Significant outcomes
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The higher the FCV score, the more atrophy of the right posterior cingulate cortex was observed over time in patients with mild cognitive impairment or subjective cognitive decline.
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The COVID-19 epidemic might affect not only cognitive function but also cerebral morphology.
Limitations
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All subjects were not only exposed to psychological stress in relation to the COVID-19 disaster but also decreased their social and physical activity due to restrictions on going out to prevent the spread of infection. It is difficult to clarify the interaction among these factors.
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If changes in regional brain volume were affected by anxiety or depression, it is necessary to consider whether these changes will be reversible after the diminishment of the pandemic.
Introduction
To combat the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), on April 7, 2020 the government of Japan issued a state of emergency in seven major cities in conjunction with the Special Measures Law and then further expanded the directive to all of Japan on April 16th. As a result, people refrained from going out and attending schools, and the operation of restaurants and entertainment facilities was restricted. The state of emergency was lifted after approximately 6 weeks, but the infection has continued to spread since then, and the government has urged people to change their lifestyles, such as by taking various measures to prevent infection and curtail their activities.
Hospitals were also required to undergo major changes. Each hospital was required to set up a dedicated COVID-19 ward, and measures were taken such as restricting visits, limiting acceptance of inpatients and bed occupancy rates, reducing the frequency of outpatient visits, and replacing various types of hospital visits with telephone visits. In addition, in psychiatric departments, dementia day care had to be interrupted, and the rehabilitation of cognitive functions for day care users was temporarily suspended (at our hospital, Tsukuba University Hospital, dementia day care was suspended from March 2020 to October and has since restarted with limited activity). Restrictions of hospital visits were similarly initiated by the patients themselves, who tended to avoid going out in their daily lives, and refrained from visiting the hospital due to the fear of COVID-19 infection. With increasing reports of the severity of COVID-19 infections, fear of infection grew stronger, especially in the elderly (Alonso-Lana et al., Reference Alonso-Lana, Marquié, Ruiz and Boada2020; Shahid et al., Reference Shahid, Kalayanamitra, McClafferty, Kepko, Ramgobin, Patel, Aggarwal, Vunnam, Sahu, Bhatt, Jones, Golamari and Jain2020).
Reduction of social activities, such as restrictions on going out to prevent the spread of COVID-19, caused deterioration of cognitive function in patients with dementia. Isolation has been reported to impair cognitive function in patients with dementia, including by deteriorating memory (Ismail et al., Reference Ismail, Kamel and Al-Hashel2021) and by promoting agitation, depression, anxiety, and apathy (Barguilla et al., Reference Barguilla, Fernández-Lebrero, Estragués-Gázquez, García-Escobar, Navalpotro-Gómez, Manero, Puente-Periz, Roquer and Puig-Pijoan2020; Lara et al., Reference Lara, Carnes, Dakterzada, Benitez and Piñol-Ripoll2020). It has also been reported that the longer the isolation, the more severe these neuropsychiatric symptoms become (Boutoleau-Bretonnière et al., Reference Boutoleau-Bretonnière, Pouclet-Courtemanche, Gillet, Bernard, Deruet, Gouraud, Mazoue, Lamy, Rocher, Kapogiannis and El Haj2020). Moreover, actual infection with the SARS-CoV-2 virus has been reported to have direct effects on the brain, such as olfactory bulb inflammation and oedema (Mahalaxmi et al., Reference Mahalaxmi, Kaavya, Mohana Devi and Balachandar2021; Miners et al., Reference Miners, Kehoe and Love2020; Paliwal et al., Reference Paliwal, Garg, Gupta and Tejan2020).
