J Clin Neurol.  2014 Oct;10(4):296-303. 10.3988/jcn.2014.10.4.296.

Contingent Negative Variation Is Associated with Cognitive Dysfunction and Secondary Progressive Disease Course in Multiple Sclerosis

• Uysal U
• Idiman F
• Idiman E
• Ozakbas S
• Karakas S
• Bruce J

• KMID: 2287508
• DOI: http://doi.org/10.3988/jcn.2014.10.4.296

Abstract

BACKGROUND AND PURPOSE
The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients.
METHODS
The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode.
RESULTS
RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall.
CONCLUSIONS
CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas.

Keyword

relapsing-remitting multiple sclerosis; secondary progressive multiple sclerosis; contingent negative variation cognitive dysfunction; event-related potentials; neuropsychological test

MeSH Terms

Area Under Curve
Automatic Data Processing
Cognition
Contingent Negative Variation*
Disease Progression
Electrodes
Evoked Potentials
Healthy Volunteers
Humans
Multiple Sclerosis*
Multiple Sclerosis, Chronic Progressive
Multiple Sclerosis, Relapsing-Remitting
Neuropsychological Tests
Verbal Learning

Figure

• 

  Fig. 1 CNV recording of a patient with RRMS. Red marks (x) are reference points used for the AUC calculation. AUC: area under the curve, CNV: contingent negative variation, RRMS: relapsing-remitting multiple sclerosis.

Reference

1. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991; 41:685–691.

2. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology. 1991; 41:692–696.

3. Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001; 58:1602–1606.

4. Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol. 2003; 16:283–288.

5. Wishart H, Sharpe D. Neuropsychological aspects of multiple sclerosis: a quantitative review. J Clin Exp Neuropsychol. 1997; 19:810–824.

6. Deloire M, Ruet A, Hamel D, Bonnet M, Brochet B. Early cognitive impairment in multiple sclerosis predicts disability outcome several years later. Mult Scler. 2010; 16:581–587.

7. Benedict RH, Fischer JS, Archibald CJ, Arnett PA, Beatty WW, Bobholz J, et al. Minimal neuropsychological assessment of MS patients: a consensus approach. Clin Neuropsychol. 2002; 16:381–397.

8. Oken BS. Endogenous event-related potentials. In : Chiappa KH, editor. Evoked Potentials in Clinical Medicine. 2nd ed. New York, NY: Raven Press;1990. p. 563–592.

9. Oishi M, Mochizuki Y, Du C, Takasu T. Contingent negative variation and movement-related cortical potentials in parkinsonism. Electroencephalogr Clin Neurophysiol. 1995; 95:346–349.

10. Drake ME Jr, Weate SJ, Newell SA. Contingent negative variation in epilepsy. Seizure. 1997; 6:297–301.

11. van Deursen JA, Vuurman EF, Smits LL, Verhey FR, Riedel WJ. Response speed, contingent negative variation and P300 in Alzheimer's disease and MCI. Brain Cogn. 2009; 69:592–599.

12. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69:292–302.

13. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33:1444–1452.

14. Umaç A. Normal deneklerde frontal hasarlara duyarlı bazı testlerde performansa yaş ve eğitimin etkisi [dissertation]. İstanbul: İstanbul Üniversitesi;1997.

15. Ozakbas S, Ormeci B, Akdede BB, Alptekin K, Idiman E. Utilization of the auditory consonant trigram test to screen for cognitive impairment in patients with multiple sclerosis: comparison with the paced auditory serial addition test. Mult Scler. 2004; 10:686–689.

16. Hisli N. Beck Depresyon Envanteri'nin üniversite öğrencileri için geçerliği, güvenirliği. Psikoloji Dergisi. 1989; 7:3–13.

17. Winkelmann A, Engel C, Apel A, Zettl UK. Cognitive impairment in multiple sclerosis. J Neurol. 2007; 254:Suppl 2. II35–II42.

18. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935; 18:643–662.

19. Denney DR, Lynch SG. The impact of multiple sclerosis on patients' performance on the Stroop Test: processing speed versus interference. J Int Neuropsychol Soc. 2009; 15:451–458.

20. Benton AL. Development of a multilingual aphasia battery. Progress and problems. J Neurol Sci. 1969; 9:39–48.

21. Mohr DC, Goodkin DE, Likosky W, Beutler L, Gatto N, Langan MK. Identification of Beck Depression Inventory items related to multiple sclerosis. J Behav Med. 1997; 20:407–414.

