Effectiveness of neurocognitive exercises on cognition among post-chemotherapy cancer survivors

INTRODUCTION

Cancer is an illness that occurs when cells in the body grow out of proportion, and it can happen in any tissue or organ. Cancer spreads to body parts that are near or far from the site of cancer, which is called metastasis, and it can be fatal. In every country of the world, cancer is a major cause of mortality and a major impediment to raising life expectancy [1, 2].
Based on estimates from the World Health Organisation for 2019, cancer ranks third or fourth in 23 countries for deaths occurring before the age of 70 years, and first or second in 112 out of 183 countries. Globally, the burden of cancer incidence and death is steadily increasing, which is due to changes in the prevalence and distribution of the key cancer-related risk factors as well as population ageing and expansion [3]. It was estimated that in Asia, which accounts for 59.5% of the world’s population, is predicted to have half of all cancer diagnoses and 58.3% of cancer fatalities for both genders combined. Estimates from 2020 GLOBOCAN state that there will be 2 million new instances of cancer in India by 2040, an increase of 57.5% from 2020 [4, 5].
Chemotherapy is the most commonly utilised treatment after a cancer diagnosis, and it is frequently combined with local treatments like surgical excision of the tumour and radiation. Although chemotherapy is effective in the treatment of a number of cancers, it is also accompanied by several side effects, such as exhaustion, nausea, and vomiting. Additionally, between 15 and 50% of cancer patients develop cognitive abnormalities after chemotherapy, which is otherwise known as “chemo brain”, “chemo fog”, or cancer-related cognitive impairment (CRCI) [6].
Finding the primarily afflicted sites of the brain by chemotherapy has been achieved using brain MRI. Neuroimaging scans of individuals with breast cancer have shown reduced grey matter density in the right thalamus, frontal, temporal, and cerebellar regions, especially one month after chemotherapy. Later research revealed that among breast cancer patients receiving chemotherapy, the prefrontal cortex was the primary site of neuronal injury. The hippocampus dysfunction contributed to the development of CRCI in rats. Because the hippocampus and prefrontal cortex are the main learning and memory regions, any impairment to these regions might lead to cognitive dysfunction. Therefore, altered behaviour and memory are associated with impaired neuronal functioning in the hippocampus and frontal cortex [7]. “Cancer-related cognitive impairment” denotes the decline in cognitive functions among patients, encompassing attention, perception, cognition, learning, memory, action planning, comprehension, reasoning, and problem-solving abilities [8]. The immediate and long-term effects of cancer treatment on cognitive performance may have a detrimental impact on quality of life (QoL). The facets of everyday life, such as employment, interpersonal interactions, and social integration, are impacted by perceived cognitive impairment. Domains of cognitive function that can be improved with cognitive therapy include executive functions, domains of memory and processing including verbal, visual, auditory, and spatial systems, attention, and processing speed. This research primarily focuses on improving the following domains of cognition: memory, attention, executive function, and processing speed, through cognitive exercises [9–11].
At present, there is evidence suggesting that aerobic exercise or aerobic exercise combined with resistance training for the whole body and mind/body exercises such as yoga and tai chi improve cognitive function [11]. Neurocognitive exercises are a multimodal exercise programme that incorporates various motor coordination exercises and cognition. These exercises focus on improving the different domains of cognition, they progress from easy to difficult, and consist of simple and complex tasks. Cognitive training includes repeated practice of the exercises on the tasks that are problematic, targeting specific cognitive domains. The cognitive exercise used and the degree of difficulty of the task are provided by different stimuli, which include visual and auditory signals [12].
Neurocognitive exercises are designed to stimulate specific areas of the brain responsible for cognition, memory, and learning. Regularly participating in these exercises enables individuals to enhance their cognitive capabilities by fostering neuroplasticity, which refers to the brain’s capacity to restructure itself through the establishment of fresh neural connections. Research has shown that neuro-cognitive exercises can lead to significant improvements in cognitive abilities in various populations, including individuals with traumatic brain injury, stroke, multiple sclerosis, and neurodegenerative disorders such as Alzheimer’s disease. By exercising, it strengthens existing neural pathways, creates new ones, and enhances overall brain health. Incorporating neuro-cognitive exercises into rehabilitation programs can be a highly beneficial and cost-effective way to improve cognitive function and QoL among post-chemotherapy cancer survivors. Thus, this study focuses on determining whether neurocognitive exercises are effective on cognitive function and QoL among post-chemotherapy cancer survivors.

