Anxiety and Cognition in Multiple Sclerosis: A Narrative Review

ABSTRACT

BACKGROUND:

People with multiple sclerosis (MS) often experience psychiatric symptoms, such as anxiety and depression, that impact disease progression and quality of life. Cognitive impairment, particularly in processing speed and episodic memory, is common in MS. There are several studies studying the relationship between anxiety and cognition in the population with MS. This study reviews that literature.

METHODS:

This bibliographic review covers publications in Spanish and English from January 2006 to June 2022. It focuses on quantitative investigations of the relationship between anxiety symptoms and cognitive variables in people with MS.

RESULTS:

A majority of studies found an association between anxiety and cognition in people with MS. Anxiety significantly affects information processing speed, learning, memory, attention, working memory, and verbal fluency in people with MS. However, some studies find no association. The impact of depressive symptoms and the bidirectional relationship between anxiety and cognition are highlighted.

CONCLUSIONS:

Anxiety in people with MS is associated with cognitive impairment. Further research is needed to understand the mechanisms and establish causal relationships between anxiety and cognition in this population.

Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. It is the most common cause of neurologic disability in young adults.¹ Psychiatric manifestations, such as symptoms of anxiety and depression, are prevalent in people with MS and are associated with disease progression and a poorer quality of life.^2,3 Although these manifestations are present in up to 60% of people with MS, they are often not adequately treated.⁴ In contrast, the prevalence of cognitive impairment in adults with MS ranges from 34% to 65% and symptoms vary according to the course of the disease.⁵ Cognitive impairment is also a neglected but common symptom with a profound effect on essential activities of daily living. Neuropsychological research suggests that cognitive processing speed and episodic memory are the most frequently affected cognitive domains.⁶

MS can be described as a pathology with an uncertain outcome: a chronic, unpredictable neurological disorder with recurrent relapses (the most common form of MS, the relapsing-remitting MS phenotype) that seem to occur at random; it carries the risk of eventual progression to a chronic progressive disease after years or decades of stability. Therefore, it is quite possible that the unpredictable nature of this disease, particularly with regard to relapses and the potential for future progression and disability, causes anxiety.

Clinical anxiety is defined as an intermittent or persistent feeling of apprehension or fear that can be associated with physical symptoms, including tachycardia, sweating, palpitations, dizziness, and autonomic gastrointestinal symptoms.⁷ The severity of anxiety symptoms can be assessed in 2 ways: (1) via self-report scales or questionnaires that measure the patient's current self-perceive1d mood, such as the Hospital Anxiety and Depression Scale (HADS),⁸ or (2) through clinical reporting, such as the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID), which uses more formal diagnostic criteria to establish the presence of a possible or proven anxiety disorder.^9,10 Studies indicate that between 30% and 50% of people with MS present with clinically significant anxiety^11,12 and it is associated with negative health-related outcomes, such as lower adherence to treatment^2,3; increased fatigue; physical, psychiatric, and social dysfunction¹³; and cognitive impairment.¹⁴

Depression is known to be a common comorbid symptom with anxiety in people with MS, and anxiety was found to be a strong predictor of depression through both direct and indirect pathways, suggesting a possible causal relationship.¹⁵ Although the role of each variable has been studied separately, recently, the presence of multiple comorbidities in people with MS has drawn the attention of clinicians and researchers, which has led to mediation studies¹¹ that seek to understand the interaction of both variables and their relationship with cognition.

There is evidence of prefrontal cortical atrophy in people with MS who have anxiety, involving structures that resemble known neurobiological circuits of anxiety. MRI studies found an association between atrophy in the superior and middle gyri of the right frontal lobe and anxiety scores in people with MS.¹³ These findings clarify the appearance of anxiety as part of the pathology of the disease.

It is known that the influence of emotional stimuli—especially stimuli of a threatening or anxiogenic nature—interferes with performance in attention tasks, working memory, and cognitive inhibition.¹⁶ This is important for understanding the relationship between anxiety and cognition in MS; some authors have proposed that it is bidirectional or synergistic, which would imply that anxiety can negatively affect domains such as complex attention and processing speed, thus interrupting cognition. In addition, anxiety contributes to slower processing speed, which creates anxiety symptoms and, therefore, negatively affects cognition.¹¹ The neuropsychological findings regarding the relationship between anxiety and cognition are not consistent, both those that refer to people without MS¹⁷ and those with MS.¹⁵ Is it possible to identify a neuropsychological profile and establish a characteristic pattern of functioning across the different cognitive domains in people with anxiety and MS? We conducted a narrative review of the bibliography available to date on the relationship between anxiety and cognition in people with MS to investigate.

