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Orienting network dysfunction in progressive multiple sclerosis

Journal of the Neurological Sciences, 1-2, 351, pages 206 - 207

1. Introduction

Among patients with multiple sclerosis (MS), cognitive impairment affects up to 70% of the population [1] . The most frequently impaired domains are memory, processing speed and attention. Three main attentional networks were described [2] : the alerting network responsible for controlling vigilance and performance during tasks, the orienting network in charge of orientation to external stimuli, and the executive control network that deals with solving conflicts, detecting targets, and focal attention. The evaluation of these networks is possible by the means of the Attention Network Test (ANT) [3] . To our knowledge, this test has been studied in patients with relapsing–remitting MS (RRMS) [1] but not in MS patients with progressive subtypes. We postulated that the increase in lesion load and cerebral atrophy throughout disease progression might have more impact on the attentional capacities in progressive MS.

2. Methods

25 patients with primary (n = 10) or secondary (n = 15) progressive MS and 25 age and sex matched healthy controls were enrolled ( Table 1 ). All participants were right-handed.

Table 1 Demographic and clinical data of patients and their controls. F: Female, M: Male, SD: standard deviation, EDSS: Expanded disability status scale, N/A: not applicable.

  MS patients (n = 25) Healthy controls (n = 25)
Sex (F/M) 12/13 12/13
Age (years, mean ± SD; range) 57.7 ± 10; 38–74 54.1 ± 7; 45–70
Disease duration (range in years) (mean ± SD) 4–44 (22.48 ± 11.25) N/A
Progressive phase duration (range in years) (mean ± SD; range) 3–33 (13.84 ± 8.37) N/A
EDSS (range) (mean ± SD) 2.5–8 (5.7 ± 1.5) N/A

For the patients group, inclusion was based on a definite diagnosis of progressive MS according to the revised 2010 McDonald criteria, and stable treatments since at least one month. Exclusion criteria included (i) relapsing remitting MS, (ii) comorbid neurologic or psychiatric disorders, particularly depression defined as Beck Depression Inventory score > 19, (iii) severe upper limb impairment and (iv) visual acuity or field deficits.

The study protocol was approved by the local ethical committee and performed in compliance to the declaration of Helsinki.

Cognitive screening was performed using the Symbol Digit Modality Test (SDMT) [4] , known to rely on perceptual and spatial abilities, and processing speed. The attention function was explored using ANT [3] , which assesses attention by terms of mean reaction time (MRT), mean accuracy (MA), and the efficiency of each network. Statistical analysis was performed using the Mann–Whitney test for comparisons and the Spearman rank test for correlations between clinical data (age, EDSS, and disease or progressive phase duration) and cognitive test variables.

3. Results

Regarding ANT performance, MS patients were found slower (MRT: 816.84 ± 142.8 vs 683.5 ± 93.1;p = 0.0006), and less accurate (MA 94.2 ± 9.4 vs 97.7 ± 5.8;p = 0.002) than their healthy counterparts. Looking at the network effect, MS patients had a significant deficit in the orienting network (54.2 ± 55.5 vs. 24.9 ± 29.4;p = 0.047), but not in the alerting (24.0 ± 32.1 vs. 27.3 ± 26.5;p = 0.53) or the executive control (159.1 ± 74.9 vs. 134.5 ± 37.7;p = 0.23) networks. Finally, MS patients scored significantly less than healthy subjects on the SDMT (32.7 ± 11.8 vs 47 ± 11.9;p = 0.005). Their SDMT scores were around 2 SD below the recommended normative cut-off score for age and educational level [5] .

In MS patients, EDSS scores correlated positively with MRT (r: 0.48,p = 0.02) and negatively with MA (r: − 0.42,p = 0.04) of ANT performance. The duration of the progressive phase also correlated positively with MRT (r: 0.44,p = 0.03). No other correlations between clinical and ANT variables were found. In addition, SDMT scores did not correlate with any ANT variable.

4. Conclusion

In this study, MS patients were slower and less accurate than controls in information processing. A delayed information processing is among the most frequently reported cognitive symptoms in MS patients[1] and [5]and linked to cerebral lesion load [6] .

