Neurological Sciences

https://doi.org/10.1007/s10072-021-05653-w

COVID-19

Cognitive, behavioral, and psychological manifestations

of COVID‑19 in post‑acute rehabilitation setting: preliminary data
of an observational study
Silvia Bonizzato1 · Ada Ghiggia2 · Francesco Ferraro3 · Emanuela Galante3

Received: 10 December 2020 / Accepted: 6 October 2021

© The Author(s) 2021

Abstract
Psychological, emotional, and behavioral domains could be altered in COVID-19 patients and measurement of variables
within these domains seems to be mandatory. Neuropsychological assessment could detect possible cognitive impairment
caused by COVID-19 and the choice of appropriate tools is an important question. Aim of this exploratory study was to verify
the effectiveness of an assessment model for patients with COVID-19. Twelve patients were enrolled and tested with Mini-
Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Anxiety and Depression Short Scale (AD-R),
and the Neuropsychiatry Inventory (NPI), at the time of their entrance (T0) and discharge (T1) from a rehabilitative unit.
Moreover, a follow-up evaluation after 3 months (T2) has been conducted on eight patients. Results showed that at baseline
(T0), 58.3% of the patients reported a score below cut-off at MMSE and 50% at MoCA. Although a significant amelioration
was found only in NPI scores, a qualitative improvement has been detected at all tests, except for MoCA scores, in the T0-T1
trend analysis. A one-way repeated measures analysis of variance showed a significant variation in AD-R depression score,
considering the three-assessment time (T0, T1, and T2). The evaluation and tracking over time of the impact of COVID-19
on cognitive, psychological, and behavioral domains has relevant implications for rehabilitation and long-term assistance
needs planning. The choice of assessment tools should consider patients vulnerability and match the best compromise among
briefness, sensitivity, and specificity.

Keywords COVID-19 · Neuropsychological deficit · Psychological assessment · Behavioral alterations

Introduction In the past months, reports from different countries sug-

gested that SARS-CoV-2 could directly and indirectly infect
Severe acute respiratory syndrome coronavirus 2 (SARS- structures of the nervous system [1–4]. The central (CNS)
CoV-2) is the cause of the coronavirus disease 2019 and peripheral nervous system (PNS) involvement may be
(COVID-19), mainly characterized by respiratory illness. It related to hypoxia and endothelial damage, uncontrolla-
emerged in Wuhan, China, in December 2019 and caused a ble immune reaction and inflammation, electrolyte imbal-
pandemic outbreak, according to the World Health Organi- ance, hypercoagulable state and disseminated intravascular
zation (WHO). coagulation, septic shock, and/or multiple organ failure [5,
6]. Moreover, the adhesion mechanism of SARS-CoV-2 to
ACE2 receptors gains implications on blood pressure cer-
* Ada Ghiggia ebral regulation and on the question about neurotropism of
[email protected] SARS-CoV-2 [7]. COVID-19 can complicate or co-exist
1 with cerebrovascular disease [8] or other neurological dis-
Department of Psychology, University of Milan-Bicocca,
Piazza dell’Ateneo Nuovo 1, Milan, Italy ease like multiple sclerosis [9], Alzheimer’s disease [10],
2 and Parkinson’s disease [7] suggesting CNS involvement
Department of Psychology, University of Turin, Via Verdi
10, 10124 Turin, Italy and complex neurological clinical complications.
3 It has been suggested that, beside neurological symp-
Neuro‑Motor Rehabilitation Unit, Neuroscience Department,
Azienda Socio Sanitaria Territoriale Di Mantova, via XXV toms, it is important monitoring potential late COVID-19
Aprile 71, Bozzolo, Mantova, Italy

