Shaping a suitable EU HTA dossier template: why the German template is not fit for purpose.

From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG's benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement.

Classification of age groups and task conditions provides additional evidence for differences in electrophysiological correlates of inhibitory control across the lifespan.

The aim of this study was to extend previous findings on selective attention over a lifetime using machine learning procedures. By decoding group membership and stimulus type, we aimed to study differences in the neural representation of inhibitory control across age groups at a single-trial level. We re-analyzed data from 211 subjects from six age groups between 8 and 83 years of age. Based on single-trial EEG recordings during a flanker task, we used support vector machines to predict the age group as well as to determine the presented stimulus type (i.e., congruent, or incongruent stimulus). The classification of group membership was highly above chance level (accuracy: 55%, chance level: 17%). Early EEG responses were found to play an important role, and a grouped pattern of classification performance emerged corresponding to age structure. There was a clear cluster of individuals after retirement, i.e., misclassifications mostly occurred within this cluster. The stimulus type could be classified above chance level in ~ 95% of subjects. We identified time windows relevant for classification performance that are discussed in the context of early visual attention and conflict processing. In children and older adults, a high variability and latency of these time windows were found. We were able to demonstrate differences in neuronal dynamics at the level of individual trials. Our analysis was sensitive to mapping gross changes, e.g., at retirement age, and to differentiating components of visual attention across age groups, adding value for the diagnosis of cognitive status across the lifespan. Overall, the results highlight the use of machine learning in the study of brain activity over a lifetime.

Using EEG to study sensorimotor adaptation.

Sensorimotor adaptation, or the capacity to flexibly adapt movements to changes in the body or the environment, is crucial to our ability to move efficiently in a dynamic world. The field of sensorimotor adaptation is replete with rigorous behavioural and computational methods, which support strong conceptual frameworks. An increasing number of studies have combined these methods with electroencephalography (EEG) to unveil insights into the neural mechanisms of adaptation. We review these studies: discussing EEG markers of adaptation in the frequency and the temporal domain, EEG predictors for successful adaptation and how EEG can be used to unmask latent processes resulting from adaptation, such as the modulation of spatial attention. With its high temporal resolution, EEG can be further exploited to deepen our understanding of sensorimotor adaptation.

Task Feedback Processing Differs Between Young and Older Adults in Visuomotor Rotation Learning Despite Similar Initial Adaptation and Savings.

Ageing has been suggested to affect sensorimotor adaptation by impairing explicit strategy use. Here we recorded electrophysiological (EEG) responses during visuomotor rotation in both young (n = 24) and older adults (n = 25), to investigate the neural processes that underpin putative age-related effects on adaptation. We measured the feedback related negativity (FRN) and the P3 in response to task-feedback, as electrophysiological markers of task error processing and outcome evaluation. The two age groups adapted similarly and showed comparable after effects and savings when re-exposed to the same perturbation several days after the initial session. Older adults, however, had less distinct EEG responses (i.e., reduced FRN amplitudes) to negative and positive task feedback. The P3 did not differ between age groups. Both young and older adults also showed a sustained late positivity following task feedback. Measured at the frontal electrode Fz, this sustained activity was negatively associated with both the amount of voluntary disengagement of explicit strategy and savings. In conclusion, despite preserved task performance, we find clear differences in neural responses to errors in older people, which suggests that there is a fundamental decline in this aspect of sensorimotor brain function with age.

Neuromuscular Properties of the Human Wrist Flexors as a Function of the Wrist Joint Angle.

