Brain Outcome after Cardiac Arrest
Modifying working memory with non-invasive brain stimulation - A series of SCEDs

Increasing number of cardiac arrest survivors with cognitive impairment
The worldwide incidence of out of hospital cardiac arrest (OHCA) is estimated
at 50-55 events per 100.000 citizens a year (Berdowski, Berg, Tijssen, &
Koster, 2010; Waalewijn, De Vos, & Koster, 1998). The survival rate of OHCA
with attempted resuscitation lies between 10% and 25%, but differs a lot
between regions (Dyson et al., 2019; Nichol et al., 2008; Yan et al., 2020). In
the Netherlands, a large network of civilian volunteers with basic life support
skills has been set up, the density of easily accessible automated external
defibrillators has increased, and the healthcare system has been improved.
Consequently, the survival rate of OHCA has increased in the past decades from
9.1% (1995) to 23% (2021) (Beesems, Stieglis, & Koster, 2012; Berdowski,
Waalewijn, & Koster, 2006).

In sharp contrast with increased survival, neurological and cognitive outcome
of cardiac arrest survivors have changed only marginally over the past twenty
years. Still, approximately half of the people who survive a cardiac arrest
have enduring cognitive impairments (Boyce & Goossens, 2017; V. Moulaert,
Verbunt, van Heugten, & Wade, 2009; Zook et al., 2021). These impairments arise
because of a temporary deprivation of oxygen- and glucose-rich blood to the
brain during the arrest. This causes ischemic-hypoxic brain damage, which may
lead to lasting cognitive impairment (Sandroni, Cronberg, & Sekhon, 2021). In
cardiac arrest survivors, these impairments are most prevalent in the domains
of memory, attention, and executive functioning (Cronberg et al., 2020; V.
Moulaert et al., 2009).

Current treatment of OHCA
Currently, there are no treatments of proven benefit for cognitive impairment
after cardiac arrest. Moulaert et al. (2015) showed that recognition of and
attention for cognitive impairment after a cardiac arrest have a positive
effect on the long-term quality of life of patients. Cognitive rehabilitation
therapies or other treatments to improve cognitive functions could possibly
enhance these positive effects. This implies a need for evidence of efficacy of
treatments to improve cognitive functioning in this group of patients.

Non-invasive brain stimulation as treatment option
Promising new treatment options are arising in the field of non-invasive brain
stimulation (NIBS). Repetitive transcranial magnetic stimulation (rTMS) is a
form of NIBS that has been studied in a wide range of patient groups
(Lefaucheur et al., 2020). rTMS is a non-invasive way to induce an electrical
current in the brain through electromagnetic induction (Lefaucheur et al.,
2020). A magnetic field generated by the TMS coil passes through the skull,
inducing an electric field. This electric field causes a current to flow within
the brain. The presumed final common path of rTMS is modification of brain
plasticity by stimulation of intrinsic plasticity mechanisms such as synaptic
changes by promoting long-term potentiation (LTP) or long-term depression (LTD)
(Klomjai, Katz, & Lackmy-Vallée, 2015). Faciliatory stimulation protocols, such
as high-frequency rTMS, generally strengthens excitatory brain circuits. On the
other hand, inhibitory protocols, such as low frequency rTMS, generally target
inhibitory circuits and downregulate excitability and activity. In the last 15
years, a specific rTMS protocol called intermitted theta burst stimulation
(iTBS) has been used a lot (Huang, Edwards, Rounis, Bhatia, & Rothwell, 2005).
Advantages of this protocol is that it is shorter than the regular rTMS
protocol (190 seconds instead of 20 minutes). TBS paradigms have large effect
sizes and acceptable interinvidusal variability compared with traditional rTMS
paradigms (Huang et al., 2005).

TMS as a potential cognitive treatment
rTMS has been studied for, amongst other, motor and cognitive recovery after
stroke (Corti, Patten, & Triggs, 2012; Zhang et al., 2021). Many studies show
that rTMS can improve global cognitive functioning (Q.-M. Chen et al., 2021; H.
Li et al., 2021; W. Li et al., 2022; Liu et al., 2020; Lu, Zhang, Wen, & Sun,
2015; Tsai, Lin, Tsai, Kuo, & Lin, 2020; Wang et al., 2021) and memory
functions (J. Li et al., 2016; Lu et al., 2015; Yin et al., 2020) after stroke.
RTMS also improved working memory and executive working performance compared to
sham stimulation in traumatic brain injury patients (Ahorsu, Adjaottor, & Lam,
2021; Hoy et al., 2019). TMS has been used for almost 40 years and is a
generally approved and accepted therapy by the FDA for treatment of psychiatric
disorders (e.g. depression) (Cohen, Bikson, Badran, & George, 2022). Various
TMS protocols have been developed and approved by the FDA. The dorsolateral
prefrontal cortex (DLPFC), is related to working memory processes, and
therefore a common target in those studies.


