Computerized Cognitive Rehabilitation in ICU Survivors ... · Computerized Cognitive ... the Tennessee Valley Healthcare System Geriatric Research ... three participants were excluded

Computerized Cognitive Rehabilitation in ICU Survivors: RETURN-CCR Pilot Investigation

Jo Ellen Wilson MD MPH1, Erin M. Collar MPH

2, Amy L. Kiehl MA

2, Hyunkyu Lee PhD

3, Michael

Merzenich PhD3, E. Wesley Ely MD MPH

4,5 and James Jackson PsyD

2 for the Returning to

Everyday Tasks Using Rehabilitation Networks - Computerized Cognitive Rehabilitation

(RETURN-CCR) Investigators

1Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine,

Nashville, TN

2Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN

3Posit Science, San Francisco, CA

4Veteran’s Affairs TN Valley, Geriatrics Research, Education and Clinical Center (GRECC)

5Department of Medicine, Division of Pulmonary and Critical Care, and the Center for Health

Services Research, Vanderbilt University Medical Center, Nashville, TN

Corresponding Author:

Jo Ellen Wilson, MD MPH

The Vanderbilt Psychiatric Hospital

1601 23rd

Avenue South

Nashville, TN 37212

Phone: (615)-719-0464

Fax: (615)-322-4856

Email: [email protected]

Web: www.icudelirium.org

Author Contributions: All authors listed above have contributed substantially to the conception

or design of the work; or the acquisition, analysis, or interpretation of data for the work and

have participated in drafting the work or revising it critically for important intellectual content.

Additionally, each author has given their approval to the final version of the manuscript and has

agreed to be accountable for all aspects of the work in ensuring that questions related to the

accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflicts of Interest and Source of Funding: Dr. Wilson would like to acknowledge salary

support from the Vanderbilt Faculty Research Scholars Program (KL2). Drs. Ely and Jackson as

well as Mrs. Collar and Kiehl all receive funding for their time working on this investigation from

AG035117 and HL111111. Dr. Ely would additionally like to acknowledge salary support from

the Tennessee Valley Healthcare System Geriatric Research Education and Clinical Center

(GRECC). Dr. Ely will also disclose additional funding for his time from AG027472 and having

received honoraria from Orion and Hospira for CME activity; he does not hold stock or

consultant relationships with those companies. None of the Vanderbilt investigators received

any consulting fees, stocks, or other financial support from Posit Science, the company that

provided Brain-HQ, the computer program used in this investigation. Dr. Lee would like to

disclose salary support from the Posit Science and that she is a research scientist and employee

of Posit Science. Dr. Merzenich would like to disclose being a developer of the technology used

Page 1 of 15 ANNALSATS Articles in Press. Published on 18-June-2018 as 10.1513/AnnalsATS.201709-744RL

Copyright © 2018 by the American Thoracic Society

in the computerized rehabilitation Brain HQ used in this investigation and that he is a founder

and employee of Posit Science.

Running Head: Computerized Cognitive Rehabilitation in ICU Survivors

Subject Category: 4.4 Clinical Trials in Critical Care Medicine

MeSH Key Words: cognitive neuroscience, training, delirium, cognitive impairment

Word Count: 1710



Utilization and cost of critical care medicine have risen steadily since 2000 (1, 2). Nearly one-

third of patients who survive their critical illness will suffer from newly acquired or accelerated

post-ICU cognitive impairment (3). One-third to one-half of all survivors of critical illness are

newly unemployed at 12 months, likely attributable to newfound cognitive deficits (4-6). This

public health problem is growing, poorly addressed, and requires innovation to reduce suffering

and help patients return to normal functioning. By monitoring delirium (7, 8), we have shown

that delirium duration (3, 9) is associated with white matter disruption after a critical illness

(10). While therapeutic approaches are emerging in the context of critical care delivery to

reduce delirium and enhance patient safety by reducing the duration of delirium and coma (11),

few therapeutic approaches have been tested in this population to regain acquired cognitive

deficits. What remains unknown is whether we can help patients recover cognitive abilities

once lost.