METHODS

We searched for the following terms in PubMed and the Scientific Electronic Library online (SciELO): esclerosis múltiple, multiple sclerosis, ansiedad, anxiety, anxiety symptoms, neuropsychiatric disorders, and neuropsychiatry symptoms combined with cognición, cognitivo, cognition, cognitive, cognitive ability, cognitive dysfunction, cognitive function, and cognitive deficits. We selected articles published from January 2006 to June 2022 that quantitatively investigated the relationship between anxiety symptoms and 1 or more cognitive variables in people with MS. The search yielded 53 articles. After discarding 10 papers that addressed anxiety and cognition outside the scope of MS and 8 that addressed anxiety and MS but did not include cognitive variables, 35 studies remained.

RESULTS

Anxiety in MS

Assessment of Anxiety in MS

Anxiety is a complex construct that implies a multidimensional conceptualization. It includes physiological, behavioral, cognitive, and affective variables; thus, its evaluation requires the assessment of multiple dimensions.¹⁸ Indeed, in the MS clinic, anxiety symptoms can be measured in many ways, for example, indirectly by taking standardized interviews that complement psychopathology and mental health manuals, such as the Schedules for Clinical Assessment in Neuropsychiatry¹⁹ or the aforementioned SCID-I.⁹ Another possibility is using scales, questionnaires, and inventories, including subjective measures such as the patient's self-report, to complete what is referenced in the medical records and in the direct objective measures of the physiological and behavioral dimension of the anxiety spectrum.¹⁸ Some of these scales and questionnaires are used as early detection or screening tools and may require additional evaluation to confirm a diagnosis.²⁰ Several of these instruments have been validated to measure anxiety in people with MS: the Hamilton Anxiety Rating Scale,²¹ the State-Trait Anxiety Inventory (STAI),²² HADS,⁸ and the Beck Anxiety Inventory (BAI).²³ Because some common symptoms of MS, eg, tingling, dizziness, or muscle tension, can overlap with the somatic symptoms of anxiety and lead to misclassification or overestimation of anxiety presentations or criterion contamination, investigators of the Canadian Institutes of Health Research²⁰ evaluated the validity and reliability of dimensional measures of anxiety in people with MS and concluded that the HADS anxiety subscale (HADS-A) is a reliable assessment with greater sensitivity and specificity for people with MS than other tools, such as the BAI or the Generalized Anxiety Disorder 7-Item scale.²⁴ We found that the HADS-A cutoff points used for other medical populations were also appropriate for those with MS. Scores greater than or equal to 8 indicate clinically significant anxiety, while scores greater than or equal to 11 indicate an anxiety disorder with a sensitivity of 88.5% and a specificity of 80.7%.^20,25,26 Of the 35 articles reviewed, 21 used the HADS-A to measure clinically significant anxiety,^11,14,27-45 11 used the STAI,^46-56 1 used the Mental Health Inventory with the Neuroticism scale from the NEO Five-Factor Inventory,⁵⁷ 1 used the Depression Anxiety Stress Scales,⁵⁸ and 1 used the Zung Self-Rating Anxiety Scale.⁵⁹ Only 5 of the studies supplemented the anxiety measures with evaluations from standardized neuropsychiatric interviews for anxiety disorders (SCID)^{28,29,39,41,54} and only 2 added a second tool to measure anxiety, the Symptom Checklist-90-Revised with the HADS³⁵ and the Penn State Worry Questionnaire with the STAI.⁵²

Prevalence of Anxiety Disorders and Anxiety Symptoms in MS: Associated Factors

According to previous studies, the prevalence of anxiety is 3 times higher in people with MS than in the general population.^60-62 A prevalence rate close to 30% was replicated in a cross-sectional study from 2018 in a sample of 244 people with MS in Canada. That study found that higher odds of anxiety were associated with depression, low levels of education, and impaired quality of life.³ The RELACCEM study, a multicenter investigation that evaluated neuropsychiatric symptoms among participants from Argentina, Chile, Colombia, Mexico, Uruguay, and Venezuela, found that anxiety symptoms were present in up to 33% of people with MS.⁶³ An Argentinian cross-sectional study that evaluated 88 people with MS found that 45% of their sample presented with anxiety and anxiety was significantly associated with younger age, shorter time from diagnosis, history of other psychiatric disorders, depression, and poor quality of life.⁶⁴ A recent systematic review with a meta-analysis found that the overall prevalence of anxiety in people with MS is 35.19%, which is higher than the prevalence reported in previous studies.¹² This review also found that anxiety is more prevalent in different clinical forms of MS—21.40% in relapsingremitting MS (RRMS) and 24.07% in progressive MS (PMS)—than depression (15.78% in RRMS and 19.13% in PMS).