MATERIAL AND METHODS

This experimental study was conducted at Physiotherapy out patient department of a private hospital. The Institutional Scientific Review Board (ISRB) of Saveetha Institute of Medical and Technical Sciences approved the study, and the ISRB number is 01/056/2023/ISRB/PGSR/SCPT.
Inclusion criteria:
a. subjects who had received chemotherapy as their primary treatment following cancer diagnosis and recovered following the completion of treatment,
b. subjects with basic level of literacy,
c. subjects who scored 1 or more after screening using the fast-cognitive evaluation and scoring system (FaCE) tool,
d. age – 40–65 years,
e. gender – male and female.
Exclusion criteria:
a. subjects diagnosed with psychiatric disorders,
b. subjects with visual and hearing disabilities,
c. subjects with difficulty in understanding the language and instructions,
d. subjects who are bedridden following chemo- therapy.
Outcome measures:

1. functional assessment of cancer therapy-cognitive function (FACT-Cog) – is an instrument that assesses the patient’s different aspects of cognition and their impact on the patient’s quality of life. This study measures only perceived cognitive impairments (20 items, the scoring range is 0–80) and the impact of perceived cognitive impairments on QoL (4 items, the scoring ranges 0–16). Response is based on the preceding 7 days of the patient’s life. A higher score implies better cognition and QoL;
2. EORTC-QLQ (C30) – it includes 9 multi-item scales and 6 single-item scales. The multi-item scales cover five functional aspects (physical, role, cognitive, emotional, and social functioning), three symptom areas (fatigue, pain, and nausea/vomiting), and a global health status/QoL scale. Additionally, there are 6 single-item scales (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). Scores for all scales and measures range 0–10, with higher scores indicating higher response levels. A high score on a functional scale reflects better functioning, while a high score on the global health status/QoL scale indicates a higher quality of life. However, a high score on a symptom scale/item suggests more severe symptoms or problems.

A valid license has been obtained to utilise the tools in accordance with all applicable terms and conditions before commencing the study.

Materials required

Papers printed with cognitive domain-specific tasks, blank papers, colour sketch pens, dumbbells of varying weights, exercise mat, 4 training cones, and a writing pad.

Study procedure

Patients who came for review to the Medical Oncology Department of a private hospital were referred to the Physiotherapy Out Patient Department (OPD) where the participants were given an explanation about the importance of the study, the intervention procedures, and its potential benefits, in their native language. Based on the selection criteria and after obtaining their written consent to participate in the study according to the Declaration of Helsinki, the participants were recruited and were instructed to report at the Phy- siotherapy Out Patient Department (OPD) 3 times a week, based on their preference but with prior notice to the principal investigator via a phone call to avoid collision between the timings of 2 participants, for 6 consecutive weeks. This study included a total of 70 potential participants following the screening of cognitive impairment using the FaCE tool. Those who scored 1 or more points using the tool and met other selection criteria proceeded to the pre-intervention evaluation. This evaluation used the FACT-Cog scale (version 3) and EORTC-QLQ (C30) questionnaire. Following this, participants were divided into 2 groups – the cognitive exercise group (Group A) and the aerobic exercise group (Group B). The intervention lasted for 6 weeks and recommended 30 minutes of exercise per day, 3 days per week.

