Neuropsychological Rehabilitation
An International Journal
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/pnrh20
Cognitive remediation therapy for post-acute
persistent cognitive deficits in COVID-19 survivors:
A proof-of-concept study
Mariagrazia Palladini, Beatrice Bravi, Federica Colombo, Elisa Caselani,
Camilla Di Pasquasio, Greta D’Orsi, Patrizia Rovere-Querini, Sara Poletti,
Francesco Benedetti & Mario Gennaro Mazza
To cite this article: Mariagrazia Palladini, Beatrice Bravi, Federica Colombo, Elisa Caselani,
Camilla Di Pasquasio, Greta D’Orsi, Patrizia Rovere-Querini, Sara Poletti, Francesco Benedetti
& Mario Gennaro Mazza (2022): Cognitive remediation therapy for post-acute persistent
cognitive deficits in COVID-19 survivors: A proof-of-concept study, Neuropsychological
Rehabilitation, DOI: 10.1080/09602011.2022.2075016
To link to this article: https://doi.org/10.1080/09602011.2022.2075016
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NEUROPSYCHOLOGICAL REHABILITATION
https://doi.org/10.1080/09602011.2022.2075016
Cognitive remediation therapy for post-acute persistent
cognitive deficits in COVID-19 survivors: A proof-ofconcept study
Mariagrazia Palladini a,b, Beatrice Bravi a,b, Federica Colomboa,b,
Elisa Caselania, Camilla Di Pasquasioa, Greta D’Orsia, Patrizia Rovere-Querini
Sara Polettia,c, Francesco Benedetti a,c and Mario Gennaro Mazzaa,b
c,d
,
a
Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San
Raffaele, Milano, Italy; bPhD Program in Cognitive Neuroscience, University Vita-Salute San Raffaele,
Milan, Italy; cVita-Salute San Raffaele University, Milano, Italy; dDivision of Immunology,
Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
ABSTRACT
Cognitive impairments figure prominently in COVID-19
survivors. Cognitive remediation therapy (CRT) improves
functional outcomes reducing long-term cognitive deficits
in several neurological and psychiatric conditions. Our casecontrol study investigates the efficacy of a CRT programme
administered to COVID-19 survivors in the post-acute phase
of the illness. Seventy-three COVID-19 survivors presenting
cognitive impairments at one-month follow-up were
enrolled. Among them, 15 patients were treated with a
two-month CRT programme, and 30 non-treated patients
were matched conditional to their baseline cognitive
functioning. Cognitive functions were assessed before and
after treatment. Depression and quality of life were also
evaluated. Mixed model ANOVA revealed a significant effect
over time of the CRT programme on global cognitive
functioning (F = 4.56, p = 0.039), while no significant effect
was observed in the untreated group. We observed a
significant effect of the improvement in verbal fluency (χ 2 =
7.20, p = 0.007) and executive functions (χ 2 = 13.63, p < 0.001)
on quality of life. A positive significant correlation was found
between depressive symptomatology and verbal fluency (r =
−0.35), working memory (r = −0.44), psychomotor
coordination (r = −0.42), and executive functions (r = −0.33).
Our results could pave the way to a plausible innovative
treatment targeting cognitive impairments and ameliorating
the quality of life of COVID-19 survivors.
ARTICLE HISTORY
Received 24 August 2021
Accepted 4 May 2022
KEYWORDS
Covid-19; SARS-CoV-2;
Cognitive impairment;
Cognitive remediation
therapy; Depression
Introduction
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by the
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to
CONTACT Mariagrazia Palladini
palladini.mariagrazia@hsr.it
Istituto Scientifico IRCCS Ospedale San
Raffaele, Dipartimento di Neuroscienze Cliniche, San Raffaele Turro, Via Stamira d’Ancona 20, 20127 Milano, Italy
Supplemental data for this article can be accessed online at https://doi.org/10.1080/09602011.2022.2075016
© 2022 Informa UK Limited, trading as Taylor & Francis Group
2
M. PALLADINI ET AL.
nearly 500 million cases and over 6 million deaths worldwide (WHO, 2021).