Relationship Between Anxiety and Cognition in MS

Assessment of Cognition in MS

In the field of MS, neuropsychological batteries are used to assess cognition, including the classic Brief Repeatable Battery for Neuropsychological evaluation (BRB-N) by Rao,⁶⁵ or the Minimal Assessment of Cognitive Function in MS (MACFIMS),⁶⁶ which assess attention, working memory, learning, and verbal and visual episodic memory, as well as verbal fluency. MACFIMS can also be used to assess executive functions and visuospatial processing. In 2012, a committee of experts proposed the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) as a brief, practical, and universal cognitive assessment instrument.⁶⁷ Some of the studies included in this review used one of these cognitive assessment batteries: 8 used the BRB-N,^{33,36,40,44,48,50,54,55} 2 used the MACFIMS,⁵⁴ and 2 used the BICAMS.^29,42 Other studies used different neuropsychological batteries or combinations of tests to measure 1 or more domains in particular: Three used tests from the Behavioural Assessment of the Dysexecutive Syndrome (BADS),^35,45,56 3 evaluated using portions of the Test of Everyday Attention (TEA),^49,52,56 2 used the Montreal Cognitive Assessment,^27,43 2 used the Neuropsychological Screening Battery for MS,^39,59 1 used the Luria–Nebraska Neuropsychological Battery,³⁸ 11 used a set of tests selected ad hoc or as a screening method,^{11,14,28,41,45-47,51,52,56,57} 2 evaluated only 1 area or cognitive domain,^37,53 and lastly, 2 used computerized batteries.^32,58

Relationship Between Anxiety and Cognition in MS

Studies investigating the association between anxiety and cognition in MS trend toward 3 different conclusions: confirming that anxiety is a predictor of cognitive functioning (12 cross-sectional studies^{11,27-30,46-49,55,57,58} and 3 studies of longitudinal design^41,42,54); finding that anxiety predicts subjective cognitive functioning, ie, the perception of cognitive impairment or cognitive difficulties (12 cross-sectional studies^{14,31-36,45,50,51,56,59}); and finding no association between anxiety and cognition (5 cross-sectional studies^37-39,52,53 and 3 longitudinal studies^40,43,44).

Studies confirming the association between anxiety and cognition in MS.

Several studies found that cognitive dysfunction correlates significantly with an increase in anxiety,^34,52 or that anxiety independently predicts objective cognitive performance.^47-49 One longitudinal study even suggests that anxiety is a significant predictor of cognitive changes over time.⁵⁴ A recent article, with a 2-year follow-up, found that correlations between scores on anxiety and cognitive measures (HADS and BICAMS) were not significant at baseline, but weak to moderate negative correlations were found at follow-ups after 1 and 2 years.⁴² A subsequent article, with a 3-year follow-up, found that at any point in time, individuals with high anxiety symptoms exhibited lower performance in processing speed, verbal learning, and working memory.⁴¹ Other current cross-sectional studies also confirm that anxiety correlates with certain measures of cognitive functioning.^{11,27-30,46,55,57,58}

Information processing speed appears in several investigations as the function most affected by anxiety.^{11,28-30,41,46,48,49} Cross-sectional studies that included the Symbol Digit Modalities Test,⁶⁸ validated for people with MS,⁶⁹ to measure information processing speed, reported that people with MS who had anxiety were less efficient on executive tasks, particularly tasks that included a processing speed component.^29,49 Another study that controlled for associated demographic and clinical factors, such as depression and fatigue, reported that anxiety in people with MS was independently related to lower information processing speed.⁴⁸ Similarly, a significant difference was found in measures of processing speed in people with MS who had anxiety compared with people with MS who did not have anxiety.³⁰ Another study found that lower disability, shorter disease duration, and lower levels of anxiety predicted performance in processing speed.⁴⁶ This relationship was also found in a longitudinal study that followed the evolution of cognitive measures and values of associated clinical factors for 3 years in 4 cohorts of people with inflammatory diseases, including MS.⁴¹ These authors concluded that, at any point in time, individuals with high symptoms of anxiety exhibited lower processing speed. Vissicchio et al¹¹ conducted 2 mediation analyses to explore the relationships between anxiety, processing speed, and verbal learning. The first analysis revealed that anxiety affects verbal learning through processing speed. The second analysis established that processing speed influences verbal learning while being mediated by anxiety. The results suggest a bidirectional relationship between anxiety and processing speed, with both factors influencing performance in verbal learning.¹¹

