Cognitive Rehabilitation of Brain Tumor Survivors: A Systematic Review

Abstract

Background

Cognitive decline is commonly seen in brain tumor (BT) patients and is associated with a worsened prognosis. Cognitive rehabilitation (CR) for cancer-related cognitive dysfunction has been widely studied for non-central nervous system cancers; however, recent emerging research has commenced documenting CR strategies for BT patients and survivors. Our objective was to review the current literature on various CR modalities in patients and BT survivors.

Methods

The review was conducted in accordance with the PRISMA guidelines. The studies on CR were searched across 3 databases using a predefined search strategy. After removing duplicates, performing initial and full-text screenings, and applying inclusion criteria, relevant articles were selected. The demographic details, CR technique, cognitive tasks/tests administered, cognitive functions assessed, follow-up time, and outcomes of the intervention were assessed.

Results

A total of 15 studies were included in the review. Neuropsychologist-guided training sessions to improve memory, attention, and executive functioning are effective in improving the mentioned domains. Younger and more educated patients benefited the most. Holistic mnemonic training and neurofeedback were not shown to affect overall cognitive functioning. Computer-based training programs showed improvements in executive functions of pediatric BT survivors, however, feasibility studies showed conflicting results. Aerobic exercises improved executive functions and decreased symptoms of the tumor. Both yoga and combined aerobic and strength training improved overall cognitive functioning. Active video gaming may improve motor and process skills; however, no effect was seen on cognitive functioning.

Conclusion

Neuropsychologic training, computer-based programs, and physical exercise have been found effective in improving or preventing decline in cognitive functions of BT patients. Given the limited trials and methodological variations, a standardized CR program cannot be established at present. Ongoing trials are expected to provide valuable data in the near future.

INTRODUCTION

Cognitive dysfunction is a common complication of brain tumors (BTs), which can be correlated to the tumor itself [1,2] or various treatment modalities [3,4,5,6,7]. Central nervous system (CNS) tumor incidence is 24.71 per 100,000 population, and they are among the most common cancers in children [8,9]. The high-intensity treatments in these children cause structural and functional damage leading to significant long-term cognitive deficits [10,11].

Cognitive dysfunction is often associated with a poor prognosis [7,12,13] and can be the first indicator of subclinical tumor progression [7,14]. Tumor type, grade, and location affect various cognitive functions. Frontal lobe tumors are associated with overall worse cognition [14]. Tumors in the left hemisphere are associated with a decline in verbal function, attention, and working memory, whereas right-sided tumors are associated with poor facial recognition [14,15]. Higher-grade tumors such as glioblastoma multiforme are associated with poor psychomotor speed and visual tracking [16]. Tumor volume, surrounding edema, and greater residual volume after surgery are associated with cognitive decline [14]. Other contributing factors include preoperative epilepsy, the use of corticosteroids and anti-epileptics intake, and advanced age at diagnosis [14].

Compromised cognition in BT survivors may lead to a compromised health-related quality of life (HRQoL) [17]. Pediatric BT survivors suffer from lower levels of self-esteem, greater depressive symptoms, and greater severity of compromised quality of life (QoL) than survivors of other pediatric cancers [18]. Adults with even lower-grade gliomas suffer from cognitive functioning decline and fatigue leading to a decreased HRQoL [19]. The long-term survivors are at risk of mild cognitive impairment (MCI) [20].

Cognitive rehabilitation (CR) works on refining language, attention, spatial perception, memory, praxis, and calculation, following acquired cognitive damage [21]. CR for cancer-related cognitive dysfunction has been widely studied for non-CNS cancers [22]; however, emerging research has commenced documenting CR strategies for BT patients. Early rehabilitation strategies may decrease subsequent cognitive decline [23]. These strategies of CR can be broadly classified into computer-based programs (mostly for survivors of pediatric BTs), physical exercise interventions, and neuropsychologic training. We aim to review the outcomes of these CR modalities.

METHODOLOGY

The PRISMA guidelines were used as a template for the methodology of our review. This review was registered on PROSPERO (CRD42023435594).

Search strategy

A comprehensive literature search through three online databases: PubMed, Scopus, and Cochrane Library was conducted with the following search terms “(Treatment OR management OR rehabilitation) AND (Cognitive OR Neurocognitive) AND (function* OR assessment OR deficits OR decline) AND Brain Tumors.” Only clinical trial articles from 2005 to 2023 were included.

Inclusion and exclusion criteria

Clinical trials, including retrospective case-control, prospective cohorts, and case series reporting CR strategies based on computer-based programs, physical exercise, and multidisciplinary therapy, were included.

Review articles, case reports, editorials, conference papers/posters, and incomplete or ongoing trials were excluded. Pharmacologic treatment modalities for cognitive decline were excluded. Articles that only assessed cognitive functions without any rehabilitation strategy or any rehabilitation strategy without cognitive assessment were also excluded. Articles in languages other than English without available translation and articles whose full text was not available were also excluded.

Study selection

The initial articles extracted from the database search were added to a combined library and duplicates were removed. A preliminary screening was done by two authors followed by a full-text screen of the remaining articles by two authors. The conflicts were discussed and resolved with the senior author. The final articles included were assessed and approved by all the authors.