It is known that anxiety promotes the progression of dementia (Mah et al., Reference Mah, Binns and Steffens2015) and reduces the volume of brain regions including the amygdala (Blackmon et al., Reference Blackmon, Barr, Carlson, Devinsky, DuBois, Pogash, Quinn, Kuzniecky, Halgren and Thesen2011; Yang et al., Reference Yang, Yin, Svob, Long, He, Zhang, Xu, Li, Liu, Dong, Zhang, Wang and Yuan2017), but there has been no report on the relationship between the fear caused by COVID-19 and brain volume. Therefore, we hypothesised that fear of COVID-19 may cause brain atrophy, just as anxiety causes atrophy in amygdala.
In this study, we analysed potential associations between changes in regional brain volume over time, as measured by magnetic resonance imaging (MRI), and COVID-19-related fear, as quantified by the Fear of Coronavirus Disease 2019 Scale (FCV-19S).
Methods
Participants
Twenty-five elderly participants who regularly attended our hospital’s dementia day care programme and were diagnosed with mild cognitive impairment (MCI) (Petersen, Reference Petersen2004) were enrolled. All participants had a score of 24–30 on the Mini-Mental State Examination (MMSE-J) (Ideno et al., Reference Ideno, Takayama, Hayashi, Takagi and Sugai2012) or a Clinical Dementia Rating (CDR) (Morris, Reference Morris1993) of 0.5 or had been diagnosed with subjective cognitive decline (SCD) (Jessen et al., Reference Jessen, Amariglio, van Boxtel, Breteler, Ceccaldi, Chételat, Dubois, Dufouil, Ellis, van der Flier, Glodzik, van Harten, de Leon, McHugh, Mielke, Molinuevo, Mosconi, Osorio, Perrotin, Petersen, Rabin, Rami, Reisberg, Rentz, Sachdev, de la Sayette, Saykin, Scheltens, Shulman, Slavin, Sperling, Stewart, Uspenskaya, Vellas, Visser, Wagner and Group2014) at the time of examination in 2020.
All participants regularly visited the outpatient Department of Psychiatry at the University of Tsukuba Hospital and undertook cognitive tests and an MRI scan once a year. Applicants were excluded if they had a prior medical history of central nervous system disease or severe head injury, or if they met the criteria for substance abuse or dependence. After the study was explained to each participant, his or her written informed consent was obtained for participation in the study. This study was approved by the Ethics Committee of the University of Tsukuba Hospital, Japan (approval no. H28-187).
The Fear of Coronavirus Disease 2019 Scale (FCV-19S)
FCV-19S is a quantitative measure of COVID-19 fear (Ahorsu et al., Reference Ahorsu, Lin, Imani, Saffari, Griffiths and Pakpour2020), and previous studies have validated its usefulness (Midorikawa et al., Reference Midorikawa, Aiba, Lebowitz, Taguchi, Shiratori, Ogawa, Takahashi, Takahashi, Nemoto, Arai and Tachikawa2021). The FCV-19S includes seven items with a 5-point Likert scale (1–5) (1: strongly disagree; 2: disagree; 3; neither agree nor disagree; 4: agree; 5: strongly agree) and has the following two subscales: emotional fear reaction consisting of anxiety and fear (factor 1: questions 1, 2, 4, and 5) and symptomatic expressions of fear consisting of sweating, palpitation, insomnia, etc. (factor 2: questions 3, 6, and 7). They indicated validity and reliability by verifying the correlation between the total score and subscale (factor 1, factor 2) of FCV-19S and Kessler Screening Scale for Psychological Distress, Generalized Anxiety Disorder-7 and Impact of Event Scale-Revised (Midorikawa et al., Reference Midorikawa, Aiba, Lebowitz, Taguchi, Shiratori, Ogawa, Takahashi, Takahashi, Nemoto, Arai and Tachikawa2021).
In this study, the total score and subscales were evaluated. The participants took the FCV-19S during the COVID-19 outbreak period.