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neurological sequelae like possible neuropsychological Methods

deficits [2, 11], as well as seen in other viral infection [11].
In recent studies [12–15], attention has been paid to low Participants
cognitive performance caused by COVID-19. Cognitive
impairment has been put in relation with headache [11], Twelve patients with COVID-19 were included in the study;
inflammatory processes [13], clinical and metabolic altera- they were transferred to the Physical Therapy Department of
tions [14], and length of stay in intensive care unit [12]. To the Carlo Poma Hospital in Mantua (Italy) after hospitaliza-
date, few studies evaluated over time neuropsychological tion for COVID-19. The study was approved by the Institu-
deficits of COVID-19 patients. These studies showed a tional Ethic Committee and was conducted in accordance
poor performance in attention and executive domain tests with the Declaration of Helsinki. All the participants gave
suggesting a dysexecutive syndrome related to COVID-19 their written informed consent to participate in the study.
[14, 15]. Only one study [16] proposed possible presence All patients met COVID-19 diagnostic criteria and
of focal neuropsychological disorders, such as agraphia after the acute phase of the disease have been moved to
and conduction aphasia, but the authors did not neces- the rehabilitative unit. No other inclusion criteria were
sarily link them to the COVID-19. The importance of a requested. Exclusion criteria were disorders, which pre-
specific neuropsychological rehabilitation has also been cluded answering to the tests, such as delirium, aphasia, or
suggested [12, 15], highlighting the importance of inves- overt dementia. Six patients met severe pneumonia caused
tigating long-term cognitive functional trends in patients. by COVID-19 infection, four were affected by stroke com-
In addition, few authors emphasized the importance plicated by the infection, one met COVID-19 infection
of monitoring and managing the possible behavioral and after an organ transplant, and one had some degree of
psychological consequences of neurobiological factors, memory impairment before contracting the virus. This last
traumatic experiences, and setting organization (i.e., patient was already known to our Neuropsychology Unit
social isolation, immobilization) [17, 18]. Psychological for a previous evaluation, which has been considered as a
and behavioral manifestations should be considered in baseline respect to the present assessment.
COVID-19 patients. Some studies showed that psycho- Patients were tested at the arrival (T0) and discharge from
logical symptoms are more prevalent than neurological their rehabilitative hospitalization (T1, after about a month)
ones [15, 19]. Moreover, previous studies of similar viral with screening tools for global cognitive evaluation. Eight
respiratory diseases, such as severe acute respiratory syn- of them were also evaluated after 3 months (T2) to moni-
drome (SARS) during the 2002–2004 outbreak in China, tor the impact on cognitive-behavioral psychological profile
indicated that behavioral alterations of infected individuals over time. Four patients refuse to come back for follow up
should not be ignored [20]. Studies on the mental status of and were considered dropped out. Six of them were tested
COVID-19 patients show the presence of depression, anxi- at T2 through an extended cognitive assessment, in addition
ety, and possible post-traumatic stress disorders (PTSD) to the screening tests in order to better detect the presence
[21]. Correlation between physical condition and psycho- in the long term of possible mild impairment or deficit. The
logical morbidities is evident and has been highlighted in remaining two patients were too weak to complete the inves-
few studies [15, 22, 23]. tigation with the extended cognitive profile.
The evaluation and tracking over time of the impact of During the rehabilitation, patients received an individu-
COVID-19 on cognitive, psychological, and behavioral ally tailored multidisciplinary intervention (physical therapy,
patient conditions have relevant implications for rehabili- psychological support, cognitive stimulation, and occupa-
tation planning and long-term assistance needs. However, tional therapy). Due to infection limitations, such as move-
the choice of appropriate tools is still open to debate. In ment restrictions, contact isolation, and oxygen dependence,
particular, concerning our experience, at the arrival in the cognitive stimulation interventions were limited in time
post-acute rehabilitative setting, patients are physically and (about 20 min per patients) and in content. General stimula-
mentally vulnerable due to the relevant metabolic altera- tion included temporal and spatial orientation and exercises
tions, long immobilization, and social isolation to which of general attention and some executive functions (room and
they have been subjected. Therefore, instruments for a first picture description, daily planning, verbal fluency).
evaluation should match the best compromise among brief-
ness, sensitivity, and specificity.
Aim of this exploratory study was to verify the effective- Assessment
ness of an assessment model for patients recovering from
COVID-19, at the time of their entrance and discharge from MMSE (Mini-Mental State Examination) [24] and MoCA
the rehabilitative hospital (T0 and T1) and after 3 months (Montreal Cognitive Assessment) [25] were selected as
(T2).

