cognitive characteristics of pain would be integrated with rudimentary and
attentional emotional mechanisms (Price 2000b) (Figure 2). Thus, the ACC coordinates the
association of somatosensory characteristics of pain with pre-frontal brain mechanisms
involved in the association of significance and long-term implications for pain (Figure 2).
Studies show the involvement of these areas not only in the processing of physical
pain but also in social pain. Social pain is defined as the unpleasant experience that is
associated with actual or potential damage to one’s sense of social connection or social
value; such as showing to social rejection, exclusion, negative social evaluation, or loss
(MacDonald and Leary 2005). The analysis of neuroimaging has shown the activation of
structures like the dorsal (d) part of the ACC and insular cortex anterior in individuals who
have experienced social exclusion (Eisenberger 2012a). These regions are known to play a
role in the distressing experience of physical pain. Moreover, the dACC and AI may have a
modulatory role in the links between social rejection and both inflammatory activity and
depression. If we consider the components of pain, sensory-discriminative, and affective-
motivational, the last one is related to aspects of emotion, arousal, and behavioural
programming (Treede et al. 1999) (Figure 2).
Figure 2: Neural areas that have been shown to related physical pain, affective (emotive)
pain, social pain (Source authorship).
In this way, the processing of social suffering is dependent on the activity of brain
regions associated with the affective component of pain, involving the prevention of social
damage hazards and serves as a punishment-based reinforcement to teach organisms to
avoid threatening stimuli in the future.
In investigations performed in laboratory animals, the ACC injury (dorsal and/or
ventral divisions) reduces anguish-related vocalizations, behaviours related to social
separation in non-human mammals. In experiments of isolation and maternal separation
another encephalic area involved in the processing of suffering is the PAG (Hadland et al.
In human beings, cingulotomy induces in decreased self-awareness, together with a
reduced concern for other people's opinions or social judgments (Tow and Whitty, 1953).
Associated with that, patients can still feel and localize pain sensation (sensory component
intact) but the pain no longer “bothers” them (Foltz and White 1968). In addition,
individuals with more social support or who spend more time with friends show reduced
activity in the dACC and insula in response to social exclusion (Eisenberger, Taylor, et al.
2007). In contrast, greater self-reported social disconnection during real-world social
interactions is associated with greater activity in the dACC and PAG in response to social
exclusion (Eisenberger, Gable, et al. 2007). In this sense, there is support in the literature
for the critical role played by ACC in the processing the distress associated with social
separation or disconnection.
Another aspect that can be changed due to social isolation is the inflammatory
process in addition to changes in the transcriptional activity of the human genome. The
increased activity of the pro-inflammatory transcription controls neural pathways with
glucocorticoids responsible for the high risk of inflammatory disease in individuals who
experience chronically high levels of subjective social isolation (Wager et al. 2009). Also,
the increased activity of dACC and AI in a stressful situation and/or social isolation can
contribute to the increase in inflammatory activity (Wager et al. 2009). The increased
circulation of pro-inflammatory cytokines, such as IL-6, mediates the relationship between
social exclusion and depression and is related to the intensity of pain in some populations
(Sturgeon and Zautra 2016).
In a neurochemical perspective, opioids have already been shown to affect not only
analgesic but also to reduce the distress associated with separation (Eisenberger 2012a).
The endogenous opioid system is associated with regulation of the distress caused by
physical pain-inducing a neurochemical regulation of the distress associated with social
separation. In animals, low doses of exogenous opiates reduced distress-induced
vocalizations of socially isolated puppies as well as the pleasure associated with the social
connection (Panksepp et al. 1978). According to Way and collaborators (2009), individuals
with the G allele showed greater reactivity to social rejection in encephalic structures
(dACC and AI) previously demonstrated to be involved in the processing of social and
physical pain. Thus, dACC is considered a critical place for the influence of opioids on
social pain. The authors suggest that the A118G polymorphism, specifically related to the
µ-opioid receptor is generally involved in both social pain and physical pain (Way et al.
In rodents, social isolation is associated with a decrease of neurogenesis in the
hippocampus, an increase in cortisol levels (indicative of stress), and with anxiety-like
behaviour (Cinini et al. 2014). Among puppies, it has been shown that early life stress can
permanently impair hippocampus-dependent learning and memory in addition to increasing
susceptibility to depression by reducing adult neurogenesis in the hippocampus (Karten et
The social isolation causes neurological changes that can induce social pain.
