Variability in the analysis of a single neuroimaging dataset by many teams.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2-5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.

Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024.

Reward enhances connectivity between the ventral striatum and the default mode network.

The default mode network (DMN) has been theorized to participate in a range of social, cognitive, and affective functions. Yet, previous accounts do not consider how the DMN contributes to other brain regions depending on psychological context, thus rendering our understanding of DMN function incomplete. We addressed this gap by applying a novel network-based psychophysiological interaction (nPPI) analysis to the reward task within the Human Connectome Project. We first focused on the task-evoked responses of the DMN and other networks involving the prefrontal cortex, including the executive control network (salience network) and the left and right frontoparietal networks. Consistent with a host of prior studies, the DMN exhibited a relative decrease in activation during the task, while the other networks exhibited a relative increase during the task. Next, we used nPPI analyses to assess whether these networks exhibit task-dependent changes in connectivity with other brain regions. Strikingly, we found that the experience of reward enhances task-dependent connectivity between the DMN and the ventral striatum, an effect that was specific to the DMN. Surprisingly, the strength of DMN-VS connectivity was correlated with personality characteristics relating to openness. Taken together, these results advance models of DMN by demonstrating how it contributes to other brain systems during task performance and how those contributions relate to individual differences.

Modulation of Metacognitive Confidence Judgments Through Provision of Performance Feedback in Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) may result in metacognitive impairments. Enhancing memory in healthy adults can improve metacognitive accuracy, but it is unclear whether such interventions apply to individuals with TBI. This study examined the effects of manipulating target memory experiences on metacognitive accuracy in TBI. PARTICIPANTS: Fourteen community-dwelling adults with TBI and 17 healthy controls. MAIN MEASURES: Memory was manipulated through performance feedback (monetary, nonmonetary, or none) presented during a word-pair learning task. Recognition of the word pairs was assessed, and metacognition was evaluated by retrospective confidence judgments. RESULTS: Both groups demonstrated greater recognition performance for items learned with nonmonetary feedback. Healthy individuals demonstrated improved metacognitive accuracy for items learned with nonmonetary feedback, but this effect was not seen in individuals with TBI. A notable (but statistically nonsignificant) effect was observed whereby adults with TBI overestimated performance for items learned with monetary feedback compared with other feedback conditions. CONCLUSION: Provision of feedback during learning enhances recognition performance. However, target memory experiences may be utilized differently after injury to facilitate confidence judgments. In addition, the type of feedback provided may have different effects on metacognitive accuracy. These results have implications for rehabilitative efforts in the area of memory and metacognition after injury.

Corticostriatal Hyperactivation to Reward Presentation in Individuals With TBI With High Depressive Symptomatology: A Pilot Study.

OBJECTIVE: To examine the impact of depression on neural mechanisms associated with outcome processing (rewarding and punishing outcomes) in persons with traumatic brain injury (TBI). SETTING: Kessler Foundation's Rocco Ortenzio Neuroimaging Center. PARTICIPANTS: A total of 16 adults with moderate to severe TBI. MAIN MEASURES: Chicago Multiscale Depression Inventory (CMDI); Behavioral Inhibition/Behavioral Activation Scale (BIS/BAS); functional MRI of the head while performing a gambling task, with a reward (+$1.00) and punishment (-$0.50). RESULTS: Individuals with TBI reporting high depressive symptomatology exhibited increased activation in the ventromedial prefrontal cortex (VMPFC) and striatum during presentation of rewarding outcomes compared with individuals with TBI reporting low depressive symptomatology. Punishing outcome presentation was not associated with any change in brain activation. No differences in volume of the striatum and VMPFC were observed between groups. CONCLUSIONS: Current findings provide the first evidence of differences in neural mechanisms underlying outcome processing between individuals with TBI with and without depression. The results suggest that depressive symptomatology might have a different effect on individuals with TBI than what is typically observed in individuals without TBI reporting with depression, with the possibility of rewards becoming more reinforcing as depressive symptomatology increases. Future studies should explore the potential implications of behavioral responses to rewards and punishments in TBI and how they can affect rehabilitation approaches and activities of daily living.

Fronto-striatal network activation leads to less fatigue in multiple sclerosis.