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screening tests for global cognitive assessment. While the were any statistically significant differences between the
MMSE is universally used as a screening test for possible score of the neuropsychological and behavioral variables
cortical dementia (this test covers the domains of temporal at the three different times of evaluation. Where signifi-
and spatial orientation, attention, memory, language, and cant differences were observed, a Wilcoxon rank-test was
visual-spatial abilities), the MoCA is more sensitive to applied to determine between what times these differences
detect impairment of executive functions, having subtests were observed.
of attention shifting, concentration, abstraction, phone- For all analyses, p values < 0.05 were considered sta-
mic fluency, and subtests investigating the same cognitive tistically significant.
domains as the MMSE.
An extended cognitive evaluation has been performed, in
order to investigate memory, attention, executive functions,
and verbal fluency domains, according to the neuropsycho- Results
logical clinical practice [26], which requires an extended
assessment through the different domains. We selected the Demographic characteristics and testing results
following tests: Digit and Corsi span forward and backward
[27] for short-term and working verbal and visuo-spatial Participants were 12 adults (mean age 71.33 ± 10.08 year;
memory; Rey Auditory Verbal Learning (RAVL) [28]; range 47–85), and 41.7% were females; education year was
Spatial Recall Test (SPART) [29] for respectively long-term 7.25 ± 3.34 (range 4–13).
verbal and visuo-spatial memory; Symbol Digit Modalities At T0, seven patients (58.3%) had a performance
Test (SDMT) [30] for selective attention; Trail Making Test below cut-off at the MMSE and six (50%) at MoCA. Four
(TMT) [31] for attentional shift; Stroop Test [32]; and Fron- patients (33.3%) obtained critical scores at the anxiety
tal Assessment Battery (FAB) [33] for executive functions, scale and two (16.6%) at the depression scale. Five sub-
such as processing speed, motor programming, inhibitory jects (41.66%) reported abnormal scores to NPI.
control and environmental autonomy, verbal abstraction, and At discharge (T1), four patients (33.3%) obtained scores
phonemic fluency FAS [34] for language. below cut-off at the MMSE, and six (50%) at the MoCA.
The possible presence of behavioral and psychological Three patients (25%) had high anxiety level and only two
symptoms was investigated through a psychological inter- (16.66%) reported behavioral symptoms by means of the
view and instruments selected to gather information on NPI (see Table 1).
anxiety, depression (Anxiety and Depression Short Scale Among the eight patients tested at T2, two (25%) had a
— AD-R) [35], and behavioral alterations (Neuropsychiatry poor performance at the MMSE, four (50%) at the MoCA,
Inventory — NPI) [36]. Score of the AD-R anxiety scale one patient (8.3%) presented depressive symptoms, and
is considered critical when it is above the 80° percentile only two (25%) critical behavioral scores at the NPI. Two
[35], while the score of AD-R depression scale is consid- participants tested at T2 were too weak to approach the
ered critical when is above the 90° percentile. Presence of complete cognitive profile. Among remaining participants,
any delusions or hallucinations, depression scores above six, five (62.5%) provided a performance below cut-off at the
disinhibition scores above four, and irritability score above SDMT, and three (37.5%) to some memory test (RAVL,
two are to be taken into account at the NPI [36]. Trained Corsi span backward, and SPART).
psychologists administered tests and questionnaires. Data on neuropsychological assessment at T2 are
reported in Table 2.
Statistical analysis
Table 1  Number and percentage of patients with test scores below the
Statistical analyses were performed using the Statistical threshold values
Package for Social Science — for Mac, Version 26.0 (SPSS
Variables T0 T1 T2
Inc., Chicago, IL, USA).
N = 12 N = 12 N=8
Descriptive statistics were used to describe socio-demo-
graphic, cognitive, and psychological data; data that did not MMSE 7 (58.3%) 4 (33.3%) 2 (25%)
follow a normal distribution were described using medians MoCA 6 (50%) 6 (50%) 4 (50%)
and the lower and upper quartiles. Given the small sample AD-R, anxiety scale 4 (33.3%) 3 (25%) 0 (0%)
size, Wilcoxon’s rank sum test was applied for comparison AD-R, depression scale 2 (16.6%) 0 (0%) 1 (8.3%)
of the cognitive and psychological variables at baseline (T0) NPI, total score 5 (41.66%) 2 (16.66%) 2 (25%)
and at the time of hospital discharge (T1).
Abbreviations: MMSE, Mini-Mental State Examination; MoCA, Mon-
Different one-way repeated measures analysis of vari- treal Cognitive Assessment; AD-R, Anxiety and Depression Short
ance (ANOVA) were launched to determine whether there Scale; NPI, Neuropsychiatry Inventory Scale