SARS-CoV-2 infection causes a broad spectrum of manifestations ranging
from asymptomatic infection to life-threatening multiorgan disease, also inducing, among the others, neurologic and neuropsychiatric complications (Ellul
et al., 2020; Varatharaj et al., 2020). Moreover, heterogeneous and systemic dysfunctions may persist in the post-acute phase and constitute the long-COVID
syndrome (Huang et al., 2021; Nalbandian et al., 2021). In the context of the
long-COVID syndrome, also characterized by fatigue, post-exertional malaise,
anxiety, and depression, cognitive impairment is now recognized as one of
the leading complaints in COVID-19 survivors (Davis et al. 2021; Nalbandian
et al., 2021; World Health Organization, 2021). In addition, persistent subjective
and objective neurocognitive impairments after acute infection have been
reported at short and long-term follow-up (Almeria et al., 2020; Helms et al.,
2020; Mendez et al., 2021). Executive functions and attention seem to be the
most affected cognitive domain in COVID-19 survivors. In this context, we
have previously observed that 78% of COVID-19 survivors showed a poor performance in at least one cognitive domain three months after hospital discharge, with the executive functions being impaired in about 50–60% of
survivors (Mazza et al., 2021). Moreover, consistently with literature we found
that cognitive performances were influenced both by depressive symptomatology (Almeria et al., 2020; Mendez et al., 2021) and by levels of inflammation at
the time of hospital admittance (Mazza et al., 2021; Zhou et al., 2020). In this
regard, recent studies from our group point toward a partially comparable cognitive profile between COVID-19 survivors and patients diagnosed with Major
Depressive Disorder, with the two groups showing overlapping performances
in verbal fluency and executive functions tasks (Poletti et al., 2021). Similar cognitive impairments and their relationship with depressive symptoms have been
observed following acute respiratory distress syndrome (ARDS) of other aetiologies where up to 70% of ARDS survivors had presented deficits affecting predominantly, executive functions, and memory (Hopkins et al., 2005; Hopkins
et al., 2006; Sasannejad et al., 2019). Little is known about the progression or
remission of cognitive deficits over time in the aftermath of COVID-19,
although a recent study from our group suggests that cognitive impairments
tend to remain stable in a time frame from one to six months after hospital
discharge (Poletti et al., 2021). Furthermore, available evidence suggests
that cognitive dysfunctions seem to be independent of COVID-19 severity
proxied by the need for hospitalization, NIV, and ICU admission (Beaud
et al., 2021; Hopkins et al., 2006; Jaywant et al., 2021; Mazza et al., 2021;
Woo et al., 2020). Notably, persistent cognitive impairment showed a detrimental effect on the quality of life and daily global functioning of COVID-19
survivors (Mantovani et al., 2020; Miskowiak et al., 2021). The underlying
mechanism of the cognitive sequelae is multifactorial and mainly related to
the COVID-19 associated systemic inflammation, hypoxia, and cerebrovascular
NEUROPSYCHOLOGICAL REHABILITATION
3
events (Achar and Ghosh, 2020; Beaud et al., 2021; Couzin-Frankel, 2020; Varatharaj et al., 2020).
Cognitive remediation therapy (CRT) encompasses a wide range of therapeutic cognitive interventions targeting cognitive deficits to improve functional
outcomes by reinforcing, strengthening, or reestablishing previous cognitive
abilities (Kim et al., 2018). In this regard, CRT seems to reduce long-term cognitive impairment and the related social and psychological consequences
(Medalia and Bowie, 2016), showing potential benefits in several neurological
and psychiatric conditions with cognitive impairment similar to that observed
in COVID-19 survivors (Cappa et al., 2005; Kim et al., 2018). Moreover, existing
evidence reveals enhanced restorative effects of CRT when implemented in
the framework of a metacognitive therapeutic approach on severe medical
and psychiatric populations (Birnboim and Miller, 2004; Breitborde et al., 2017).
Despite the high rate of persistent and disabling cognitive sequelae, no
report is available about the efficacy of CRT in COVID-19 survivors enrolled in
the sub-acute stages. We hypothesized that a CRT focused on the rehabilitation
of the most affected cognitive domains could be used to reduce the cognitive
deficits observed in COVID-19 survivors in order to maximize the level of daily
functioning and facilitate re-integration into daily activities. Following this line
of reasoning, in a proof-of-concept study in a homogeneous cohort of COVID19 survivors presenting cognitive impairments at one-month follow-up here,
we report the effects of a 2-month CRT programme compared with the naturalistic evolution of cognition in untreated patients.