The joint angle dependence of voluntary activation and twitch properties has been investigated for several human skeletal muscles. However, although they play a key role for hand function and possess a unique neural control compared to muscles surrounding other joint complexes, little is known about the wrist flexors innervated by the median nerve. Therefore, isometric voluntary and electrically evoked contractions of the wrist flexors were analyzed at three wrist joint angles (extension: -30°, neutral: 0°, flexion: 30°) to quantify the joint angle dependence of (i) voluntary activation (assessed via peripheral nerve stimulation and electromyography [EMG]), (ii) unpotentiated twitch torques, and (iii) potentiated twitch torques. Maximum voluntary torque was lower in extension compared to neutral and flexion. Although voluntary activation was generally high, data indicate that voluntary activation of the wrist flexors innervated by the median nerve was lower and the antagonist·agonist-1 EMG ratio was higher with the wrist joint in flexion compared to extension. Peak twitch torque, rate of twitch torque development, and twitch half-relaxation time increased, whereas electromechanical delay decreased from flexion to extension for the unpotentiated twitch torques. Activity-induced potentiation partly abolished these differences and was higher in short than long wrist flexors. Different angle-dependent excitatory and inhibitory inputs to spinal and supraspinal centers might be responsible for the altered activation of the investigated wrist muscles. Potential mechanisms were discussed and might have operated conjointly to increase stiffness of the flexed wrist joint. Differences in twitch torque properties were probably related to angle-dependent alterations in series elastic properties, actin-myosin interaction, Ca2+ sensitivity, and phosphorylation of myosin regulatory light chains. The results of the present study provide valuable information about the contribution of neural and muscular properties to changes in strength capabilities of the wrist flexors at different wrist joint angles. These data could help to understand normal wrist function, which is a first step in determining mechanisms underlying musculoskeletal disorders and in giving recommendations for the restoration of musculoskeletal function after traumatic or overuse injuries.

A Non-linear Relationship Between Selective Attention and Associated ERP Markers Across the Lifespan.

The ability to selectively attend to task-relevant information increases throughout childhood and decreases in older age. Here, we intended to investigate these opposing developmental trajectories, to assess whether gains and losses early and late in life are associated with similar or different electrophysiological changes, and to get a better understanding about the development in middle-adulthood. We (re-)analyzed behavioral and electrophysiological data of 211 participants, who performed a colored Flanker task while their Electroencephalography (EEG) was recorded. Participants were subdivided into six groups depending on their age, ranging from 8 to 83 years. We analyzed response speed and accuracy as well as the event replated potential (ERP) components P1 and N1, associated with visual processing and attention, N2 as marker of interference suppression and cognitive control, and P3 as a marker of cognitive updating and stimulus categorization. Response speed and accuracy were low early and later in life, with peak performance in young adults. Similarly, ERP latencies of all components and P1 and N1 amplitudes followed a u-shape pattern with shortest latencies and smallest amplitudes occurring in middle-age. N2 amplitudes were larger in children, and for incongruent stimuli in adults middle-aged and older. P3 amplitudes showed a parietal-to-frontal shift with age. Further, group-wise regression analyses suggested that children's performance depended on cognitive processing speed, while older adults' performance depended on cognitive resources. Together these results imply that different mechanisms restrict performance early and late in life and suggest a non-linear relationship between electrophysiological markers and performance in the Flanker task across the lifespan.

Increased preparation time reduces, but does not abolish, action history bias of saccadic eye movements.

The characteristics of movements are strongly history-dependent. Marinovic et al. (Marinovic W, Poh E, de Rugy A, Carroll TJ. eLife 6: e26713, 2017) showed that past experience influences the execution of limb movements through a combination of temporally stable processes that are strictly use dependent and dynamically evolving and context-dependent processes that reflect prediction of future actions. Here we tested the basis of history-dependent biases for multiple spatiotemporal features of saccadic eye movements under two preparation time conditions (long and short). Twenty people performed saccades to visual targets. To prompt context-specific expectations of most likely target locations, 1 of 12 potential target locations was specified on ~85% of the trials and each remaining target was presented on ~1% trials. In long preparation trials participants were shown the location of the next target 1 s before its presentation onset, whereas in short preparation trials each target was first specified as the cue to move. Saccade reaction times and direction were biased by recent saccade history but according to distinct spatial tuning profiles. Biases were purely expectation related for saccadic reaction times, which increased linearly as the distance from the repeated target location increased when preparation time was short but were similar to all targets when preparation time was long. By contrast, the directions of saccades were biased toward the repeated target in both preparation time conditions, although to a lesser extent when the target location was precued (long preparation). The results suggest that saccade history affects saccade dynamics via both use- and expectation-dependent mechanisms and that movement history has dissociable effects on reaction time and saccadic direction. NEW & NOTEWORTHY The characteristics of our movements are influenced not only by concurrent sensory inputs but also by how we have moved in the past. For limb movements, history effects involve both use-dependent processes due strictly to movement repetition and processes that reflect prediction of future actions. Here we show that saccade history also affects saccade dynamics via use- and expectation-dependent mechanisms but that movement history has dissociable effects on saccade reaction time and direction.

