Content

Issues

Research

Permissions

Community Content

Videos and Multimedia

IJMSC Awards

Cover Art

For Authors

Information for Authors

Manuscript Submission

Patient Consent Form

About IJMSC

Aim and Scope

Ethics

Editorial Board

Peer Review

Contact Us

Home

Advertising

IJMSC

1rem

Authors

People with multiple sclerosis (MS) residing in rural regions in the United States, as well as globally, face similar barriers to accessing MS care and experience poorer disease outcomes. 

Unique Health Care Delivery Considerations in Rural America

Letter From the Guest Editor - Volume 24, Issue 6 - November 2022

People with multiple sclerosis (MS) frequently use cannabis to manage symptoms such as pain, spasticity, and sleep disturbance. During abstinence, withdrawal symptoms may overlap with MS-related complaints, complicating cessation. This study examined whether cannabis withdrawal trajectories differ by sex during monitored abstinence in people with MS.

Nineteen frequent cannabis users with MS (11 women) completed 28 days of monitored abstinence. Withdrawal symptoms were assessed using the Cannabis Withdrawal Questionnaire (CWQ) at baseline and weekly through day 28. Abstinence was verified using creatinine-adjusted urinary THC-COOH ratios. Mood was assessed using the Hospital Anxiety and Depression Scale (HADS) at baseline and day 28. A repeated-measures analysis of covariance examined time × sex effects, adjusting for demographic, disability, and cannabis-use covariates.

At baseline (preabstinence), women reported higher CWQ scores than men. On day 28, women again showed higher scores. A significant time × sex interaction (Pillai trace = .784; 

 = .018; partial η² = .784) indicated distinct symptom trajectories across abstinence. Women reported greater irritability, sleep disturbance, physical tension, nausea, and headaches. HADS scores remained stable and within normal limits for both sexes.

Women with MS demonstrated a more pronounced and sustained increase in CWQ symptom burden over the abstinence period than men. These findings likely reflect both withdrawal-related effects and the unmasking of underlying MS-related symptoms. Cannabis cessation appears psychologically tolerable in people with MS, though women may require closer monitoring and targeted support during abstinence.

This study was supported by a grant from the Multiple Sclerosis Society of Canada (EGID 2626).

 Cecilia Meza, MA, reports no competing interests. Anthony Feinstein, MD, reports grants from MS Canada; book royalties from Amadeus Press, Cambridge University Press, Glitterati Editions, and Johns Hopkins University Press; and speaker honoraria from Merck, Novartis, and Roche.

Individuals with chronic medical or psychiatric conditions may experience heightened or prolonged withdrawal symptoms.

 Multiple sclerosis (MS) is a chronic disease of the central nervous system associated with fatigue, sleep disturbance, mood instability, and cognitive impairment.

 Several of these features, particularly fatigue, sleep disruption, and mood changes, overlap with symptoms reported during cannabis withdrawal,

 potentially intensifying distress and complicating cessation.

In a study of 136 treatment-seeking but otherwise healthy cannabis users (45 women, 91 men), Herrmann et al

 found that women experienced greater and more persistent withdrawal symptoms than men despite comparable use patterns. Neurobiological evidence suggests that sex differences in the endocannabinoid system may contribute to greater withdrawal severity in women.

Despite consistent findings in the general population, sex-based differences in cannabis withdrawal have not been systematically examined in people with MS. To address this gap, we conducted a secondary analysis of frequent cannabis users with MS from an existing database to evaluate the severity and trajectory of withdrawal symptoms during 28 days of monitored abstinence. We hypothesized that women would report more severe and persistent symptoms than men. This study extends prior work in the same cohort,

 in which withdrawal symptoms were not a primary outcome, by examining withdrawal symptom trajectories longitudinally.

Nineteen frequent cannabis-using people with MS (11 women) were drawn from a previously published study examining the cognitive and neuroimaging effects of cannabis abstinence in MS.The parent cohort comprised 40 patients recruited from a tertiary MS clinic.

 Demographic and neurological variables included age, education, disease duration, and Expanded Disability Status Scale (EDSS) scores. Inclusion criteria required confirmed MS and frequent cannabis use (≥4 days per week) after disease onset.

The parent study employed a prospective, longitudinal, interventional design in which the users with MS were followed over a 28-day period and allocated to either a cannabis continuation or withdrawal condition using an odd-even allocation procedure. Participants underwent repeated cognitive and MRI assessments at baseline and day 28.

The present study is a secondary analysis of the withdrawal cohort (n = 19), comprising individuals who successfully completed 28 days of monitored abstinence. Only individuals with objective global cognitive impairment were included, resulting in a clinically selected sample. All participants were able to complete study procedures independently, suggesting sufficient functional capacity for reliable self-report despite the presence of cognitive impairment. This approach was used to enhance sensitivity in detecting meaningful change, as the inclusion of cognitively preserved individuals may introduce ceiling effects.