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Table 2  Number and percentage of patients (N = 6) with neuropsy- One-way repeated measures ANOVAs were conducted to
chological test scores below the threshold values at the follow-up determine whether there were significant differences in neu-
assessment (T2)
ropsychological, psychological, and behavioral tests over the
Memory course of the rehabilitation program and after 3 months. The
Digit span forward 1 (12.5%) assumption of sphericity was met, as assessed by Mauchly’s
Digit span backward 1 (12.5%) test of sphericity. No significant differences were found over
RAVL-immediate recall 3 (37.5%) time in MMSE [F(2, 6) = 0.836, p > 0.05; ηp2 = 0.09] and
RAVL-delayed recall 2 (25%) MoCA total scores [F(2, 6) = 1.517, p > 0.05, ηp2 = 0.34].
Corsi span forward 1 (12.5%) As regard to the psychological scores, no significant changes
Corsi span backward 3 (37.5%) were found in anxiety score at AD-R scale, [F(2, 6) = 1.492,
SPART​ 3 (37.5%) p > 0.05, ηp2 = 0.33], whereas a significant variation in
SPART-D 1 (12.5%) AD-R depression score emerged over time [F(2, 6) = 14.93,
Attention and executive functions p < 0.01; ηp2 = 0.83]. Post hoc analysis with Wilcoxon rank-
SDMT 5 (62.5%) test indicated that depression score at AD-R significantly
TMT — A 2 (25%) decreased from T0 to T1, with a reduction from 4.33 ± 3.00
TMT — B 2 (25%) to 3.00 ± 3.16 (z =  − 2.304, p = 0.021). Furthermore, a sig-
TMT — B-A 2 (25%) nificant increase was found from T1 to T2 (follow-up) from
Test di Stroop (Caffarra et al., 2002) 3.00 ± 3.16 to 5.88 ± 4.32 (z =  − 2.371, p = 0.018), but not
Stroop test — errors 2 (25%) from T0 to T2, with a not significant increase (z =  − 0.940,
Stroop test — time 0 (0%) p = 0.347) — see Fig. 1 for the trend of AD-R depression
FAB 2 (25%) scores at the different testing time.
FAS 2 (25%) Regarding behavioral alterations, analysis of variance did
not show any significant difference in NPI scores among T0,
Abbreviations: RAVL-I, Rey auditory verbal learning-immediate
T1, and T2, [F(2, 6) = 3.17, p > 0.05; ηp2 = 0.51].
recall; RAVL-D, Rey auditory verbal learning-delayed recall; SPART​
, spatial recall test; SPART-D, spatial recall test-delayed; SDMT, sym-
bol digit modalities test; TMT, trail making test; FAB, frontal assess-
ment battery; FAS, phonemic fluency Discussion