Data extraction

The demographic details including the study population, study type, mean age, tumor types, tumor location, surgical outcomes, and adjuvant chemo- or radiotherapy were tabulated in a table. The CR technique, cognitive tasks/tests administered, type of cognitive functions assessed, follow-up time, and outcomes of the intervention were assessed. The details of the CR modalities were enlisted in Supplementary Table 1 (in the online-only Data Supplement).

RESULTS

A total of 15 studies with 561 participants treated for BTs were included in the study. Details of the study selection are given in Fig. 1.

Fig. 1. PRISMA flowchart. BTs, brain tumors; QoL, quality of life.

The demographic details of individual studies including the study population, study type, mean age, tumor types, tumor location, surgical outcomes, and adjuvant chemo- or radiotherapy are reported in Table 1. The CR technique, cognitive tasks/tests administered, cognitive functions assessed, follow-up time, and outcomes of the intervention are tabulated in Table 2.

Table 1. Demographic details of individual studies.

Study and study type	Population	Mean age at evaluation (yr)	Tumor type	Tumor location	Surgical management	Adjuvant therapy
Carlson-Green et al. [29] Descriptive case series	20 (19 completed training)	11 (8–18)	Germinoma (n=4), medulloblastoma (n=11), ependymoma (n=4), other tumor types (not specified, n=2)	NA	NA	NA
Cox et al. [35] Controlled clinical trial	25 (Group 1: n=11, no exercise for 12 weeks, followed by exercise in next 12 weeks; Group 2: n=14, exercise for 12 weeks, followed by no exercise in next 12 weeks)	Group 1: 12.47±2.94 Group 2: 11.10±3.19	Anaplastic astrocytoma (n=1), ependymoma (n=3), anaplastic ependymoma (n=2), medulloblastoma (n=14), pineoblastoma (n=1), sarcoma (n=1), germ cell tumors (n=2), astroblastoma (n=1)	Hemispheric (n=5), posterior fossa (n=20)	Surgical intervention (n=25) (GTR [n=11])	Radiotherapy: focal (n=8), CS (n=16), periventricular (n=1) Chemotherapy: n=22
de Ruiter et al. [28] Randomized clinical trial	Training group (n=34), control group (n=37)	Training: 14.45±2.99 Control: 13.45±3.28	High grade (n=28) Low grade (n=43)	Supratenorial (n=40), infratentorial (n=31)	NA	NA
Dülger et al. [36] Randomized cross over study	n=10 (all female)	47.5	Secretory pituitary adenoma (prolactin [n=2], GH [n=5], FSH [n=1], ACTH n=1, plurihormonal [n=1])	Pituitary region	n=10	NA
Gehring et al. [24,25] Randomized clinical trial	Intervention group (n=70), control group (n=70)	Intervention: 42.0± 9.4 Control: 43.8±10.5	Astrocytoma (n=67), oligodendroglioma (n=45), oligoastrocytoma (n=20), presumed glioma (n=8)	Left hemisphere (n=78), right hemisphere (n=58), bilateral (n=4)	No surgery (n=8), biopsy (n=40), resection (n=92)	Radiotherapy: n=86 Chemotherapy: n=15
Gehring et al. [37] Randomized clinical trial	Exercise group (n=21), control group (n=11)	Exercise: 49.2±8.9 Control: 48.0±11.9	Astrocytoma (n=11), oligodendroglioma (n=17), oligoastrocytoma (n=4)	Left hemisphere (n=14)	Biopsy (n=3), resection (n=28)	Radiotherapy: n=17 Chemotherapy: n=12
Hansen et al. [38] Randomized clinical trial	Intervention group (n=32), control group (n=32)	Intervention: 56.1±11.6 Control: 52.1±3.4	Gliomas: grade 2 (n=11), grade 3 (n=10), grade 4 (n=43)	Left hemisphere (n=27), right hemisphere (n=35), bilateral (n=2)	Decompression (n=17), STR (n=13), GTR (n=34)	Surgery and radiation therapy (n=13), surgery and chemotherapy (n=2), radio- and chemotherapy (n=45)
Hassler et al. [1] Prospective case series	11	N/A	GBM (n=7), anaplastic astrocytoma (n=2), anaplastic oligoastrocytoma (n=1), oligodendroglioma (n=1)	Frontal (n=3), parietal (n=2), temporal (n=2), fronto-parietal (n=2), fronto-temporal (n=1), parieto-occipital (n=1) Left hemisphere (n=5), right hemisphere (n=6)	Biopsy (n=1), STR (n=8), GTR (n=2)	Radiotherapy: n=9 Chemotherapy: TMZ concomitant+adjuvant (n=10) TMZ concomitant+adjuvant imatinib+hydroxyurea (n=1)
Hocking et al. [30] Prospective cohort	Standard group, (n=14), combined group (n=13)	Standard: 10.4±2.4 Combined: 11.9±2.7	Astrocytoma (n=7), low grade glioma (n=1), ependymoma (n=6), medulloblastoma (n=6), others (n=7) Grade 1 (n=9), grade 2 (n=8), grade 3 (n=2), grade 4 (n=8)	Infratentorial (n=14), supratentorial (n=13)	n=10	Radiation therapy only (n=3), surgery and chemotherapy (n=2), surgery and radiation therapy (n=5), surgery, radio- and chemotherapy (n=4)
Locke et al. [26] Controlled clinical trial	Treatment group (n=12), control group (n=7)	Treatment: 49.8±16.4 Control: 56.6±13.9	Glioma (n=17), meningioma (n=2) Low grade (n=6), high grade (n=13)	Left hemisphere (n=14), right hemisphere (n=3), bilateral (n=2)	n=10	Radiotherapy: n=18 Chemotherapy: n=12
Richard et al. [27] Randomized clinical trial	GMT group (n=11), BHP (n=8), WAIT (n=6)	47.7±11.5	Meningioma (n=7) Low grade glioma (n=8), high grade glioma (n=6); others (n=4)	Frontal (n=15), fronto-temporal (n=4), fronto-occipial (n=3), subcortical/cerebellar (n=3) Left hemisphere (n=15), right hemisphere (n=6), bilateral (n=4)	Biopsy (n=4), resection (n=18)	Partial-brain or intensitymodulated radiotherapy (n=18), whole-brain radiotherapy (n=3) Chemotherapy: n=11
Sabel et al. [31] Randomized clinical trial	Intervention first (n=7), waiting first (n=6)	Intervention first: 11.9±3.6 Waiting first: 13.2±1.9	Anaplastic astrocytoma (n=1), choroid plexus carcinoma (n=1), germinoma (n=3), medulloblastoma (n=3), pilocytic astrocytoma (n=3), primitive neuroectodermal tumor (n=2)	Supratentorial (n=10), posterior fossa (n=3)	NA	Focal (n=3), CS+focal (n=10)
van der Linden et al. [33] Randomized clinical trial	Intervention group (n=23), control group (n=26)	Intervention: 45.7±11.7, control: 52.6±10.4	Grade 1 meningioma (n=27), grade 2 meningioma (n=2), grade 2 glioma (n=19), grade 3 glioma (n=1)	Frontal (n=24), parietal (n=5), temporal (n=12), occipital (n=3), parieto-occipital (n=2), temporo-parietal (n=1), temporo-insular (n=2) Left hemisphere (n=22), right hemisphere (n=25), bilateral (n=2)	NA	Radiotherapy: n=14 Chemotherapy: n=10
Zucchella et al. [34] Randomized clinical trial	Intervention group (n=25), control group (n=28)	Intervention: 58.7±13.9, control: 52.7±17	High grade glioma (n=25), low grade glioma (n=7), meningioma (n=16), others (n=5)	Frontal (n=19), parietal (n=2), temporal (n=7), occipital (n=2), fronto-temporal (n=9), frontoparietal (n=4), parieto-occipital (n=1), temporo parietal (n=1), temporo-parieto-occipital (n=3), cerebellum (n=5) Left hemisphere (n=23), right hemisphere (n=30)	NA	NA