Materials and methods
Participants
COVID-19 survivors were recruited from 24 November 2020 to 27 April 27 2021
at one-month after hospital discharge during an ongoing longitudinal cohort
study at IRCSS San Raffaele Hospital in Milan. The current study included only
patients who were admitted to Emergency Department for COVID-19 pneumonia, as suggested by clinical and radiological findings. The infection was
confirmed by positive real-time reverse-transcriptase polymerase chain reaction
(RT–PCR) from a nasopharyngeal and/or throat swab. Exclusion criteria were:
age above 70, non-Italian speakers, and patients with any form of documented
or suspected neurological symptoms or intellectual disability. Given the small
number of critical illness patients followed-up at our outpatients service and
the remarkable neurocognitive implication of pneumonia-induced hypoxia,
patients who need intensive care unit level care during the acute phase were
also excluded from the study. Overall, 73 patients who meet the above criteria
completed the neuropsychological assessment at one- and three-month followups and were therefore considered eligible for the study (48 male; mean age
4
M. PALLADINI ET AL.
58.2 ± 9.16). Among them, 16 were enrolled for the CRT, while 57 did not receive
the treatment. The group of untreated patients included COVID-19 survivors
who showed different levels of cognitive performance at the first neuropsychological assessment. In order to meet the clinical need and considering the
limited health care resources, CRT was administered to COVID-19 survivors
who exhibited cognitive deficits at the baseline and were in the position to conclude the entire CRT programme. One of the CRT participants did not complete
the training sessions, and thus was excluded from the analysis (see online supplement Figure 1). CRT patients were matched based on cognitive functioning
one month after discharge with untreated patients (1:2 ratio), reaching a final
matched sample of 15 treated and 30 untreated COVID-19 survivors (for
further details see Design Section). We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. 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. Written informed consent to participate in the study was obtained
from all participants. All procedures involving human patients were approved
by the Ethics Committee of San Raffaele Hospital (COVID-BioB protocol
NCT04318366).
Measures
Assessment of cognitive functions was performed through the Brief Assessment
of Cognition in Schizophrenia (BACS) (Keefe et al., 2004), a neuropsychological
screening test covering the evaluation of verbal memory, verbal fluency,
working memory, attention, and speed information processing, psychomotor
coordination, and executive functions. The first neuropsychological assessment
was performed one month after hospital discharge (33.53 ± 9.89 days), while the
post-treatment evaluation was performed three months after discharge (89.16
± 10.12 days). Two versions (A and B) of BACS were administered at the baseline
and at follow-up respectively, to reduce recall effects. BACS scores were
adjusted for age, sex, and educational level (years of schooling) and then converted into a 5-point interval scale to compute equivalent scores for each cognitive domain, where 0 reflects a deficient performance and 4 an optimal one
(Anselmetti et al., 2008). As such, the equivalent scores standardization
method also accounts for socio-demographics influencing cognitive performance and allows a direct comparison among different tests. We delivered CRT
only for patients presenting a failure in one or more cognitive domains as
proxied by 0 or 1 equivalent score, which reflect performance scores falling in
the left tail of area 0.05 or 0.10 respectively under the normal distribution
curve (Anselmetti et al., 2008). To assess the improvement of cognitive functions
over time, a delta score was calculated for each cognitive domain (equivalent
NEUROPSYCHOLOGICAL REHABILITATION
5
score at follow-up – equivalent score at baseline). Beyond equivalent scores for
the single domains, also a global index of cognitive functioning was computed
as the mean of the six equivalent scores for each participant. To evaluate the
depressive symptomatology, participants completed the Zung Severity Rating
Scale (ZSDS) (Zung, 1965), which, thanks to its behavioural and somatic orientation in assessing depressive symptomatology, proved a valid instrument to
differentiate depressed from non-depressed groups in the general population
(Sepehry, 2014), including COVID-19 survivors (Benedetti et al., 2021; Mazza
et al., 2020; Mazza et al., 2021; Nie et al., 2021; Yuan et al., 2020). The commonly
suggested ZSDS index ≥ 50 cut-off was considered indicative of relevant
depressive symptomatology. In the treated group, the World Health Organization Quality of Life assessment (WHOQOL-BREF) (Skevington et al., 2004 Mar)
was used to gather information about changes in quality of life before and
after CRT. Sociodemographic and clinical data were available for all the included
patients, thus we had no missing data.