Trend of cognitive, psychological, and behavioral To date, few studies have evaluated and tracked over
measures along time time cognitive, psychological, and behavioral domains of
COVID-19 patients. In the present study, we observed the
Preliminary analysis was conducted to find possible differ- trend of cognitive, psychological, and behavioral variables
ences in neuropsychological, psychological, and/or behav- in patients recovering from COVID-19 in a rehabilitation
ioral variables between T0 and T1 (Table 3). A significant setting (entrance, T0; discharge, T1) and after a 3-month
decrease was found in NPI scores, z =  − 2.304, p < 0.05. No interval (T2).
other significant median changes emerged at the Wilcoxon The importance of detecting neuropsychological and psy-
signed-rank test, neither in neuropsychological screening chological consequences of this novel coronavirus has been
tests (MMSE: z =  − 0.366, p = 0.714; MoCA: z =  − 1.846, already claimed [3, 11]. This is relevant in order to acquire
p = 0.065) nor in psychological measures (AD-R), for anxi- more knowledge on the possible side effects of COVID-19
ety (z =  − 1.183, p = 0.237) or depression (z =  − 1.798, and to plan appropriate cognitive rehabilitation and psycho-
p = 0.072). logical support for inpatients. Moreover, the evaluation of

Table 3  Neuropsychological Variables T0 T1 p-value*

and behavioral tests, median
(IQR), and Wilcoxon signed‐ MMSE, total score 22.5 (16.39-26.61) 25.5 (16.22–29.28) 0.714
rank test between T0 and T1
MoCA, total score 14.5 (7.95–18.55) 13.0 (8.77–20.98) 0.065
(N = 12)
AD-R, anxiety scale 21.5 (14.39–28.11) 17.5 (13.36–24.14) 0.237
AD-R, depression scale 4.0 (2.47–8.03) 1.5 (0.32–5.68) 0.072
NPI, total score 8.5 (3.16–18.09) 4.5 (0.88–9.12) 0.021

*p-value < 0.05

Abbreviations: MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; AD-R,
Anxiety and Depression Short Scale; NPI, Neuropsychiatry Inventory Scale

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Fig. 1  The trend of mean scores

of the AD-R depression scale
(N = 8)