GTR, gross total resection; CS, cranio-spinal; GH, growth hormone; FSH, follicle-stimulating hormone; ACTH, adrenocorticotrophic hormone; GBM, glioblastoma multiforme; STR, subtotal resection; TMZ, temozolomide; GMT, goal management training; BHP, brain health program; WAIT, wait-list

Table 2. CR strategies and outcomes.

Study	Rehabilitation technique	Tasks/tests (baseline assessments)	Training duration	Outcome(s)
Carlson-Green et al. [29]	Home-based working memory training (CogMed)	Automated WM Assessment (visuo-spatial and verbal WM) Woodcock-Johnson Tests of Achievement (academic achievements) Achenbach Child Behavior Checklist (emotional and behavioral problems) Adaptive Behavior Assessment System (adaptive functioning) Behavior Rating Inventory of Executive Function (BRIEF; executive functioning) Neurological Predictor Scale (treatment severity)	6 months	- Significant improvements in verbal WM as well as visual-spatial WM. Improvements were also seen in math achievement at training completion as well as 6-month follow-up. - Parents reported improved executive functioning and social skills. - Reading comprehension was not improved. - Program-based WM skills did not change with prolonged training.
Cox et al. [35]	Aerobic exercise training	Go and Go/No-Go tasks during MEG (processing speed, controlled attention, and neural communication)	12 weeks	- Sustained improvement with response accuracy in No-Go trials could be predicted by exercise training. - Altered functional connectivity was reported in theta (4–7 Hz) alpha (8–12 Hz) and high gamma (60–100 Hz) frequency bands in Go and Go/No-Go trials.
de Ruiter et al. [28]	Neurofeedback	Visual sequencing task (memory) Attention network task (ANT; attention) Baseline speed ANT (processing speed) Digit span (verbal WM) Abbreviated WAIS-III (intellectual functioning, WM, processing speed) Abbreviated WISC-III (intellectual functioning) BRIEF (Parent and Teacher versions; executive functioning)	6 months	- There were no beneficial effects of neurofeedback and no significance in the effects of training × time
Dülger et al. [36]	Combined aerobic-strength training and yoga	Pittsburg Sleep Quality Index (sleep quality) FACT-Br (HRQoL) Fatigue Severity Scale (fatigue) Hospital Anxiety and Depression Scale (anxiety and depression) Female Sexual Function Index (sexual function) MoCA (cognitive functions)	6 weeks	- The yoga program showed a significant increase in HRQoL score as well as a significant decrease in anxiety score. - Both yoga as well as aerobic and strength trainings improved cognitive functioning.
Gehring et al. [24]	Neuropsychologic CR program	Stroop task (attention) Letter Digit Substitution Test (information processing speed) Digit Span (verbal WM) Memory Scanning Test (memory) Concept Shifting Test (attention, mental control, memory) Visual Verbal Learning Test (verbal learning) Cognitive Failure Questionnaire (attention) Community Integration Questionnaire Multidimensional Fatigue Inventory (fatigue)	6 months	- Significant group differences were found post-treatment in self-reported cognitive functioning (Cohen’s d=0.31 to 0.48), which did not persist at the 6-month follow-up. - At the follow-up, there was significant improvement in objective neuropsychologic measures of verbal memory (Cohen’s d=0.48 and 0.43) and combined attention tests (Cohen’s d=0.23 to 0.55).
Gehring et al. [25]	Neuropsychologic CR program	Stroop task (attention) Letter Digit Substitution Test (information processing) Digit Span (verbal WM) Memory Scanning Test (memory) Concept Shifting Test (attention, mental control, memory) Visual Verbal Learning Test (verbal learning) Cognitive Failure Questionnaire (attention) Community Integration Questionnaire Multidimensional Fatigue Inventory (fatigue)	6-months	- Level of education and age predicted reliable improvement. Odds of improvement increased 0.9 times per year of age and 4.7 times greater for higher education levels vs. low to medium education levels.
Gehring et al. [37]	Home-based remotely coached exercise	Stroop task (attention, executive function) Letter Digit Substitution Test (attention, information processing) Test of Everyday Attention (attention) Digit Span (attention, WM) WMS-III Verbal Paired Associates (memory) Concept Shifting Test (executive function) GIT Category Fluency (executive function) GIT Letter Fluency (executive function) Cognitive Failure Questionnaire (subjective cognitive function) MOS Cognitive Functioning Scale (subjective cognitive function) Multidimensional Fatigue Inventory (subjective fatigue and sleep) Brain-cancer specific HRQoL questionnaire (HRQoL) Pittsburgh Sleep Quality Index (subjective fatigue and sleep) MOS Short-Form (HRQoL)	6-months	- Scores during follow-up were significantly better in exercise group compared to the controls in verbal recall, attention, information processing speed, self-reported cognitive symptoms, auditory working memory, sleep, fatigue, mood, and mental health related QoL. The control group scored slightly better on sustained selective attention.
Hansen et al. [38]	Physical and occupational therapy-based interventions	Karnofsky Performance Status Scale (HRQoL)	6-weeks	- No significant difference was observed in the overall HRQoL score. - Intervention group had a significantly higher score on HRQoL domain cognitive functioning, fewer symptoms, and greater functional performance outcomes scores.