MRI data acquisition and processing
MRI scans were undertaken twice for each participant, once before (from January 2019 to February 2020) and once after the outbreak of the COVID-19 pandemic (after April 2020). MRI scans were performed on a 1.5-tesla MR system (Avanto, Siemens, Erlangen, Germany). Three-dimensional T1-weighted images were acquired in the sagittal plane (repetition time/echo time, 2400/3.52; voxel size, 1.25 × 1.25 × 1.2 mm3; field of view, 240 × 240 mm; flip angle, 8°; number of signals acquired, 1), yielding 160 contiguous slices through the brain.
Post-processing of the MRI data
To evaluate the individual differences of regional brain volume longitudinally, we calculated the regional grey matter volume and intracranial volume automatically using the longitudinal image processing function in the Freesurfer (ver. 6.0.0) software package (http://surfer.nmr.mgh.harvard.edu/fswiki/Fstutorial/LongitudinalTutorial) running on Ubuntu 18.04 based Lin4Neuro (Nemoto et al., Reference Nemoto, Dan, Rorden, Ohnishi, Tsuzuki, Okamoto, Yamashita and Asada2011). FreeSurfer automatically segmented the brain along the line of the Desikan-Killiany and Aseg atlas. Then, we estimated the atrophy rate of the regional grey matter using the following formula:
atrophy rate per day = [(regional volumespre/eTIVpre) − (regional volumespost/eTIVpost)]/duration of the scans
Here, eTIV means the estimated total intracranial volume automatically calculated using the Freesurfer software.
Statistical analysis
The statistical analyses were performed using SPSS software ver. 23 (SPSS Japan, Tokyo). We also evaluated the relationship between the atrophy rate per day and the scores of FCV-19S by partial correlation analysis using the subjects’ age, sex, and years of education as covariates. For multiple comparisons, a p value ≦0.001 was regarded as statistically significant.
Results
The demographic and clinical characteristics of the participants are shown in Table 1. The mean age was 75.6 ± 6.5 years (range: 61–90 years), and there were 15 men and 10 women. The mean score on the MMSE performed in 2020 was 27.8 ± 1.8 (range: 24–30), and the mean education history was 14.0 ± 3.0 years (range: 6–20 years). The mean interval between the MRI examinations in 2019 and 2020 was 424.2 ± 72.7 days.
Table 1. Characteristics of the participants
MMSE: Mini-Mental State Examination; SD: standard deviation.
We compared brain MRIs in 2019 (pre-epidemic) and 2020 (post-epidemic). The mean regional grey matter volumes are shown in Table 2. Table 3 shows the correlation between the daily atrophy rate and FCV-19S. There was a positive correlation between the total score of FCV-19S and the atrophy rate per day in the right posterior cingulate cortex (p = 0.002, r = 0.617). We then evaluated the correlation between the subscales of the FCV-19S and grey matter shrinkage of the subjects. We found that there was also a significant positive correlation between the score of factor 2 and the reduction of the right posterior cingulate cortex volume per day (p < 0.001, r = 0.657).
Table 2. Regional mean volumes of the participants
Table 3. Relationships between the regional atrophy rate and the fear of COVID-19 scale
* p < 0.005.
** p < 0.001.
Discussion
In this study, we examined changes in regional brain volume on head MRI between before and after the start of the COVID-19 epidemic in patients with MCI or SCD to clarify the effect of fear of COVID-19 on the regional brain volume over time. We found that the FCV-19S score was associated with the right posterior cingulate cortex volume. To our knowledge, this is the first study to show a relationship between fear of COVID-19 and the rate of regional brain atrophy.
