Brain Stress Mapping in COVID-19 Survivors Using MR Spectroscopy: New Avenue of Mental Health Status Monitoring

Abstract

Background: Coronavirus (COVID-19) has emerged as a human catastrophe worldwide and it has impacted human life more detrimentally than the combined effect of World war I and II. Various research studies reported that the disease is not confined to the respiratory system but also leads to neurological and neuropsychiatric disorders suggesting that the virus is potent to affect the Central Nervous System (CNS). Moreover, the damage to CNS may continue to rise even after the COVID-19 infection subsides which may further induce a long-term impact on the brain, resulting in cognitive impairment.
Proposed Hypothesis: Neuroimaging techniques provide the ability to detect and quantify pathological manifestations in the brain of COVID-19 survivors. In this context, a scheme based on structural, spectroscopic, and behavioral studies could be executed to monitor the gradual changes in the brain non-invasively due to COVID-19 which may further help in quantifying the impact of COVID-19 on the mental health of the survivors.
Discussion: Extensive research is required in this direction for identifying the mechanism and implications of COVID-19 in the brain. Additionally, longitudinal follow-up studies are also needed to perform for monitoring the effects of this pandemic on individuals over a prolonged period.

Full text

Journal of Alzheimer’s Disease 83 (2021) 523–530
DOI 10.3233/JAD-210287
IOS Press
523
Hypothesis
Brain Stress Mapping in COVID-19
Survivors Using MR Spectroscopy:
New Avenue of Mental Health Status
Monitoring$
Avantika Samkariaa, Khushboo Punjabia, Shallu Sharmaa, Shallu Joona, Kanika Sandala,
Tirthankar Dasguptab, Pooja Sharmacand Pravat K. Mandala,d,∗
aNeuroimaging and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre, Gurgaon, India
bMoner Alo, Psychiatric Clinic, Kolkata, West Bengal, India
cMedanta Institute of Education and Research, Medicity, Gurgaon, India
dFlorey Institute of Neuroscience and Mental Health, Melbourne School of Medicine Campus,
Melbourne, Australia
Accepted 29 June 2021
Pre-press 9 July 2021
Abstract. Coronavirus (COVID-19) has emerged as a human catastrophe worldwide, and it has impacted human life more
detrimentally than the combined effect of World Wars I and II. Various research studies reported that the disease is not
confined to the respiratory system but also leads to neurological and neuropsychiatric disorders suggesting that the virus
is potent to affect the central nervous system (CNS). Moreover, the damage to CNS may continue to rise even after the
COVID-19 infection subsides which may further induce a long-term impact on the brain, resulting in cognitive impairment.
Neuroimaging techniques is the ideal platform to detect and quantify pathological manifestations in the brain of COVID-19
survivors. In this context, a scheme based on structural, spectroscopic, and behavioral studies could be executed to monitor the
gradual changes in the brain non-invasively due to COVID-19 which may further help in quantifying the impact of COVID-
19 on the mental health of the survivors. Extensive research is required in this direction for identifying the mechanism and
implications of COVID-19 in the brain. Cohort studies are urgently required for monitoring the effects of this pandemic on
individuals of various subtypes longitudinally.
Keywords: Brain, cognition, COVID-19, gamma-aminobutyric acid, glutathione, magnetic resonance spectroscopy, mental
health, psychiatry
$Prof. Pravat Mandal dedicates this article to the fond memory
of Prof. Partha Raghunathan, a brilliant mind, who left us due to
COVID-19.
∗Correspondence to: Pravat Kumar Mandal, Professor and Sci-
entist VII, Neuroimaging and Neurospectroscopy Laboratory,
National Brain Research Centre, India. E-mails: pravat.mandal@
gmail.com, pravat@nbrc.ac.in; Honorary Professor, Florey Inst-
itute of Neuroscience and Mental Health, Melbourne School of
Medicine Campus, Melbourne, Australia. E-mail: pravat.mandal
@florey.edu.au.
INTRODUCTION
Coronavirus (COVID-19) is an infectious disease
caused by severe acute respiratory syndrome corona
virus-2 (SARS-CoV-2). COVID-19 came into exis-
tence from Wuhan City, China in December
2019 [1]. The World Health Organization (WHO)
declared COVID-19 a pandemic on 11 March
2020 due to the continual dissemination of this
disease throughout the world [2]. According to
ISSN 1387-2877/$35.00 © 2021 – IOS Press. All rights reserved.