Hassler et al. [1]	Holistic mnemonic training	Hopkins Verbal Learning Test (verbal memory) Controlled Oral Word Association test (verbal fluency) TMT A and B (psychomotor speed, sustained attention)	12-weeks	- Apart from verbal memory, no other significant change was reported.
Hocking et al. [30]	Computerized working memory training (CogMed)	Feasibility and Acceptability of CogMed WASI II Vocabulary and Matrix Reasoning (IQ) Digit Span (working memory) Spatial Span (working memory) Processing Speed Index (visual-motor processing speed) Letter-Number Sequencing (WISC-IV; working memory) Creature Counting from the Test of Everyday Attention for Children (selective attention, flexibility, shifting attention) BRIEF (behavioral aspects of executive function and attention) Child Behavior Checklist (behavioral aspects of executive function and attention)	5–6 weeks	- Fourteen out of 27 participants completed a minimum of 20 sessions.
Locke et al. [26]	CR and problem solving	Compensation Techniques Questionnaire (compensation techniques) Functional Assessment of Cancer Therapy–Brain version and the Mayo-Portland Adaptability Inventory (HRQoL, functional capacity) Linear Analogue Self-Assessment scale (QoL) Repeatable Battery for the Assessment of Neuropsychological Status (cognitive functioning) Profile of Mood States (mood, distress) Caregiver QoL Index-Cancer (caregiver burden) Brief Fatigue Inventory (fatigue)	2-weeks Delayed F/U 3-months and would recommend it to another person	- Most participants and their caregivers described the intervention as “very helpful” or “somewhat helpful” and would recommend it to another person diagnosed with brain tumor.
Richard et al. [27]	Goal management training	TMT A and B (executive functions) Sustained Attention to Response Task (executive functions) Test of Everyday Attention (executive functions) Hopkins Test of Verbal Memory-Revised (memory) Behavioral Assessment of the Dysexecutive Syndrome (executive functions) BRIEF-A (cognitive symptoms) Positive and Negative Affect Schedule (emotional functioning) Fontal Systems Behavior Scale (cognitive symptoms) Illness Intrusiveness Rating Scale (coping and adjustment) Hospital Anxiety and Depression Scale (emotional functioning) Goal attainment scaling (everyday life functional measures)	4-months	- The goal management group reported improvements in executive functions as well as the highest functional goal attainment. - Less cognitive concerns were reported by the intervention groups.
Sabel et al. [31]	Physically active video gaming	Assessment of Motor and Process Skills (AMPS; activities of daily living) Visual scanning Delis- Kaplan executive function system (visual attention) Conner’s continuous performance test II (sustained attention, disinhibition, reaction time) Auditory consonant trigrams (verbal working memory) Digit Span (working memory) Spatial span (simple spatial span, complex spatial span, spatial working memory) Rey auditory verbal learning test (immediate memory, complex word span) WISC IV (IQ, psychomotor processing speed) Controlled oral word association test (verbal fluency) Stroop task (interference) TMT (psychomotor speed, sustained attention)	10–12 weeks	- The participants improved in motor part of AMPS after active video gaming when compared with baseline (standardized response mean=0.74). - The improvement in process part of AMPS was statistically significant in both groups (standardized response mean=1.43). - No significant changes were found in cognitive tests, however, sustained and selective attention trended towards improvement after active video gaming.
van der Linden et al. [33]	iPad-based CR program ReMind	Computerized neuropsychological test battery Central Nervous System Vital Signs (verbal memory, visual memory, processing speed, psychomotor speed, reaction time, complex attention, and cognitive flexibility) Digit Span (working memory) Letter Fluency test (verbal fluency) Cognitive Failures Questionnaire (self-reported cognitive failures)	10-week Delayed F/U 12-month	- Processing speed, complex attention, cognitive flexibility, and working memory were significantly improved after the program. - Between 3-month and 1-year follow-up, improvements were seen in 35% of the intervention group vs. 24% of the participants in the control group, and a decline in 20% vs. 32%, respectively.
Zucchella et al. [34]	CR program	MMSE (global cognitive functioning) Digit span (verbal and spatial immediate memory span) Rey Auditory Verbal Learning Test (verbal memory, immediate and delayed recall) Raven’s Colored Progressive Matrices 47 (non-verbal reasoning) TMT A and B (speed processing, complex attention) Frontal Assessment Battery (frontal functionality) Attentive Matrices (visual selective attention) Rey-Osterrieth complex figure (visuo-constructional ability, and verbal fluency)	4-weeks	- At the end of the treatment period, significant improvement was seen in all the study group’s neuropsychological measures, while the control group trended towards improvement, however, this was not statistically significant.

