The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study

BACKGROUND: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear. METHODS: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5). RESULTS: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = −0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = −0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = −1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC. CONCLUSIONS: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and “natural” (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity

Fractionating the neurocognitive mechanisms underlying working memory: independent effects of dopamine and Parkinson’s disease

Deficits in working memory (WM) in Parkinson's disease (PD) are often considered to be secondary to dopaminergic depletion. However, the neurocognitive mechanisms by which dopamine causes these deficits remain highly contested, and PD is now also known to be associated with nondopaminergic pathology. Here, we examined how PD and dopaminergic medication modulate three components of WM: maintenance over time, updating contents with new information and making memories distracter-resistant. Compared with controls, patients were disproportionately impaired when retaining information for longer durations. By applying a probabilistic model, we were able to reveal that the source of this error was selectively due to precision of memory representations degrading over time. By contrast, replenishing dopamine levels in PD improved executive control over both the ability to ignore and update, but did not affect maintenance of information across time. This was due to a decrease in guess responses, consistent with the view that dopamine serves to prevent WM representations being corrupted by irrelevant information, but has no impact on information decay. Cumulatively, these results reveal a dissociation in the neural mechanisms underlying poor WM: whereas dopamine reduces interference, nondopaminergic systems in PD appear to modulate processes that prevent information decaying more quickly over time

Fractionating the neurocognitive mechanisms underlying working memory: independent effects of dopamine and Parkinson’s disease

Deficits in working memory (WM) in Parkinson's disease (PD) are often considered to be secondary to dopaminergic depletion. However, the neurocognitive mechanisms by which dopamine causes these deficits remain highly contested, and PD is now also known to be associated with nondopaminergic pathology. Here, we examined how PD and dopaminergic medication modulate three components of WM: maintenance over time, updating contents with new information and making memories distracter-resistant. Compared with controls, patients were disproportionately impaired when retaining information for longer durations. By applying a probabilistic model, we were able to reveal that the source of this error was selectively due to precision of memory representations degrading over time. By contrast, replenishing dopamine levels in PD improved executive control over both the ability to ignore and update, but did not affect maintenance of information across time. This was due to a decrease in guess responses, consistent with the view that dopamine serves to prevent WM representations being corrupted by irrelevant information, but has no impact on information decay. Cumulatively, these results reveal a dissociation in the neural mechanisms underlying poor WM: whereas dopamine reduces interference, nondopaminergic systems in PD appear to modulate processes that prevent information decaying more quickly over time

Ignoring versus updating in working memory reveal differential roles of attention and feature binding

Ignoring distracting information and updating current contents are essential components of working memory (WM). Yet, although both require controlling irrelevant information, it is unclear whether they have the same effects on recall and produce the same level of misbinding errors (incorrectly joining the features of different memoranda). Moreover, the likelihood of misbinding may be affected by the feature similarity between the items already encoded into memory and the information that has to be filtered out (ignored) or updated into memory. Here, we investigate these questions. Participants were sequentially presented with two pairs of arrows. The first pair of arrows always had to be encoded into memory, but the second pair either had to be ignored (ignore condition) or allowed to displace the previously encoded items (update condition). To investigate the effect of similarity on recall, we also varied, in a factorial manner, whether the items that had to be ignored or updated were presented in the same or different colours and/or same or different spatial locations to the original memoranda. By applying a computational model, we were able to quantify the levels of misbinding. Ignoring, but not updating, increased overall recall error as well as misbinding rates, even when accounting for the retention period. This indicates that not all manipulations of attention in WM are equal in terms of their effects on recall and misbinding. Misbinding rates in the ignore condition were affected by the colour and spatial congruence of relevant and irrelevant information to a greater extent than in the update condition. This finding suggests that attentional templates are used to evaluate relevant and irrelevant information in different ways during ignoring and updating. Together, the results suggest that differences between the two functions might occur due to higher levels of attentional compartmentalisation e or protection e during updating compared to ignoring