BACKGROUND: The fronto-striatal network has been implicated in both fatigue, a common multiple sclerosis (MS) symptom, and goal attainment, which has been shown to reduce fatigue in healthy individuals. OBJECTIVES: To investigate whether stimulation of the fronto-striatal network through goal attainment (potential monetary gain) leads to fatigue reduction in MS and healthy control (HC) participants. METHODS: In all, 14 healthy and 19 MS participants performed a gambling task during functional magnetic resonance imaging (fMRI). Participants were presented with an opportunity to receive monetary reward during the outcome condition of the task but not during the no outcome condition. Self-reported fatigue measures were obtained after each condition and outside of the scanner. Structural alterations were also examined. RESULTS: A significant decrease in fatigue was observed after the outcome condition compared to the no outcome condition in both groups. Significantly greater activation was observed in the ventral striatum in association with the outcome condition compared to the no outcome condition in both groups. Ventromedial prefrontal cortex showed significantly greater activation during the no outcome condition compared to the outcome condition with greater difference between conditions in the HC group. CONCLUSION: This is the first functional neuroimaging study showing that stimulation of the fronto-striatal network through goal attainment leads to decreased on-task fatigue in MS and healthy participants.

Modulation of ventral striatal activity by cognitive effort.

Effort discounting theory suggests that the value of a reward should be lower if it was effortful to obtain, whereas contrast theory suggests that the contrast between the costly effort and the reward makes the reward seem more valuable. To test these alternative hypotheses, we used functional magnetic resonance imaging (fMRI) as participants engaged in feedback-based learning that required low or high cognitive effort to obtain positive feedback, while the objective amount of information provided by feedback remained constant. In the low effort condition, a single image was presented with four response options. In the high effort condition, two images were presented, each with two response options, and correct feedback was presented only when participants responded correctly to both of the images. Accuracy was significantly lower for the high effort condition, and all participants reported that the high effort condition was more difficult. A region of the ventral striatum selected for sensitivity to feedback value also showed increased activation to feedback presentation associated with the high effort condition relative to the low effort condition, when controlling for activation from corresponding control conditions where feedback was random. These results suggest that increased cognitive effort produces corresponding increases in positive feedback-related ventral striatum activity, in line with the predictions made by contrast theory. The accomplishment of obtaining a hard-earned intrinsic reward, such as positive feedback, may be particularly likely to promote reward-related brain activity.

Altered neural mechanisms of cognitive control in patients with primary progressive multiple sclerosis: An effective connectivity study.

Primary progressive multiple sclerosis (PPMS) leads to physical and cognitive disability. Specifically, cognitive deficits in PPMS have been explained by both grey matter atrophy and white matter lesions. However, existing research still lacks in the understanding of how the brain of a patient with PPMS functions under cognitive control demands. Thus, the aim of the current study was to examine information integration in patients with PPMS using a search-based effective connectivity method. Fourteen patients with PPMS and 22 age- and gender-matched healthy controls (HC) performed the Stroop task, a cognitively demanding interference task that taxes neural resources required for cognitive control and response inhibition. Results showed that compared to HC, PPMS patients exhibited poor behavioral performance and alterations in information flow, manifested in the form of the loss of top-down connections, reversal of connections, and hyperconnectivity. Significant correlations were observed between connection strengths and behavioral measures. The connection between the posterior parietal cortex (PCC) and left posterior parietal lobule, which was present in both groups, showed a negative correlation with performance accuracy on incongruent trials. The connection between the left dorsolateral prefrontal cortex and PCC showed a positive correlation with performance accuracy on incongruent trials. However, the adaptive nature of this connection was not significant on a behavioral level as the PPMS group performed significantly worse compared to the HC group during the Stroop task. Thus, the current study provides important evidence about effective connectivity patterns that can be characterized as maladaptive cerebral re-organization in the PPMS brain. Hum Brain Mapp 38:2580-2588, 2017. © 2017 Wiley Periodicals, Inc.

Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study.