WM, working memory; MEG, magnetoencephalography; WAIS, Wechsler Adult Intelligence Scale; FACT-Br, Functional Assessment of Cancer Therapy–Brain; HRQoL, health-related quality of life; MoCA, Montreal Cognitive Assessment; CS, cognitive rehabilitation; WMS, Wechsler Memory Scale; GIT, Groningen Intelligence Test; MOS, Medical Outcomes Study Cognitive Functioning Scale; TMT, Trail Making Test; QoL, quality of life; WISC, Wechsler Intelligence Scale for Children; MMSE, Mini-Mental State Examination; CR, cognitive rehabilitation

Neuropsychologic CR programs

Gehring et al. [24] conducted a randomized controlled trial (RCT) investigating the effectiveness of a CR program conducted by a neuropsychologist with compensatory strategies for memory, executive functioning, and attention as well as an attention-based computer program in survivors of gliomas. Directly after treatment, there were no group differences in verbal memory or attention scores; however, at the 6-month follow-up, there was improvement in objective neuropsychologic measures of verbal memory and attention, but no significant group differences for the rest of the self-report measures. A significant group difference was also seen in the combined attention tests and the combined tests of verbal memory after 6-months of follow-up. Furthermore, a significant difference was observed in the percentage of patients who did not meet the cognitive impairment criteria at the 6-month follow-up in the intervention group compared to the control group (39% vs. 21%). Directly after treatment, significant differences were observed in self-reported cognitive functioning; however, these differences did not persist at 6 months post-assessment follow-up. Maintenance of self-reported cognitive functioning was observed in the intervention group; however, the control group had continued gains as time passed.

In a follow-up study, greater age, increased duration of disease (dichotomized: 0.525 years/0.5 years), epileptic seizures in the previous year, and comorbid conditions were associated with poor outcomes of the multifaceted CR program; however, on regression analysis, younger age and higher education were the only predictors of reliable improvement. Additional variables including epileptic seizures, comorbidity, and disease duration did not bring about significant improvements in the model [25].

CR was also investigated by Locke et al. [26]. They reported that most participants and their caregivers (88%; n=7/8) identified that the intervention was “very helpful” or “somewhat helpful” and would recommend it to another BT patient. The QoL scores improved on the follow-up, however, there was no significant difference when compared with the control group. There was a tendency for improvement, however, not statistically significant, in the functional status of both groups reported by the patients and caregivers.

Holistic mnemonic training, based on a “holistic form of memory empowerment” (Supplmentary Table 1 in the online-only Data Supplement) was investigated by Hassler et al. [1]. Every aspect of mental activity is addressed separately in each session via exercises designed to train concentration, perception, memory, attention, verbal memory, creativity, and retentiveness. Apart from verbal memory, no other significant change was reported at follow-up when compared to baseline.