A Randomized Controlled Trial on the Effects of Aerobic and Coordinative Training on Neural Correlates of Inhibitory Control in Children.

Whereas aerobic training has found to be beneficial for inhibitory control, less is known on the efficiency of other exercise types in children. The present study compared the effects of aerobic and coordinative training on behavioral and neurophysiological measures of inhibitory control. Forty-five children were randomly assigned (1:1:1 ratio) to groups performing aerobic training, coordinative training or assisted homework sessions over 10 weeks. Before and after intervention, all participants completed a Flanker task. The P300 component of event-related potentials elicited from the task was recorded via electroencephalography. Additionally, aerobic fitness and gross-motor skills were assessed using 20 m Shuttle Run and Heidelberg Gross-Motor Test, respectively. Statistical analyses revealed no time by group interactions for the P300 component (amplitude, latency), p = 0.976, η² = 0.007, and behavioral performance (reaction time, accuracy), p = 0.570, η² = 0.045. In contrast, there was a significant group-difference in pre- to post-test changes in aerobic fitness, p = 0.008, η² = 0.246, with greater improvements following aerobic and coordinative training compared to assisted homework sessions. In conclusion, no differences regarding the efficiency of aerobic and coordinative training for the enhancement of inhibitory control were found as both exercise programs failed to elicit changes in speed and accuracy of stimulus evaluation and the allocation of attentional resources.

Pushing attention to one side: Force field adaptation alters neural correlates of orienting and disengagement of spatial attention.

Sensorimotor adaptation to wedge prisms can alter the balance of attention between left and right space in healthy adults, and improve symptoms of spatial neglect after stroke. Here we asked whether the orienting of spatial attention to visual stimuli is affected by a different form of sensorimotor adaptation that involves physical perturbations of arm movement, rather than distortion of visual feedback. Healthy participants performed a cued discrimination task before and after they made reaching movements to a central target. A velocity-dependent force field pushed the hand aside during each reach, and required participants to apply compensatory forces toward the opposite side. We used event-related potentials (ERPs) to determine whether electroencephalography (EEG) responses reflecting orienting (cue-locked N1) and disengagement (target-locked P1) of spatial attention are affected by adaptation to force fields. After adaptation, the cue-locked N1 was relatively larger for stimuli presented in the hemispace corresponding to the direction of compensatory hand force. P1 amplitudes evoked by invalidly cued targets presented on the opposite side were reduced. This suggests that force field adaptation boosted attentional orienting responses toward the side of hand forces, and impeded attentional disengagement from that side, mimicking previously reported effects of prism adaptation. Thus, remapping between motor commands and intended movement direction is sufficient to bias ERPs, reflecting changes in the orienting of spatial attention in the absence of visuo-spatial distortion or visuo-proprioceptive mismatch. Findings are relevant to theories of how sensorimotor adaptation can modulate attention, and may open new avenues for treatment of spatial neglect.

Improved Neural Control of Movements Manifests in Expertise-Related Differences in Force Output and Brain Network Dynamics.

It is well-established that expertise developed through continuous and deliberate practice has the potential to delay age-related decline in fine motor skills. However, less is known about the underlying mechanisms, that is, whether expertise leads to a higher performance level changing the initial status from which age-related decline starts or if expertise-related changes result in qualitatively different motor output and neural processing providing a resource of compensation for age-related changes. Thus, as a first step, this study aims at a better understanding of expertise-related changes in fine motor control with respect to force output and respective electrophysiological correlates. Here, using a multidimensional approach, we investigated fine motor control of experts and novices in precision mechanics during the execution of a dynamic force control task. On the level of force output, we analyzed precision, variability, and complexity. We further used dynamic mode decomposition (DMD) to analyze the electrophysiological correlates of force control to deduce brain network dynamics. Experts' force output was more precise, less variable, and more complex. Task-related DMD mean mode magnitudes within the α-band at electrodes over sensorimotor relevant areas were reduced in experts, and lower DMD mean mode magnitudes related to the force output in novices. Our results provide evidence for expertise dependent central adaptions with distinct and more complex organization and decentralization of sensorimotor subsystems. Results from our multidimensional approach can be seen as a step forward in understanding expertise-related changes and exploiting their potential as resources for healthy aging.