Safety
The safety of rTMS is well studied and the overall safety profile is good (Loo,
McFarquhar, & Mitchell, 2008). The study of Bakker et al. (2015) did not
encounter any seizure or other serious adverse event in over 7912 runs of
stimulation (4274 rTMS and 3638 iTBS runs). A recent meta-analysis reported
that a seizure has only occurred once with TBS to date, and it accounts for the
crude risk of seizure per session of 0.02%. The overall crude risk of mild
adverse events was estimated to be 1.1%, and these findings were comparable
with high frequency rTMS protocols (Oberman, Edwards, Eldaief, & Pascual-Leone,
2011).


rTMS and working memory assessed with the N-back task
The N-back task is a commonly used and valid task to assess working memory. In
the N-back task a subject is presented with a sequence of stimuli, and the task
consists of indicating when the current stimulus matches the one from n steps
earlier in the sequence. The load factor n can be adjusted to make the task
more or less difficult. Outcome variables of the N-back task include accuracy,
reaction times, and working memory accuracy (d*). D* is the standardized
difference between the means of the signal present and signal absent
distributions. The advantage of d* is that it is robust to the response bias.

rTMS studies assessing n-back performance in healthy controls and patient
populations have shown mixed results (Boggio et al., 2006; Esslinger et al.,
2014; Teo, Hoy, Daskalakis, & Fitzgerald, 2011), Brunoni and Vanderhasselt
(2014) conducted a systematic review and meta-analysis on working memory
improvement, based on the n-back task, with non-invasive brain stimulation of
the dorsolateral prefrontal cortex. Based on 14 experiments they found that
participants (healthy and people with schizophrenia) after receiving active
rTMS compared to those receiving sham stimulation, were faster and more
accurate on the N-back task with a medium effect size. They also found that
non-invasive brain stimulation techniques showed superior improvement in
clinical populations on the N-back task.


Single Case Experimental Design
Patients with cognitive impairment after OHCA are a heterogeneous population.
This means that they differ on many characteristics, such as baseline cognitive
functioning and severity and type of cognitive impairment. A classical clinical
trial comparing groups of patients is therefore not an ideal study design.
First, because of the heterogeneity it is not expected that one outcome measure
is suitable for all included patients. Secondly, large numbers of patients
would be needed for sufficient statistical power in a group-design trial,
limiting the feasibility of the study.

A promising study design that is increasingly used in the field of
rehabilitation is the single case experimental design (SCED). In this design
the unit of intervention and data analysis consists of a single or a few cases
that provide their own intervention and control data. A main characteristic of
this design is that the outcome

Aim of the study
This is a proof-of-concept study to investigate the effects of rTMS (iTBS
protocol) on working memory of people with memory impairments after a cardiac
arrest in the past. We propose a series of single case experimental design
(SCED) studies to study the causal relationship between a manipulated
independent variable (iTBS yes or no) and our outcome variable (working memory)
in a relatively small number of participants.

Primary objective
The primary objective of the present study is to test whether iTBS over the
left dorsolateral prefrontal cortex enhances the accuracy of working-memory
performance, defined as the percentage hits minus the percentage false alarms,
on the N- back task, in participants with working memory impairment after a
cardiac arrest.

Secondary Objectives
- To estimate iTBS effects on reaction time (RT).
- To estimate iTBS effects on an individual*s ability to detect signals
expressed as changes in sensitivity (d*)

This study will consist of single blinded replicated randomized SCED withdrawal
designs in nine participants at the NIBS laboratory at Maastricht University.
The intervention contrast will be iTBS versus sham stimulation. The reason for
adding sham stimulation is to minimize placebo effects of rTMS. The study will
be split up in two days. During the first day the eligibility of the potential
participant will be determined, which takes approximately 1 - 1,5 hour. On the
second day the experiment will be conducted, which takes approximately 200
minutes.

The participant will receive sham iTBS. The participant is not aware what type
of stimulation he/she receives. Directly after stimulation the participant is
asked to perform the N-back task on a computer for 8-12 minutes, with a small
break of 30 seconds after every 2 minutes. After this, the participant can rest
for approximately 45 min (making sure there is at least 50 minutes between
stimulation and the next N-back session). The participant can do his / her
personal relaxing activity during this break. Then the same procedure is
repeated with active, sham, and active iTBS. The total time of the experiment
session will be approximately 200 minutes.

Potential risk: The potential risks are the side effects of TMS, including
common side effects: headache, scalp discomfort, tingling or twitching of the
facial muscles, and light-headedness. Serious side effects are very rare and
may include: seizures.

Potential benefit: Working memory performance may be enhanced.