The neural basis of executive functioning deficits in adolescents with epilepsy: a resting-state fMRI connectivity study of working memory

Abstract

Working memory deficits are common in youth with epilepsy and consistently associated with long-term negative outcomes. Existing research on the neural basis of working memory disruptions in pediatric epilepsy is limited. The question of whether differences in the functional connectivity of neural networks underlie working memory disruptions in pediatric patients with epilepsy remains unanswered. A total of 49 adolescents between the ages of 13–17 years participated in this study. Twenty-nine adolescents had confirmed epilepsy (n = 17 generalized epilepsy, n = 6 localization-related, n = 6 unclassified). The control group included 20 healthy adolescents. A total of 10-min resting state functional magnetic resonance imaging was obtained for all participants. NeuroSynth-derived regions of interest were used as nodes that comprise working memory neural networks. Group differences in resting state functional connectivity were examined between adolescents with epilepsy and controls. Functional connectivity was computed as the temporal correlation of functional magnetic resonance imaging signal fluctuations between any two regions of interest. Compared to controls, adolescents in the epilepsy group demonstrated both hypoconnectivity and hyperconnectivity in cortical areas that map onto fronto-parietal and cingulo-opercular networks, as well as cerebellar regions. Functional connectivity between pairs of regions of interest was also significantly associated with behavioral measures of working memory across epilepsy and control groups. This study demonstrates that the presence of abnormal patterns in resting state neural network connectivity may underlie the working memory disruptions that frequently characterize the neurocognitive profile of youth with epilepsy.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Albert, D., Chein, J., & Steinberg, L. (2013). Peer influences on adolescent decision making. Current Directions in Psychological Science, 22(2), 114–120. https://doi.org/10.1177/0963721412471347.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bechtel, N., Kobel, M., Penner, I. K., Specht, K., Klarhofer, M., Scheffler, K., et al. (2012). Attention-deficit/hyperactivity disorder in childhood epilepsy: A neuropsychological and functional imaging study. Epilepsia, 53(2), 325–333. https://doi.org/10.1111/j.1528-1167.2011.03377.x.

    CAS  Article  PubMed  Google Scholar 

  3. Behzadi, Y., Restom, K., Liau, J., & Liu, T. T. (2007). A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. Neuroimage, 37(1), 90–101. https://doi.org/10.1016/j.neuroimage.2007.04.042.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate - a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B-Statistical Methodology, 57(1), 289–300 Retrieved from <Go to ISI>://WOS:A1995QE45300017.

    Google Scholar 

  5. Berl, M. M., Terwilliger, V., Scheller, A., Sepeta, L., Walkowiak, J., & Gaillard, W. D. (2015). Speed and complexity characterize attention problems in children with localization-related epilepsy. Epilepsia, 56(6), 833–840. https://doi.org/10.1111/epi.12985.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Braakman, H. M., Vaessen, M. J., Jansen, J. F., Debeij-van Hall, M. H., de Louw, A., Hofman, P. A., et al. (2015). Aetiology of cognitive impairment in children with frontal lobe epilepsy. Acta Neurologica Scandinavica, 131(1), 17–29. https://doi.org/10.1111/ane.12283.

    CAS  Article  PubMed  Google Scholar 

  7. Caller, T. A., Secore, K. L., Ferguson, R. J., Roth, R. M., Alexandre, F. P., Henegan, P. L., et al. (2015). Design and feasibility of a memory intervention with focus on self-management for cognitive impairment in epilepsy. Epilepsy & Behavior, 44, 192–194. https://doi.org/10.1016/j.yebeh.2014.12.036.

    Article  Google Scholar 

  8. Dosenbach, N. U., Fair, D. A., Miezin, F. M., Cohen, A. L., Wenger, K. K., Dosenbach, R. A., et al. (2007). Distinct brain networks for adaptive and stable task control in humans. Proceedings of the National Academy of Sciences of the United States of America, 104(26), 11073–11078. https://doi.org/10.1073/pnas.0704320104.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Dosenbach, N. U., Fair, D. A., Cohen, A. L., Schlaggar, B. L., & Petersen, S. E. (2008). A dual-networks architecture of top-down control. Trends in Cognitive Sciences, 12(3), 99–105. https://doi.org/10.1016/j.tics.2008.01.001.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fastenau, P. S., Shen, J., Dunn, D. W., Perkins, S. M., Hermann, B. P., & Austin, J. K. (2004). Neuropsychological predictors of academic underachievement in pediatric epilepsy: Moderating roles of demographic, seizure, and psychosocial variables. Epilepsia, 45(10), 1261–1272. https://doi.org/10.1111/j.0013-9580.2004.15204.x.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Friston, K. J., Williams, S., Howard, R., Frackowiak, R. S., & Turner, R. (1996). Movement-related effects in fMRI time-series. Magnetic Resonance in Medicine, 35(3), 346–355. https://doi.org/10.1002/mrm.1910350312.