Richard et al. [27] recruited patients expressing cognitive concerns and divided them into those who were given goal management training, those enrolled in a brain health program, and a control group receiving passive training (Supplmentary Table 1 in the online-only Data Supplement). Executive functions were reported to improve in the goal management training group only. Fewer cognitive concerns were reported by both groups. Functional goal attainment was highest with goal management training.

de Ruiter et al. [28] studied the effect of neurofeedback in a pediatric population of BT survivors. Neurofeedback, which is based on operant conditioning principles, involves direct visual or auditory brain activity feedback to regulate brain activity. Brain activity may be described by a quantified electroencephalogram (qEEG) and can have an association with different mental states. Externally focused concentration is associated with beta frequencies (>12 Hz) and beta frequencies are reinforced to increase arousal and attention. This study revealed no beneficial effects of neurofeedback when compared to the placebo group as both groups improved over time. Even though there was no significant difference in overall HRQoL between both groups, there were significant improvements in the “autonomy and parents” part of the self-reported HRQoL, the social-emotional functioning reported by both self and parents, as well as the “behavioral conduct” part of self-reported self-esteem, the self-reported fatigue’s “concentration” subscale, and parent-reported executive functions. Therefore, neurofeedback may improve parent-report executive functions but does not affect the overall HRQoL.

Computer based training

Carlson-Green et al. [29] assessed CogMed, a computer-based program used in training attention and working memory (WM). They reported that the majority of participants (n=11; 73.3%) and their parents (n=14; 82.4%) were satisfied with the training. Participants demonstrated significant improvement in digit recall, word recall, visuospatial WM tasks, and spatial recall 6 months post-completion of the intervention. At 6 months, reading comprehension did not significantly improve, however, applied math achievement did significantly improve. An additional 10 sessions of extended training did not significantly improve program-based performance. Parents rated significant improvements in inhibitory control, self-monitoring, planning/organization, and social skills. They also reported significant decreases in participants’ somatic complaints and attention problems.

The feasibility as well as acceptability of CogMed were analyzed by Hocking et al. [30] who found significant feasibility-related difficulties in using CogMed. Despite incentives for completion of sessions, about 18.5% of their participants completed no sessions, whereas 48.1% did not finish the intervention. Parents of participants who did not complete the training recognized the child’s lack of interest toward the intervention as well as schedule conflicts as being the primary reasons for not completing sessions. Other reasons included time taken, difficulties related to session supervision, scheduling conflicts, and family priorities. In terms of acceptability, the majority of caregivers of participants who completed the training reported satisfaction with the participation of their child (93.7%) as well as their own (93.7%), however, those who could not complete the training signified dissatisfaction with the participation of both their child (60%) as well as their own (80%).

Sabel et al. [31] utilized activity-based video games (Nintendo^® Wii) as an intervention that is home-based for childhood survivors of BTs to improve their motor and process skills. They found a significant improvement in selective and sustained attention, however, other domains of cognition remained unaffected. The mean score for activities of daily life (ADL) was significantly lower before the intervention, and even though it improved, it was still below the norm post-intervention. The mean ADL motor skills score improved after the intervention period.

van der Linden et al. [32] evaluated an iPad-based CR program ReMind. In their pilot study, they established the feasibility of the program. They reported that an average of 71% strategy training and 76% retraining were completed. The intervention was evaluated as “good” or “excellent” by 85% of the participants and all participants denoted that they would give their recommendation for the program to another BT patient. In the follow-up RCT, in the initial assessment, processing speed, complex attention, cognitive flexibility, and working memory were significantly improved after the program. On the 3-month follow-up, 48% of the intervention group participants and 23% of the control group participants exhibited improvements in one or more cognitive outcomes, while 30% and 15%, respectively, showed declines. Between 3-month and 1-year follow-up, improvement was seen in 35% of the intervention group participants compared to 24% of the control group participants, and the decline was 20% vs. 32%, respectively. Of those who declined, 56% reported burdensome participation. There was no significant difference between the groups in cognitive performances (intervention vs. control) at 3-month and 6-month follow-up, with percentages lying around 70%. At the 1-year follow-up, significantly fewer participants from the intervention group showed cognitive impairment. Overall, the effects were not reported to be significant, while the eHealth program adherence and satisfaction were reported to be satisfactory [33].

Zucchella et al. [34] combined computer exercises with metacognitive training for their CR program. At the treatment period’s end, significant improvement was observed in all neuropsychological measures in the study group, while the control group trended towards improvement, however, this was not statistically significant. Significant differences were observed between the two groups in immediate recall, delayed recall, task shifting, and attention. Overall, the program successfully enhanced cognitive performance.

Physical exercise

Cox et al. [35] assessed aerobic exercise training on controlled attention via go-no-go tests and functional connectivity via magnetoencephalography (MEG) in pediatric BT survivors. Response accuracy in the Go/No-Go task was greater (12 weeks after intervention) following exercise suggesting a beneficial role of exercise on attention, however, no significant difference was observed in response latency. Functional connectivity was assessed using latent variables from mean-centered partial least squares analysis of phase lag index. Included frequency bands were theta (4–7 Hz), alpha (8–12 Hz), low gamma (30–59 Hz), and high gamma (60–100 Hz). Phase coherence was increased in the theta band as well as the high gamma band following exercise compared to no exercise. There was also a decrease in the phase coherence of the alpha band after exercise. These results indicated an improvement in patients’ neural communication in frequencies associated with visual attention and information processing in high task loads.