A need exists to develop cognitive rehabilitation approaches for patients with critical

illnesses who despite our best care go on to acquire post-ICU cognitive impairment even

without prior stroke or head injury. While cognitive rehabilitation has historically been

employed with predominantly brain-injured populations (TBI, stroke), it has only recently been

trialed in primary medical populations such as individuals with “chemo-fog”, HIV-associated

neurologic dysfunction and only minimally among those with post-intensive care syndrome

(12). Computerized Cognitive Rehabilitation (CCR) is a novel approach of traditional cognitive

rehab through the use of computerized “brain exercises”. A recent systematic review of 16

computerized cognitive training trials found moderate effect sizes in improvement of attention,

executive function and memory, in individuals with cognitive impairment, which persisted at



follow-up (13). Despite early promising results, many in the scientific community have

questioned whether computerized cognitive exercises have any real impact (14, 15). To the

contrary, others suggest that CCR holds the promise of accelerating recovery by harnessing

neuroplasticity (16-18). We hypothesized that application of CCR would improve key cognitive

abilities in ICU survivors even years after the original brain injury.

Methods

The Returning to Everyday Tasks Using Rehabilitation Networks – Computerized Cognitive

Rehabilitation (RETURN-CCR) pilot investigation was designed by Posit Science, to test feasibility

and proof of principle of specially designed computer exercises in addressing cognitive

impairment in ICU survivors (19). IRB-approval was obtained, and patients from the BRAIN-ICU

observational cohort study (3) as well as our group’s ongoing studies were enrolled after we

obtained their informed consent. These patients had survived ICU treatment with mechanical

ventilation or vasopressors in the context of severe critical illness and had since shown

persistent long-term cognitive impairment. A convenience sample (N=33) of patients was

recruited to participate in RETURN-CCR. In general, if patients had completed their

participation in one of the above studies and were alive and felt to be able to participate in this

trial (i.e., had previously followed up with former study assessments) they were approached for

participation in RETURN-CCR.

Patients received the CCR program, which was comprised of adaptive exercises focused

on optimizing speed and memory accuracy and auditory verbal processing (16, 17). Patients

completed 7 cognitive exercises daily (~42 minutes), 5 days a week, over the 12-week trial



period, with core therapeutic tasks built into a game-like experience. Use of the program was

tracked from Posit Science BrainHQ’s experimental portal, where the experimenter can easily

track progress of each participant, number of training days, and overall performance.

During a session, patients performed trials, with auditory and visual feedback and

rewards to indicate if the trial was performed correctly or incorrectly. After each session, the

difficulty of the next session was titrated to ensure appropriate difficulty based on immediate

preceding performance. That is, patients excelling experienced progressively more challenging

tasks whereas patients performing poorly engaged in tasks that were easier.

The brain-training program included 18 computerized training exercises. Core training

targets include visual and auditory processing accuracy, speed, and sequencing; phasic,

sustained, and divided attention; memory and memory association; and executive control

abilities. For each session, participants were given 7 computer exercises and each game lasted

about 6 minutes. During the 6-minute time window, participants played a certain level of game

multiple times (usually between 2-4 times, varying based on participants’ response speed and

number of trials). Baseline was set by the performance of very first attempt. On repetition, the

initial difficulty was set by the previous trial’s best performance to promote performance

improvement. As each session progresses, improvements in processing speed and/or

performance accuracy and in their controlled, higher-order performance operations are

challenged at progressively more cognitively demanding task levels, to maintain ~75-85%

accuracy. By this adaptive training strategy, virtually all trainees, regardless of learning rate,

were continuously challenged at an appropriate difficulty level as their abilities improved.

We compared the baseline (Pre-CCR) scores versus post-CCR scores to assess



improvement in performance. Each computerized cognitive exercise has multiple levels,

presented to participants in fixed order (i.e., from easy to more complex levels). Participants set

the baseline or “pre” cognitive training score from their individual performance on the initial

trial and their “post” score representing their individual best performance within the trial

period. Pre and post-scores for each exercise were calculated by averaging the normed pre and

post-scores of all levels. Normed pre and post scores from each exercise were averaged to

produce a composite score for each cognitive domain. Mixed-effects linear regression was

performed for each cognitive domain separately with time (pre and post performance) as a

factor. Mixed linear regression models were used to assess the effect of user group (super,

high, normal) on improvement (pre- and post-) of untrained neuropsychological tests (including

Digit Span, Spatial Span and Trail Making A and B). To assess for group effect we then used a

one-way ANOVA with group as a factor to assess for differences between groups. All statistical

analyses were run in Python (version 3.5.3).

