Working memory in the presence of distraction in people with Multiple Sclerosis: underlying neural mechanisms of a novel paradigm

Working memory (WM), a brain system that temporarily stores, maintains and
manipulates information (1), plays a crucial role in the age-related decline of
cognitive functions (2) and can be impaired as the result of various clinical
conditions, including Multiple Sclerosis (MS) (3). In MS, a neurodegenerative
and inflammatory disease of the central nervous system, cognitive impairment
including WM is among the most prevalent symptoms reported by patients within
the first year of the disease (4,5). Due to its central role in higher order
cognitive functions such as planning, reasoning or learning, WM impairments can
lead to serious problems in daily life. Hence, major effort is devoted in
developing WM interventions to improve cognitive functioning in the general
population and rehabilitate patients with impaired WM (6-8).
As patient-specific rehabilitation typically focuses on the
rehabilitation of motor and occupational skills, cognitive problems receive
less attention during multidisciplinary inpatient rehabilitation (9). This
observation indicates a limited availability and dissemination problem of
cognitive rehabilitation in the clinical context, especially when considering
the extensive research on cognitive training that has been performed in healthy
people. Indeed, WM interventions have shown small to medium effects for
improving related tasks, but increases in WM capacity or transfer to other
cognitive functions have been reported inconsistently in healthy older adults
and people with MS (PwMS) (10-12). This inconsistency may be explained through
task-related processes of WM training that may influence the performance on
outcome tasks (13). Thus, we studied WM capacity improvements after an in-house
developed, digital model-based WM training with distractors by comparing it to
the same training without distractors, a dual-n-back and a control training in
a randomized clinical trial on 120 healthy older adults. The results showed
improved WM capacity after WM and distractor training only, suggesting that
distraction filtering might be sensitive to WM capacity improvements when
trained with WM in older adults (14) and thus to be a promising approach in
increasing WM capacity not only in older adults but also in patients with WM
impairment such as pwMS.
Recent findings suggest the importance of WM to be resilient to
distraction of irrelevant information when understanding WM functioning in the
real world (15). Distractors in WM tasks can either be presented together with
to-be-remembered items (encoding distraction) or while they are held in mind
(delay distraction) (16), leading to a distorted task-response which limits WM
capacity or degrades memory completely (15) and results in forgetting (2). It
has been described that older adults and people with impaired WM performance
have difficulties to suppress distractors during WM tasks (16-18). In PwMS,
impaired recall has been described compared to healthy controls if distractors
are presented during encoding and retention of a WM task (19). However, it has
been hypothesized that auditory distractors in spatial WM tasks may serve as
cues for shifting attention to target items as it led to improved performance
in PwMS compared to healthy controls (20). Thus, distractor resilience has not
only been discussed as a critical source of individual differences in WM
capacity (16,17) but as a proxy for memory-related deficits (2,19).
Recent functional Magnetic Resonance Imaging (fMRI) findings support
the presence of different pathways coping with distraction during WM tasks in
healthy people. Whereas an active top-down inhibition through the lateral
prefrontal gyrus has been shown to inhibit sensory processing of distractors,
the striatum has been suggested to act as a gate, that blocks distractors from
being encoded into WM (15). Increased cortical activity has been observed when
distractors were present during encoding and delay, but not when participants
were asked to suppress distractors during encoding. These findings have been
linked to performance, where people with higher ability to suppress delayed
distractors show greater suppression of distractors during encoding (21). When
comparing younger and older adults on a WM and distraction task in their
corresponding brain activity, differences were only detected behaviorally with
older adults showing difficulties in task performance, but not in brain
activation. Results suggest that both young and old adults reach a neural
capacity limit, suggesting a shared use of neural resources with increasing
distractor and WM load (22).
In summary, the investigation of WM in the presence of distraction has
gained in interest in the past years. Behavioral work suggests resilience to
distraction in WM as a crucial proxy for individual WM capacity differences
among cognitively healthy (16,17) as well as impaired people (2,18,20) and that
WM in presence of distraction is sensitive to improve WM capacity after
training (14). Although neural mechanisms involved in the suppression of
distractors have been described, the link between behavioral and neural
correlates for a comprehensive understanding of real-world WM functioning is
still unclear (15). In addition, the underlying neural differences of WM and
distraction between cognitively healthy and PwMS have not been investigated
(19,20).