Cannabis-related data included frequency and duration of use, and average monthly consumption in grams. Cannabis use in the parent study was naturalistic and self-directed rather than prescribed or experimentally controlled.

 Cannabis was predominantly inhaled (smoked), consistent with both the parent study and self-reported use patterns in this sample, although formulation and potency were not systematically recorded. Urine analyses indicated predominantly tetrahydrocannabinol (THC) exposure. Creatinine-adjusted urinary cannabidiol (CBD) concentrations were also available but were not included in primary analyses due to their low levels and limited variability in this sample. The source of cannabis (medical vs recreational) was not formally controlled, reflecting real-world use patterns.

Urine samples were collected at baseline and weekly to verify abstinence using creatinine-adjusted THC-COOH ratios. Abstinence was confirmed at the individual participant level, with concentrations declining toward near-zero levels in all participants who completed the protocol. One participant with toxicological evidence of continued cannabis use was excluded. Creatinine normalization accounted for variability in urine concentration.⁸

Baseline Cannabis Withdrawal Questionnaire (CWQ)

scores were obtained before abstinence and therefore do not reflect cannabis withdrawal, but rather preabstinence symptom reporting. Cannabis withdrawal was assessed using the CWQat baseline and on days 7, 14, 21, and 28, with higher scores indicating greater withdrawal distress. Mood was evaluated using the Hospital Anxiety and Depression Scale (HADS)

 at baseline and day 28, with the Wechsler Test of Adult Reading (WTAR)

 administered only at baseline to estimate premorbid intelligence.

All participants gave written informed consent. The protocol was approved by the Sunnybrook Health Sciences Centre Research Ethics Board.

Data were screened for outliers and normality. Assumptions for repeated-measures analysis of covariance (ANCOVA) were verified. Group differences in demographic, item-level CWQ, and clinical variables between men and women were assessed with independent-samples 

The primary analysis was a repeated-measures ANCOVA investigating a putative time × sex interaction for CWQ total scores across the 28-day abstinence period, controlling for between-group demographic, clinical, and cannabis-use differences. Baseline CWQ was not included as a covariate because it reflected preabstinence MS-related symptoms rather than withdrawal and could obscure true between-participant differences. The Mauchly test indicated that the assumption of sphericity was violated; therefore, multivariate test statistics (ie, Pillai trace) were used for within-participant effects.

Secondary analyses included 1-way ANCOVAs comparing CWQ total scores between sexes at each time point. All analyses were conducted in IBM SPSS Statistics for Windows, version 29.0.

This study represents a secondary analysis and was not prospectively powered to detect sex differences; therefore, findings should be interpreted as exploratory.

Compared with women, men (n = 8) were older, had higher EDSS scores, and reported greater monthly cannabis use in grams (all 

 ≤ .050). Men also demonstrated higher WTAR scores (

 = .003). Creatinine-adjusted THC-COOH ratios declined steadily across days 7, 14, 21, and 28 for both sexes, confirming adherence to abstinence. HADS anxiety and depression scores remained within normal limits at baseline and day 28 and did not differ between men and women at either time point (all 

 ≥ .73), indicating overall mood stability (

At baseline (preabstinence), women reported higher CWQ symptom scores than men on several individual items, including difficulty falling asleep, early awakening, physical tension, nausea, restlessness, headaches, and imagining being stoned (all 

 < .05). Total CWQ scores were higher among women (52.36 ± 22.13) compared with men (24.00 ± 29.55; 

 = .033). By day 28, sex differences persisted and, in several domains, widened. Women reported significantly greater trouble sleeping, physical tension, irritability, nausea, stomachaches, headaches, and angry outbursts (all 

 < .05). Total CWQ scores remained statistically higher for women (79.36 ± 32.24) compared with men (40.00 ± 21.09; 

A repeated-measures ANCOVA examined change in CWQ total scores over the 28-day abstinence period as a function of sex, adjusting for between-group differences that included EDSS, age, monthly cannabis use (grams), WTAR, and THC-COOH/creatinine ratio. A significant main effect of time emerged (

 = .035; partial η² = .732). The time × sex interaction was also significant (

 = .018; partial η² = .784), indicating that withdrawal trajectories differed significantly between men and women across the abstinence period. A significant time × monthly cannabis use (grams) interaction was observed (F

 = .004; partial η² = .866), suggesting that heavier cannabis use predicted greater variability and change in withdrawal severity over time. A significant time × THC-COOH/creatinine ratio interaction was also observed (

Between-participant effects showed that sex did not significantly predict overall CWQ severity when averaged across time points (

 = .919), nor did any covariate significantly predict overall levels of withdrawal (all 

 > .15). This pattern indicates that sex differences were specific to the trajectory of withdrawal rather than absolute symptom levels averaged across all days (Table 3). Although differences were observed at specific time points (eg, baseline and day 28), these do not reflect a significant overall main effect of sex across the entire abstinence period.