Group A – cognitive exercise group

Domain-specific neurocognitive exercises given to the patients were as follows (Fig. 1):

• identifying the colour of the word and not what the word is – a paper with names of the colours written in different colours were given to the participants, and they were asked to read out the colour used to write the name of the colour,
• identifying the count of the numbers rather than the number itself – a paper in which a single number was written multiple times and the participants had to identify the number of repetitions rather than the number itself,
• substituting the pre-assigned symbol to the associated digits – digits 0–9 were assigned with individual symbols, and the participants had to look at it for a maximum of 2 minutes and fill the symbol associated with that specific digit in a paper that had the digits mentioned,
• identifying and connecting the trails – based on the numbers, alphabets, and colour association,
• identifying the odd one out – objects that were similar with a single odd object were printed on paper and given to the participants, who were asked to circle the odd one out,
• repeating a selected set of words at the beginning of the session and at the end,
• building on a set of words of the same category and recalling it later – based on the participant’s interest, a specific category is chosen (e.g. fruits, movie names) and the set of words recalled,
• walking between different points of reference based on stimuli – 1 clap/name of a fruit (between cones 1 and 3), 2 whistles/name of a fruit (between cones 1 and 2).

All the cognitive exercises were given with a break of 30 seconds between each exercise, and the stimulus-specific aerobic exercise were given for a duration of 8 minutes followed by 2 minutes of cool-down exercise.

Group B – aerobic exercise group

Participants in this group were given warm-up exercises for 5 minutes, following which they were encouraged to walk along a straight corridor for 5 minutes and perform stationary cycling for 10 minutes, following which they carried out resistance training focused on major muscle groups of the body for 10 minutes. The warm-up activity included neck and shoulder range of movement exercises, forward and backward bending, and stretches for the trapezius, sternocleidomastoid, latissimus dorsi, biceps brachii, triceps brachii, quadriceps, hamstrings, and gastrocnemius (Table 1).
After 6 weeks of intervention, the participants were again evaluated for their perceived cognitive impairments (PCI) and their effect on QoL using the FACT-Cog (version 3) questionnaire and EORTC-QLQ (C30) questionnaire, and the findings obtained were statistically analysed.

Statistical analysis

The data obtained pre and post intervention using the outcome measures FACT-Cog (Version 3) and EORTC-QLQ (C-30) were analysed using the software Sigma Plot (version 13). The Mann-Whitney U test was used to analyse significant changes between pre-test and post-test measurements of groups A and B, and the Wilcoxon signed-rank test was used to analyse significant changes within the groups.

RESULTS

This experimental study was conducted for 6 weeks to study the effects of domain-specific neurocognitive exercise on CRCI. The demographics of the participants are shown in Table 2. In our study, comprising 70 participants, all participants (100%) were found to be literate. Among them, 31 patients (44.2%) were diagnosed at stage II while 39 patients (55.7%) were diagnosed at stage III. Chemotherapy was administered adjuvant in 49 patients (70.0%) and neo-adjuvant in 21 patients (30.0%). Furthermore, 25 patients (35.7%) exhibited a primary onset of the disease, while 45 patients (64.2%) had a secondary onset. From the statistical analysis using the paired Student t-test, there was a significant difference between pre-test and post-test values at a p-value of < 0.05.
The pre- and post-test analysis of group A and group B using the Wilcoxon signed rank test is shown in Tables 3 and 4. Table 5 delineates and depicts the post-intervention findings using the outcomes of FACT-Cog and EORTC-QLQ (C30). From the statistical analysis using the Mann-Whitney U test, there is a significant difference between the post-test values of groups A and B, at a p-value of < 0.05