Different findings confirm that verbal episodic memory and visual episodic memory are 2 of the cognitive domains affected or interfered with by anxiety.^{11,27-30,41,54,55,57,58} A longitudinal study exploring cognitive changes in people with MS, who were assessed at baseline and after 1 year of followup, found that baseline measures of negative affect, including depressed mood and anxiety, tended to more strongly predict changes (25% of variability) in verbal and visuospatial episodic memory measures; however, the relationship between negative affect and cognition was not reciprocal.⁵⁴ Another cross-sectional study showed that, in combination with gender, age, and disability, anxiety explained 24% of the variance in the memory domain in people with MS.⁵⁸ A study that investigated the established relationship between anxiety and verbal learning and memory in people with MS found that anxiety was a significant predictor of deficits in verbal learning.¹¹ Likewise, other studies found that high anxiety present in people with RRMS or in the early stages of the disease was associated with cognitive memory impairment and language disorders.²⁷ A recent paper that studied the relationship between cognitive impairment, sleep disorders, and the role of anxiety and depression among people with MS established that memory scores were negatively correlated with state anxiety, whereas a high level of trait anxiety moderated the relationship between waking up at night and worse memory performance.⁵⁵ Recent studies also report that a current diagnosis of anxiety disorder or elevated anxiety symptoms, even in the absence of a diagnosed anxiety disorder, were associated with reduced information processing speed, lower working memory performance, and lower learning and verbal memory performance.^28,29,41 A 2016 study agreed that there was a relationship between anxiety and visual episodic memory and concluded that levels of impairment measured by the HADS-A were significantly related to measures of visual episodic memory, as well as visual episodic memory processing speed and working memory.³⁰ Other articles identify strong relationships between cognition and mood and suggest that both anxiety and depression correlate with cognition in MS, even though they both have dissociable cognitive patterns: A lower level of anxiety is associated with better visual memory while a lower level of depression is related to better attention and information processing speed.⁵⁷

Several studies concluded that complex attention—either sustained or divided attention—and working memory are also affected by anxiety.^{28,30,41,46-49} Previous research examining the impact of anxiety on the cognitive performance of people with MS found that anxiety as a state, measured by the STAI, predicted performance on the executive functioning index.⁴⁹ Likewise, anxiety has been independently related to lower performance in complex attention tasks and information speed processing⁴⁸ as well as alterations in inhibition processes, verbal fluency, and practical-constructive problem solving.⁴⁷ Other studies also found a significant difference between loading measures for working memory in anxious and nonanxious people with MS.³⁰ A recent study showed that disease duration, physical disability, and high levels of state anxiety significantly and negatively predict performance on the Paced Auditory Serial Addition Test (PASAT), a test validated among the population with MS that requires complex attention and working memory.⁴⁶ Similarly, 2 of the papers cited above found that self-reported anxiety symptoms were associated with lower working memory performance and processing speed.^28,41

Most of the aforementioned studies included language tests, but only 2^27,47 found that anxiety measures were associated with language measures, and more specifically, with verbal fluency tasks. One concluded that high levels of anxiety and depression can be predictors of alterations in phonological and semantic verbal fluency.⁴⁷ The other, seeking to establish cognitive phenotypes in people with MS, indicated that elevated anxiety are present in people with RRMS, people in the early stages of the disease, and people with memory and language disorders.²⁷

Studies That Find Association Between Anxiety and Subjective Cognitive Impairment in MS.

Twelve articles indicate that anxiety, along with other clinical variables (depression, fatigue, etc), in people with MS makes them more likely to report cognitive difficulties.^{14,31-36,45,50,51,56,59} In 10 of these studies, depression was present, suggesting that this variable could be involved in subjective rather than objective measures of cognition. Cross-sectional and longitudinal research studies have investigated the relationship between anxiety and subjective measures of cognitive impairment in MS using, for the most part, self-report questionnaires such as the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ),⁷⁰ the Cognitive Failures Questionnaire (CFQ),⁷¹ the Dysexecutive Questionnaire (DEX)⁷² of the BADS,⁷³ the Prospective and Retrospective Memory Questionnaire (PRMQ),⁷⁴ or the Cognitive Emotion Regulation Questionnaire (CERQ).⁷⁵ Of all the studies in this review, 3 used the MSNQ,^33,34,36 2 used the CFQ,^14,59 2 used the DEX,^45,56 another 2 used the PRMQ,^50,51 1 used the CERQ,³⁵ and 1 used the 8-item Short Form Health Survey.³¹ Finally, the last and most current study used a computerized cognitive battery,³² the Mindstreams computerized cognitive assessment system,⁷⁶ which yields a composite of global cognitive functioning. A pioneering study from 2006 found that levels of education, depression, anxiety, fatigue, and disability were significantly related to how people with MS perceived their cognitive functioning.⁵⁹ The authors found that anxiety predicted perceptions of cognitive functioning at a daily global performance, but not an objective cognitive performance assessed by a battery of cognitive tests. They concluded that perceived cognitive functioning is subject to a number of noncognitive influences such as the patient's emotional state (depression and anxiety) and mental and physical state (fatigue and disability), which account for a considerable proportion of the variability (approximately 40%) of such perceived cognitive functioning. Subsequent studies also found that anxiety in concert with depression predicts self-reported cognitive decline in people with different clinical forms of MS.^35,36,45 In contrast, an investigation that evaluated the subjective perception of memory problems found that they are associated with more reports of depression, anxiety, and neuroticism. The same investigation also found that the relationship between anxiety and self-reported memory is stronger than that between depression and self-reported memory.⁵¹ Other studies have also shown that self-reported executive dysfunction by people with MS predicts greater depression, stress severity, trait anxiety, mental health, and general quality of life.⁵⁶ A more recent study that investigated the possible relationship between cognitive impairment, mood disorders (eg, anxiety and depression), and falls in people with MS found that those who were depressed and anxious were almost 4 times more likely to perceive cognitive alterations than those who were not depressed or anxious. It also noted that anxiety without depression was associated with a lower risk of falls, even when compared with people with MS who do not have depression or anxiety.³² In line with these findings, a 2019 study also found a significant correlation among anxiety, depressive symptoms, fatigue, cognitive difficulties, and psychiatric history,¹⁴ with only depressive symptoms and cognitive issues remaining significantly related to anxiety. Even though the latter search indicated that anxiety was associated with cognitive difficulties in people with MS, none of the objective neuropsychological tests showed significant correlations with anxiety.