22. Ashton H, Marsh VR, Millman JE, Rawlins MD, Telford R, Thompson JW. Biphasic dose-related responses of the CNV (contingent negative variation) to I.V. nicotine in man. Br J Clin Pharmacol. 1980; 10:579–589.

23. Bruce JM, Harrington CJ, Foster S, Westervelt HJ. Common blood laboratory values are associated with cognition among older inpatients referred for neuropsychological testing. Clin Neuropsychol. 2009; 23:909–925.

24. Finch H. Comparison of the Performance of Nonparametric and Parametric MANOVA Test Statistics when Assumptions Are Violated. Methodology (Gott). 2007; 1:27–38.

25. Kiiski H, Reilly RB, Lonergan R, Kelly S, O'Brien M, Kinsella K, et al. Change in PASAT performance correlates with change in P3 ERP amplitude over a 12-month period in multiple sclerosis patients. J Neurol Sci. 2011; 305:45–52.

26. Matas CG, Matas SL, Oliveira CR, Gonçalves IC. Auditory evoked potentials and multiple sclerosis. Arq Neuropsiquiatr. 2010; 68:528–534.

27. Ivica N, Titlic M, Pavelin S. P300 wave changes in patients with multiple sclerosis. Acta Inform Med. 2013; 21:205–207.

28. Aminoff JC, Goodin DS. Long-latency cerebral event-related potentials in multiple sclerosis. J Clin Neurophysiol. 2001; 18:372–377.

29. Gonzalez-Rosa JJ, Vazquez-Marrufo M, Vaquero E, Duque P, Borges M, Gomez-Gonzalez CM, et al. Cluster analysis of behavioural and event-related potentials during a contingent negative variation paradigm in remitting-relapsing and benign forms of multiple sclerosis. BMC Neurol. 2011; 11:64.

30. Vázquez-Marrufo M, Galvao-Carmona A, González-Rosa JJ, Hidalgo-Muñoz AR, Borges M, Ruiz-Peña JL, et al. Neural correlates of alerting and orienting impairment in multiple sclerosis patients. PLoS One. 2014; 9:e97226.

31. Bonnet MC, Deloire MS, Salort E, Dousset V, Petry KG, Brochet B, et al. Evidence of cognitive compensation associated with educational level in early relapsing-remitting multiple sclerosis. J Neurol Sci. 2006; 251:23–28.

32. Staffen W, Mair A, Zauner H, Unterrainer J, Niederhofer H, Kutzelnigg A, et al. Cognitive function and fMRI in patients with multiple sclerosis: evidence for compensatory cortical activation during an attention task. Brain. 2002; 125(Pt 6):1275–1282.

33. Forn C, Barros-Loscertales A, Escudero J, Benlloch V, Campos S, Antònia Parcet M, et al. Compensatory activations in patients with multiple sclerosis during preserved performance on the auditory N-back task. Hum Brain Mapp. 2007; 28:424–430.

34. Bonnet MC, Allard M, Dilharreguy B, Deloire M, Petry KG, Brochet B. Cognitive compensation failure in multiple sclerosis. Neurology. 2010; 75:1241–1248.

35. Bares M, Rektor I, Kanovský P, Streitová H. Cortical and subcortical distribution of middle and long latency auditory and visual evoked potentials in a cognitive (CNV) paradigm. Clin Neurophysiol. 2003; 114:2447–2460.

36. Nagai Y, Critchley HD, Featherstone E, Fenwick PB, Trimble MR, Dolan RJ. Brain activity relating to the contingent negative variation: an fMRI investigation. Neuroimage. 2004; 21:1232–1241.

37. Minagar A, Barnett MH, Benedict RH, Pelletier D, Pirko I, Sahraian MA, et al. The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. Neurology. 2013; 80:210–219.

38. Brass SD, Benedict RH, Weinstock-Guttman B, Munschauer F, Bakshi R. Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis. Mult Scler. 2006; 12:437–444.

39. Batista S, Zivadinov R, Hoogs M, Bergsland N, Heininen-Brown M, Dwyer MG, et al. Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis. J Neurol. 2012; 259:139–146.

40. Benedict RH, Hulst HE, Bergsland N, Schoonheim MM, Dwyer MG, Weinstock-Guttman B, et al. Clinical significance of atrophy and white matter mean diffusivity within the thalamus of multiple sclerosis patients. Mult Scler. 2013; 19:1478–1484.

41. Rocca MA, Mesaros S, Pagani E, Sormani MP, Comi G, Filippi M. Thalamic damage and long-term progression of disability in multiple sclerosis. Radiology. 2010; 257:463–469.