Recent neuroimaging research identified different pathways of how distraction
is processed in WM, showing involvement of the lateral prefrontal cortex and
striatum (15,21,22). It has been described that if a combined demand of WM and
distraction is present, the brain might reach a neural capacity limit,
indicating no additional available resources to respond to the increase in
cognitive demand(22). However, behavioural work suggests resilience to
distraction in WM as a crucial proxy for individual WM capacity differences
among cognitively healthy (16,17) and impaired people (18,20). Thus, the
proposed study aims at studying regional brain activity in PwMS and healthy
controls on two WM tasks including distractors as well as the differences in
behavioural task performance and brain activation between both groups.

Primary Objective:
I. To examine regional brain activity measured by fMRI during a visual and
verbal WM task with delayed distraction and distraction at encoding compared
to a control condition without distraction in PwMS and healthy controls.

Secondary Objectives:
I. To examine differences in regional brain activity between PwMS and healthy
controls on a visual and verbal WM task with delayed distraction and
distraction at encoding
II. To examine differences in behavioural task performance on two WM tasks
including distraction between PwMS and healthy controls
III. To examine differences in resting state brain activity measured by fMRI
between PwMS and healthy controls

This study follows a cross-sectional design with one single assessment
including a cognitive assessment and MRI session that will be performed at the
Leiden Institute of Brain and Cognition (LIBC) at the Leiden University Medical
Center (LUMC) in Leiden. In total 68 participants will be included in the
study. The sample will consist of 34 PwMS recruited from the Dutch MS Society
and social media (e.g. Facebook groups) and 34 age and sex matched healthy
adults recruited from public notice boards, in order to study if brain
activation during the WM and distraction paradigm is related to the clinical
condition or not. Each participant, patient and control, will undergo a single
appointment of the duration of approximately 120 minutes, including a cognitive
assessment (approximately 30 minutes), an structural and functional brain MRI
(approximately 45 minutes) and an online questionnaire which can be filled out
after the study session at home (approximately 15 minutes).

The risk of the proposed cognitive assessments as well as the task performed
during the MRI scan is negligible, as the task difficulties are adjusted to the
patient population. Brain imaging using MRI is a non-invasive and safe
procedure, where thorough screening for compatibility is done. To exclude any
risks, all participants will be screened for contraindications including metal
parts, pregnancy and claustrophobia before undergoing the MRI scan. The
confined space inside the MRI device for the duration of 45 minutes of the scan
as well as the time investment of the participant for travel to the study
location and participation involves some burden for the participants.
Therefore, all participants are asked to undergo the cognitive and MRI
assessment once with a maximal duration of 90 minutes for the whole study
participation to ensure a minimal burden for patients.

In daily life we are constantly confronted with co-occurring inputs from visual
or verbal sources that demand the ability to select relevant information.
Impaired ability to filter distracting information may limit the WM capacity
and thus hamper the independent conquering of daily life tasks. Studying if WM
and distraction may differentiate between cognitively healthy and impaired
people and identifying neural mechanisms at play will be beneficial in the
sense that it will lead to novel insights on how WM is impaired. Furthermore,
the current study will follow the current notion that including distractors in
neuropsychological tasks may detect real-world deficits and thus offer a
strategy to prevent cognitive impairment (53). To that end, the proposed study
displays the first step in understanding if WM in presence of distraction can
act as a target to improve WM functioning in PwMS. In summary, the insights of
the proposed research would pave the way for understanding WM and developing
accessible rehabilitation strategies that can ameliorate WM impairments and
thus benefit patients in increasing their quality of life.