Although neuroimaging studies show the activation of the same areas in situations of
physical and social pain, there is evidence that these same areas are activated in other
stressful situations (Eisenberger 2012b; Sturgeon and Zautra 2016). Thus, the role of these
structures, anterior cingulate córtex and the anterior insula, can be broader as a neural alarm
system for survival (Eisenberger 2012c). Almeida-Santos et al. (Almeida-Santos et al.
2019) demonstrated that animals in social isolation had alterations in the glutamatergic
neurotransmission in the olfactory bulb and the dorsal hippocampus, a neurochemical
phenomenon that the authors associate with the deficit of social memory in addition to
compromising communication between areas.
Interestingly, daily administration of acetaminophen compared to placebo in two
studies showed reduced self-reports of social pain, as well as reduced activity in both
dACC and AI, when experiencing social exclusion (DeWall et al. 2010).
1.7 The treatment of pain in the post-pandemic COVID-19
The return to clinical pain management will have to deal with the biopsychosocial
requirements of the post-Pandemic period of COVID-19. The resumption of clinical pain
management will have to cope with the biopsychosocial requirements of the post-pandemic
period of COVID-19. The health care professionals will have to face the challenge of
dealing with the overlap of physical and emotional pain and the possible process of
catastrophic pain triggered or aggravated by the COVID-19 pandemic.
Beyond the typical challenges of self‐managing a chronic disease, disease
management has become significantly more complex with the implementation of social
distancing, including limiting nonessential health care visits. This has led to confusion
about how patients with chronic diseases should balance managing their disease and
reducing their risk of infection. That adaptative process directly impacts clinical symptoms,
especially pain (Michaud et al. 2020).
The exposure of the population to traumas, such as witnessing and caring for
seriously ill people, perceived life threat, mortality and mourning, deaths of health
professionals, can impair the mental health of the population, and consequently, increase
the risks of developing psychological distress and progression to psychopathology,
including post-traumatic stress disorder (Neria and Sullivan 2011; Schultz and Engelhardt
Concerning the comprehension or eliminating the epidemic-associated stigma, it is
necessary to create strategies to deal with the psychological stress of the post-pandemic
period (C. Wang et al. 2020) and to identify its possible implications for the rehabilitation
process and management of pain. In fact, there is evidence that shows increased levels of
distress to suffering in people living in countries significantly affected by COVID-19 (C.
Wang et al. 2020; Xiang et al. 2020).
In addition, it is suggested that patients with suspected or confirmed infection with
SARS-CoV2 may experience fear and anxiety about the consequences of COVID-19,
including death and severe physical disability. Besides, the boredom, loneliness and anger
can be experienced by quarantined individuals. It is also suggested that the symptoms of
anxiety and distress can be aggravated in these people, symptoms that can also occur in
those who are in social isolation (Jahanshahi et al. 2020).
Studies show that individuals with severe illness or multiple comorbidities have
higher levels of psychological symptoms in the face of that crisis. The impact of the
COVID-19 pandemic in Spain was assessed and it was demonstrated that individuals who
reported chronic illnesses had higher average levels of stress, anxiety and depression in
comparison with participants who did not report such illnesses (Ozamiz-Etxebarria et al.
2020). In this sense, post-pandemic patients may become more vulnerable to the
frustrations and disabilities resulting from the disease and its physical symptoms,
particularly pain. People with chronic pain such as those with orthopedic or rheumatic
pathology often tend to manifest emotions of revolt, anger, anxiety or even depressive
symptoms, which are not only reflected in the interaction with others, but can also influence
negative, symptomatology and disease progression (Ozamiz-Etxebarria et al. 2020).
In a study that evaluate experiences of patients with rheumatic diseases in the
United States of America during the COVID‐19 (Michaud et al. 2020), the most commonly
reported emotions were anxiety, nervousness, worry, and fear. Some observed that
anxiety/stress seemed to worsen their arthritis symptoms.
Approximately half of the patients in a North American cohort described significant
disruption to their rheumatology care, including disrupted or postponed appointments and
self‐imposed or physician‐directed changes to medications (Sirotich et al. 2020). The
change or interruption of treatment can cause worse chronic pain, both due to treatment
failure and to the psychic symptoms of the post-pandemic period.
The perceived intensity of the painful symptoms is thus exacerbated by the
symptoms of disability, anxiety, depression, sleep disorders, poor quality of life and health
costs. Likewise, psychological distress has been identified as a potential way in which an
episode of pain influences the development of persistent disabling symptoms (Park and
Park 2020). Thus, health professionals may encounter the challenge of dealing with the
increase in painful symptoms and the difficulty of reducing the levels of physical disability
of patients. A good way to assess this intensity of pain perception is to adopt assessment
instruments that assess broader aspects of pain.
