Is there evidence for a relationship between cognitive impairment and fatigue after acquired brain injury: a systematic review and meta-analysis

Figures & data

Table 1. Demographic characteristics, clinical variables in ABI, study participants (n = 1,745), and risk of bias.

	Study	Ns	Gender	Time since onset	Education	Country	Relationship cognitive & fatique	Risk of bias
	TBI studies
15	Azouvi et al. (2004)	43	♂ 11	10 Months	11 years (SD 2.6)	France	Yes	Fair
38	Beaulieu – Bonneau et al. (2017)	22	♂ 5	53 Months	12.41 yrs (S.D 2.46)	Canada	No	Fair
16	Belmont et al. (2009)	27	♂ 6	9 Months	13.45 yrs (SD 2.63)	France	Yes	Low
31	Sinclair et al. (2013)	20	♂ 14	133 Days to 13.4 years	15.2 yrs (S.D 3.4)	Australia	Yes	Low
	Stroke studies
40	Delva et al. (2017)	156	♂ 73	6 Months	34% Higher Ed	Ukraine	Yes	Low - Fair
41	Drummond et al.(2017)	268	♂ 168	24 Days	NS	UK	No	Low
44	Goh & Stewart (2019)	53	♂ 35	20 Months	0 yrs n = 2%; 6yrs n = 32%; 9 yrs n = 28%; 12yrs n = 17%; 16yrs n = 15%; >16yrs n = 6%	USA	Yes	Fair
11	Hubacher et al. (2012)	31	♂ 6	51 Days	Secondary Ed n = 16%; college Ed n = 65%; university Ed n = 19%	Switzerland	Yes	Fair
37	Park et al. (2009)	40	♂ 26	33 Months	NS	South Korea	No	Fair
43	Pihlaja et al. (2014)	133	♂ 86	85 Days	12 yrs	Finland	Yes	Low
42	Morsund et al. (2019)	325	♂ 205	3–12 Months	NS	Norway	No	Low
12	Radman et al. (2012)	109	♂ 72	6 Months & 12 months	NS	Switzerland	Yes	Low
32	Holmberg et al. (2021)	311	♂ 180	3 Months	NS	Sweden	No	Low
36	Ulrichsen et al. (2020)	53	♂ 38	6–45 Months	14.56 yrs (S.D 3.65)	Norway	Yes	Low
	SAH studies
10	Boerboom et al. (2017)	46	♂ 29	4.7 Years	41.3% = > High school	Netherlands	Yes	Low
45	Passier et al.. (2011)	108	♂ 19	11 Weeks	Low/Intermediate n = 91 (83.5%), high n = 18 (16.5%)	Netherlands	Yes	Fair
	Total: 16 studies						Total: 11 studies

Figure 1. Preferred reporting item for systematic review and meta – analysis flow chart study selection.

A PRISMA flow diagram to represent the flow of information through the four phases of this Systematic Review: Identification, Screening, Eligibility and Included studies. The name of each phase is listed in the left columns. The middle columns illustrate the results of each phase. The right column shows the reason for exclusion throughout each round. Phase one shows 421 papers were identified, once exclusion and duplicates were removed. Papers were then screened by title and abstract in phase two. Phase three shows how 74 full-text papers were assessed for eligibility. Phase four shows that 16 papers met the inclusion criteria.

Table 2. Study details and overall findings.