Results

Between April 2015 and April 2016, 113 former study participants were approached for

participation in RETURN-CCR (Figure 1). Thirty-three patients were initially enrolled, however of

these, three participants were excluded at enrollment as they declined to participate in the full

program (Figure 1). Ultimately, 24 of the 30 (80%), who engaged in the program, completed

both a baseline and post-training assessment at 12 weeks after initiation of the trial.



At the time of their original critical illness, patients who remained in the pilot at the 12

week mark, had a median (IQR) age of 60 (52-70), 96% Caucasian, 52% male, with 16 years (12-

16) of education, were not cognitively impaired, spent a median (IQR) of 15 days (7-21) in the

hospital and 6 days (3-15) in the ICU (Table 1). Amongst those who completed the 12 week

assessment, 75% had experienced at least one day of delirium and 58% experienced at least 1

day of coma and all but one patient required mechanical ventilation for at least 1 day during

their original critical illness. Patients (N=24) completed a median of 517.5 levels of

rehabilitation (IQR 240, 862) (each daily rehabilitation session was comprised of a number of

“levels”) and showed a significant (p<0.01) improvement comparing baseline Pre-CCR vs. Post-

CCR composite z-score performances in 4 key domains of cognitive functioning: attention,

processing speed, memory and executive function (Figure 2a).

Next, the improvement of untrained cognitive exercises (i.e., a carryover effect of

training) was measured by comparing baseline (prior to use of computerized cognitive

exercises) and post-training cognitive assessment measures (such as the: Digit Span, Spatial

Span and Trail Making A and B). At protocol completion, ICU-survivors demonstrated

improvement on some of the measures of cognitive abilities (Digit Span: t = -1.91; p =.06;

Spatial Span: t = -1.39; p >.05; Trail Making A: t = - 2.26; p < .05; Trail Making B: t = -0.78; p >.05;

Trails B-A (cost): t = 0.62; p>.05).

In a linear regression model, the amount of improvement was positively correlated with

the number of training hours, suggesting that benefits from training will transfer to general

untrained cognitive abilities (F(1,22) = 3.0, p = .097, see Figure 2b). Super users (or those who

played at least 1000 levels) had a significantly higher mean z-score on untrained



neuropsychological tasks than normal users (less than 500 levels) after participating in the 12-

week trial (p-value = 0.046). When we analyzed the improvement in the untrained

neuropsychological tests by user group (super, high, normal) in a one-way ANOVA model, with

group as a factor, the group effect was significant at p = 0.03. This effect was mainly driven by

the difference between the super and normal groups. In an ANOVA with group (super and

normal) as a factor, the group difference was significant (p=0.005). There was no significant

difference between "super and high" (high users = <1000 and >500 levels played) and "high and

normal" user groups.

Discussion

In this limited proof of concept pilot study we showed that survivors of critical illness with

cognitive impairment had significant improvement in important neuropsychological domains

and that improvement in untrained cognitive abilities was positively correlated with the

amount of levels played. This investigation is the first to our knowledge to evaluate feasibility of

a computer gaming approach of cognitive rehabilitation in survivors of non-neuro/non-trauma

critical illness. Such an approach is appealing as it is more scalable than traditional cognitive

rehabilitation interventions that require intensive face-to-face interaction between patients

and clinical professionals.

Although we did not reach statistical significance on the individual untrained

neuropsychological assessments before and after the 12 week trial, we were underpowered to

do so. In order to answer questions of efficacy, a randomized clinical trial would be required.

We did however find a statistically significant effect of user group (super, high and normal) on



untrained neuropsychological assessments, suggesting that the most “robust” improvement in

higher order cognitive tasks occurs in the super user group.