DISCUSSION

To our knowledge, this is the first study that has investigated the effect of domain-specific cognitive exercise focusing on CRCI among patients after chemotherapy treatment. The results obtained from the study show that a neurocognitive exercise regimen can be used to treat patients who have cognitive deficits in the domains of executive function, processing speed, memory, and attention.
Campbell et al., through the systemic review on the effects of exercise on CRCI, stated that a commonly encountered side effect of cancer treatment, particularly chemotherapy, is decreased cognitive function, and it has been reported that mild to severe cognitive symptoms (executive function, processing speed, memory, and attention) are reported by up to 85.0% of cancer patients; there was a significant improvement in cognitive function through aerobic and resistance training (20 minutes of aerobic training combined with resistance training focusing on major muscle groups, on the basis of 2 sessions per week for 4–52 weeks) [11]. In a study conducted by Naung et al. among breast cancer patients, to improve their QoL through peer support intervention, it was stated that cancer diagnosis and chemotherapy has an impact on patients’ QoL due to financial burden and treatment side effects; thus, improving QoL could significantly reduce the rate of mortality and extend the survival both qualitatively and quantitatively, and the author used EORTC-QLQ (C30) as a validated tool to measure the QoL [9]. The survival rate of cancer is increasing greatly, so interventions focusing on improving their QoL is of great importance. Building upon the findings highlighted, our study was directed towards investigating the impact of exercise interventions on specific cognitive domains in cancer patients and their QoL.
Immediately after the treatment and 6 months later, FACT-Cog questionnaires and neuropsychological tests were used predominantly to assess cognitive function. The intervention group significantly improved in terms of perceived cognitive impairment, and there were no significant differences between the groups in neuropsychological testing. The intervention group also showed lower levels of anxiety/depression and fatigue at both assessment times. Chemotherapy has been linked to a decrease in 4 domains of cognition: memory, attention, psychomotor speed, and executive function. Moreover, the severity of CRCI is influenced by the chemotherapy dose. According to one study, after receiving high- or standard-dose chemotherapy, patients experienced cognitive impairment at rates of 32.0% and 17.0%, respectively, while the control group experienced this effect at a rate of 9% [13–15]. Based on these findings, our study was focused on the 4 domains of cognition following chemotherapy, and the FACT-Cog questionnaire was utilised.
According to a follow-up study by Schagen et al., patients in both the high- and low-dose groups saw improvements in their cognitive function over the course of the next 4 years, and the change in cognitive function brought on by chemotherapy was thought to be temporary [16, 17]. Országhová et al. stated that because physical activity is currently supported by evidence as a viable therapeutic method for CRCI, additional study is needed to determine the best timing, duration, style, and intensity of the exercise [8]. Pendergrass et al. concluded that cognitive function and self-reported QoL were positively impacted by cognitive rehabilitation and training strategies that used repetitive skills training, awareness practice, and adaptive challenge levels [10]. Wongarsa et al., through a study on integrated interventions for mild cognitive impairment among the geriatric population, stated that brain training through memorising and word guessing, image classification, responding based on music, simple arithmetic calculation, writing a recipe step-wise, and cooking significantly improved the attention, memory, and processing speed [18]. Exercises on a regular basis yielded positive outcomes on various psychosocial and physical outcomes during and after cancer therapy, which includes cognitive impairment according to a study conducted on patients with testicular cancer. Therefore, the available data supports exercise as a potential management for CRCI, even though future research should address the best times, lengths, modes, and intensities of exercise and tailor it to each patient’s unique needs and preferences in terms of their psychosocial and physical limitations [19]. With the insights gathered from the aforementioned studies, domain-specific cognitive and aerobic exercises were curated and applied. The limitation of the study is that it does not have a follow-up to ascertain whether the cognition level achieved through the neurocognitive exercise is maintained in the long term, and it lacks the use of quantitative measures of cognition.

CONCLUSIONS

This experimental study has demonstrated that there is a strong association between domain-specific cognitive exercises and cognitive function improvements in post-chemotherapy cancer survivors. Future studies can focus on the impact of specific/commonly used chemotherapy drugs on CRCI and on finding the correlation between other chemotherapy-related side effects such disrupted sleep, cancer-related fatigue, psychological distress, and CRCI.

DISCLOSURES

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

REFERENCES