Age- and Expertise-Related Differences of Sensorimotor Network Dynamics during Force Control.

Age-related deterioration of force control is evident on behavioral and neural levels. Extensive and deliberate practice can decrease these changes. This study focused on detecting electrophysiological correlates of age- and expertise-related differences in force control. We examined young (20-27 years) and late middle-aged (57-67 years) novices as well as late middle-aged experts in the field of fine motor control. Therefore, EEG data were recorded while participants performed a force maintenance task. Variability and complexity of force data were analyzed. To detect electrophysiological correlates, dynamic mode decomposition (DMD) was applied to EEG data. DMD allows assessing brain network dynamics by extracting electrode interrelations and their dynamics. Defining clusters of electrodes, we focused on sensorimotor and attentional networks. We confirmed that force control in late middle-aged novices was more variable and less complex than in other groups. Analysis of task-related overall network characteristics, showed a decrease within the α band and increase within low ß, high ß, and  θ  band. Compared to the other groups young novices presented a decreased α magnitude. High ß magnitude was lower in late middle-aged novices than for other groups. Comparing left and right hands' performance, young novices showed higher low ß magnitude for the left hand. Late middle-aged novices showed high values for both hands while late middle-aged experts showed higher values for the right than for their left hand. Activation of attentional networks was lower in late middle-aged experts compared to novices. These results may relate to different control strategies of the three groups.

Greater neural responses to trajectory errors are associated with superior force field adaptation in older adults.

Although age-related declines in cognitive, sensory and motor capacities are well documented, current evidence is mixed as to whether or not aging impairs sensorimotor adaptation to a novel dynamic environment. More importantly, the extent to which any deficits in sensorimotor adaptation are due to general impairments in neural plasticity, or impairments in the specific processes that drive adaptation is unclear. Here we investigated whether there are age-related differences in electrophysiological responses to reaching endpoint and trajectory errors caused by a novel force field, and whether markers of error processing relate to the ability of older adults to adapt their movements. Older and young adults (N = 24/group, both sexes) performed 600 reaches to visual targets, and received audio-visual feedback about task success or failure after each trial. A velocity-dependent curl field pushed the hand to one side during each reach. We extracted ERPs time-locked to movement onset [kinematic error-related negativity (kERN)], and the presentation of success/failure feedback [feedback error-related negativity (fERN)]. At a group level, older adults did not differ from young adults in the rate or extent of sensorimotor adaptation, but EEG responses to both trajectory errors and task errors were reduced in the older group. Most interestingly, the amplitude of the kERN correlated with the rate and extent of sensorimotor adaptation in older adults. Thus, older adults with an impaired capacity for encoding kinematic trajectory errors also have compromised abilities to adapt their movements in a novel dynamic environment.

It Pays to Prepare: Human Motor Preparation Depends on the Relative Value of Potential Response Options.

Alternative motor responses can be prepared in parallel. Here, we used electroencephalography (EEG) to test whether the parallel preparation of alternative response options is modulated by their relative value. Participants performed a choice response task with three potential actions: isometric contraction of the left, the right, or both wrists. An imperative stimulus (IS) appeared after a warning cue, such that the initiation time of a required action was predictable, but the specific action was not. To encourage advanced preparation, the target was presented 200 ms prior to the IS, and only correct responses initiated within ±100 ms of the IS were rewarded. At baseline, all targets were equally rewarded and probable. Then, responses with one hand were made more valuable, either by increasing the probability that the left or right target would be required (Exp. 1; n = 31) or by increasing the reward magnitude of one target (Exp. 2, n = 36). We measured reaction times, movement vigor, and an EEG correlate of action preparation (value-based lateralized readiness potential) prior to target presentation. Participants responded earlier to more frequent and more highly rewarded targets, and movements to highly rewarded targets were more vigorous. The EEG was more negative over the hemisphere contralateral to the more repeated/rewarded hand, implying an increased neural preparation of more valuable actions. Thus, changing the value of alternative response options can lead to greater preparation of actions associated with more valuable outcomes. This preparation asymmetry likely contributes to behavioral biases that are typically observed toward repeated or rewarded targets.