Mean scores of AD-R depression scale

T0 T1 T2

cognitive, behavioral, and psychological conditions is cru- express global cognitive functioning that can be tracked over
cial for decisions on adequate post-hospitalization setting time and they proved not too stressful for our patients. A
patients. similar choice has been made in a recent study [12] where
Our data, in accordance with the current literature, show the authors tested COVID-19 patients through the MMSE
that more than 50% of examined patients provided a poor for the global cognitive functioning, and the FAB to evalu-
cognitive performance at screening tests at T0. The finding ate executive functions. Furthermore, Almeria et al. [14]
of behavioral alterations in five out of twelve patients seems administered to their patients Global Cognitive Index, and
to support the necessity to monitor behavioral domains about a selected set of tests for memory, attention and executive
possible presence of changes in eating, sleep, or usual behav- functions, mental flexibility, and phonemic fluency. Our
ior (i.e., onset of emotional lability, irritability). Moreover, choice of tests for the analysis of cognitive profile at T2
delirium might be present in post-COVID patients [17]. In seems to be appropriate and in line with the rationale of
the present study, only two patients exhibited at T0 delusions colleagues.
and hallucinations. Otherwise, the presence of psychologi- No significant differences were found over time to the
cal distress emerged from AD-R scale in our sample (33.3% screening test (MMSE or MoCA), but between T0 and T1,
showed anxiety and 16.6% depression). These data should the mean scores at MoCA showed a slight difference, which
be taken into account to underline the importance of offering on a qualitative level could be representative of a greater
psychological support during the recovery of post-COVID deficit in the executive domains or greater sensitivity of the
patients. instrument, as suggested by Ortelli et al. [15]. Our finding of
In the post-acute phase of the disease, patients who have poor performance at SDMT in about 62.5% of patients at T2
suffered from COVID-19 are very vulnerable concerning is in accordance with the data of Zhou et al. [13] who found
both their physical and mental health. This seems to be poor performance of their patients at the Continuous Perfor-
ascribed to multiple factors, such as prolonged immobiliza- mance Test (CPT) and seem to show a prolonged impairment
tion, isolation [37, 38] from their loved ones and from health of selective and sustained attention in post-COVID patients.
workers because of the risk of infection, having experienced According to the literature, abnormal behavior (i.e., halluci-
the risk of dying, and feeling the uncertainties related to the nations) could also be present in post-COVID patients [17].
few knowledge about novel coronavirus. The administration of a scale to detect behavioral alterations
Assessment of post-COVID patients must take into as the NPI, therefore, seems to be appropriate. In addition,
account that they are living with physical and emotional AD-R Scale has been selected being a psychometric instru-
trauma. Our choice of brief and easily administrable tests at ment developed to identify clinically significant conditions
T0 has been mainly due to patients’ physical and psychologi- of distress in patients with cardiac and/or pulmonary dis-
cal weakness and to setting adjustment linked to infection ease [35]. We consider important to include these question-
risk. We chose two neuropsychological screening tests in naires during an appropriate psychological interview that is
order to have the possibility to detect possible global cogni- important to know the patient and to capture the presence of
tive impairment with the MMSE or prevalent dysexecutive psychological distress.
syndrome with MoCA [15]. Screening tests are not exhaus- We chose not to evaluate the presence of post-traumatic
tive to a complete neuropsychological assessment, but they stress disorder (PTSD) at T0, T1, and T2, considering the

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possibility of the onset of this disorder later in the recov- should take into account the vulnerability of these patients in
ery phase [39]. A further evolution of our study will be to the immediate post-acute phase of the disease, but it does not
perform a long-term cognitive and behavioral assessment, rule out the possibility of detailed assessment at follow-up
approximately 6 months after T2. The possible presence of visits, when they usually have recovered part of their physi-
PTSD will be then evaluated towards an appropriate ques- cal capacity. In conclusion, we believe that this explora-
tionnaire, like IES-R (Impact of Event Scale-Revised) [40]. tory study could be a proposal for an assessment model of
Our results show an improvement of NPI and AD-R patients recovering from COVID-19 even if the discussion
depression scores during hospitalization. The reduction of about times and tools for the evaluation of cognitive, behav-
behavioral alterations between T0 and T1 may be due to the ioral, and psychological alterations in COVID-19 patients is
natural evolution of clinical features and to specific physi- still open to debate.
cal, psychological, and cognitive improvement due to the
rehabilitative training. Moreover, the rehabilitative setting Acknowledgements The authors thank Emma Calzoni for her help
about data collection and bibliography research.
is usually perceived as protective and supportive, promoting
emotional and behavioral as well as a physical enhancement.
The increase of depressive symptoms between T1 and T2
Declarations
may be related to the emotional reactions of these patients Ethical approval The study was conducted according to the principles
when they get back to face the difficulties of current daily of the Declaration of Helsinki. Patients gave their informed consent
living possibly experiencing feelings of uncertainty and fear. to participate.
Our experience seems to support the need for an adequate
assessment of cognitive, behavioral, and psychological vari- Conflict of interest The authors declare no competing interests.
ables in post-COVID patients.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
Limitations as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
The present study has some limitations, the major one being were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
the small sample size, which does not allow a generalization otherwise in a credit line to the material. If material is not included in
of our results and limits the possibility of controlling data the article's Creative Commons licence and your intended use is not
with regard to other clinical or socio-demographic variables. permitted by statutory regulation or exceeds the permitted use, you will
Dropout is a possible limitation of any study, especially if it need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
consists of a longitudinal research.
Moreover, another limitation of this study is the het-
erogeneity of our sample: due to the different neurologi-
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