The shock caused by the COVID-19 pandemic is severe, and previous studies have shown an increase in mental problems, including anxiety, depression, insomnia, and post-traumatic stress disorder (PTSD), in the general population (Serafini et al., Reference Serafini, Parmigiani, Amerio, Aguglia, Sher and Amore2020, Talevi et al., Reference Talevi, Socci, Carai, Carnaghi, Faleri, Trebbi, di Bernardo, Capelli and Pacitti2020). The FCV-19S is a scale that quantitatively evaluates COVID-19 fear with seven questions (Midorikawa et al., Reference Midorikawa, Aiba, Lebowitz, Taguchi, Shiratori, Ogawa, Takahashi, Takahashi, Nemoto, Arai and Tachikawa2021), and the Japanese version has also been verified (Midorikawa et al., Reference Midorikawa, Aiba, Lebowitz, Taguchi, Shiratori, Ogawa, Takahashi, Takahashi, Nemoto, Arai and Tachikawa2021; Masuyama et al., Reference Masuyama, Shinkawa and Kubo2020, Wakashima et al., Reference Wakashima, Asai, Kobayashi, Koiwa, Kamoshida and Sakuraba2020). The total score is 7–35, and the higher the score, the stronger the fear of COVID-19. This scale has been validated to correlate with the symptom intensity of anxiety and stress (Midorikawa et al., Reference Midorikawa, Aiba, Lebowitz, Taguchi, Shiratori, Ogawa, Takahashi, Takahashi, Nemoto, Arai and Tachikawa2021).
The significant new finding in this study is the association between the FCV-19S score and the volume reduction of the right posterior cingulate cortex. Concerning the involvement of the posterior cingulate cortex in psychiatric symptoms, previous reports showed an association between the features found in this region by brain imaging analyses and PTSD. Ke et al. (Ke et al., Reference Ke, Chen, Qi, Xu, Zhong, Chen, Li, Zhang and Lu2017) reported an association between the activity in the posterior cingulate gyrus on functional neuroimaging and PTSD symptom severity. Zhang et al. (Reference Zhang, Li, Shu, Zheng, Zhang, Zhang, He, Hou, Li, Liu, Wang, Duan, Jiang and Li2012) showed that the white matter integrity of the posterior cingulate gyrus was linked to affective processing in PTSD by diffusion tensor imaging. When taken together with these findings indicating an association between the function of the posterior cingulate gyrus and the psychiatric symptoms of PTSD, the results of the present study suggest that the posterior cingulate cortex is involved in the processing of anxiety or fear caused by COVID-19. This may be an issue to be clarified in the future.
Another important point is that the posterior cingulate cortex is a region where glucose hypometabolism and hypoperfusion are observed in the early stages of Alzheimer’s disease (AD) (Valotassiou et al., Reference Valotassiou, Malamitsi, Papatriantafyllou, Dardiotis, Tsougos, Psimadas, Alexiou, Hadjigeorgiou and Georgoulias2018), a condition associated with memory impairment (Jones et al., Reference Jones, Barnes, Uylings, Fox, Frost, Witter and Scheltens2006; Leech & Sharp, Reference Leech and Sharp2014; Scahill et al., Reference Scahill, Schott, Stevens, Rossor and Fox2002). Other studies reported that anxiety was associated with the progression of dementia and decreased brain volume in patients with MCI or SCD (Johansson et al., Reference Johansson, Stomrud, Lindberg, Westman, Johansson, van Westen, Mattsson and Hansson2020, Mah et al., Reference Mah, Binns and Steffens2015). Age-related brain atrophy was reported to be exacerbated by anxiety-related stress in healthy subjects (Laird et al., Reference Laird, Siddarth, Krause-Sorio, Kilpatrick, Milillo, Aguilar, Narr and Lavretsky2019). Further, it is known that cognitive decline, including memory impairment, occurs in elderly people affected by disasters such as earthquakes (Furukawa et al., Reference Furukawa, Ootsuki, Kodama and Arai2012; Hikichi et al., Reference Hikichi, Tsuboya, Aida, Matsuyama, Kondo, Subramanian and Kawachi2017). Collectively, these findings may suggest that the posterior cingulate region is vulnerable to mental stress caused by disasters (earthquakes, pandemics, etc.), and resultant atrophy and cognitive decline, especially in elderly people. Our hypothesis that COVID-19 fear might cause atrophy of the amygdala was not observed in this study. It was considered that this was because the atrophy of the medial temporal lobe including the amygdala had already been caused in the early stage of dementia such as MCI (Tang et al., Reference Tang, Holland, Dale, Younes, Miller and Initiative2015).