Studies That Find No Association Between Anxiety and Cognition in MS.

Finally, 5 cross-sectional studies^37-39,52,53 and 3 longitudinal studies^40,43,44 concluded that there is no association between anxiety and cognition.

One of the cross-sectional studies compared cognitive performance between people with MS both with and without anxiety and found no significant differences on the neuropsychological measures administered.³⁹ Another study examined anxiety as a trait and a state via the STAI inventory in a sample of 50 people with MS and 45 subjects without MS, and also found no associations with neuropsychological functioning.⁵² A final study reported that anxiety is not associated with cognitive deficits, but that depressive symptoms may have a more disabling impact on the functional results of people with MS.⁵³

Longitudinal design studies also report that anxiety does not correlate with neuropsychological performance over time. One study found a significant association between anxiety and depression with perceived cognitive deterioration at the beginning of the study, however, in the follow-up measures, no relationship was found with neuropsychological performance.⁴⁴ Another study, which followed a cohort of 608 people with MS for 1 year, found no clinically significant relationship between cognitive functioning and anxiety, even though other clinical variables were related.⁴³ Likewise, a longitudinal study followed 165 people with RRMS for a period of 3 years and reported that only depression was significantly associated with an increased risk of cognitive impairment.⁴⁰

CONCLUSIONS

This literature review presents studies supporting the association between anxiety and cognitive performance in individuals with MS; there were 12 cross-sectional studies^{11,27-30,46-49,55,57,58} and 3 longitudinal studies.^41,42,54 Anxiety significantly affects cognitive domains such as information processing speed, learning, verbal and visual episodic memory, attention, working memory, and verbal fluency. These findings are consistent with existing literature showing poorer cognitive performance in patients with anxiety disorders compared with the general population.^16,77,78

Notably, some researchers highlight a bidirectional relationship between anxiety and cognition, suggesting that higher anxiety levels impair information processing speed, while lower processing speed is associated with higher anxiety. This supports Eysenck's theory of attentional control,⁷⁹ which posits that anxiety disrupts cognitive processes by increasing attention to both internal and external distractors, thereby affecting cognitive performance.

Despite these insights, the mechanisms linking anxiety and cognitive performance in people with MS are not fully understood. Research is needed to establish a causal relationship between these variables. This review also indicates that while anxiety can influence cognitive difficulties, depression is a stronger predictor of cognitive impairment in MS.^37-40,43,44

Given these data, it is reasonable to increase efforts to study the correlation between anxiety and its impact on cognition in people with MS. The conclusions drawn from this review have some limitations. It is important to be aware of the variability in the characteristics of the samples (eg, demographics, measure of cognitive impairment before evaluation). Another variable is the techniques used for measuring anxiety and for assessing cognitive components. Finally, the different methods for comparing data and measuring their effects and directions may influence the differences between the findings of the reviewed studies. It is also worth noting that only 17% of the reviewed papers were longitudinal studies (6 of 35). Despite these limitations, this review confirms that the association between anxiety and cognition in MS is validated by numerous studies that aim to expand knowledge about the impact of 1 variable on the other. Future research might consider discrepancies among the findings of the studies to provide a more precise understanding of the main mechanisms at play between anxiety and cognitive functioning. Prioritizing the study of the effects of anxiety in people with MS would optimize management and treatment, and likely lead to improvements in depressive symptoms and other comorbidities such as fatigue or cognitive impairment. Similarly, addressing cognitive problems could have a beneficial impact on mood symptoms, contributing to greater stability over the disease course and, consequently, a better quality of life.

PRACTICE POINTS

• Several studies of people with multiple sclerosis (MS) confirm that anxiety is a predictor of cognitive functioning.

• Studies show that the perceived cognitive functioning of people with MS is subject to a range of noncognitive influences highlighting the importance of considering the assessment and monitoring of mood-related disturbances.

• Anxiety is related to cognition in MS, although further research is needed to fully understand this relationship.

TABLE 1.