Follow-up 1-way ANCOVAs comparing CWQ total scores at each time point revealed significant between-sex differences at both baseline (

 = .012), with women reporting higher CWQ symptom scores at both assessments. Baseline scores were obtained before abstinence. No significant sex differences were observed at days 7, 14, or 21 (all 

Our results suggest that sex influenced CWQ symptom trajectories during cannabis abstinence, with women showing a more pronounced and sustained increase in symptom burden than men.

Although men reported heavier cannabis use at baseline, consistent with epidemiological patterns of higher cannabis consumption among men,

 baseline THC/creatinine ratios did not differ significantly, indicating comparable physiological exposure before cessation. Because withdrawal had not yet begun at baseline, group differences in CWQ scores at this time likely reflected sex-related differences in MS symptom burden, such as sleep disturbance, fatigue, and physical tension, rather than withdrawal-specific effects.

These baseline differences represent a potential confound and limit causal interpretation of sex differences observed during abstinence. This limitation is particularly relevant given the cognitively impaired nature of the sample, which may influence both symptom perception and reporting. The CWQ may have limited specificity in people with MS, given the overlap with MS-related symptoms.

An alternative explanation for the observed trajectories is that cannabis cessation may have unmasked underlying MS-related symptoms rather than reflecting withdrawal alone. Differences from prior analyses of this cohort (Meza et al, 2024

) may be explained by the analytic approach. In that study, CWQ was included as a covariate, whereas in the present analysis it was treated as a primary longitudinal outcome, allowing trajectory-based differences to emerge. Minor numerical discrepancies reflect covariate-adjusted vs unadjusted estimates rather than differences in the underlying sample.

During abstinence, women showed higher CWQ scores at specific time points (eg, baseline and day 28) and a more sustained increase over time, which may reflect both withdrawal-related effects and greater underlying MS symptom burden, most notably irritability, sleep disturbance, physical tension, nausea, and headaches. These results parallel previous findings in people without MS, showing a more pronounced withdrawal trajectory among women.

 They also align with evidence that endocannabinoid signaling and CB

 receptor regulation are sexually dimorphic.

 Fluctuations in ovarian hormones, particularly estradiol, have been shown to modulate cannabinoid receptor sensitivity and endocannabinoid signaling.

 In people with MS, these hormonal effects may plausibly interact with neuroinflammatory and neuroendocrine alterations inherent to the disease, further shaping withdrawal expression.

Mood remained stable over the withdrawal period. HADS anxiety and depression scores were within normal limits and unchanged across time, and CWQ items related to depression were rarely endorsed. This pattern suggests that the distress items on the CWQ reported by women during abstinence were mild rather than indicative of clinical mood disturbance.

A significant main effect of time indicated that withdrawal severity changed across the 28-day abstinence period. However, the pattern of change was not uniform, as demonstrated by significant interactions between time, sex, and monthly cannabis use. Women exhibited a sustained increase across the 28-day period, whereas men demonstrated a more transient pattern. This contrasts with findings in people without MS, where withdrawal typically peaks early and resolves within 2 to 3 weeks.

 Ongoing neurological and somatic symptoms such as fatigue, sleep disturbance, and physical discomfort may obscure or prolong the subjective withdrawal experience, particularly for women with MS, who demonstrated a more pronounced pattern of withdrawal-related distress across abstinence. Heavier cannabis use was associated with greater variability in symptom change over time. Given the documented use of cannabis among people with MS, this variability may further complicate the interpretation of underlying neurological and somatic symptom burden.

Laboratory findings offer a mechanistic framework for these sex differences. Cooper and Haney

 reported that women demonstrate heightened subjective and physiological responses to cannabinoids when matched with men for dose and frequency, an effect attributed to hormonal modulation of the endocannabinoid system rather than metabolic factors. This enhanced responsivity may underlie the more pronounced withdrawal symptoms observed among women with MS in the present study.

Limitations include a modest sample size, potential selection bias given the predominance of relapsing-remitting MS, the absence of a healthy comparison group, and a follow-up period restricted to 28 days, which may not capture the full course of withdrawal in people with MS. In addition, detailed information regarding cannabis formulation (eg, edibles, tinctures, or potency) was not systematically collected, limiting precise characterization of pharmacological exposure.

Participants were restricted to individuals with objectively defined global cognitive impairment, resulting in a clinically selected sample. This may limit the generalizability of findings to cognitively preserved individuals with MS or to broader cannabis-using populations. Given that all participants had cognitive impairment, deficits in memory and attention may have introduced variability in self-reported withdrawal symptoms, potentially affecting reporting accuracy.