Study	Cognitive domain: cognitive assessment	Fatigue measure	Relationship found	Total associations investigated	Positive associations found	Test analysis	Domain – specific neuropsychological assessment batteries	Reaction Time based Ax.	Domain general screen	Timing of fatigue Ax. indicated
	TBI
15	Divided Attention: Go No / Go	VAS	Yes	12	10	ANOVAs/chi –square/Spearman r	No	Yes	No	Yes
38	Selective attention: TMT tasks 1–5: visual scanning: TMT 1; number sequencing: TMT 2	VAS-f	No	5	0	ANOVAs/MANOVAs/spearman correlations	Yes	Yes	No	No
	Letter sequencing: TMT 3; number-letter seq: TMT 4; motor speed: TMT 5
	Memory: Auditory Consonant Trigrams (ACT)			3	0
	Sustained attention: Continuous Performance Test (CPT-II)			5	0
	Attention & information processing: driving simulator			3	0
16	Sustained selective attention: Go/No Go	FSS	Yes	14	6	ANOVAs/Pearson correlations	No	Yes	No	Yes
31	Sustained attention: Psychomotor Vigilance Task (PVT)	FSS	Yes*	4	0	t-Tests/chi square/Ancova/correlation	No	Yes	No	Yes
	Stroke Studies
40	Global domain screen: MOCA	MFI − 20 (mental domain)	Yes	3	3	Logistic regression with OR	No	No	Yes	Yes
41	Sustained attention: Dot cancellation tasks	FSS	No	1	0	Multivariable regression	Yes	No	No	No
	Selective attention: Stroop		No	1	0
	Information processing: adult memory and information		No	1	0
	Processing battery (AMIPB)
44	Global domain screen: MOCA	FSS	Yes	1	3	Spearman correlation	Yes	Yes	Yes	Yes
	Information processing speed & attention/vigilance: simple choice reaction time SRT			1
	Information processing speed & attention / vigilance: Choice reaction time CRT			1
11	Verbal short -term memory: SRT – LTS/	Yes FSS 0; MFIS-C 1;FSMC 1		3	2	Bivariate correlations	Yes	Yes	No	Yes
	Verbal short – term memory: SRT – CLTR	FSS 0; MFIS-C 1; FSMC 1		3	2
	Verbal long – term memory: SRT – DR	FSS 0; MFIS-C 0; FSMC 0		3	0
	Visual short – term memory: 10/36 Spatial Recall Test	FSS 0; MFIS-C 0; FSMC 0		3	0
	Visual long – term memory: 10/36 – DR	FSS 0; MFIS-C 0; FSMC 0		3	0
	Working memory: PASAT	FSS 0; MFIS-C 0; FSMC 1		3	1
	Information processing & mental speed: SMDT	FSS 0; MFIS-C 1; FSMC 1		3	2
	Executive function: word list generation	FSS 0; MFIS-C 1; FSMC 0		3	1
37	Global domain screen: MMSE (Korean version)	FSS	No	1	0	Spearman correlation	No	No	Yes	No
43	Processing speed sum score: TMT/Stroop/digit symbol coding	POMS-f	Yes	3	2	Chi-square tests/Mann Whitney/MANOVAs	Yes	No	No	No
	Processing speed: TMT A			3	0
	Processing speed Stroop colour naming			3	0
	Processing speed: digit symbol coding			3	2
	Memory sum score			3	1
	Memory: Logical Memory Test I			3	0
	Memory: 10 – word list learning task			3	1
	Memory: Benton Visual Retention Test			3	0
	Executive function sum score			3	0
	Executive function: TMT B & A			3	0
	Executive function: Stroop			3	0
	Executive function: phonemic fluency task			3	0
	Reasoning sum score			3	0
	Reasoning: similarities			3	0
	Reasoning: block design			3	0
42	Global cognitive functioning and visuospatial test: MMSE & Clock drawing task	FSS	No	2	0	Correlations/linear regressions	Yes	No	Yes	No
	Memory: 10 –word list learning task; 10 – word learning task delayed			2	0
	Executive function: TMT forms A & B, verbal – fluency: colour word interference tests			11	0
	(Naming/reading); colour word reading (inhibition/switching); Error tests (naming errors,
	Reading errors, inhibition errors, inhibition/switching errors).
12	Attention: TEA (phasic alert & divided attention)	FAI	Yes	4	3	Logistic regression	Yes	No	No	No
	Attention: D2 (sustained attention)			2	2
	Long term memory: Rey Auditory verbal memory task			2	1
	Short – term memory: Digit span			2	0
	Short – term memory: Corsi Blocks test			2	0
	Language: Boston Naming test			2	1
	Language: Boston diagnostic aphasia			2	1
	Executive function: Stroop			2	1
	Executive function: category & fluency tasks			2	1
	Global cognitive score			2	2
32	Global domain screen: MOCA	Likert scale	No	1	0	Binary logistic regression	No	No	Yes	No
36	Attention: ANT	FSS	Yes	25	7	ANOVA/t- tests/beta/linear regression	Yes	Yes	No	Yes
	SAH studies
10	Attention and concentration: D2 concentration performance	FSS	Yes	2	1	t-Test/chi-square/correlation	Yes	No	No	Yes
	Attention and concentration: digit span forwards			3	3
	Speed of information processiNG: D2 total performance			2	1
	Speed of information processing: TMT A			2	1
	Speed of information processing: symbol substitution (total good)			2	2
	Memory: 15 words task (WT) total score			2	0
	Memory: 15 WT total recognition			2	0
	Memory: 15 WT total recall			2	0
	Memory: Rey complex figure, recall score			2	0
	Memory: word fluency, semantic			1	1
	Memory: digit span, backwards			2	0
	Menory: digit span, total score			2	0
	Executive function: Tower Test, total performance			2	0
	Executive function: word fluency phonological			3	2
	Executive function: TMT –B			1	0
	Visuoconstruction: Rey complex figure, copy score			1	0
	Subjective cognitive functioning: Cognitive Failure Questionnaire total score			1	0
45	Sum score of: verbal memory: digit span backward; semantic memory: category fluency	FSS	Yes	1	1	ANOVAs/t tests/RR	Yes	No	No	Yes
	Verbal learning: Rey Auditory Verbal Learning Task (RAVLT)
	Non – verbal learning: Osterrieth Complex Figure Test
	Executive Function: Brixton Spatial Anticipation Test
	Attention: digit span forward, Stroop
	Visuoconstruction: Rey complex figure, copy score

*Study [31] association found in subset sample only. Abbreviation: Ax: assessment.