524 A. Samkaria et al. / Monitoring COVID-19 Induced Mental Health Using MRS
the WHO, as of 29 June 2021, a total of
181,176,715 cases including 3,930,496 deaths have
been confirmed globally due to COVID-19, where
30,316,897 cases with 397,637 fatalities are reported
solely from India [3]. A variety of precautionary
measures have been outlined by the WHO to pro-
tect humans from this infectious disease such as
social distancing, wearing a mask, avoiding crowds,
and regular cleaning of hands, etc. [4]. Despite con-
sidering these protective measures, the virus is still
continuously spreading worldwide and the number
of individuals affecting by COVID-19 is increasing
day by day. The mortality rate is too high in elderly
patients with low immunity due to nutritional defi-
ciencies [5]. In view of this, the identification of
effective drugs is vital for eradicating viral load from
the body of the individuals affected with COVID-
19 [6]. According to the WHO, a total of fifteen
vaccines have been developed up to now and some
of them are approved to use on an emergency basis
from the United States of America, Germany, United
Kingdom, Russia, China and India.
The main characteristic of this disease is pneumo-
nia [7]; however, cough, fever, dyspnea, anosmia,
myalgia, sore throat, gastrointestinal penetrations,
and rhinorrhea are the clinical manifestations that
are possessed by an individual infected by COVID-
19 [2, 8–10]. The infection is not limited to the
respiratory system but also adversely affects other
vital organs such as the heart, liver, and kidney as
well as brain [10–12]. Increased loneliness, isola-
tion, distress, anxiety, and depression can trigger the
onset of psychological illness in people [9, 13]. As
a matter of this fact, post-traumatic stress disorder,
depression, obsessive-compulsive disorder, and anx-
iety have been found as the most prevalent disorders
in the patients recovered from COVID-19 [14–16].
Human ability to perceive, manage, update, and
act on information in accordance with past experi-
ences contribute to cognitive function which largely
depends on the structural and functional integrity of
the prefrontal cortex [17]. Exposure to stress can
disrupt prefrontal cortex (PFC) function, causing
cognitive impairments [18, 19]. Numerous mental
illnesses—including obsessive-compulsive disorder,
depression, and anxiety disorders, etc., are character-
ized by PFC dysfunction [20]. Two recent studies,
one from the ward of a general hospital and the other
from a temporary quarantine facility, have shown
that as high as 9.4%, 15.1%, 24.5%, and 96.2% of
the COVID-19 patients had severe depressive, anx-
iety, and post-traumatic stress disorder symptoms.
COVID-19 itself can put a lot of stress on the brain
due to lockdown and complete isolation [21–23].
Many researchers and scientists have determined the
presence of the SARS-CoV-2 virus in a variety of
brain tissues such as cerebrospinal fluid (CSF), glial,
and neuronal cells via genomic sequencing which is
indicative of serious damage to the CNS [24]. The
presence of SARS-CoV-2 RNA in CSF suggests a
possible association of SARS-CoV-2 infection with
neurological symptoms in COVID-19 patients [10,
25–27].
The FLAIR and diffusion weighted images have
also reported non confluent multifocal white mat-
ter hyper-intensities in the affected individuals along
with other imaging alterations [8, 28–30]. More-
over, the damage to CNS may continue to rise even
after the pulmonary infection subsides. COVID-19
infection in the brain can be associated with ext-
reme physical and psychological stress which stim-
ulates the hypothalamic-pituitary-adrenal axis and
aggravates neuroinflammation [31]. It is important
to note from a previous study that cognitive dis-
orders and neuroinflammation are correlated with
each other [9, 32]. A significant decline in cog-
nitive functioning has also been identified through
low scores of neuropsychological tests (continuous
performance test), greater reaction time, a deficit
in attention and executive functioning of COVID-
19 recovered patients [21, 22, 33–36]. Structural
changes have also been determined in the brain of
COVID-19 patients as compared to the non-infected
ones from a variety of studies where the researchers
claimed enlarged volumes of several brain regions
like the hippocampus, Heschl’s gyrus, olfactory cor-
tices, cingulate gyrus, and Rolandic operculum [23,
37]. Anatomically distinct regions of the nasophar-
ynx and brain show the presence of SARS-CoV-2
RNA and protein. This has been confirmed by the
autopsy studies of the patients [37]. Furthermore, a
description of morphological changes related to the
infection such as thromboembolic ischemic infarc-
tion of the CNS has been given. This suggests the
evidence of SARS-CoV-2 neurotropism. A meta-
analysis study indicates that no virus is present in
the CSF of patients and there is no direct neuroinva-
sion [38]. However, other groups of researchers have
suggested that SARS-CoV-2 seems to follow neu-
roanatomical structures which further penetrates into
defined neuroanatomical areas such as the primary
respiratory and cardiovascular control center in the
medulla oblongata [37, 39]. Therefore, it is impor-
tant to implement long-term studies for determining