The CWQ may have limited specificity as a measure of cannabis withdrawal in people with MS, given the overlap with MS-related symptoms. This limitation may be further compounded by underlying cognitive impairment, and findings should therefore be interpreted as reflecting overlapping contributions of withdrawal and MS-related symptom expression.

Women with MS showed a more pronounced and sustained increase in CWQ symptom burden across the abstinence period. These findings likely reflect sex-specific differences in the interaction between cannabis cessation and underlying MS-related symptoms, rather than purely greater withdrawal severity. Withdrawal did not decline uniformly, with differences most evident early and late in abstinence. Depression and anxiety remained stable, suggesting cessation is psychologically tolerable despite a more sustained symptom burden in women. Tailored monitoring and sex-specific support may improve cessation success. Further research with larger samples and longer follow-up is needed to clarify mechanisms.

Because cannabis withdrawal symptoms overlap with common MS-related complaints, clinicians should differentiate among MS-related symptom fluctuations and effects associated with cannabis cessation when evaluating new or worsening symptoms.

Unequal Burden: Sex Differences in Cannabis Withdrawal Symptom Severity in People With  Multiple Sclerosis—A Short Report

 Balance impairments and cognitive deficits are both prevalent in individuals with multiple sclerosis (MS) and contribute to elevated fall risk. Although prior studies have examined global cognition and balance, few have investigated the relation between specific cognitive domains and balance performance under progressively challenging static conditions.

 Fifty-four ambulatory individuals with MS completed 4 standing balance tasks that increased in difficulty by altering visual input (eyes open/closed) and stance (feet apart/together). Sway velocity was measured using inertial sensors. Participants also completed assessments of processing speed (Symbol Digit Modalities Test [SDMT]), attention and cognitive flexibility (Trail Making Test parts A [TMT-A] and B), verbal and visuospatial memory (California Verbal Learning Test, Brief Visuospatial Memory Test-Revised), and concern about falling (Falls Efficacy Scale-International [FES-I]). Spearman correlations and linear regressions, adjusted for age, sex, and disability level, were used to examine associations between cognitive/psychological variables and balance performance.

 Processing speed (SDMT) was significantly associated with sway during the least complex condition (eyes open, feet apart). Under more challenging conditions (eyes closed), attention (TMT-A) and concern about falling (FES-I) emerged as significant predictors of balance performance. They remained significant after adjusting for disability level.

Domain-specific cognitive performance and concern about falling are associated with postural control in people with MS, particularly under sensory-conflicting conditions. These findings highlight the multifactorial nature of balance impairment in MS and suggest that cognitive and psychological assessments may aid in identifying individuals at increased fall risk.

The authors would like to thank all participants for taking part in this study.

 The authors have no financial or personal relationship that would inappropriately bias or influence their work.

This research was supported by a National Multiple Sclerosis Society research grant (RG-2111-38718), the National Multiple Sclerosis Society Mentor-Based Postdoctoral Fellowship in Rehabilitation Research (MB-2107-38295), and the National Institutes of Health (R21HD106133, F31HD116491).

Multiple sclerosis (MS) is a neurodegenerative disease characterized by axon demyelination in the central nervous system.

 Balance difficulties are among the most disabling symptoms of MS, affecting approximately 75% of individuals with MS.

 Balance impairments are a key contributor to fall risk in MS,

 with 56% of individuals with MS experiencing a fall in any 3 months and 37% classified as frequent fallers.

 Falls in MS can lead to physical injury,

 Importantly, these experiences often lead to increased concern about falling, reported by up to 60% of individuals with MS,

 and have been associated with motor impairment.

 Together, these findings underscore the need for a deeper understanding of balance dysfunction in people with MS.

In addition to motor impairments, cognitive deficits are common in MS and have been identified as significant risk factors for falls.

 In individuals with MS, declines in cognitive domains such as information processing, attention, and memory,

 which can impair everyday functioning and quality of life,

 have been noted. Prior research data have demonstrated that adding a cognitive task during postural assessments reduces balance performance in individuals with MS.

In addition, greater cognitive impairment has been linked to higher fall frequency and accelerated mobility decline.

Although these findings support an interaction between cognitive and balance function in people with MS, most studies have relied on simple balance assessments and global cognitive scores, limiting insight into how specific cognitive domains contribute to postural control. Although prior work has linked cognitive domains such as processing speed, attention, verbal function, and memory to static balance performance, many study designs have relied on relatively simple or low-demand balance assessments, such as quiet standing under eyes-open conditions or clinical balance tests that do not systematically manipulate sensory input or base of support.

 Conversely, studies that have employed more comprehensive or complex postural sway assessments, such as instrumented posturography involving sensory manipulation (eg, eyes closed, unstable surfaces) or dual-task paradigms, have often relied on global cognitive measures, limiting insight into domain-specific contributions.