Dülger et al. [36] examined the effects of yoga and aerobic and strength combined training (Supplmentary Table 1 in the online-only Data Supplement) in females with a history of pituitary adenomas. Following the program involving yoga, a significant increase in HRQoL scores was observed when compared with baseline and a significant decrease in anxiety score, however, the effect on sleep quality, fatigue, depression, and sexual function was not significant. Combined aerobic and strength training did not have a significant effect on any parameter of HRQoL. Both yoga and combined aerobic and strength trainings improved cognitive functioning from baseline as measured by Montreal Cognitive Assessment (MoCA).

Gehring et al. [37] observed the effects of a remotely coached intervention which was home-based (Supplmentary Table 1 in the online-only Data Supplement) in patients with stable glioma. A reliable improvement in two or more cognitive measures was seen in 24% (n=5) of participants in the exercise group and 18% (n=2) in the control group. A reliable decline in 2 or more measures was seen in 19% (n=4) of exercise group, versus 27% (n=3) of the control group. The exercise group had better outcomes on self-reported sleep, cognitive functioning, and fatigue compared to the control group. Patients had observed better mood and mental HRQoL in the exercise group, however, there were no differences between groups for the brain cancer specific HRQoL.

Hansen et al. [38] tested the effect of occupational and physical therapy (Supplmentary Table 1 in the online-only Data Supplement) in glioma patients undergoing treatment. Even though there was no significant difference in the overall HRQoL scores of the intervention and control groups, the intervention group had a significantly higher score in the HRQoL domain of cognitive functioning, significantly lessened symptoms (fatigue, visual disorder, communication deficits, drowsiness, itchy skin), as well as significantly higher scores in functional performance outcomes (aerobic power, muscle strength of leg press, elbow extension, and elbow flexion).

DISCUSSION

We reviewed the current and emerging evidence on the methodologies and outcomes of various CR modalities in BT patients and survivors. We found that neuropsychologist-guided training sessions for attention, executive functioning [24], and memory [24,26] were shown to be efficacious for improving the mentioned domains of cognition. Younger and more educated patients benefit the most from neuropsychologic CR programs [25]. Holistic mnemonic training [1] and neurofeedback [28] were not shown to affect overall cognitive functioning.

CR has shown conflicting outcomes for neurocognitive deficits in various neurologic etiologies including traumatic brain injury (TBI) [21,39], MCI and dementia [40], stroke [39,41], and multiple sclerosis [42]. Unlike global neurologic deficits associated with MCI and dementia, tumors are responsible for focal deficits; and unlike sudden events such as stroke and TBI, tumors are longstanding lesions that cause gradual decline accounting for the radically different cognitive and/or behavioral consequences [43].

Computer-based training programs have shown improvements in executive functions (including working memory, attention, and recall) of pediatric BT survivors [29,32,33]. Feasibility studies showed difficulties while using CogMed [30], whereas ReMind was reported to be feasible for usage [32]. CogMed shows significant improving cognitive functions when compared to other digital interventions (Nintendo Wii, “Training di riabilitazione cognitiva,” and “Una palestra per la mente”), whereas the effects of ReMind are being studied, and are yet to be established [44,45]. The effects of CogMed on WM and academic performance have been widely studied in various pediatric populations. Contrary to the results in pediatric BT survivors, a meta-analysis of 50 studies analyzing the effect of CogMed reported no appreciable impact on overall cognitive ability or academic skills. CogMed specifically targets WM, which may be correlated with the changes in academic performance and intelligence, often observed in tumor survivors with late cognitive effects [46], which may explain why the program yields better outcomes in BT survivors. Despite some limitations in feasibility, computerized training of pediatric BTs may be promising for preserving their cognitive functioning. A systematic review of digital therapeutics for pediatric BT survivors concluded that they could be safe and effective for an improvement of the HRQoL of the patients and their families [47].

Exercise is a cost-effective and feasible intervention with very few side effects with appropriate supervision, thus an effective intervention in neuro-oncologic patients and survivors [48]. Aerobic exercises have been shown to improve executive functions [35,37] and decrease symptoms of the tumor [38]. Following aerobic exercise changes may be observed in behavior and functional connectivity, consistent with enhanced attention and inhibition [35]. Yoga has been shown to improve overall HRQoL, and both yoga and combined aerobic and strength training improved cognitive functioning [36]. Active video gaming was shown to improve motor and process skills, however, no effect was seen in cognitive functioning [31]. This may be because the activity-based video games physical activity sessions had low to moderate intensity, thus it did not show a significant effect on daily energy expenditure level to affect cognitive outcome measures [31]. Neural communication within different frequency bands on MEG, specifically theta (4–7 Hz), alpha (8–12 Hz), low gamma (30–59 Hz), and high gamma (60–100 Hz), play a role in facilitating information processing and controlled attention with an increase in task-load. Cox et al. [35] showed that high motor region gamma activity was associated with response latency in task-assessing inhibition (Go and Go/No-Go). Physical exercise thus had the potential to improve cognition, especially in conditions where task demands are higher, therefore regular aerobic exercise leads to improved cognitive abilities necessary for handling increased task loads. Khaleqi-Sohi et al. [49] conducted a systematic review on physical exercise’s effects on pediatric BT survivors and reported improved motor proficiency as well as physical fitness following exercise interventions and these had consistency with MRI findings of increased cortical thickness in the right somatosensory cortex, greater fractional anisotrophy in the corpus callosum, and the right corticospinal pathway as well as in the cingulum. Physical exercise needs wide neural connections between motor neurons within both hemispheres explaining the greater fractional anisotrophy in the corpus callosum which represents attention and motor control as well, thus explaining the white matter growth in the cingulum [50]. Furthermore, the hippocampus also has a role in cognition and mental ability [42]. Williams and Shellenberger’s learning pyramid also describes the perceptual-motor and sensory-motor development relation to cognition [49,51].