Design
We implemented a matching strategy in order to limit confounding effects
arising from non-random assignment of participants. Considering the investigation of CRT effect on cognitions as the primary aim of the current study,
patients included in the analyses have been selected based on their a priori individual probability (i.e., propensity score) to be allocated to the treated group,
conditional to their baseline equivalent scores. Propensity scores were
derived through a logistic regression model fitted on equivalent scores
obtained at the baseline neuropsychological assessment. Treated and untreated
patients were matched using the optimal pair matching method without replacement and a matching ratio of 2:1. Therefore, CRT patients were matched with
two untreated patients showing the same cognitive profile at baseline. A comparison of baseline equivalent scores between matched groups was performed
using standardized mean difference (Ho et al., 2007), where a difference less
than 0.05 was considered as an acceptable balance (Belitser et al., 2011) (see
online supplement Methods 2). Matching routine was run within R version
3.6.3 using the package MatchIt version 4.2.0 (Stuart et al., 2011) (https://
www.jstatsoft.org/v42/i08/). The final matched sample of 45 COVID-19 survivors
(15 in the CRT group and 30 in the control one) was considered for the following
analysis, thus removing the selection bias introduced in the first phase of
patients’ enrolment (see online supplement Table 1).
Intervention
A two-month CRT protocol was administered by trained psychologists to
COVID-19 survivors enrolled at one-month follow-up after hospital discharge.
6
M. PALLADINI ET AL.
The treatment started within 15 days from the baseline neuropsychological
assessment (on average, 6.34 ± 3.33 days). The face-to-face CRT protocol was
carried out through COGPACK® software version 6. (http://www.
markersoftware.com/) under the supervision of trained psychologists who
administered the neuropsychological assessment, motivating and assisting
the patients during the cognitive remediation programme. This software
includes 64 test and training programmes, with 537 different task sets to
improve neurocognitive functioning. The package includes both domainspecific tasks in the same cognitive domains investigated by the BACS, and
non-domain-specific exercises, focusing on everyday skills and knowledge.
The protocol consisted of training series based on the impaired cognitive
domains (i.e., equivalent score 0–1), with a maximum of 10 tasks per subject.
According to the number of impaired domains and their severity, a training
session was tailored for each participant, including up to five domain-specific
exercises. This procedure allows customizing the training while maintaining a
fixed duration of the session, resulting in comparable outcomes. Domainspecific exercises have been selected according to the general process involved
and following the DSM taxonomy on neurocognitive domains (Sachdev et al.,
2014) in order to match the domains measured by the BACS (i.e., Perceptual
motor function – Psychomotor coordination; Language – Verbal Fluency; Executive Functions – decision making; Learning and Memory – free recall; Complex
attention – selective attention and processing speed). Mainly adaptive exercises
were chosen, thus setting training at a challenging level of difficulty. Once the
training tasks were selected, a minimum of 2 non-domain-specific tasks were
added as a placebo to complete the series. Each training session was 60 min
long and was performed once a week over a period of 6 consecutive weeks,
for a total of 6 sessions per subject. After 3 weeks of treatment, a new set of
different domain-specific exercises was built, keeping the general structure of
the series unchanged. Given the lack of literature directly proposing specific
rehabilitation protocols targeting cognitive deficits in survivors of coronaviruses
epidemics, the current CRT programme design partially overlap with previously
implemented CRT protocols in psychiatric population (Cavallaro et al., 2009;
Schneider et al., 2020). However, the duration and intensity of the intervention
were moderated according to the target group’s clinical needs. Indeed, COVID19 survivors showed a less compromised cognitive profile compared to the clinical populations mentioned in the existing literature on CRT (Poletti et al., 2021).
Data analysis
Based on our previous findings showing an association between cognitive performances and depressive symptomatology in COVID-19 survivors (Mazza et al.,
2021), we computed a non-parametric Spearman correlation between ZSDS
scores and equivalent scores at baseline to test their association.