Characteristics of the Studies on the Relationship Between Anxiety and Cognition in People With MS

First author year	Sample	Anxiety measures	Cognitive measures	Other measures	Results
Riccitelli 2022	80: 74 RR, 6 SP	STAI	BRB-N	MADRS, PSQI, ESS, PSG	Episodic memory score negatively correlated with state anxiety. High level of trait anxiety moderated relationship between night awakening and worse memory performance.
Podda 2021	872: 392 RR, 365 SP, 109 PP	HADS-A > 8	MoCA; SDMT	EDSS	High anxiety present in cognitive phenotype 2 with cognitive impairment of episodic memory and language disorders > RR (59.8%) or MS early stages.
Lozano-Soto 2020	99 RR	STAI	SDMT; PASAT; WLT (WMS-III); FT	EDSS, BDI-II	Disease duration, physical disability, and anxiety levels (anxiety “state”) significantly and negatively predicted performance on PASAT-3.
Whitehouse 2019	964: 255 with MS: 72.2% RR, 18.8% SP, 9% PP	HADS-A ≥ 11; SCID ≥ 9	CVLT-II; LNS (WMS-III); SDMT	WTAR	Higher self-reported anxiety symptoms associated with slower processing speed, lower working memory performance, and reduced verbal learning.
Vissicchio 2019	141 MS	HADS-A > 8	CVLT-II; SDMT	25-FWT	Bidirectional relationship/synergistic negative effect.
Marrie 2019	111: 91 RR, 12 SP, 6 PP, 2 other	HADS-A ≥ 11; SCID-IV ≥ 9	BICAMS; COWAT	EDSS, WTAR, VC, BMI	Current diagnosis of anxiety disorder or elevated anxiety symptoms (HADS-A score = 11), associated with reduced processing speed; elevated anxiety symptoms also associated with lower verbal learning and memory. Anxiety was associated with SDMT and CVLT-II.
Leavitt 2019	255: 185 RR < 5 years DD, 70 RR > 5 years DD	MHI	CANTAB PAL; BVMT-R; FT; Digit Span; Stroop; VPAL; SRT; NIH PC; SDMT	WTAR; T2LV; FSS, BDI-II; BDI-FS; NEO-N (NEO-FFI)	Lower anxiety was associated with better nonverbal memory/visuo-spatial memory.
Morrow 2016	151 RR	HADS-A > 8	MACFIMS	NART; FSS	Significant relationship was found with PASAT and VBMT-R.
Ribbons 2016	322: 258 RR, 43 SP, 21 PP	DASS-21	ARCS	EDSS	In combination with gender, age, and EDSS, anxiety explains 24% of the variance in memory.
Martin-Ramos 2015	60: 19 RR, 7 SP, 4 PP	STAI	PASAT; WCST; Stroop; TMT-B; COWAT; Block Test (WAIS-III)	EDSS	High level of trait anxiety predicts alterations in inhibition processes, phonological, and semantic verbal fluency, and solution of practical-constructive problems.
Goretti 2014	190 RR	STAI > 40	BRB-N; Stroop	FSS; EDSS	State anxiety was independently associated with lower performance on complex attention and processing speed.
Julian 2009	77: 48 RR, 20 SP, 9 PP	STAI	Visual Elevator (TEA); PASAT; oral SDMT; RST	SVT; CMDI; EDSS	State anxiety predicts performance in executive functioning index.
Kalron 2018	122 MS	HADS ≥ 8	Mindstreams //NSBMS	EDSS	Depressed people with MS with anxiety are nearly 4 times more likely to experience cognitive impairment compared with people with MS neither depressed nor anxious. Anxiety without depression is associated with a lower risk of falls.
Wallis 2019	119 MS	HADS-A ≥ 8	LDST/SDMT;CST/ WCST; GIT/ COWAT;VGLT/ CVLT; Faces (WMT)	EDSS; FSS; CFQ	Depression and cognitive impairment are strongly related to anxiety. No relationship was found between anxiety and cognitive functioning.
Cores 2017	97: 51 RR, 46 controls	STAI	BRB-N; Cóndor Task	EDSS; BDI-II; PRMQ	Significant and negative correlation of moderate degree between PRMQ-pros, STAI Trait, and BDI-II; anxiety and depression associated with prospective memory impairment (not MP objective performance).
Grech 2015	107: 83 RR, 24 PS	STAI	IGT; BADS; MSET; ECD (TEA); HSCT; TMT; WLG; RST; SDMT	EDSS; MMSE; DEX-S; DEX-I; BDI-II; MSQOL; DHS; RPVS	No relationship between objective cognitive measures and affect self-reported and informant-reported executive dysfunction was consistently predictive of greater depression, stress severity, trait anxiety, mental health, and quality of life.
van der Hiele 2012	114: 58 RR, 45 SP, 11 PP	HADS-A	RCFT; CVLT; TMT; SCWT; WCST; BADS; PASAT	NART; EDSS; 9HPT; DEX-S; DEX-I; HADS-D; EPCL; UCL	People with MS who underestimated their cognitive performance were characterized by more depression, anxiety, and psychosocial stress. Also more frequently showed the “revealing of emotions” coping style than accurate estimators and overestimators.