The Stroop interference task is a cognitively demanding task of executive control, a cognitive ability that is often impaired in patients with multiple sclerosis (MS). The aim of this study was to compare effective connectivity patterns within a network of brain regions involved in the Stroop task performance between MS patients with three disease clinical phenotypes [relapsing-remitting (RRMS), benign (BMS), and secondary progressive (SPMS)] and healthy subjects. Effective connectivity analysis was performed on Stroop task data using a novel method based on causal Bayes networks. Compared with controls, MS phenotypes were slower at performing the task and had reduced performance accuracy during incongruent trials that required increased cognitive control. MS phenotypes also exhibited connectivity abnormalities reflected as weaker shared connections, presence of extra connections (i.e., connections absent in the HC connectivity pattern), connection reversal, and loss. In SPMS and the BMS groups but not in the RRMS group, extra connections were associated with deficits in the Stroop task performance. In the BMS group, the response time associated with correct responses during the congruent condition showed a positive correlation with the left posterior parietal → dorsal anterior cingulate connection. In the SPMS group, performance accuracy during the congruent condition showed a negative correlation with the right insula → left insula connection. No associations between extra connections and behavioral performance measures were observed in the RRMS group. These results suggest that, depending on the phenotype, patients with MS use different strategies when cognitive control demands are high and rely on different network connections. Hum Brain Mapp, 37:2293-2304, 2016. © 2016 Wiley Periodicals, Inc.

Examining the Efficacy of the Modified Story Memory Technique (mSMT) in Persons With TBI Using Functional Magnetic Resonance Imaging (fMRI): The TBI-MEM Trial.

BACKGROUND: New learning and memory deficits are common following traumatic brain injury (TBI). Yet few studies have examined the efficacy of memory retraining in TBI through the most methodologically vigorous randomized clinical trial. Our previous research has demonstrated that the modified Story Memory Technique (mSMT) significantly improves new learning and memory in multiple sclerosis. METHODOLOGY: The present double-blind, placebo-controlled, randomized clinical trial examined changes in cerebral activation on functional magnetic resonance imaging following mSMT treatment in persons with TBI. Eighteen individuals with TBI were randomly assigned to treatment (n = 9) or placebo (n = 9) groups. RESULTS: Baseline and follow-up functional magnetic resonance imaging was collected during a list-learning task. Significant differences in cerebral activation from before to after treatment were noted in regions belonging to the default mode network and executive control network in the treatment group only. Results are interpreted in light of these networks. CONCLUSIONS: Activation differences between the groups likely reflect increased use of strategies taught during treatment. This study demonstrates a significant change in cerebral activation resulting from the mSMT in a TBI sample. Findings are consistent with previous work in multiple sclerosis. Behavioral interventions can show significant changes in the brain, validating clinical utility.

Effect of methylphenidate on oculomotor function in individuals with multiple sclerosis: a pilot randomized placebo-controlled trial.

Introduction: Individuals with multiple sclerosis (MS) frequently experience visual and oculomotor symptoms that may impact and confound neuropsychological assessments of information processing speed (IPS). In this study, we examined the effect of the psychostimulant methylphenidate on oculomotor function and the association between change in oculomotor speed and change in information processing speed. Methods: We used a repeated measures crossover design in which a sample of 11 participants with MS were randomly assigned to one of two treatment arms: one that received methylphenidate for 4 weeks and another that received a placebo for 4 weeks. After a 7-day washout period, the treatments were crossed over. The King Devick test, the Symbol Digit Modalities Test, and the Paced Auditory Serial Addition Test were administered at baseline and after each of the two study arms. Results: We found a significant improvement in oculomotor speed in the methylphenidate condition as compared to placebo. This improvement was significantly correlated with improvement on a visuomotor assessment of IPS (Symbol Digit Modalities Test), but no such association was found for an auditory-verbal assessment of IPS (Paced Auditory Serial Addition Test). Discussion: These findings suggest that individuals with MS experience improved oculomotor speed while taking methylphenidate, which may, in turn, improve performance on assessments of IPS with visuomotor demands.

ENIGMA's simple seven: Recommendations to enhance the reproducibility of resting-state fMRI in traumatic brain injury.

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field.

Basal ganglia engagement during feedback processing after a substantial delay.