Increasing evidence has shown that pain science education positively affects pain,
disability, pain catastrophization, movement limitations and general health costs. For this, it
is necessary that both subjective and objective physical assessment, embrace a
biopsychosocial approach instead of just a biomedical procedure. Patients with chronic pain
suffer from severe fear, which should allow us to develop a treatment strategy that directly
reduces that aversive-stimulus-related emotion, thus improving the physical and
psychosocial well-being of these patients (Hall et al, 2020).
In a biopsychosocial view, psychological factors are believed to play an important
role in the onset and progression of chronic pain. The cognitive-behavioural model of
avoiding fear of chronic pain suggests that pain-related fear contributes to the development
and maintenance of pain-related disability (Dinner et al, 2016). Therefore, addressing the
beliefs, cognitions and behaviours associated with patients' pain symptoms has become an
important issue for consideration during the treatment, particularly of chronic pain. These
overlapping strategies impact pain surveillance, which in turn can also lead to increases in
the perception of pain severity.
Another point to be taken into account by the physician and physiotherapist in the
post-pandemic is that the process of catastrophizing pain, which worsens in the face of
psychological suffering linked or not to pain, may be present or even increased. According
to Severeijns and collaborators (2001), patients with chronic pain who catastrophize
reported greater pain intensity felt more incapacitated by their pain problem and
experienced more psychological suffering. Catastrophization was a powerful predictor of
pain intensity, disability and psychological distress, even when controlled by physical
impairment. Thus, we can conclude that catastrophization plays a crucial role in the
experience of chronic pain, contributing significantly to the variation in pain intensity, pain-
related disability and psychological suffering.
There is growing evidence that, when pain neuroscience education is provided to
patients with chronic musculoskeletal pain, it can result in decreased pain, pain
catastrophization and disability and improved physical performance (Puentedura and Flynn
2016; Wijma et al. 2016). Pain neuroscience education is increasingly used as part of a
physiotherapeutic treatment in patients with chronic pain. A thorough clinical
biopsychosocial assessment is recommended before pain neuroscience education to allow
an adequate explanation of pain neurophysiology and biopsychosocial interactions in an
interactive and patient-centred manner.
A more broadly analysis of pain, evaluating the somatic, cognitive, emotional,
behavioural and social factors trying to establish what is the most dominant mechanism of
pain, as well as assessing the provocative and disturbing biopsychosocial factors in patients
with chronic pain. The use of that approach allows the clinician to specifically classify
patients and adapt the treatment plan (Wijma et al. 2016). Concerning that approach, the
physiotherapist will be able to understand the processes of pain in the post-pandemic
period, observe its clinical implications, evaluate and outline the most assertive behaviours.
Inpatient consults require new approaches too. For example, many consultations
could occur in a nonpresential way, without the need to see the patient in person, with most
of the historic gathering occurring via telephone or videoconference with the primary team
members. The primary approach would be to assemble the patient's history, review the
data, write the note, discuss the case, formulate a differential diagnosis, and recommend a
treatment plan (Koumpouras and Helfgott 2020). That procedure, initiated on an emergency
basis for a pandemic period, can be implemented in the clinical monitoring of the patient
between consultations, as well as being a tool for interaction between the different health
professionals involved in the treatment of pain (Koumpouras and Helfgott 2020). Examples
of interventions that can effectively be delivered over the internet for patients with chronic
pain include: managing stress, addressing sleep disturbances, teaching mindfulness
practices, cognitive strategies, pacing activities, social support programs, simple physical
exercises, and observing a healthy lifestyle (Shanthanna et al. 2020).
It will be necessary to assess the impacts of COVID-19 on patients with chronic
pain, based on multidimensional and multi-professional information for better decision-
making and conducting the rehabilitation processes. The acceleration of ongoing processes
caused by pandemics can also improve medical procedures and protocols, as well as the
understanding of the need for more suitable conduct based on the individual as a human
being and not only focused on the clinical symptoms of his/her health conditions, including
2 Emotional-related neurosciences and social pain during the Covid-19
Emotion comes from the Latin "ex + movere" which means "to move out". In the
stressor event, as COVID-19 pandemic, this movement can be related to neuroplasticity
(Orrù et al. 2020). Neuroplasticity-associated emotions are inherent to the social process of
sensitization (Garland et al. 2010). Regarding that point of view, it is noticeable that the
pandemic outbreak experienced by people in several regions of the world has as a crucial
aspect for the activity of neural pathways, capable of decreasing the consciousness and
decision-making behaviours (O’Callaghan et al. 2017). The stressors processes, therefore,
promotes brain changes, coming from scientific education, which happens to produce and
preserve factors that have a social and emotional burden (Lupien et al. 2018).