 Thus, few studies have simultaneously examined the role of discrete cognitive domains in the context of complex or challenging balance tasks. Although previous research findings have established links between cognitive processes such as processing speed, immediate memory recall, visuospatial memory, and attention as well as more complex motor tasks such as backward walking and stair navigation,

 their specific associations with the complexity of standing balance assessments in MS remain poorly understood. Taken together, these gaps highlight the need for studies that simultaneously employ domain-specific cognitive measures and complex balance tasks to better characterize the interplay between cognition and postural control in MS.

Therefore, this study examines the associations between domain-specific cognitive functioning and standing balance in complex, sensory-conflicting balance conditions. Based on previous findings,

 we hypothesized that processing speed, visuospatial memory, and attention would be associated with balance performance and that stronger relationships would be observed with more complex balance tasks. Moreover, given the established link between concern about falling and impaired balance under increasingly complex conditions, we aimed to examine how concern about falling influences balance control across varying levels of postural challenge.

 By elucidating how distinct cognitive domains and fall-related concerns relate to postural control under different task demands, this study aims to deepen our understanding of cognitive-balance interactions in MS and inform more targeted fall-risk assessment and intervention strategies.

All study procedures were approved by the Wayne State University Institutional Review Board, and all participants provided informed consent before participation. Participants were recruited using convenience sampling methods through the Wayne State University MS Center, the local chapter of the National Multiple Sclerosis Society, and a laboratory registry of individuals with MS who had previously expressed interest in research participation. Participants were eligible to participate in the study if they were 18 years or older, were diagnosed with MS using the McDonald criteria,

 and reported a Patient-Determined Disease Steps (PDDS) score of 6 or less.

 Participants were excluded if they had experienced an MS relapse or exacerbation of symptoms within the past 30 days, had a comorbid neurological disorder or another condition that would impact their motor or cognitive function, or were unable to comprehend and follow study commands.

All balance and cognitive assessments were completed in a single testing session. Via REDCap, participants completed a series of surveys, which included demographic information (eg, age, sex, height, weight) and clinical history, such as disease severity (PDDS) and symptom duration. Cognitive and balance assessments were administered as well as the Falls Efficacy Scale-International (FES-I), a validated measure of concern about falling during everyday activities.

 To ensure safety, participants wore a gait belt and were continuously supervised by trained research staff during all balance assessments. To minimize fatigue, participants were offered seated rest breaks between balance trials and conditions, and rest duration was individualized based on participant need.

Participants completed 4 different balance conditions: eyes open with feet apart (EOFA), eyes open with feet together (EOFT), eyes closed with feet apart (ECFA), and eyes closed with feet together (ECFT). Each condition was performed twice for 30 seconds, and sway measures were averaged across trials. During testing, participants stood with arms crossed over their chest, facing a fixed visual target at eye level. For feet-apart trials, feet were placed shoulder-width apart; for feet-together trials, feet were placed as close together as possible. These balance conditions were designed to progressively challenge postural control by manipulating visual input and base of support, 2 key contributors to balance regulation.

 Prior studies have used similar modifications to assess balance in older adults and individuals with neurological disorders.

Participants completed a battery of standardized cognitive assessments. The Symbol Digit Modalities Test (SDMT) assesses information processing speed by asking participants to match symbols with numbers for 90 seconds. The SDMT was presented orally, and the number of correct responses within the time frame was used in the analysis.

 The Brief Visuospatial Memory Test-Revised (BVMT-R) tested visuospatial memory.

 Participants viewed a 2×3 matrix of 6 shapes for 10 seconds, which was then removed. They were then asked to recall and draw the shapes in their exact layout as accurately as possible. Immediate recall was calculated as the number of correct responses across 3 trials. The California Verbal Learning Test (CVLT) measures auditory-verbal learning and memory.

 Participants listened to and freely recalled a list of 16 items read aloud; this was repeated 5 times. The total number of correct responses across the 5 trials was used in the analysis. Finally, the Trail Making Test (TMT) parts A and B assessed attention and cognitive flexibility.

 For TMT-A, participants connected numbers in ascending numerical order from 1 to 25; for TMT-B, participants connected numbers 1 to 12 and letters from A to L in ascending numerical and alphabetical order. The time taken to complete each assessment was used in the analysis. These domains were selected based on their relevance to MS-related cognitive decline and prior associations with complex motor tasks such as backward walking and stair navigation.

Participants were equipped with wireless Opal inertial sensors (128 Hz; APDM), and quantitative balance measures were obtained via Mobility Lab’s instrumented test of postural sway (ISway) protocol.

 The ISway algorithm automatically generates sway measures in the time and frequency domains using the triaxial accelerometer from the lumbar sensor. Additional protocol details, as well as the validity and sensitivity of this approach, are described by Mancini et al.