    CAS  Article  PubMed  Google Scholar 

  12. Gioia, G. A., Isquith, P. K., Guy, S. C., & Kenworthy, L. (2000). BRIEF: The behavior rating inventory of executive function: Professional manual. Odessa: Psychological Assessment Resources, Inc..

    Google Scholar 

  13. Hermann, B. P., Jones, J. E., Sheth, R., Koehn, M., Becker, T., Fine, J., et al. (2008). Growing up with epilepsy: A two-year investigation of cognitive development in children with new onset epilepsy. Epilepsia, 49(11), 1847–1858. https://doi.org/10.1111/j.1528-1167.2008.01735.x.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Huang, W., Huang, D., Chen, Z., Ye, W., Lv, Z., Diao, L., & Zheng, J. (2015). Alterations in the functional connectivity of a verbal working memory-related brain network in patients with left temporal lobe epilepsy. Neuroscience Letters, 602, 6–11. https://doi.org/10.1016/j.neulet.2015.06.031.

    CAS  Article  PubMed  Google Scholar 

  15. Ibrahim, G. M., Morgan, B. R., Lee, W., Smith, M. L., Donner, E. J., Wang, F., et al. (2014). Impaired development of intrinsic connectivity networks in children with medically intractable localization-related epilepsy. Human Brain Mapping, 35(11), 5686–5700. https://doi.org/10.1002/hbm.22580.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kernan, C. L., Asarnow, R., Siddarth, P., Gurbani, S., Lanphier, E. K., Sankar, R., & Caplan, R. (2012). Neurocognitive profiles in children with epilepsy. Epilepsia, 53(12), 2156–2163. https://doi.org/10.1111/j.1528-1167.2012.03706.x.

    Article  PubMed  Google Scholar 

  17. Kondo, H., Morishita, M., Osaka, N., Osaka, M., Fukuyama, H., & Shibasaki, H. (2004). Functional roles of the cingulo-frontal network in performance on working memory. Neuroimage, 21(1), 2–14 Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14741637.

    Article  Google Scholar 

  18. Lin, K., de Araujo Filho, G. M., Pascalicchio, T. F., Silva, I., Tudesco, I. S., Guaranha, M. S., et al. (2013). Hippocampal atrophy and memory dysfunction in patients with juvenile myoclonic epilepsy. Epilepsy & Behavior, 29(1), 247–251. https://doi.org/10.1016/j.yebeh.2013.06.034.

    Article  Google Scholar 

  19. McGill, M. L., Devinsky, O., Kelly, C., Milham, M., Castellanos, F. X., Quinn, B. T., et al. (2012). Default mode network abnormalities in idiopathic generalized epilepsy. Epilepsy & Behavior, 23(3), 353–359. https://doi.org/10.1016/j.yebeh.2012.01.013.

    Article  Google Scholar 

  20. Modi, A. C., Vannest, J., Combs, A., Turnier, L., & Wade, S. L. (2018). Pattern of executive functioning in adolescents with epilepsy: A multimethod measurement approach. Epilepsy & Behavior, 80, 5–10. https://doi.org/10.1016/j.yebeh.2017.12.021.

    Article  Google Scholar 

  21. Modi, A. C., Gutierrez-Colina, A. M., Wagner, J. L., Smith, G., Junger, K., Huszti, H., & Mara, C. A. (2019). Executive functioning phenotypes in youth with epilepsy. Epilepsy & Behavior, 90, 112–118. https://doi.org/10.1016/j.yebeh.2018.11.026.

    Article  Google Scholar 

  22. Nakao, K., & Treas, J. (1992). The 1989 Socioeconomic Index of Occupations: Construction from the 1989 Occupational Prestige Scores. Retrieved from Chicago:

  23. Nassau, J. H., & Drotar, D. (1997). Social competence among children with central nervous system-related chronic health conditions: A review. Journal of Pediatric Psychology, 22(6), 771–793. https://doi.org/10.1093/jpepsy/22.6.771.