The heterogeneity in methodologies and outcomes across the various studies precluded the possibility of conducting a meta-analysis, limiting the generalizability of our findings. Additionally, the studies included in our review often had small sample sizes and limited populations, which may impact the robustness and external validity of the results. Furthermore, variations in the demographic and clinical characteristics of participants, such as age, education level, and tumor type, could have influenced the outcomes, highlighting the need for more standardized and comprehensive research in this field.

Future directions

The role of CR in BT patients is an expanding field. Cognitive deficits associated with BTs are well established [7,12,13], with literature supporting the effectiveness of rehabilitation in improving prognosis. Further RCTs are underway, utilizing computer-based rehabilitation, multidisciplinary CR, and physical exercise interventions to address cognitive decline (Table 3). Other potential modalities of rehabilitation, including neurofeedback [52] and transcranial magnetic stimulation [53], are yet to be investigated further. Pharmacological treatment options for cognitive decline are also being tested for efficacy with preliminary studies showing the effectiveness of modafinil [54,55], memantine [56], and donepezil [57]. Ongoing trials are currently underway to establish a definitive role of pharmacotherapy in cognitive decline associated with BTs.

Table 3. Ongoing trials assessing cognitive rehabilitation strategies in brain tumor survivors.

Study number	Start date	Rehabilitation type	Description of the rehabilitation modality
NCT02489071 [58] (Clinicaltrials.gov)	August 2014	Multidisciplinary cognitive training	- Brain training: 8 sessions of cognitive training through a behavioral brain training program - Brain health: 8 sessions of cognitive education through a behavioral brain health program
NCT03373487 [59] (Clinicaltrials.gov)	July 1, 2015	Computer-based training	- Behavioral CR using the program ReMind via an iPad. The CR includes psychoeducation, strategy training, and retraining. The intervention consists of spending 3 hours per week for a total of 10 weeks on the program.
NTR5392 [60] (WHO ICTRP)	September 14, 2015	Computer-based training	- CR program provided through a tablet app. It contains training, practicing, and retraining of strategies of memory, executive functioning, and attention. The intervention consists of spending 3 hours per week on the app for 2.5 months.
NCT01503086 [61] (Clinicaltrials.gov)	November 11, 2013		- Interactive training program: computerized, home-based, interactive program consisting of 3–5 sessions of 15–45 minutes per week for 5–9 weeks. The program consists of adaptive difficulty sessions on exercises training visual-spatial and verbal working memory. - Non-adaptive training program: computerized, home based, interactive program consisting of 3–5 sessions lasting 15–45 minutes per week for 5–9 weeks. The program consists of non-adaptive sessions on exercises training visual-spatial and verbal working memory.
NCT05202925 [62] (Clinicaltrials.gov)	October 1, 2021	Music therapy	- Weekly one-on-one 45-minute musical training lesson for 52 weeks.
NCT02129712 [63] (Clinicaltrials.gov)	February 1, 2014	Cognitive therapy	- Experimental: adaptive behavioral cognitive training. - Placebo comparator: non-adaptive behavioral cognitive training.
NCT03948490 [64] (Clinicaltrials.gov)	June 7, 2019	Multidisciplinary CR	- In person CR. - ReMind: iPad-based CR app. - Mobile phone texting cognitive intervention. - Telehealth CR.
NCT02153957 [65] (Clinicaltrials.gov)	August 21, 2014	Physical exercise	- Physical activity intervention at home for the first 12 weeks, followed by 12 weeks of self-maintained physical activity.

CR, cognitive rehabilitation

CONCLUSION

Addressing the cognitive deficits caused by BTs or their treatments has been increasingly studied in recent years, leading to a rise in new research studies on this subject. The current literature has shown neuropsychologic training sessions, computer-based training programs, and physical exercise to be effective in improving or preventing decline in cognitive functions of BT patients and survivors. However, due to a limited number of trials and differences in methodologies, the establishment of a standard cognitive rehabilitation program is not currently possible. Therefore, more long-term trials may be needed to adequately evaluate the true effect on the quality of life and the functioning of both BT patients as well as survivors. The ongoing registered trials indicate that significant data on the subject will be accessible in the coming years.

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14791/btrt.2024.0033.

Supplmentary Table 1

Descriptions of cognitive rehabilitation strategies