 Sway velocity was defined as the mean resultant sway velocity across the 30-second recording, calculated automatically by the Mobility Lab ISway algorithm from lumbar triaxial accelerometry data. This metric reflects the combined anterior-posterior and mediolateral components of postural sway.

 All participants were able to stand independently without assistive devices during testing. No trials were terminated early, and all participants completed the full 30-second duration across conditions. For safety purposes, participants wore a gait belt and were supervised by trained research staff; however, no physical assistance was provided during data collection.

All survey, balance, and cognitive outcomes are presented as mean (SD) unless otherwise noted. To assess normality of data, skewness and kurtosis values were examined. Given the nonnormality of all balance assessments (EOFA, EOFT, ECFA, ECFT), Spearman ρ was used to examine the correlations between sway velocity under all 4 balance conditions and cognitive outcomes and concern about falling. Next, a linear regression with backward selection was used to identify variables that significantly explain variance in balance performance under all 4 balance conditions. Only variables demonstrating significant associations with sway velocity within each condition were entered into the corresponding regression model to support parsimonious estimation. Variables were removed one at a time until all included variables were deemed significant predictors of the dependent variable (

 .05). All linear regression models were corrected for age, sex, and PDDS. Height was examined as a potential anthropometric confound by testing Spearman correlations with sway velocity across all balance conditions. Height was not significantly associated with sway velocity in any condition (all 

 > .15); therefore, height was not included as a covariate in subsequent regression models. To assess potential multicollinearity among predictors, variance inflation factors (VIF) and tolerance values were examined for all final regression models. VIF values ranged from 1.02 to 1.69, indicating no evidence of multicollinearity. All data analyses were performed in SPSS version 29.0 (IBM Corp).

A convenience sample of 54 participants was included in the study. 

 provides an overview of the demographic and clinical characteristics of the sample. Participants had an average (± SD) age of 50.96 (±11.56) years, ranging from 31 to 74 years. Ambulation disability, as interpreted by PDDS, ranged from 0 to 6, with a median of 2, indicating mild to moderate walking impairment.

presents the results of the correlation analyses for all balance conditions. In the eyes-open conditions, feet-apart (EOFA) balance showed a significant negative correlation with the SDMT (ρ = –.29; 

 = .04) whereas no variable tested had a significant correlation with feet together (EOFT; all 

 > .05). In the eyes-closed conditions, feet apart (ECFA) had a significant positive association with TMT-A (ρ = .42; 

 = .01) and a significant negative association with SDMT (ρ = –.43; 

 = .02). For the feet-together condition (ECFT), a significant positive association was observed with PDDS (ρ = .27; 

 .01) whereas a significant negative association was observed with SDMT (ρ = –.38; 

 .01). No significant associations were observed between sway velocity and verbal memory (CVLT) in any balance condition (all 

 > .05). Visuospatial memory (BVMT-R) and executive function (TMT-B) were associated with sway only in the ECFA condition and did not demonstrate consistent relationships across other balance tasks.

Results of backward linear regression for EOFA, ECFA, and ECFT analyses after correction for age, sex, and PDDS are presented in 

. As no significant correlations were observed for EOFT, no regression analysis was conducted. For EOFA, SDMT remained independently associated with sway velocity (β = −.34; 

 = .03). For ECFA, the final model included TMT-A (β = .37; 

 = .04), with TMT-A demonstrating the strongest association based on standardized β coefficients. For ECFT, FES-I demonstrated a strong independent association with sway velocity (β = .51; 

 < .01) after correcting for age, sex, and PDDS.

This study aimed to examine how domain-specific cognitive functioning relates to standing balance performance under increasingly challenging, sensory-conflicting conditions in individuals with MS. Although findings from prior studies have shown associations between global cognition and balance,

 few have systematically assessed how distinct cognitive domains relate to static balance, particularly under conditions that manipulate base of support and visual input. Our findings demonstrate that cognitive performance, particularly in processing speed (SDMT) and attention (TMT), is associated with postural control and that the pattern of independent associations varies depending on the level of sensory and postural challenge. Notably, concern about falling also emerged as an independent predictor of balance performance under the most demanding conditions. Examination of standardized β coefficients further suggested a shift in the strongest independent associations across increasing task demands, with processing speed showing the strongest association under low-demand conditions, attention under moderate sensory challenge, and concern about falling under the most demanding postural condition. These results underscore the importance of integrating both cognitive and psychological screening into fall-risk assessments for individuals with MS.