The striatum has been shown to play an important role in learning from performance-related feedback that is presented shortly after each response. However, less is known about the neural mechanisms supporting learning from feedback that is substantially delayed from the original response. Since the consequences of one's actions often do not become known until after a delay, it is important to understand whether delayed feedback can produce neural responses similar to those elicited by immediate-feedback presentation. We investigated this issue by using functional magnetic resonance imaging (fMRI) as participants performed a paired-associate learning task with 180 distinct trials. Feedback indicating response accuracy was presented immediately, after a delay of 25 min, or not at all. Both immediate and delayed feedback led to significant gains in accuracy on a posttest, relative to no feedback. Replicating previous work, we found that the caudate nuclei showed greater activation for positive feedback than for negative feedback when the feedback was presented immediately. In addition, delayed feedback also led to differential caudate activity to positive versus negative feedback. Delayed negative feedback also produced significant activation of the putamen and globus pallidus (the lentiform nucleus), relative to no feedback and delayed positive feedback. This suggests that the caudate nucleus is sensitive to the affective nature of feedback, across different time scales, while the lentiform nucleus may be particularly involved in processing the information carried by negative feedback after a substantial delay.

Neural correlates of cognitive fatigue: cortico-striatal circuitry and effort-reward imbalance.

Recently, there has been renewed interest in the study of cognitive fatigue. It is known that fatigue is one of the most disabling symptoms in numerous neurological populations, including stroke, multiple sclerosis, Parkinson's disease, and traumatic brain injury. Behavioral studies of cognitive fatigue are hampered by lack of correlation of self-report measures with objective performance. Neuroimaging studies provide new insight about cognitive fatigue and its neural correlates.Impairment within the cortico-striatal network, involved in effort­reward calculation, has been suggested to be critically related to fatigue. The current review surveys the recent neuroimaging literature, and suggests promising avenues for future research.

ALFF response interaction with learning during feedback in individuals with multiple sclerosis.

Amplitude of low-frequency fluctuations (ALFF) is defined as changes of BOLD signal during resting state (RS) brain activity. Previous studies identified differences in RS activation between healthy and multiple sclerosis (MS) participants. However, no research has investigated the relationship between ALFF and learning in MS. We thus examine this here. Twenty-five MS and nineteen healthy participants performed a paired-associate word learning task where participants were presented with extrinsic or intrinsic performance feedback. Compared to healthy participants, MS participants showed higher local brain activation in the right thalamus. We also observed a positive correlation in the MS group between ALFF and extrinsic feedback within the left inferior frontal gyrus, and within the left superior temporal gyrus in association with intrinsic feedback. Healthy participants showed a positive correlation in the right fusiform gyrus between ALFF and extrinsic feedback. Findings suggest that while MS participants do not show a feedback learning impairment compared to the healthy participants, ALFF differences might suggest a general maladaptive pattern of task unrelated thalamic activation and adaptive activation in frontal and temporal regions. Results indicate that ALFF can be successfully used at capturing pathophysiological changes in local brain activation in MS in association with learning through feedback.

Altered functional connectivity during performance feedback processing in multiple sclerosis.

Effective learning from performance feedback is vital for adaptive behavior regulation necessary for successful cognitive performance. Yet, how this learning operates in clinical groups that experience cognitive dysfunction is not well understood. Multiple sclerosis (MS) is an autoimmune, degenerative disease of the central nervous system characterized by physical and cognitive dysfunction. A highly prevalent impairment in MS is cognitive fatigue (CF). CF is associated with altered functioning within cortico-striatal regions that also facilitate feedback-based learning in neurotypical (NT) individuals. Despite this cortico-striatal overlap, research about feedback-based learning in MS, its associated neural underpinnings, and its sensitivity to CF, are all lacking. The present study investigated feedback-based learning ability in MS, as well as associated cortico-striatal function and connectivity. MS and NT participants completed a functional magnetic resonance imaging (fMRI) paired-word association task during which they received trial-by-trial monetary, non-monetary, and uninformative performance feedback. Despite reporting greater CF throughout the task, MS participants displayed comparable task performance to NTs, suggesting preserved feedback-based learning ability in the MS group. Both groups recruited the ventral striatum (VS), caudate nucleus, and ventromedial prefrontal cortex in response to the receipt of performance feedback, suggesting that people with MS also recruit cortico-striatal regions during feedback-based learning. However, compared to NT participants, MS participants also displayed stronger functional connectivity between the VS and task-relevant regions, including the left angular gyrus and right superior temporal gyrus, in response to feedback receipt. Results indicate that CF may not interfere with feedback-based learning in MS. Nonetheless, people with MS may recruit alternative connections with the striatum to assist with this form of learning. These findings have implications for cognitive rehabilitation treatments that incorporate performance feedback to remediate cognitive dysfunction in clinical populations.