In fact, the encephalon is impacted by the external environment to be sensitized
(Agorastos et al. 2018). Awareness comes from a critical and reflective process that results
in the formation of experienced subjects beyond being merely informed. This perspective
enables a broader understanding of human behaviour in the face of synaptic strengthening
and weakening in emotional situations (Padilla et al. 2016), such as the Covid-19
The pain arising from this phenomenon involves neural networks that affect
memory, attention, self-regulation (risk assessment behaviours), and executive functions
(decision making, planning, logical reasoning, etc.) (Chedid 2007; Cosenza 2008; Guerra et
al. 2004; Houzel 2012; Ribeiro 2013). Emotional and social pain can trigger adaptative
responses during the organism-environment interaction, and exert influence on limbic
neural systems underlying the behaviour, modifying neural connectivity, neuroplasticity,
coding and modulation of behavioural responses related to perception, attention, memory,
reasoning and problem solving (Tyng et al. 2017).
The COVID-19 pandemic threatening may also cause influence in human brain
development, influencing the cerebral neuroplasticity, with different peaks of synaptic
density coming from environmental stimuli that occur during life (Blakemore and
Choudhury 2006). The emotional pain comes from the possible cognitive "shake" that the
Covid-19 pandemic can cause, reflecting on the neuroplastic capacity of the individual and,
consequently, his/her social behaviour. In this follow-up, the relationship between
neuroplasticity and emotional pain, in Covid-19 pandemic time, can be characterized by the
involvement of health in its broad sense: physical, social and mental health.
The generation of the negative or positive impact of Covid-19 on behaviour and
development of the central nervous system involves the need for adaptive strategies of
improved socioemotional and cognitive control capacity during life, in order to avoid
consequences such as pain (Compare et al. 2014). Thus, the neuroplasticity of emotion-
related structures is currently under the threat stimuli represented by Covid-19 pandemic.
More specifically, the integrated activity of neural networks modulates autonomic
responses as well as somatosensitivity (Christensen et al. 2020).
In this context, the limbic system, which according to recent advances in
neuroimaging, acts as the neuroanatomical basis of emotional behaviour, is highlighted as
one of the regions to be possibly affected by the SARS-Cov2 virus. Moreover, it fits the
thought that most of the ascending reticular activating Sistem (ARAS) neurons situated in
the brainstem will critically influence the activation of the cerebral cortex during pain
suffering, elaboration of emotions and during social threatening situations (Venkatraman et
At a socio-emotional consideration and the consequent emotional pain in face of the
Covid-19 pandemic, it is possible to think about the direct influence on the movement of
people in face of the prophylactic measure of social isolation, probably due to the
importance of the modulation of the connection between the ventral striatum and the motor
cortex, through the nigro-thalamic pathway (Aoki et al. 2019).
The Covid-19 pandemic, therefore, involves synaptic changes and the formation of
new patterns of neural activity. The approach on neuroplasticity has been constant in the
scientific environment, especially investigations that seek a multisensorial understanding
(Oby et al. 2019).
Notably, the number of publications involving emotional and social pain is growing;
however, significant contributions are still small. Associated with the new context of life
that the Covid-19 pandemic has imposed with direct influences on emotional and cognitive
aspects of human behaviour, and on the interaction with the social environment in which
they are living, it is suitable the improvement of our skills for the understanding the human
behaviour and the emotional pain arising from the process of adaptation in a threatening
situation. The neuroscientific approach of the human brain activity in the time of
coronavirus will contribute to the opening of paths for a broader understanding of human
behaviour, during the social isolation, highlighting the physical, emotional and social pain
during the covid-19 pandemic.
Conflict of Interest: The authors declare that there are no conflicts of interest with this
Author Contributions: P. Medeiros participated in conceptualization, writing – original
draft, Writing – review & editing; A.C Medeiros, J.P.C.Coimbra, L.E.Teixeira and C.J.
Salgado participated in writing – original draft, J.A. da Silva, N.C.Coimbra, R.L. de Freitas
conceptualization, writing – original draft, Writing – review & editing.
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