Dynamical signatures of isometric force control as a function of age, expertise, and task constraints.

From the conceptual and methodological framework of the dynamical systems approach, force control results from complex interactions of various subsystems yielding observable behavioral fluctuations, which comprise both deterministic (predictable) and stochastic (noise-like) dynamical components. Here, we investigated these components contributing to the observed variability in force control in groups of participants differing in age and expertise level. To this aim, young (18-25 yr) as well as late middle-aged (55-65 yr) novices and experts (precision mechanics) performed a force maintenance and a force modulation task. Results showed that whereas the amplitude of force variability did not differ across groups in the maintenance tasks, in the modulation task it was higher for late middle-aged novices than for experts and higher for both these groups than for young participants. Within both tasks and for all groups, stochastic fluctuations were lowest where the deterministic influence was smallest. However, although all groups showed similar dynamics underlying force control in the maintenance task, a group effect was found for deterministic and stochastic fluctuations in the modulation task. The latter findings imply that both components were involved in the observed group differences in the variability of force fluctuations in the modulation task. These findings suggest that between groups the general characteristics of the dynamics do not differ in either task and that force control is more affected by age than by expertise. However, expertise seems to counteract some of the age effects.NEW & NOTEWORTHY Stochastic and deterministic dynamical components contribute to force production. Dynamical signatures differ between force maintenance and cyclic force modulation tasks but hardly between age and expertise groups. Differences in both stochastic and deterministic components are associated with group differences in behavioral variability, and observed behavioral variability is more strongly task dependent than person dependent.

Dendritic cells tip the balance towards induction of regulatory T cells upon priming in experimental autoimmune encephalomyelitis.

Counter-balancing regulatory mechanisms, such as the induction of regulatory T cells (Treg), limit the effects of autoimmune attack in neuroinflammation. However, the role of dendritic cells (DCs) as the most powerful antigen-presenting cells, which are intriguing therapeutic targets in this context, is not fully understood. Here, we demonstrate that conditional ablation of DCs during the priming phase of myelin-specific T cells in experimental autoimmune encephalomyelitis (EAE) selectively aborts inducible Treg (iTreg) induction, whereas generation of T helper (Th)1/17 cells is unaltered. DCs facilitate iTreg induction by creating a milieu with high levels of interleukin (IL)-2 due to a strong proliferative response. In the absence of DCs, B220+ B cells take over priming of Th17 cells in the place of antigen-presenting cells (APCs), but not the induction of iTreg, thus leading to unregulated, severe autoimmunity.

Increased structural white and grey matter network connectivity compensates for functional decline in early multiple sclerosis.

BACKGROUND: The pathology of multiple sclerosis (MS) consists of demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system (CNS) maintains homeostasis to counteract clinical impairment is not known. OBJECTIVE: We analyse the structural connectivity of white matter (WM) and grey matter (GM) networks to understand the absence of clinical decline as the disease progresses. METHODS: A total of 138 relapsing-remitting MS patients (classified into six groups by disease duration) and 32 healthy controls were investigated using 3-Tesla magnetic resonance imaging (MRI). Networks were analysed using graph theoretical approaches based on connectivity patterns derived from diffusion-tensor imaging with probabilistic tractography for WM and voxel-based morphometry and regional-volume-correlation matrix for GM. RESULTS: In the first year after disease onset, WM networks evolved to a structure of increased modularity, strengthened local connectivity and increased local clustering while no clinical decline occurred. GM networks showed a similar dynamic of increasing modularity. This modified connectivity pattern mainly involved the cerebellum, cingulum and temporo-parietal regions. Clinical impairment was associated at later disease stages with a divergence of the network patterns. CONCLUSION: Our findings suggest that network functionality in MS is maintained through structural adaptation towards increased local and modular connectivity, patterns linked to adaptability and homeostasis.

Feedforward compensation for novel dynamics depends on force field orientation but is similar for the left and right arms.