The relation between cognition and balance performance in individuals with MS has been well-documented, but often in studies using less challenging tasks or global cognitive composites. In line with recent work by Kalron et al, which demonstrated associations between static posturography and executive, verbal, and memory domains in individuals with MS,

 our findings further support the presence of domain-specific cognition-balance relationships. However, the pattern of domains observed in the current study differed somewhat, with processing speed and attention emerging as the most consistent contributors. These differences likely reflect variations in task design and sample characteristics. Whereas prior studies examined static balance without systematically manipulating sensory demands, our progressively challenging conditions (altering visual input and base of support) may have more selectively taxed attentional control and sensory integration processes. In this context, attention appeared to play a more prominent role, particularly under eyes-closed conditions where reliance on nonvisual sensory systems increases. Consistent with this interpretation, sway during the least complex condition (EOFA) was associated with processing speed (SDMT), suggesting that efficient cognitive processing supports postural stability when sensory input is fully available. As task demands increased, particularly with removal of visual input, attention-based performance (TMT-A) became more strongly associated with sway. These findings extend the work of Perrochon et al, who also observed stronger cognition-balance relations under unstable surface conditions, particularly involving working memory and executive function.

 Our study builds on that work by using systematically manipulated, progressively challenging static balance conditions, allowing for clearer insight into how specific cognitive domains dominate as task demands increase.

Notably, we did not observe significant associations between standing balance performance and memory measures (CVLT, BVMT-R), nor did executive function as assessed by TMT-B emerge as an independent predictor. The absence of memory associations aligns with meta-analytic findings in older adults without MS, demonstrating limited relationships between episodic or visuospatial memory and static balance, with stronger effects observed for dynamic or dual-task conditions.

 Although executive functions have been linked to balance in findings from prior studies, these associations appear more robust for dynamic or cognitively loaded motor tasks than for quiet standing. TMT-B primarily indexes set shifting, which may be less engaged during constrained static postural tasks. In MS, impairments in processing speed and complex attention are more prominent at the group level than executive dysfunction,

 and task-switching research suggests greater difficulty maintaining attentional sets than switching.

 Together, these findings suggest that static balance in MS may rely more heavily on attentional capacity and processing efficiency than on memory or executive set-shifting.

This pattern also highlights potential differences in task-specific cognitive control between static and dynamic motor behaviors. Static standing primarily requires sustained attention and sensory integration to maintain postural stability within a relatively constrained motor framework. In contrast, dynamic mobility tasks such as gait and backward walking demand continuous motor adaptation, anticipatory control, and flexible cognitive engagement. Consistent with this distinction, prior findings in studies of people with MS have shown that executive functions, visuospatial memory, and higher-order cognitive control processes are more strongly associated with dynamic tasks, including backward walking and gait adaptability, than with quiet standing.

 For example, recent data have shown that attention, visuospatial memory, and executive function are linked to backward walking performance in individuals with MS.

 As a more complex gait task, backward walking imposes greater cognitive and sensory integration demands compared with forward walking.

 A recent systematic review identified processing speed as uniquely associated with laboratory-based mobility measures,

 whereas another study highlighted the relationship between processing speed, fear of falling, and real-world mobility outcomes.

 Additionally, processing speed and immediate memory recall were found to be associated with backward walking speed modulation, a key marker of gait adaptability and complexity.

 Together, these findings underscore the critical role of cognitive resources in maintaining balance as motor tasks become more complex, whether dynamic (eg, backward walking) or static (eg, eyes closed with a narrow base).

An additional and important finding from this study was the contribution of concern about falling, particularly under eyes-closed conditions. Concern about falling was a significant predictor of sway in both eyes-closed conditions, even after adjusting for ambulation disability (PDDS). Neuroimaging findings complement these results, showing that heightened concern about falling is associated with lower volumes in visual processing brain regions.

 When visual input is removed, reliance on proprioceptive and vestibular systems increases, and heightened concern or anxiety may further impair balance performance. This aligns with theoretical models demonstrating that postural threat increases sway amplitude due to anxiety-induced shifts in attentional focus and motor stiffening.

 Recent work offers further insight, proposing that low perceived control over balance, such as in situations without visual feedback, amplifies threat perception that disrupts automatic balance control.

 Moreover, concern about falling can trigger defensive responses such as rigidity and hypervigilance, which may destabilize posture in complex sensory contexts.

 Our findings support this idea in people with MS, suggesting that concern-related attentional shifts or fear-driven rigidity may partially explain postural instability in challenging sensory contexts.

Our data are consistent with recent MS-specific research, indicating that concern about falling and avoidance behavior are closely linked to dynamic balance dysfunction, mobility limitations, and cognitive load.

 A recent scoping review further emphasized the multifactorial nature of fall risk in people with MS, as psychological concerns interact with physical and cognitive deficits.

 Similarly, data from a systematic review support this association, describing a vicious cycle in which concern about falling contributes to worsening gait, balance deficits, fatigue, and cognitive impairments, each of which, in turn, increases fall risk.

 Collectively, these results suggest a multifactorial destabilization mechanism in people with MS, where cognitive processing demands, sensory integration deficits, and psychological factors, such as concern about falling, interact in complex ways to influence balance performance.