NEUROPSYCHOLOGICAL REHABILITATION
7
Then, the effect of treatment on cognition was analysed in three sequential
steps. First, in order to explore the effect of treatment on changes in cognitive
performance over time, we performed a mixed model ANOVA analysis on the
global cognitive index. According to Spearman correlations results, we considered ZSDS scores as confounding variable together with age, sex, and
number of cognitive impaired domains at baseline as an index of cognitive
impairment severity at baseline.
Second, the effect of CRT on each cognitive domain was investigated
through a mixed model ANOVA considering the equivalent scores of each
domain both at the baseline and the follow-up. Time and domain were modelled as within effects, whereas CRT treatment as between effect. Age, sex,
ZSDS, number of impaired domains at baseline were entered as covariates.
Post-hoc Fisher’s least significant difference (LSD) was performed as
appropriate.
Third, to investigate whether CRT is specifically effective in recovering the
most impaired cognitive functions, decomposition of single effects was performed only for cognitive domains which resulted severely impaired (equivalent scores ≤1). In accordance with this criterion, we further explore the effect
of CRT on the recovery of verbal fluency, which resulted in the most
damaged dimension on average. Analyses were computed within the generalized linear model (GLZM) with homogeneity of slope design, modelling CRT
as group factor and considering CRT * baseline equivalent score in verbal
fluency as the main effect of interest. We entered CRT and baseline equivalent score as predictors, and delta score in the target domain as dependent
variable, also adjusting for sex, age, and ZSDS. As such, it was possible to
figure out if the improvement in verbal fluency associated to CRT was
affected by the initial equivalent score in that domain. In the presence of a
significant interaction of CRT * baseline equivalent, stratification of patients
was applied on the initial equivalent score. More specifically, only subjects
who scored 0 in the domain of interest were considered in the following
analysis.
Given possible violation of parametric assumptions (e.g., normal distribution
of dependent variable, homogeneity of variances) we tested the effect of CRT on
the improvement of the performances using a GLZM model, again controlling
for age, sex and ZSDS. Multinomial ordered distribution was assumed for the
dependent variable, setting probit as link function.
Finally, to test the effect of all single cognitive domain variations on changes
in quality of life and considering the a priori expected significant interaction
with other independent factors (age, sex, and ZSDS), independent variables
were entered into a GLZM (McCullagh and Nelder, 1989). Likelihood Ratio statistic (LR) was used to calculate the significance of the effect for all the previous
GLZM specified analysis, providing an estimate of the increment in the log-likelihood of the model attributed to each predictor.
8
M. PALLADINI ET AL.
Results
The optimal matching routine returned balanced baseline equivalent scores as
evaluated through standardized mean difference (SMD) values, thus allowing
meaningful comparison of cognitive improvement between the treated and
the untreated group (SMD values for the matched sample ranged between
-0.05 and 0.02). Demographic, clinical, and cognitive characteristics of the
matched sample were summarized in Table 1.
Spearman correlations highlighted a significant association (p < 0.05)
between ZSDS scores and: (i) verbal fluency (r = −0.35), (ii) working memory
(r = −0.44), (iii) psychomotor coordination (r = −0.42), and (iv) executive functions (r = −0.33).
Mixed model ANOVA predicting the effect of CRT on the global cognitive
index changes (i.e., mean of all the equivalent scores) revealed a significant
time * CRT interaction (F = 4.56, p = 0.039, η 2 = 0.104) (shown in Figure 1) as
well as a main effect of the number of impaired domains (F = 84.35, p < 0.001,
η 2 = 0.662). No significant main effect of time was observed.
Given the obtained significant result on the global cognitive index, each of
the six cognitive functions was individually considered (shown in Figure 2). A
significant interaction of time * CRT was detected (F = 4.56, p = 0.039, η 2 =
0.104) only for executive functions. Post-hoc inspection showed that the
treated group performed better at the follow-up than controls in executive
functions (p < 0.001). Furthermore, investigating the effect over time in single
domains among the two groups, we observed a significant improvement
among both treated and untreated patients in executive functions (treated: p
< 0.001; untreated: p < 0.001) and verbal fluency (treated: p = 0.006; untreated:
Table 1. Demographic, clinical, and cognitive characteristics of the matched sample according
to treatment. ZSDS, Zung self-rating depression scale.