Akbar 2011	140: 73 RR, 25 SP, 10 PP	HADS-A > 8	BRB-N; MSNQ	NART; NEO-FFI; EDSS	Anxiety mediates the relationship between personality (neuroticism) and reported cognitive dysfunction. Anxiety significantly predicts perceived cognitive dysfunction.
Farrel 2011	101 MS	HADS	MSNQ		Significant correlation between anxiety, reported cognitive difficulties, and depression.
Bruce 2010	98: 71 RR, 8 SP	STAI	SDMT; WCST; Stroop; AVLT; LNS	EDSS; PRMQ; DES-II; NEO-FFI; BDI-FS	Self-reported memory problems were associated with more depression, anxiety, and neuroticism. The relationship between anxiety and self-reported memory was stronger than the relationship between depression and self-reported memory.
Visser 2009	708 MS	HADS; SCL-90-R	BADS; DEX	CERQ; DIP; FIS; AMS; UCL	Patients with cognitive difficulties presented more frequently with signs of depression, anxiety, fatigue, agoraphobia, somatic issues, sleep disturbances, and more disability compared with patients without cognitive impairment.
Olivares-Pérez 2009	100: 33 RR, 67 controls	HADS-A > 8	BRB-N; MSNQ	FSS; EDSS	Greater severity of anxious symptoms related to a shorter disease duration and lower educational level; anxiety and depression predict the perception of subjective cognitive impairment.
Bamer 2008	1271 MS	HADS	SF-8		Anxiety associated with thinking difficulties, higher depressive symptoms, more pain, more stress, more trouble sleeping, ambulating without a wheelchair, and in better health via SF-8.
Middleton 2006	128: 92 RR, 30 SP, 6 PP	HADS-A > 8	SDMT	EDSS; FSS	Depression was associated with greater fatigue and physical disability, less employment, lower processing speed. Depressive symptoms have more disabling impact on functional outcomes than anxiety symptoms.
Maia 2011	25 MS	HADS	LNNB	FACES-III	Higher prevalence of neuropsychological deficits were associated with higher incidence of depressive symptoms and family dissatisfaction.
Bruce 2009	95: 39 RR, 11 SP	PSWQ > 45; STAI 20-80	SILS; SRT; SDMT; Visual Elevator (TEA)	EDSS; FIS; BPI	Excessive worry was associated with increased anxiety, pain, fatigue, sleep disturbances, and problem-solving skills. Trait and state anxiety were significantly associated with depression. No significant relationships were found between anxiety and neuropsychological functioning.
Kostaras 2008	60 MS	STAI	SDMT	BDI	No correlation between anxiety and SDMT.
Korostil 2007	140 MS	HADS ≥ 10; SCID-IV	NSBMS	EDSS; BSS; SSSI	People with MS who have anxiety did not have more cognitive impairment than patients with MS who do not have anxiety.
van Ballegooijen 2022	165 RR	HADS-D ≥ 8	BRB-N	EDSS; MFIS	Depression ≥ 8 was significantly associated with a higher risk of low cognitive status.
Marrie 2020	962: 255 MS: 72.2% RR, 18.8% SP, 9% PP	HADS-A ≥ 11; SCID-IV	CVLT-II; LNS; SDMT	WTAR	At any point in time, individuals with elevated anxiety symptoms exhibited lower performance in processing speed, verbal learning, and working memory.
Skorve 2020	58 RR	HADS-A ≥ 8	BICAMS	FSMC ≥ 43	Correlations between HADS-A, FSMC, and BICAMS scores were not significant at baseline, but weak-to-moderate negative correlations were found at 1- and 2-year follow-up visits.
Podda 2020	608: 263 RR, 345 P	HADS	MoCA; PASAT; SDMT	EDSS; FIM; MFIS; LSI; OAB; ABILHAND	Lower educational level, RR course, clinically significant anxiety at baseline, and higher perception of depression and fatigue were significant predictors of clinically significant anxiety at 1-year follow-up. No relationship was found between cognitive functioning and clinically significant anxiety.
Olivares-Perez 2012	50: 6 CIS, 41 RR, 3 SP	HADS	BRB-N; MSNQ	FSS; MSQOL	Neuropsychological performance did not reveal significant correlations with anxiety or depression over time.
Christodoulou 2009	76: 28 RR, 10 SP	STAI; SCID	BRB-N; MACFIMS	EDSS; CES-D; CMDI; PANAS; AES; FSS	Baseline measures of negative affect (ie, depressed mood, state anxiety, and negative affect) tended to more strongly predict changes (25% of the variability) in cognitive measures of episodic verbal and visuospatial memory. Relationship between negative affect and cognition was not reciprocal.

