Effectiveness of computerized training of attention and working memory in Post COVID-19 patients with cognitive complaints

Since 2019, the world has been overwhelmed by COVID-19, a respiratory
infectious disease. A few years in the pandemic, the persistence of symptoms
after the acute phase is a well-recognized phenomenon. Most people who develop
COVID-19 fully recover, but current evidence suggests approximately 10%-20% of
people experience a variety of mid- and long-term effects after they recover
from their initial illness. These mid- and long-term effects are collectively
known as post COVID-19 condition (PCC) or *long COVID*. According to the World
Health Organization PCC is defined as the illness that occurs in people who
have a history of probable or confirmed SARS-CoV-2 infection; usually within
three months from the onset of COVID-19, with symptoms and effects that last
for at least two months. Multiple studies show a variety of symptoms of PCC.
Common symptoms include, but are not limited to, fatigue, shortness of breath,
cognitive dysfunction and / or subjective cognitive complaints, even after 1
year or more after hospitalization. Patients with PCC have lower general
cognition compared to healthy controls. Overall reviews show that attention,
memory and executive functions appeared to be affected domains. Detailed
research show deficits in attention, both in sustained and executive
components. Furthermore, less capacity of working memory, inhibition deficits
and lower information processing speed are also frequently reported. These
functions are related to fatigue . Fatigue and cognitive impairment have been
consistently reported to be some of the most common and debilitating features
of PCC. Cognitive dysfunction is associated with anxiety and depression and
have an impact on every day functioning, return to work and account for
diminished quality of life. Unlike other common symptoms of PCC including
dyspnea there are no established and effective treatments yet for post-viral
fatigue and cognitive impairment for these patients. Multiple studies already
emphasized the urge for (cognitive) rehabilitation programs for post COVID-19
victims. In the Netherlands rehabilitation centers have developed
multidisciplinary care pathways without any cognitive rehabilitation elements.
Computer-based attention training (a component of RehaCom computerized
cognitive therapy software) resulted in significant improvements on attention
in acquired brain injury patients, indicating both a direct benefit and
generalization of training effects. Also, similar results are found in other
patient groups like patients with MS.This study aims to evaluate the effect of
computerized cognitive training on attention and working memory in post
COVID-19 patients.

Primary Objective: The aim of this study is to research the effect of a
computerized cognitive rehabilitation program (RehaCom) in post COVID-19
patients with cognitive complaints on their sustained and divided attention and
their working memory.
Secondary Objective(s): To evaluate the effect of a computerized cognitive
rehabilitation program (RehaCom) on subjective cognitive complaints,
psychological outcome measures and HR-QoL.

Randomized wait-list controlled pilot trial. Patients with persistent cognitive
complaints of the CO-FLOW study, a prospective multi-centre cohort study
(NL74252.078.20) will be invited. In this study, the Cognitive Failure
Questionnaire (CFQ) was used to measure subjective cognitive complaints. After
1 year 22% (103/468) of the participants showed deviant results on the CFQ .
Preliminary results show that these problems did not improve after 2 years,
with preliminary results showing deviant results in 24% (67/279). In addition,
53 to 57% of the CO-FLOW participants reported symptoms of concentration and/or
memory problems, respectively.

The total group will be divided randomized 1:1, to the intervention or control
group. First, both group will have a baseline measurement. Both groups of
patients will receive the computerized training, using a waiting list
procedure. 1 group will directly after the baseline measurement start the
online (at home) computerized cognitive training for 10 weeks, 3 times a week,
each session 15-30 minutes (RehaCom). Directly after the intervention this
group will be retested. Also, follow-up 3 months after the intervention will be
performed to study preservation of training effects. The other group also
receives the same intervention, after a 3 months waiting period, starting after
the second measurement. This group will also be tested after the intervention.

Investigational product/treatment
RehaCom is a software program consisting of 29 different therapy modules in
multiple cognitive domains (attention, memory, executive functioning, visual
field and visual motor coordination. Each domain has several subtasks. The
cognitive domain **attention** for example, consists of therapy modules about
alertness, vigilance, selective attention, sustained attention, visuospatial
attention and visuoconstruction. Each module has different levels of
difficulty. Starting at a low level of difficulty, the patient can progress to
solve increasingly complex tasks. RehaCom is an auto-adaptive program which
adapts the complexity of each task automatically to the patients actual
performance. The computer operates as a neutral observer making objective
comments on the patient performance and gives, if necessary, error-specific
feedback.

RehaCom saves all training results. A new training session starts where the
last one has been finished. The therapist has the ability to monitor all data
to further develop the therapy strategies.

In this study the following training modules will be used as intervention:
Attention:
* The module **Sustained Attention** (SUSA) aims to train the ability to
maintain the focus and level of attention during high frequencies of stimuli
and high demands on the selection process for longer periods. This module has 9
levels.
* The module **Attention and Concentration** (AUFM) is based on the principle
of pattern comparison. The client has to find one picture in a matrix that
matches exactly the *comparison picture*. This is used to train selective
attention and concentration. This module has 24 levels.
* In the module **Divided Attention** (GEAU) several stimuli have to be
observed simultaneously as often demanded in everyday life. Like a train
driver, the patient has to monitor the driver*s cab, regulate the speed, and
react to different signals during the train run. This module has 14 levels.
* In the module **Divided Attention 2** (GEA2), patients have to pay attention
to several external stimuli whilst driving a car (divided attention). They have
to observe the landscape passing in front of them as well as the car dashboard
and react to acoustic information in a differentiated way. This module has 22
levels.
* The module **Working Memory** (WOME) is a training that exercises the ability
to remember information and to manipulate it. Maintaining attention and the
resistance to interference play a central role. Depending on the level of
difficulty, the patient has to remember an increasing number of playing cards
(memory system), select them from different distractors (selective attention)
and later mentally manipulate them (central executive). This module has 70
levels.
* The module **Memory Strategy Training** (LEST) introduces and consolidates a
learning strategy and thus improves the memorization and retrieval of
Information. This module has 18 levels.
* The module **Verbal Memory** (VERB) aims to improve the short-term memory of
verbal information. For this purpose, short stories are displayed on the
screen. The patients have to memorize all details in the story. Afterwards,
they must reproduce them when asked by the program. This module has 10 levels.
Patients will be trained with Rehacom 3 times a week 15-30 minutes for 10
weeks.

The intervention is an online cognitive rehabilitation program, 3 times a week
15-30 minutes per session during 10 weeks. Participants can choose what time of
the day is most convenient for them to engage in the program, so they can
optimize their circumstances as much as possible. Participating in the
computerized training program might lead to temporary fatigue. Patients will
be advised to rest before and after the training. There are no extra risks
involved in participating in the intervention.

In 3 visits assessments will be performed using short tests and questionnaires.
Questionnaires and neuropsychological tests (pen and papertasks) are minimally
physically demanding and have a maximum duration of 60 minutes per session,
including regular breaks.

We expect that after the computerized training patients will be able to better
concentrate and divide their attention. We hypothesize that this will decrease
subjective cognitive and psychological complaints and improve quality of life.
By repeating the tests in the long term, participants will gain more insight in
their recovery after COVID-19.