    CAS  Article  PubMed  Google Scholar 

  24. Oyegbile, T. O., VanMeter, J. W., Motamedi, G. K., Bell, W. L., Gaillard, W. D., & Hermann, B. P. (2019). Default mode network deactivation in pediatric temporal lobe epilepsy: Relationship to a working memory task and executive function tests. Epilepsy & Behavior, 94, 124–130. https://doi.org/10.1016/j.yebeh.2019.02.031.

    Article  Google Scholar 

  25. Parrish, J., Geary, E., Jones, J., Seth, R., Hermann, B. P., & Seidenberg, M. (2007). Executive functioning in childhood epilepsy: Parent-report and cognitive assessment. Developmental Medicine and Child Neurology, 49(6), 412–416. https://doi.org/10.1111/j.1469-8749.2007.00412.x.

    Article  PubMed  Google Scholar 

  26. Pulsipher, D. T., Seidenberg, M., Guidotti, L., Tuchscherer, V. N., Morton, J., Sheth, R. D., & Hermann, B. (2009). Thalamofrontal circuitry and executive dysfunction in recent-onset juvenile myoclonic epilepsy. Epilepsia, 50(5), 1210–1219. https://doi.org/10.1111/j.1528-1167.2008.01952.x.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sadaghiani, S., & D'Esposito, M. (2015). Functional characterization of the Cingulo-Opercular network in the maintenance of tonic alertness. Cerebral Cortex, 25(9), 2763–2773. https://doi.org/10.1093/cercor/bhu072.

    Article  PubMed  Google Scholar 

  28. Slick, D. J., Lautzenhiser, A., Sherman, E. M., & Eyrl, K. (2006). Frequency of scale elevations and factor structure of the behavior rating inventory of executive function (BRIEF) in children and adolescents with intractable epilepsy. Child Neuropsychology, 12(3), 181–189. https://doi.org/10.1080/09297040600611320.

    Article  PubMed  Google Scholar 

  29. Song, J., Nair, V. A., Gaggl, W., & Prabhakaran, V. (2015). Disrupted brain functional Organization in Epilepsy Revealed by graph theory analysis. Brain Connectivity, 5(5), 276–283. https://doi.org/10.1089/brain.2014.0308.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wallis, G., Stokes, M., Cousijn, H., Woolrich, M., & Nobre, A. C. (2015). Frontoparietal and Cingulo-opercular networks play dissociable roles in control of working memory. Journal of Cognitive Neuroscience, 27(10), 2019–2034. https://doi.org/10.1162/jocn_a_00838.

    Article  PubMed  Google Scholar 

  31. Widjaja, E., Skocic, J., Go, C., Snead, O. C., Mabbott, D., & Smith, M. L. (2013). Abnormal white matter correlates with neuropsychological impairment in children with localization-related epilepsy. Epilepsia, 54(6), 1065–1073. https://doi.org/10.1111/epi.12208.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhao, Q., Li, H., Yu, X., Huang, F., Wang, Y., Liu, L., et al. (2017). Abnormal resting-state functional connectivity of insular subregions and disrupted correlation with working memory in adults with attention deficit/hyperactivity disorder. Frontiers in Psychiatry, 8, 200. https://doi.org/10.3389/fpsyt.2017.00200.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the families, health providers, and research members who made this study possible.

Funding sources

Supported by the Cincinnati Children’s Hospital Medical Center Research Innovation Pilot (RIP) Program.

Author information

Affiliations

Authors

Contributions

Author contributions included conception and study design (AM, JV, SW), data collection or acquisition (JV and AC), statistical analysis (TM, AGC, and JV), interpretation of results (AM, JV, AGC, SW, TH), drafting the manuscript work or revising it critically for important intellectual content (All authors) and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (All authors).

Corresponding author

Correspondence to Avani C. Modi.

Ethics declarations

This research is in compliance with the ethical standards of the Institutional Review Board of Cincinnati Children’s Hospital Medical center. All study participants provided written informed consent/assent.

Conflict of interest

None of the authors has any conflict of interest to disclose.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gutierrez-Colina, A.M., Vannest, J., Maloney, T. et al. The neural basis of executive functioning deficits in adolescents with epilepsy: a resting-state fMRI connectivity study of working memory. Brain Imaging and Behavior 15, 166–176 (2021). https://doi.org/10.1007/s11682-019-00243-z

Download citation

Keywords

  • Pediatric
  • Fronto-parietal network
  • Cingulo-opercular network
  • Neuroimaging