A. Samkaria et al. / Monitoring COVID-19 Induced Mental Health Using MRS 525
the correlations among the clinical profile, laboratory
investigations, and radiological observations besides
neuropathological studies for an in-depth understand-
ing of the neurological manifestations in the patients
recovered from COVID-19. In this context, a scheme
for examining the glutathione (GSH), glutamatergic,
and GABAergic systems in hippocampal and dorso-
lateral prefrontal cortex (DLPFC) area of the brain
has been proposed. Additionally, the implications of
neuropsychological evaluation in diagnosing early
mental health problems in COVID-19 survivors has
also been outlined. The major rationale behind the
proposed scheme is the increased level of oxidative
stress in COVID-19 survivors which further con-
tributes to the pathogenesis of several neurological
diseases due to depletion of antioxidants.
COVID-19 INFECTION IN BRAIN: A
POSSIBLE MECHANISM
Recent research findings suggest that coronavirus
may enter the CNS via two pathways: direct [40] and
indirect [41]. In the direct pathway, the virus may
enter via the blood-brain barrier, blood-CSF barrier,
and retrograde axonal transport to reach the neuronal
cell bodies in the CNS (see Fig. 1). The olfactory,
respiratory, and enteric nervous system networks are
the three possible pathways through which retro-
grade axonal transport can occur [12–15]. Ongoing
research suggests that SARS-CoV-2 is likely to enter
the nervous system by crossing the neural–mucosal
interface in olfactory mucosa, which subsequently
deteriorates the close domain of olfactory endothelial,
mucosal, and nervous tissue, involving the delicate
sensory and olfactory nerve endings [37]. Other
researchers have also reported that from the olfac-
tory bulb, the virus may tend to target deeper parts of
the brain such as the brainstem and thalamus by trans-
synaptic transfer which has also been described for
several distinct viral diseases. They suggest that the
infection of the respiratory center of the brain might
take place which explains the respiratory breakdown
in patients [42].
In respect to the indirect mechanisms, researchers
proposed that respiratory failure-induced hypoxia
and immune system malfunction may lead to neu-
ronal damage [4, 43]. The pro-inflammatory cytok-
ines (IL-6 and TNF-␣) are released in abundance in
response to a viral infection which causes excessive
Fig. 1. A schematic representation of COVID-19 virus routes to the respiratory system and the brain. A) COVID-19 infection routes for brain
and lung damage, B) invasion of the SARS-CoV-2 into the nervous system through the blood-brain barrier, and C) intrusion of SARS-CoV-2
into lungs by fusing with an angiotensin-converting enzyme (ACE2). Reproduced with permission from the publisher [40]. Ab, antibody;
ACE2, angiotensin-converting enzyme 2; CSF, cerebrospinal fluid; ER, endoplasmic reticulum; TNF, tumor necrosis factor.

526 A. Samkaria et al. / Monitoring COVID-19 Induced Mental Health Using MRS
inflammation of the blood-brain barrier [10, 41]. Con-
sequently, the permeability of the blood-brain barrier
is increased which further provides a pathway for
the virus to enter the brain indirectly. Infection of
the peripheral myeloid cells is another possibility
through which the virus may give rise to the psy-
chiatric symptoms indirectly by causing neuroinflam-
mation and virus-induced neuropathology [44].
OXIDATIVE STRESS, ANTIOXIDANTS
AND NEUROTRANSMITTERS
Oxidative stress can be described as the increased
production of reactive oxygen species and deple-
tion of antioxidants which further contributes to the
pathogenesis of several neurological diseases [5].
In patients infected with COVID-19, a high neu-
trophil to lymphocyte ratio has been observed which
is strongly associated with an excessive level of reac-
tive oxygen species. Consequently, the increasing
load of viral infection causes a decrease in antioxi-
dant defense. GSH deficiency appears to be a primary
factor in enhancing SARS-CoV-2-induced oxidative
damage which further gives rise to many clinical
expressions such as multiorgan failure, acute respi-
ratory distress syndrome, and even death in patients
with COVID-19 infection [40]. GSH is the most
important antioxidant in the human brain which
plays a vital role in antioxidant defense. A variety
of studies related to postmortem and neurologi-
cal disorders have observed a significant depletion
in GSH through magnetic resonance spectroscopy
(MRS) [45]. Detection of extended and closed con-
formers of GSH has also been performed using the
MEGA-PRESS sequence [46]. Alterations of GSH
conformers is also detected [47]. Thus, measuring
GSH for comparison between patient and control
groups can be performed. Recently, it has also been
found that GSH and its precursor’s supplements aid in
recovery from respiratory distress in patients infected
with COVID-19 [48, 49]. GSH has been identified as
a source that can inhibit the main protease (Mpro) of
COVID-19 [50]. In this context, the use of GSH as
a supportive strategy for the treatment of COVID-19
infection can be recommended after a successful trial.
Primary excitatory and inhibitory neurotransmit-
ters, i.e., GABA and glutamate also play a key
role in modulating activity in the brain circuitry
[51, 52]. Prolonged stress can cause loss of pre-
frontal glutamate transmission that may alter the
hippocampal memory formation leading to dysfunc-
tion in cognitive function [53]. Dysfunction of the
glutamatergic system can give rise to defects in
neurotransmission, and cell viability which is fur-
ther implicated in various psychiatric disorders [54].
Stress-induced alterations in the functionality of
GABAergic inhibitory neurotransmission and synap-
Fig. 2. Detection of GSH, GABA+, and Glx metabolite from the DLPFC of a healthy young volunteer using 3T (Philips, Innova) scanner
at NBRC. A) T2w image with a voxel placed in DLPFC region in the brain for acquiring GSH and GABA. B) Closed and extended GSH
conformers at 2.95 and 2.80 ppm [46] with aspartate moiety signals from N-Acetyl-Aspartate at 2.67 ppm (NAA). C) MRS signal representing
the peaks of GABA and glutamine/glutamate (Glx) where the baseline spectra and fitted spectra are shown in blue and red, respectively.