In addition, balance impairments in MS are multifactorial and may be influenced by musculoskeletal and sensorimotor factors, including muscle weakness, spasticity, altered lower-limb biomechanics, and impaired proprioception.

 These physical contributors are well-established determinants of postural instability and likely play an important role in static balance performance, particularly under conditions that increase reliance on somatosensory input.

 Although PDDS was included as a measure of ambulatory disability, we did not directly assess specific neuromuscular or proprioceptive impairments. The present study was designed to isolate domain-specific cognitive and psychological contributions to balance performance; however, these findings should be interpreted within the broader context of multifactorial balance dysfunction in MS. Future studies incorporating comprehensive biomechanical, sensory, and cognitive assessments will be important to more fully characterize the interactive contributions of motor, sensory, and cognitive systems to postural control.

This study should be interpreted in light of several limitations. First, the sample size was modest, which may limit the generalizability of findings. Further, although MS subtype was recorded, the sample was predominantly relapsing-remitting, with limited representation of progressive phenotypes. Future studies with larger and more balanced subtype representation are needed to determine whether MS disease course moderates cognitive-balance associations. Second, the cross-sectional design precludes any conclusions about causality or directionality between cognitive function, concern about falling, and balance performance. Third, only static balance assessments were included; dynamic balance and dual-task paradigms, which may elicit stronger cognitive-motor interactions, were not examined. Additionally, balance conditions were administered in a fixed order that progressed from less to more challenging tasks. Although this approach prioritized safety and standardized task exposure, it may have introduced potential order effects. Future studies employing randomized condition order may help further isolate task-specific cognitive-balance associations. Finally, participants were relatively homogeneous in age and disability status (PDDS score ≤ 6), which may limit insight into how these associations manifest in older adults with MS or those with more advanced functional impairments, as both may experience additional age-related changes in postural control and cognition.

Findings from this study provide novel evidence that specific cognitive domains, particularly processing speed and attention, are associated with postural control in individuals with MS and that these associations become more pronounced under sensory-conflicting balance conditions. In addition, concern about falling independently contributed to sway performance in more challenging tasks, highlighting the interplay between psychological and cognitive factors in balance regulation. Clinically, these findings suggest that incorporating brief cognitive assessments (eg, SDMT, TMT) and measures of concern about falling (eg, FES-I) may aid in identifying individuals with MS who are at increased risk of balance impairment, particularly under more challenging conditions. Although further research is needed, rehabilitation strategies that address cognitive, psychological, and motor factors in tandem may offer added value for fall-risk management in MS.

Cognitive and psychological factors may contribute to balance performance and could be considered when interpreting fall risk in clinical assessments.

Domain-Specific Cognitive Associations With Standing Balance in Multiple Sclerosis

Health-related quality of life (HRQOL) is a key health outcome and often compromised in people with multiple sclerosis (MS). Yet the associations between symptoms and HRQOL across racial subgroups remain unclear. To that end, this cross-sectional, comparative study examined symptoms as correlates of HRQOL in Black and White individuals with MS.

Black (n = 136) and White (n = 273) individuals with MS completed an online survey assessing walking impairment (12-Item Multiple Sclerosis Walking Scale [MSWS-12]), fatigue (Fatigue Severity Scale [FSS]); depression and anxiety (Hospital Anxiety and Depression Scale [HADS-A and HADSD]); and HRQOL (12-Item Short Form Survey Physical and Mental). Bivariate correlations and stepwise linear regression were performed to identify associations between symptoms and HRQOL.

MSWS-12, FSS, and HADS-D were significantly associated with physical HRQOL, and HADS-A, HADS-D, and FSS were significantly associated with mental HRQOL within both groups: Black (

 < .01) individuals with MS. Regression analyses identified MSWS-12 and FSS as significant correlates of physical HRQOL in both groups (

 < .05) after controlling for age and household income. For mental HRQOL, HADS-A and HADS-D were significant correlates among White participants (

 < .05), whereas HADS-A was the only significant correlate among Black participants (

 < .01) after controlling for age and disease duration.

Our findings highlight symptoms, including walking impairment, fatigue, anxiety, and depression, as correlates of HRQOL among Black and White individuals with MS and may inform intervention development that targets the symptoms to improve HRQOL across racial groups.

We would like to express our gratitude to the individuals who participated in this study. We further thank the National MS Society and other collaborators for assistance with the recruitment process.

 The authors have reported no relevant disclosures.

Research reported in this publication was supported in part by the National Heart, Lung, and Blood Institute (T32HL134634), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD113333), and the National Cancer Institute (1F31CA295016-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Multiple sclerosis (MS) is a debilitating, immune-mediated neurodegenerative disease with a prevalence of approximately 1 million adults in the United States.

The management of walking impairment and fatigue may be appropriate for improving physical health-related quality of life among Black and
White people with multiple sclerosis.

Marisa McGinley, DO

Articles

Latest Updated Articles