Males (Females)
Age (mean ± SD)
ZSDS index score (mean ± SD)
ZSDS index > 50 Yes (No)
Hospitalization Duration in days (mean ± SD)
Mean Equivalent Score (mean ± SD)
Verbal Memory (Equivalent mean ± SD)
Verbal Fluency (Equivalent mean ± SD)
Working Memory (Equivalent mean ± SD)
Speed Information Processing (Equivalent mean ± SD)
Psychomotor Coordination (Equivalent mean ± SD)
Executive Functions (Equivalent mean ± SD)
Impaired Verbal Memory (n–%)
Impaired Verbal Fluency (n–%)
Impaired Working Memory (n–%)
Impaired Speed of Information Processing (n–%)
Impaired Psychomotor Coordination (n–%)
Impaired Executive Functions (n–%)
Controls (n = 30)
Treated (n = 15)
t or χ 2
pvalue
23 (7)
59.60 ± 10.00
44.25 ± 11.23
10 (20)
15.70 ± 14.41
1.73 ± 0.78
2.87 ± 1.17
0.43 ± 0.63
2.10 ± 1.30
2.03 ± 1.54
1.40 ± 1.16
1.57 ± 1.57
5–16.67%
28–93.33%
9–30%
12–40%
14–46.67%
18–60%
9 (6)
56.80 ± 7.09
46.43 ± 10.27
11 (4)
17.87 ± 19.45
1.74 ± 0.53
2.87 ± 0.83
0.40 ± 0.63
2.13 ± 1.30
2.07 ± 1.44
1.40 ± 1.45
1.60 ± 1.59
1–6.67%
14–93.33%
5–33.3 %
5–33.3%
8–53.33%
9–60%
1.32
0.97
−0.63
0.21
−0.42
−0.50
0.00
0.17
−0.08
−0.07
0.00
−0.07
0.87
0.00
0.05
0.19
0.18
0.00
0.245
0.339
0.531
0.649
0.675
0.496
1.000
0.868
0.936
0.945
1.000
0.947
0.352
1.000
0.819
0.664
0.673
1.000
NEUROPSYCHOLOGICAL REHABILITATION
9
Figure 1. Mixed model ANOVA considering the change over time of the mean equivalent score
in the two groups, according to age, sex, ZSDS, number of impaired cognitive domains at baseline. Error bars represent the 95% Confidence Intervals.
p = 0.016), while only the treated patients showed significant improvement in
psychomotor coordination (p = 0.012).
GLZM homogeneity of slopes highlighted a significant effect of CRT * baseline verbal fluency interaction on improvement in the same domain (χ 2 = 4.68,
p = 0.030). Consistent with previous results, stratifying for baseline equivalent
scores, the GLZM model showed a significant effect of CRT in predicting
Figure 2. Mixed model ANOVA considering the change over time of the single domain equivalent scores in the two groups, according to age, sex, ZSDS, number of impaired cognitive
domains at baseline.
10
M. PALLADINI ET AL.
increment in verbal fluency in the most impaired patients only (equivalent
score = 0) (χ 2 = 8.19, p = 0.004).
With regards to the analysis on quality of life, we observed a significant effect
of improvement in verbal fluency (χ 2 = 7.20, p = 0.007) and executive functions
(χ 2 = 13.63, p < 0.001) on variation in WHOQOL-BREF scores.
Discussion
To the best of our knowledge, this is the first study to demonstrate the beneficial effect of a personalized CRT programme delivered one month after hospital discharge in a cohort of COVID-19 survivors showing cognitive impairment.
Here we reported a significant global effect of CRT over time, while time per se
did not affect cognition performances. When considering specific cognitive
domains, we found a significant effect of CRT on executive functioning,
verbal fluency, and psychomotor coordination, which interestingly were
among the most compromised cognitive functions at baseline. Moreover, the
improvements in verbal fluency and executive functions improved the global
quality of life of survivors.
Previous insights suggest high prevalence of cognitive impairment among
COVID-19 survivors in short, middle, and long time, thus suggesting an enduring pattern of cognitive deterioration even following the complete virus clearance (Rabinovitz et al., 2020; Sheng et al., 2005). Accordingly, recent
investigations from our group documented a large incidence of cognitive
deficits (about 79%) one month after hospital discharge, that seem to remain
stable up to three- and six-month follow-ups (about 75%) (Poletti et al., 2021).