There are well-documented differences in the way that people typically perform identical motor tasks with their dominant and the nondominant arms. According to Yadav and Sainburg's (Neuroscience 196: 153-167, 2011) hybrid-control model, this is because the two arms rely to different degrees on impedance control versus predictive control processes. Here, we assessed whether differences in limb control mechanisms influence the rate of feedforward compensation to a novel dynamic environment. Seventy-five healthy, right-handed participants, divided into four subsamples depending on the arm (left, right) and direction of the force field (ipsilateral, contralateral), reached to central targets in velocity-dependent curl force fields. We assessed the rate at which participants developed predictive compensation for the force field using intermittent error-clamp trials and assessed both kinematic errors and initial aiming angles in the field trials. Participants who were exposed to fields that pushed the limb toward ipsilateral space reduced kinematic errors more slowly, built up less predictive field compensation, and relied more on strategic reaiming than those exposed to contralateral fields. However, there were no significant differences in predictive field compensation or kinematic errors between limbs, suggesting that participants using either the left or the right arm could adapt equally well to novel dynamics. It therefore appears that the distinct preferences in control mechanisms typically observed for the dominant and nondominant arms reflect a default mode that is based on habitual functional requirements rather than an absolute limit in capacity to access the controller specialized for the opposite limb.

Prospective clinical observational study evaluating gender-associated differences of preoperative pain intensity.

Previous studies reported conflicting results concerning different pain perceptions of men and women. Recent research found higher pain levels in men after major surgery, contrasted by women after minor procedures. This trial investigates differences in self-reported preoperative pain intensity between genders before surgery.Patients were enrolled in 2011 and 2012 presenting for preoperative evaluation at the anesthesiological assessment clinic at Charité University hospital. Out of 5102 patients completing a computer-assisted self-assessment, 3042 surgical patients with any preoperative pain were included into this prospective observational clinical study. Preoperative pain intensity (0-100 VAS, visual analog scale) was evaluated integrating psychological cofactors into analysis.Women reported higher preoperative pain intensity than men with median VAS scores of 30 (25th-75th percentiles: 10-52) versus 21 (10-46) (P < 0.001). Adjusted multiple regression analysis showed that female gender remained statistically significantly associated with higher pain intensity (P < 0.001). Gender differences were consistent across several subgroups especially with varying patterns in elderly. Women scheduled for minor and moderate surgical procedures showed largest differences in overall pain compared to men.This large clinical study observed significantly higher preoperative pain intensity in female surgical patients. This gender difference was larger in the elderly potentially contradicting the current hypothesis of a primary sex-hormone derived effect. The observed variability in specific patient subgroups may help to explain heterogeneous findings of previous studies.

A novel automated segmentation method for retinal layers in OCT images proves retinal degeneration after optic neuritis.

AIM: The evaluation of inner retinal layer thickness can serve as a direct biomarker for monitoring the course of inflammatory diseases of the central nervous system such as multiple sclerosis (MS). Using optical coherence tomography (OCT), thinning of the retinal nerve fibre layer and changes in deeper retinal layers have been observed in patients with MS. Here, we first compare a novel method for automated segmentation of OCT images with manual segmentation using two cohorts of patients with MS. Using this method, we also aimed to reproduce previous findings showing retinal degeneration following optic neuritis (ON) in MS. METHODS: Based on a 5×5 expansion of the Prewitt operator to efficiently calculate the gradient of image intensity, we introduce an automated algorithm for the segmentation of intraretinal layers. We evaluated this algorithm by comparison to manually segmented two-dimensional OCT images at the macular level for 125 patients from two separate cohorts of patients with MS. Of these patients, 52 had suffered from unilateral ON+ within 6 months prior to measurement. RESULTS: When comparing ON+ eyes with ON- eyes, both manual and automated segmentation demonstrated a significant inter-eye thinning in the ganglion cell layer in ON+ eyes. We also observed an increased thickness of the inner nuclear (INL) and the outer segment-retinal pigment epithelium (OS-RPE) layers of ON+ eyes in both cohorts. These findings corroborate previous data, thus demonstrating the validity of our approach. CONCLUSIONS: The algorithm presented here was found to be a valid tool for replacing cumbersome manual segmentation methods in the quantification of inner retinal layers in OCT. The observed increases in thickness of INL and OS-RPE may be attributed to primary retinal inflammation, repair and/or plasticity mechanisms following the immune attack.