Abbreviations: 9HPT, 9-Hole Peg Test; 25-FWT, 25-Foot Walk Test; AES, Apathy Evaluation Scale; AMS, Aging Males’ Symptoms; ARCS, Audio Recorded Cognitive Screen; AVLT, Auditory Verbal Learning Test; BADS, Behavioral Assessment of Dysexecutive Syndrome; BDI, Beck Depression Inventory; BDI-FS, Beck Depression Inventory, Fast Screen; BICAMS, Brief International Cognitive Assessment for Multiple Sclerosis; BMI, Body Mass Index; BPI, Brief Pain Inventory; BRB-N, Brief Repeatable Battery of Neuropsychological Tests for Multiple Sclerosis; BSS, Beck Suicide Scale; BVMT-R, Brief Visuospatial Memory Test-Revised; CANTAB PAL, Cambridge Neuropsychological Test Automated Battery Paired Associates Learning; CERQ, Cognitive Emotion Regulation Questionnaire; CES-D, Center for Epidemiologic Studies-Depression Scale; CFQ, Cognitive Failure Questionnaire; CIS, Clinically Isolated Syndrome; CMDI, Chicago Multiscale Depression Inventory; COWAT, Controlled Oral Word Association Test; CST, Concept Shifting Test; CVLT-II, California Verbal Learning Test-second edition; DASS-21, Depression Anxiety Stress Scales; DD, disease duration; DES-II, Dissociative Experiences Scale; DEX-I, Dysexecutive Questionnaire informant report; DEX-S, Dysexecutive Questionnaire self-report; DHS, Daily Hassles Scale; DIP, Disability Impact Profile; ECD, Elevator Counting with Distraction of the TEA; EDSS, Expanded Disability Status Scale; EPCL, Everyday Problem Checklist; ESS, Epworth Sleepiness Scale; FACES-III, Family Adaptability and Cohesion Evaluation Scale; FIM, Functional Independence Measure; FIS, Fatigue Impact Scale; FSMC, Fatigue Scale for Motor and Cognitive Functions; FSS, Fatigue Severity Scale; FT, Fluency Test; GIT, Groninger Intelligence Test; HADS, Hospital Anxiety and Depression Scale; HSCT, Hayling Sentence Completion Test; IGT, Iowa Gambling Task; LDST, Letter Digit Substitution Test; LNNB, Luria–Nebraska Neuropsychological Battery; LNS, Letter Number Sequencing; LSI, Life Satisfaction Index; MACFIMS, Minimal Assessment of Cognitive Function in Multiple Sclerosis; MADRS, Montgomery-Asberg Depression Rating Scale; MFIS, Modified Fatigue Impact Scale; MHI, Mental Health Inventory; MMSE, Mini Mental State Examination; MoCA, Montreal Cognitive Assessment; MS, multiple sclerosis; MSET, Modified Six Elements Task; MSNQ, Multiple Sclerosis Neuropsychological Questionnaire; MSQOL, MS Quality of Life; NART, North American Adult Reading Test; NEO-FFI, NEO Five-Factor Inventory; NEO-N, neuroticism scale of the NEO-FFI; NIH PC, National Institutes of Health Pattern Comparison test; NSBMS, Neuropsychological Screening Battery for MS; OAB, Overactive Bladder questionnaire; PANAS, Positive and Negative Affect Scale; PASAT, Paced Auditory Serial Addition Test; PP, primary progressive; PRMQ, Prospective and Retrospective Memory Questionnaire; PSQI, Pittsburgh Sleep Quality Index; PSWQ, Pennsylvania State Worry Questionnaire; RCFT, Rey Complex Figure Test; RPVS, Rosenbaum Pocket Vision; RR, relapsing-remitting; RST, Reading Span Task; SAS, Self-Rating Anxiety Scale; SCID-IV, Structured Clinical Interview for DSM-IV; SCL-90-R, Symptom Checklist 90-Revised; SCWT, Stroop Color Word Test; SDMT, Symbol Digit Modalities Test; SF-8, 8-item Short Form Health Survey; SILS, Shipley Institute of Living Scale; SP, secondary progressive; SRT, Selective Reminding Test; SSSI, Social Stress and Support Interview; STAI, State-Trait Anxiety Inventory; SVT, Shipley Vocabulary Test; T2LV, T2 lesion volume; TEA, Test of Everyday Attention; TMT-B, Trail Making Test-B; TOL, Tower of London; UCL, Utrecht Coping List; VC, vascular comorbidity; VGLT, Dutch version of California Verbal Learning Test; VPAL, Verbal Paired Associates Learning; WAIS-III, Wechsler Adult Intelligence Scale-third edition; WCST, Wisconsin Card Sorting Test; WLG, Word List Generation; WLT, word list test of the WMS-III; WMS-III, Wechsler Memory Scale-third edition; WMT, Wechsler Memory Test; WTAR, Wechsler Test of Adult Reading.