Table 3. Fatigue scales and dimensions assessed.

Measure	Number of studies	Dimension of fatigue assessed
Unified scales
Fatigue Severity Scale – FSS	10	General experience of fatigue
Visual Analog Scale – VAS/VAS–f	2	General experience of fatigue
Profile of Mood States fatigue subscale – POM–f	1	General experience of fatigue
Fatigue Likert scale, unspecified*	1	General experience of fatigue
Subtotal : 4
Multi – dimensional scales
Modified Fatigue Inventory – MFI − 20	1	Five domains: general fatigue, physical fatigue, reduced motivation, reduced activity, mental fatigue
Modified Fatigue Impact Scale – MFIS	1	Four domains: cognitive, physical, psychosocial functioning.
Fatigue Assessment Inventory – FAI	1	Four domains: severity; pervasiveness associated consequences; response to sleep.
Fatigue Scale of Motor and Cognitive Functions – FMSC	1	Two domains: cognitive & Motor subscales.
Subtotal: 4
Total: 8 measures of fatigue

*Unspecified: Study [32], own non – standardized scale used.

Figure 2. Forest plot displaying reaction time scores in Pearson’s r and relationship between cognitive measures/fatigue scales.

A forest plot, graphical displaying the results of meta-analysis from five studies. The left column shows the reaction-time based cognitive measure/fatigue measure used when investigating for a relationship. The most frequently used cognitive assessment was the Go/No/Go and associations were found with fatigue in all instances. Associations were found with all comparisons made with Multi-Dimensional fatigue scales. The middle column are the associated findings for each comparison made, and are displayed in a hierarchal manner. Though, wide confidence intervals are used in certain instances, which are shown in the right column.

Table 4. Summary of domain specific comparisons made, associations found, rate of positivity (%).

	No. of studies	Study making investigations	No. of studies with significant associations	Positive associations found/total associations investigated	Rate of positivity %	Studies finding positive associations
Relationship of domain specific
cognitive impairments to fatigue
Information processing	5	10,11,41,43,44	4	11/23	48	10,11,43,44
Attention	10	10,12,15,16,31,36,38,41,44,45	7	33/82	40	10,12,15,16,36,44,45
Memory	7	10,11,12,38,42,43,45	4	9/55	16	10,11,12,43
Executive function	6	10,11,12,42,43,45	3	6/35	17	42,43,45
Language	1	12	1	2/4	50	12
Reasoning	1	43	0	0/9	0
Visuoconstuction	1	10	0	0/1	0
Subjective cognition	1	10	0	0/1	0
Relationship of fatigue scales
Unified fatigue scales
Overall scores	13	10,11,13,15,16,31,36,37,41-45	7	44/180	24	10,15,16,36,43,44,45
VAS/VAS–f	2	15,43	1	10/28	36	15
FSS	10	10,11,16,31,36,37,41,42,44,45	5	28/106	26	10,16,36,44,45
Fatigue Likert scale	1	32	0	0/1	0	0
POMS – f	1	43	1	6/45	13	43
Multi–dimensional fatigue scales
Overall scores	3	11,12,40	3	23/41	56	11,12,40
FSMC	1	11	1	4/8	50	11
MFIS – C	1	11	1	4/8	50	11
FAI	1	12	1	12/22	55	12
MFI − 20*	1	40	1	3/3	100	40
Overall associations	16		10	67/220	30	10-12,15,16,36,40,43-45
Study designs:
Design 1: domain specific assessment	9	10-12,38,41-45	6	32/141	23	10-12,43,44,45
Design 2 : RTs	7	11,15,16,31,36,38,44	6	28/71	39	11,15,16,31,36,44
Domain general	5	32,37,40,42,44	2	4/8	50	40,44
Global cognition abilities	2	12,45	2	4/5	80	12,45

Figure 3. Meta-analysis effect size in Pearson’s r.

Figure 2 &3, Abbreviations of cognitive assessments: SMDT: Symbol Digit Modalities Test; PASAT: Paced Auditory Serial Addition Test; CPT II: Continuous Performance Test II; PVT: Psychomotor Vigilance Task; SRT: simple reaction time; CRT: choice reaction time; ANT: Attention Network Test. Abbreviations of fatigue measures: FSMC – C: Fatigue Scale of Motor and Cognition – cognitive subscale; MFIS – C: Modified Fatigue Impact Scale, cognitive subscale; VAS: Visual Analog Scale; FSS: Fatigue Severity Scale. Figure 2: Positive threshold target (yellow vertical line), 0.2.

The findings from meta-analysis of the included five studies is presented across 4 columns. The reaction-time based cognitive measure/fatigue measure and study references are listed in column one. The number of participants in each study is presented in column two. The effect size found from each comparison is shown in a hierarchal manner in column three. Higher effect sizes are observed with multi-dimensional fatigue scales, though wide confidence were used in certain instances, as shown in the right column. The final row of the figure presents a significant though overall low random effect size of this meta-analysis as r = 0.234.

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