Cognitive impairments in the post-critical acute phase of COVID-19 are consistently reported irrespectively of the length of mechanical ventilation or intensive
care unit stay (Beaud et al., 2021; Jaywant et al., 2021). These deficits, if not
immediately addressed, seem to show a chronic course (Girard et al., 2018;
Jaywant et al., 2021) with residual cognitive impairments being now considered
a hallmark of the well-established long-covid syndrome (Nalbandian et al., 2021;
Taquet et al., 2021; Taribagil et al., 2021). When investigating the specific cognitive domains, previous studies found that executive function and verbal fluency
were among the most affected cognitive domains (Almeria et al., 2020; Beaud
et al., 2021; Hampshire et al. 2020; Helms et al., 2020; Jaywant et al., 2021)
both in acute and sub-acute stages. Consistently, with the long-lasting course
of cognitive impairment, in the absence of the CRT, we found no spontaneous
recovery of global cognitive functioning over time. Moreover, when investigating single cognitive domains, executive functions, and verbal fluency,
which were found to be among the most affected dimensions in our sample,
improved over time also in the untreated patients, but were especially susceptible to CRT-related enhancement. Interestingly, we found that psychomotor
coordination benefits from CRT training, whereas deficits in this domain seem
NEUROPSYCHOLOGICAL REHABILITATION
11
to be stable in the untreated group, as highlighted in our previous investigation
(Mazza et al., 2021). These findings suggest only a partial spontaneous improvement in the most affected cognitive functions over time in the absence of treatment. This is critical, specifically considering defects in executive functions are
notably reported over several months in patients with other acute respiratory
distress syndrome diseases before the COVID-19 pandemic resulting in poor
everyday functioning (Jackson et al., 2003 Apr; Sasannejad et al., 2019). Notwithstanding the partial overlap of cognitive sequelae in the ARDS survivors of other
etiologies, COVID-19 patients typically exhibit broader cognitive dysfunctions
(Lleó and Alcolea, 2020), encompassing also deficits in verbal fluency, psychomotor coordination, and sustained attention (Almeria et al., 2020; Poletti
et al., 2021; Zhou et al., 2020). Furthermore, in COVID-19 survivors, objective
cognitive complications usually associate with subjective cognitive complaints,
poorer quality of life, and psychiatric outcomes (Almeria et al., 2020). In keeping
with this, targeting post-covid cognitive outcomes with tailored CRT protocols is
of the utmost importance to restore satisfying everyday functioning. Moreover,
herein we detected a strong positive impact exerted by CRT in patients who
showed severe verbal fluency impairment at baseline. These findings suggest
that CRT not only is highly effective for those cognitive domains specifically
impaired in COVID-19 patients but, again, it’s especially successful in recovering
extremely compromised cognitive functions.
Several mechanisms have been implicated in the pathophysiology of longlasting cognitive deficits after COVID (Alnefeesi et al., 2021). A major emphasis
has been placed on the prolonged systemic inflammatory status triggered by
the virus, with an exuberant immune response leading to a “cytokine storm”
(Coperchini et al., 2020; Nalbandian et al., 2021). In this regard, we previously
demonstrated that systemic inflammation at hospital admission influences
several cognitive functions three months later, including verbal fluency
(Mazza et al., 2021). Alongside with inflammatory hypothesis, mounting evidence supports a close link between persistent hypoxemia experienced
during the hospitalization and following neuropsychiatric sequelae (Hosey
and Needham, 2020; Mazza et al., 2021). This seems to be especially relevant
for executive outcomes (Helms et al., 2020), which remain impaired up to one
year from the clearance of the virus (Pandharipande et al., 2013).
Furthermore, our results, consistent with the literature, outlined the association between depressive symptomatology and cognitive performance.