Subjective valuation of performance feedback is robust to trait cognitive fatigue in multiple sclerosis.

BACKGROUND: Performance feedback is vital to rehabilitation interventions that treat cognitive impairments from multiple sclerosis (MS). Optimal treatment relies on participants' motivation to learn from feedback throughout these interventions. Cognitive fatigue, a prevalent symptom of MS, is associated with aberrant reward processing, which necessitates research into how fatigue affects perceived reward value of feedback in these individuals. The current study investigated how trait fatigue influences subjective valuation of feedback and subsequent feedback-seeking behavior in people with MS. METHODS: 33 MS and 32 neurotypical (NT) participants completed a willingness-to-pay associative memory paradigm that assessed feedback valuation via trial-by-trial decisions to either purchase or forego feedback in service of maximizing a performance-contingent monetary reward. Participant ratings of trait fatigue were also collected. Generalized logistic mixed modeling was used to analyze factors that influenced trial-wise feedback purchase decisions and task performance. RESULTS: Despite reporting greater trait fatigue, MS participants purchased comparable amounts of feedback as NT participants. Like NT participants, MS participants were more likely to purchase feedback when they were less confident about response accuracy. MS participants also performed comparably to NT participants, who both particularly benefited from purchase decisions that yielded negative feedback (i.e., indicating a response error). CONCLUSIONS: Trait cognitive fatigue may not impact performance feedback valuation in people with MS. Nonetheless, confidence in performance may drive their feedback-seeking behavior and may serve as a target for improving learning throughout cognitive rehabilitation and maximizing treatment success.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a pilot investigation.

Outcome processing, the ability to learn from feedback, is an important component of adaptive behavior and rehabilitation. Evidence from healthy adults implicates the striatum and dopamine in outcome processing. Animal research shows that damage to dopaminergic pathways in the brain can lead to a disruption of dopamine tone and transmission. Such evidence thus suggests that persons with TBI experience deficits in outcome processing. However, no research has directly investigated outcome processing and associated neural mechanisms in TBI. Here, we examine outcome processing in individuals with TBI during learning. Given that TBI negatively impacts striatal and dopaminergic systems, we hypothesize that individuals with TBI exhibit deficits in learning from outcomes. To test this hypothesis, individuals with moderate-to-severe TBI and healthy adults were presented with a declarative paired-associate word learning task. Outcomes indicating performance accuracy were presented immediately during task performance and in the form of either monetary or performance-based feedback. Two types of feedback provided the opportunity to test whether extrinsic and intrinsic motivational aspects of outcome presentation play a role during learning and outcome processing. Our results show that individuals with TBI exhibited impaired learning from feedback compared to healthy participants. Additionally, individuals with TBI exhibited increased activation in the striatum during outcome processing. The results of this study suggest that outcome processing and learning from immediate outcomes is impaired in individuals with TBI and might be related to inefficient use of neural resources during task performance as reflected by increased activation of the striatum.

Ex-Gaussian analysis of simple response time as a measure of information processing speed and the relationship with brain morphometry in multiple sclerosis.

BACKGROUND: The polyfactorial nature of the widely used symbol digit modalities test (SDMT) introduces significant measurement challenges in characterizing information processing speed (IPS) deficits in multiple sclerosis (MS). Measures with high psychometric IPS-specificity and less contamination from other cognitive domains are necessary to fully understand IPS changes. OBJECTIVE: Investigate how three mathematical modeling ex-Gaussian parameter estimates (mu, sigma, tau) derived from a simple response time (RT) task (1) differentiate MS from healthy control participants and (2) correspond to structural brain changes, to evaluate a novel IPS measurement approach. METHODS: Persons with and without MS completed a two-minute behavioral simple RT task, structural MRI and the MS functional composite. RT distributions were deconvolved into ex-Gaussian parameter estimates using mathematical modeling. Group differences and brain-behavior relationships were statistically evaluated. RESULTS: Persons with MS experienced a general pattern of slowing as evidenced by a shift in the Gaussian (mu) component of the distribution. This correlated with whole brain volume and white matter specifically. Additionally, persons with MS had larger values of tau (elongated positively skewed tail) that may reflect attentional lapses. CONCLUSION: The ex-Gaussian approach is sensitive to disease-related IPS changes and provides nuanced information about IPS slowing in MS.