The results of the present study suggest that anxiety or fear of COVID-19 might accelerate the atrophy of the posterior cingulate gyrus in patients with SCD or MCI. Reducing stress caused by anxiety and fear in the elderly might prevent the progression of brain atrophy and thereby prevent cognitive deterioration. In Japan, it has been pointed out that the COVID-19 epidemic reduced the opportunities for elderly people with dementia to receive long-term care, including day care and day services, and these changes might have aggravated cognitive decline and behavioural and psychological symptoms of dementia (BPSD) (Niimi et al., Reference Niimi, Arai, Awata, Katayama, Tomimoto, Togo, Nakanishi, Hanyu, Fukui, Fujimoto, Yamada, Mori and Haruhiko2021). Similarly, increases in fear and anxiety in relation to COVID-19, exacerbated by elderly people with dementia being unable to receive long-term care services and withdrawing to their homes, may also contribute to the deterioration of cognitive function. For the future improvement of elderly care, measures should be taken to continue long-term care services while paying sufficient attention to infection prevention in order to alleviate the fear and anxiety of COVID-19 and prevent the progression of brain atrophy and cognitive decline.
However, this study has some limitations. It is known that dementia is a risk factor for the aggravation of COVID-19 infection and that the COVID-19 pandemic worsened the cognitive function and the severity of behavioural and psychological symptoms of dementia (BPSD) (Barguilla et al., Reference Barguilla, Fernández-Lebrero, Estragués-Gázquez, García-Escobar, Navalpotro-Gómez, Manero, Puente-Periz, Roquer and Puig-Pijoan2020; Boutoleau-Bretonnière et al., Reference Boutoleau-Bretonnière, Pouclet-Courtemanche, Gillet, Bernard, Deruet, Gouraud, Mazoue, Lamy, Rocher, Kapogiannis and El Haj2020; Canevelli et al., Reference Canevelli, Valletta, Toccaceli Blasi, Remoli, Sarti, Nuti, Sciancalepore, Ruberti, Cesari and Bruno2020; Ismail et al., Reference Ismail, Kamel and Al-Hashel2021; Lara et al., Reference Lara, Carnes, Dakterzada, Benitez and Piñol-Ripoll2020; Miners et al., Reference Miners, Kehoe and Love2020). The background to the exacerbation of dementia is not only the psychological stress of the COVID-19 disaster but also the decrease in social and physical activity due to restrictions on going out to prevent the spread of infection. Exercise and social contact play important roles in mental health (Livingston et al., Reference Livingston, Huntley, Sommerlad, Ames, Ballard, Banerjee, Brayne, Burns, Cohen-Mansfield, Cooper, Costafreda, Dias, Fox, Gitlin, Howard, Kales, Kivimäki, Larson, Ogunniyi, Orgeta, Ritchie, Rockwood, Sampson, Samus, Schneider, Selbæk, Teri and Mukadam2020). In this study, because all subjects were exposed to psychological stress in relation to the COVID-19 disaster and decreased their social and physical activity, it is difficult to clarify the interaction among these factors. In addition, if changes in regional brain volume were affected by anxiety or depression, it is necessary to consider whether these changes will be reversible after the diminishment of the pandemic. It is presumed that this point will be clarified by further longitudinal evaluation in the future.
In conclusion, there was a significant correlation between the fear of COVID-19 and regional brain atrophy rates. It was revealed that the COVID-19 epidemic has an indirect effect not only on cognitive function but also on cerebral morphology. In the future, we will conduct further longitudinal research to verify the effects on cognitive function and morphological changes.
Acknowledgements
None.
Author contributions
This study was designed by TT, MO and TA. TT, MO, YN, AK, KN, MT, MI, AM, and TA acquired the data. TT and MO analysed and drafted the article. TA revised it. All authors contributed to and have approved the final manuscript.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflict of interest
None.
Ethical standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