A. Samkaria et al. / Monitoring COVID-19 Induced Mental Health Using MRS 527
tic integrity in the PFC may lead to dysfunction of
PFC microcircuitry. This may further trigger cogni-
tive impairments due to disruption in the execution
of behavioral responses [55]. Therefore, the level
of glutamate and GABA can serve as a promising
parameter to monitor mental health and psychi-
atric disease-associated conditions. SARS-CoV-2 has
neurotrophic properties which cause various CNS
manifestations including psychiatric diseases [56].
There has been growing evidence of patients suffering
from psychiatric diseases possibly due to COVID-19
[57]. In view of this, the involvement of GABAgeric
neuronal dysfunction in psychiatric disorders and
associated mechanism has become an active area of
research. Many studies have shown heterogeneous
results while measuring the GABA level in patients
with psychiatric disorders [58]. The level of GABA
for some patients has increased while the GABA level
remained unaltered for other patients. Hence, a lon-
gitudinal follow-up study can also be performed to
correlate the GABA level with psychiatric problems.
All the above-discussed antioxidants and neu-
rotransmitters have potential implications for psy-
chiatric disorders in COVID-19 affected patients.
Implementation and validation of imaging and spec-
troscopy technologies (MRI and MRS) can help in
finding out structural as well as metabolic changes
in the brain [59]. Literature describing the neuro-
logic symptoms of COVID-19 infection is increasing
rapidly. Despite this, there are only a few pub-
lished sources that demonstrate the findings based
on neuroimaging techniques to monitor neurological
infection in COVID-19 patients [29]. Researchers are
analyzing the hyperintensities from FLAIR images
and metabolites information from single-voxel MRS
which indicates the changes in structure and the level
of metabolites in the brain, respectively [60, 61].
Based on the prior knowledge, we are proposing a
scheme for examining the GSH, glutamatergic sys-
tems in the hippocampal and dorsolateral prefrontal
cortex area of the brain. Additionally, a neuropsycho-
logical evaluation is also likely to help in diagnosing
the mental health problems in COVID-19 survivors
[62].
CONCLUSION
In this COVID-19 pandemic situation, worldwide
intense efforts have helped to detect the pathology
of the SARS-CoV-2 virus in humans and determined
the post-recovery effects of the virus on their men-
tal health. A variety of case studies and reports have
suggested a probable relationship between the viral
infection due to SARS-CoV-2, oxidative stress, and
neurological symptoms. The possibility of gradual
damage to the brain and indistinct neurologic clinical
manifestation requires further investigation to deter-
mine its long-term neurologic consequences. The
non-invasive imagining-based strategy supported by
psychiatric and neuropsychological evaluation could
be a combined initiative in the direction of finding a
correlation between the alteration in antioxidant’s and
neurotransmitters’ concentration besides the struc-
tural changes in the brain to quantify the neurological
impact caused by the virus on the mental health of
COVID-19 survivors. This manuscript is a sincere
attempt to highlight the impact of the SARS-CoV-2
for neurological and neuropsychiatric manifestation
to make a top research priority. We have initiated
cohort study specifically focused on mental health
monitoring using brain structural and neurochemi-
cal data by MRI/MRS and behavioral data analysis
longitudinally.
ACKNOWLEDGMENTS
Dr. Pravat Mandal (Principal Investigator) thanks
for partial financial support from various agencies
(Tata Innovation grant, and Indo Australian strategic
funding to PKM). Thanks to the computing support
of NBRC for basic infrastructure support.
Authors’ disclosures available online (https://
www.j-alz.com/manuscript-disclosures/21-0287r1).
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