These pilot data were designed to help generate hypotheses to shape appropriately

designed randomized trials. Future work should consider a time point more proximal to ICU

stay for maximal impact and clinical outcomes data inclusive of “real world” evaluations such as

handling money, driving simulators, work place capacity, and social interactions (14).

Additionally, future work should explore the impact of CCR on other important outcomes from

critical illness, including depression, PTSD, frailty, life space and quality of life.



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Figure 1. Flow diagram of patients through RETURN-CCR from recruitment through the 12-

week pilot trial



Figure 2. 2a.) Cognitive Performance Over Time (Pre vs. Post Computerized Cognitive Rehabilitation (CCR) by Neuropsychological Domain: Change from baseline “Pre-CCR” performance (displayed as a composite z-score) to “Post-CCR” score for each cognitive domain after the 3-month trial period (N=24). Error bars indicate standard error. For all 4 cognitive domains, a statistically significant improvement (p<0.01) in performance was demonstrated as compared to baseline performance. F2b.) Improvement of cognitive assessment by user group (Super >1000 levels played, High <1000 and >500 levels played, and Normal <500 levels played. Error bars and bands are standard errors.

2a.)

2b.)



Table 1. Demographic and Baseline Characteristics

a Median values (interquartile range).

b The Short Informant Questionnaire on Cognitive Decline in the Elderly ranges from 1 to 5, with

a score of 3 indicating no change in cognition over the past 10 yr, a score < 3 indicating

improvement, and a score > 3 indicating decline in cognition, as compared with 10 yr before. A

score of ≥ 3.6 indicates preexisting cognitive impairment. c Sepsis or Septic shock diagnosis includes individuals with Acute Respiratory Distress Syndrome

(ARDS) with Infection d Scores on the Sequential Organ Failure Assessment (SOFA) range from 0 to 24 (from 0 to 4 for

Variable

median (IQR)a

Entire RETURN-

CCR Cohort

(N=30)

Participation

Cohort (N=24)

Age at Enrollment 60 (50 – 67) 60 (52 – 70)

Gender (%)

Male

Female

53

47

50

50

Race (%)

Caucasian / White

African American / Black

97

3

96

4

Years of Education at Enrollment 15 (12 – 16) 16 (12-16)

IQCODE at Enrollmentb 3 (3 - 3.063) 3 (3 - 3.063)

Days in the Hospital 17 (8 – 21) 15 (7 -21)

Days in the ICU 6 (3 – 13) 6 (3 -15)

Admission Diagnosis (%)

Sepsis or Septic Shockc

Hepatobiliary / Pancreatic surgery

Airway Protection / Upper Airway Obstruction

Acute Myocardial Infarction

Gastric Surgery

Acute Lung Injury / ARDS without infection

CHF / Cardiogenic Shock

Orthopedic Surgery

Vascular Surgery

GI Bleed

40

13

13

10

7

3

3

3

3

3

42

13

17

13

4

4

4

4

0

0

Mean SOFA score at Enrollmentd 8 (6 – 10) 9 (6 – 10)

Mean Charlson score at Enrollmente 2 (0 – 3) 2 (0 - 3)

Percent with at least 1 day of Delirium in the ICU (%) 73 75

Percent with at least 1 day of Coma in the ICU (%) 53 58

Days spent in the ICU 6 (3 – 13) 6 (3 – 15)

Days spent in the Hospital 17 (8 – 21) 15 (7 – 21)

Ventilator Support (%)

Mechanical Ventilation (at least 1 day)

Non-Invasive Positive Pressure Ventilation

97

3

96

4



each of six organ systems), with higher scores indicating more severe organ dysfunction. We

used a modified SOFA score, which excluded the Glasgow Coma Scale components, since coma

was included separately in our models. e Scores on the Charlson comorbidity index range from 0 to 33, with higher scores indicating a

greater burden of illness.



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Computerized Cognitive Rehabilitation in ICU Survivors ... · Computerized Cognitive ... the Tennessee Valley Healthcare System Geriatric Research ... three participants were excluded