Regarding the attentional networks, our patients had an exclusive dysfunction in the orienting network. Our study is the first to report such a deficit in progressive MS. Among the four previous studies in RRMS, only one has reported such a finding [1] . Since progressive MS is characterized by a higher number of cortical lesions compared to RRMS, orientation deficit might be attributed to disease progression and the related increase in the lesion load. As for the alerting network, although we found no difference between the two groups, we cannot fully exclude a dysfunction in this network, which was previously reported to be altered in RRMS [1] and with the aging process [7] . It is noteworthy that aging alters alertness, does not affect orientation, and has a controversial impact on executive control [7] . Hence, to isolate the effects of disease progression from age, future studies with a larger sample size and different age groups, are needed. Finally, the executive control network seems to be preserved throughout the course of MS. Correlations were found between some demographic data (disease duration and EDSS) on one side, and some parameters of ANT on the other side (MRT and MA) suggesting that disease progression would be characterized by global slowing and accuracy reduction during attentional performance. This is in accordance with previous studies that demonstrated a correlation between cognitive impairment and gray matter atrophy, the latter being the best marker of disease progression [8] .

Our results have some limitations, since we compared networks using the automatic substraction method, which does not take into account attentional network interaction, notably between alertness and executive control, and might hide some specific attentional mechanisms[1], [9], and [10]. Independent analysis of each attentional network should be implemented in future studies.

Regarding SDMT, performance of MS patients was significantly less than that obtained in healthy subjects. Such findings are in accordance with previous studies which showed that poor SDMT results could be predicted by the volume of white matter lesions [6] ; the latter being important in MS patients with progressive subtypes. Finally, the lack of correlation between SDMT and ANT could be explained by the fact that each test evaluates different cognitive aspects, i.e. the speed and accuracy in visual search and scanning for SDMT [4] vs. the attentional networks for ANT [3] .

In summary, our study further supports the value of ANT and SMDT in evaluating different aspects of cognitive impairment in MS patients, and emphasizes the alteration of the orienting attentional network in MS patients with progressive subtypes.


  • [1] M. Vázquez-Marrufo, A. Galvao-Carmona, J.J. González-Rosa, A.R. Hidalgo-Muñoz, M. Borges, J.L. Ruiz-Peña, et al. Neural correlates of alerting and orienting impairment in multiple sclerosis patients. PLoS One. 2014;12(9):e97226
  • [2] S.E. Petersen, M.I. Posner. The attention system of the human brain:20 20 years after. Annu Rev Neurosci. 2012;35:73-89 Crossref
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  • [6] A. Papadopoulou, N. Müller-Lenke, Y. Naegelin, G. Kalt, K. Bendfeldt, P. Kuster, et al. Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis. Mult Scler. 2013;19:1290-1296 Crossref
  • [7] M. Knight, M. Mather. Look out-it's your off-peak time of day!. Time of day matters more for alerting than for orienting or executive attention, Exp Aging Res. 2013;39:305-321 Crossref
  • [8] S. Messina, F. Patti. Gray matters in multiple sclerosis: cognitive impairment and structural MRI. Mult Scler Int. 2014;2014:609694
  • [9] D. Fernandez-Duque, S.E. Black. Attentional networks in normal aging and Alzheimer's disease. Neuropsychology. 2006;20:133-143 Crossref
  • [10] A. Galvao-Carmona, J.J. González-Rosa, A.R. Hidalgo-Muñoz, D. Páramo, M.L. Benítez, G. Izquierdo, et al. Disentangling the attention network test: behavioral, event related potentials, and neural source analyses. Front Hum Neurosci. 2014;8:813


a EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, France

b Service de Physiologie—Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, France

c Department of Psychiatry, Psychotherapy and Psychosomatics, Ludwig-Maximilian University, Germany

d Service de Neurologie, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, France

lowast Corresponding author at: Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris, 94010 Créteil, France.

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About the Editors

  • Prof Timothy Vartanian

    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
  • Dr Rebecca Farber

    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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