Recent evidence suggests that depressive symptoms can affect neurocognitive
impairment, the latter being in turn held responsible for depressive outcomes in
those who contracted Sars-CoV-2 (Almeria et al., 2020; Miskowiak et al., 2021;
Muthukrishnan, 2020). In this context, our precedent investigation provides
early evidence about the detrimental impact of depressive symptoms on
middle-term cognitive performances in a longitudinal cohort of covid-19 survivors (Mazza et al., 2021). In keeping with this, herein we found a correlation
12
M. PALLADINI ET AL.
between depressive symptomatology and cognitive impairment. However, notwithstanding this association, depressive symptomatology accounted as a covariate, did not affect the CRT efficacy on global cognitive improvement
suggesting specific action of CRT on cognitive functioning irrespectively of
mood alterations and thus enhancing its clinical utility.
Cognitive training programmes have proven advantageous in improving
functional outcomes in several neurological and neuropsychiatric conditions
(Rodakowski et al., 2015). CRT protocols are now considered a useful adjunctive
therapy in MDD (McIntyre et al., 2013), characterized by a strict association
between depressive symptomatology and cognitive impairments that negatively affect daily functioning and significantly worsen the prognosis of traditional treatments (Rock et al., 2014). In this context, CRT is able to enhance
mood restoration and to promote substantial psychosocial recovery (Porter
et al., 2013). CRT was also found to be a possible therapeutic strategy for mild
cognitive impairment (Huckans et al., 2013). Additionally, survivors of critical
illness with cognitive impairment had significant improvement after computerized CRT (Wilson et al., 2018). Moreover, CRT was found to be effective in reducing cognitive deficits in adults with HIV (Kanmogne et al., 2020) resulting again
in a more fulfilling quality of life (Vance et al., 2012). In agreement with findings
related to different clinical populations, we observed the clinical efficacy of CRT
not only on cognitive functioning but also on the general well-being as reported
on WHO-QOL. Interestingly, the effect on quality of life was proportional to the
improvement in cognitive functions in the group of COVID-19 survivors who
received the CRT.
Nevertheless, these results must be viewed in light of some weaknesses. First,
the limited sample size of the present investigation prevents us from generalizing the favourable effect of CRT. Second, both the neuropsychological assessment and the training sessions were conducted by the same psychologist,
possibly inducing subjective influence in the post-treatment testing. As our
work only involves a passive control group, further studies should include an
active placebo condition in order to control for non-specific therapist/patientrelated effects, such as demand characteristics, attention or care. Notwithstanding the successful application of a matching routine afterward, the lack of a
structured double-blind randomization design makes it challenging to disentangle the beneficial effect of CRT from the bias related to the ability/inability
to regularly attend the full programme. However, our procedure allowed us
to meet a clinical need and preserve a more naturalistic setting.
Taken together, these findings support the clinical relevance to rapidly
address cognitive dysfunctions in order to reverse the spontaneous chronicity
of the post-COVID-19 cognitive impairments. As the world moves into the
second year of COVID-19 pandemic, delayed cognitive sequelae are becoming
increasingly appreciated. Although the calls for treatment targeting cognitive
impairments are progressively emerging, cognitive-enhancement therapies
NEUROPSYCHOLOGICAL REHABILITATION
13
have not received adequate attention thus far. Overall, we consider our results
could pave the way to a plausible treatment line targeting cognitive impairments in the COVID-19 survivors. Although further investigations are required
to replicate our findings in larger samples, we demonstrated favourable
effects of CRT seem to extend beyond cognitive functioning per se, ameliorating
quality of life of the treated subjects. Thus, we suggest mental health systems
should consider integrating cognitive enhancing-therapy into their services to
properly meet the clinical need and contribute to the full recovery of COVID19 survivors.
Acknowledgements
Authors thank Sara Bosio for directly participating in the recruitment phase and the COVID-19
BioB Outpatient Clinic Study group for general support.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The author(s) reported there is no funding associated with the work featured in this article.
Data availability statement
The data that support the findings of this study are not publicly available but are available
from the corresponding author MP upon reasonable request.
Statement of ethics
Study approval statement: this study protocol was reviewed and approved by Ethics Committee of San Raffaele Hospital (COVID-BioB protocol NCT04318366). Consent to participate statement: written informed consent to participate in the study was obtained from all participants.
ORCID
Mariagrazia Palladini
http://orcid.org/0000-0003-4616-4185
Beatrice Bravi
http://orcid.org/0000-0003-2568-4181
Patrizia Rovere-Querini
http://orcid.org/0000-0003-2615-3649
Francesco Benedetti
http://orcid.org/0000-0003-4949-856X
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