Skip to main content

Functional reorganization during cognitive function tasks in patients with amyotrophic lateral sclerosis

Abstract

Cognitive deficits, especially in the domains of social cognition and executive function including verbal fluency, are common in amyotrophic lateral sclerosis (ALS) patients. There is yet sparse understanding of pathogenesis of the underlying, possibly adaptive, cortical patterns. To address this issue, 65 patients with ALS and 33 age-, gender- and education-matched healthy controls were tested on cognitive and behavioral deficits with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Using functional magnetic resonance imaging (fMRI), cortical activity during social cognition and executive function tasks (theory of mind, verbal fluency, alternation) adapted from the ECAS was determined in a 3 Tesla scanner. Compared to healthy controls, ALS patients performed worse in the ECAS overall (p < 0.001) and in all of its subdomains (p < 0.02), except memory. Imaging revealed altered cortical activation during all tasks, with patients consistently showing a hyperactivation in relevant brain areas compared to healthy controls. Additionally, cognitively high performing ALS patients consistently exhibited more activation in frontal brain areas than low performing patients and behaviorally unimpaired patients presented with more neuronal activity in orbitofrontal areas than behaviorally impaired patients. In conclusion, hyperactivation in fMRI cognitive tasks seems to represent an early adaptive process to overcome neuronal cell loss in relevant brain areas. The hereby presented cortical pattern change might suggest that, once this loss passes a critical threshold and no cortical buffering is possible, clinical representation of cognitive and behavioral impairment evolves. Future studies might shed light on the pattern of cortical pattern change in the course of ALS.

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

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

References

  • Abrahams, S., Goldstein, L. H., Simmons, A., Brammer, M., Williams, S. C., Giampietro, V., et al. (2004). Word retrieval in amyotrophic lateral sclerosis: A functional magnetic resonance imaging study. Brain, 127, 1507–1517.

    Article  PubMed  CAS  Google Scholar 

  • Abrahams, S., Newton, J., Niven, E., Foley, J., & Bak, T. H. (2014). Screening for cognition and behaviour changes in ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15, 9–14.

    Article  PubMed  Google Scholar 

  • Abu-Akel, A., & Shamay-Tsoory, S. (2011). Neuroanatomical and neurochemical bases of theory of mind. Neuropsychologia, 49, 2971–2984.

    Article  PubMed  Google Scholar 

  • Al-Chalabi, A., Jones, A., Troakes, C., King, A., Al-Sarraj, S., & van den Berg, L. H. (2012). The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathologica, 124, 339–352.

    Article  PubMed  CAS  Google Scholar 

  • Allen, M. D., Owens, T. E., Fong, A. K., & Douglas, R. R. (2011). A functional neuroimaging analysis of the Trail making test-B: Implications for clinical application. Behavioural Neurology, 24, 159–171.

    Article  PubMed  PubMed Central  Google Scholar 

  • Andreasen, N. C., O'Leary, D. S., Cizadlo, T., Arndt, S., Rezai, K., Watkins, G. L., et al. (1995). Remembering the past: Two facets of episodic memory explored with positron emission tomography. American Journal of Psychiatry, 152, 1576–1585.

    Article  PubMed  CAS  Google Scholar 

  • Ashburner, J., & Friston, K. J. (2005). Unified segmentation. NeuroImage, 26, 839–851.

    Article  PubMed  Google Scholar 

  • Ayaz, H., Shewokis, P. A., Scull, L., Libon, D. J., Feldman, S., Eppig, J., et al. (2014). Assessment of prefrontal cortex activity in amyotrophic lateral sclerosis patients with functional near infrared spectroscopy. Journal of Neuroscience and Neuroengineering, 3, 41–51.

    Article  Google Scholar 

  • Baron-Cohen, S. (1995). Mindblindness: An essay on autism and theory of mind. Cambridge: MIT Press.

    Google Scholar 

  • Beeldman, E., Raaphorst, J., Klein Twennaar, M., de Visser, M., Schmand, B. A., & de Haan, R. J. (2016). The cognitive profile of ALS: A systematic review and meta-analysis update. Journal of Neurology, Neurosurgery and Psychiatry, 87, 611–619.

    Article  PubMed  Google Scholar 

  • Böhm, S., Aho-Özhan, H. E. A., Keller, J., Dorst, J., Uttner, I., Ludolph, A. C., et al. (2016). Medical decisions are independent of cognitive impairment in amyotrophic lateral sclerosis. Neurology, 87, 1737–1738.

    Article  PubMed  Google Scholar 

  • Bowie, C. R., & Harvey, P. D. (2006). Adminstration and interpretation of the Trail making test. Nature Protocols, 1, 2277–2281.

    Article  PubMed  CAS  Google Scholar 

  • Braak, H., Brettschneider, J., Ludolph, A. C., Lee, V. M., Trojanowski, J. Q., & Del Tredici, K. (2013). Amyotrophic lateral sclerosis - a model of corticofugal axonal spread. Nature Reviews Neurology, 9, 708–714.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brettschneider, J., Del Tredici, K., Toledo, J. B., Robinson, J. L., Irwin, D. J., Grossmann, M., et al. (2013). Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Annals of Neurology, 74, 20–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Burke, T., Pinto-Grau, M., Lonergan, K., Elamin, M., Bede, P., Costello, E., et al. (2016). Measurement of social cognition in amyotrophic lateral sclerosis: A population based study. PloS One, 11, e0160850.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cavallo, M., Adenzato, M., MacPherson, S. E., Karwig, G., Enrici, I., & Abrahams, S. (2011). Evidence of social understanding impairment in patients with amyotrophic lateral sclerosis. PloS One, 6, e25948.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cedarbaum, J. M., Stambler, N., Malta, E., Fuller, C., Hilt, D., Thurmond, B., et al. (1999). The ALSFRS-R: A revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (phase III). Journal of the Neurological Sciences, 169, 13–21.

    Article  PubMed  CAS  Google Scholar 

  • Cerami, C., Dodich, A., Canessa, N., Crespi, C., Iannaccone, S., Corbo, M., et al. (2014). Emotional empathy in amyotrophic lateral sclerosis: A behavioural and voxel-based morphometry study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 25, 21–29.

    Article  Google Scholar 

  • Chio, A., Pagani, M., Agosta, F., Calvo, A., Cistaro, A., & Filippi, M. (2014). Neuroimaging in amyotrophic lateral sclerosis: Insights into structural and functional changes. Lancet Neurology, 13, 1228–1240.

    Article  PubMed  Google Scholar 

  • Deichmann, R., & Turner, R. (2002). Improvement of local BOLD sensitivities in the presence of susceptibility gradients by using tilted slices. International Society for Magnetic Resonance in Medicine, 10, 1414.

    Google Scholar 

  • Filippi, M., Agosta, F., Grosskreutz, J., Benatar, M., Kassubek, J., Verstraete, E., et al. (2015). Progress towards a neuroimaging biomarker for amyotrophic lateral sclerosis. Lancet Neurology, 14, 786–788.

    Article  PubMed  Google Scholar 

  • Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J.-P., Frith, C. D., & Frackowiak, R. S. J. (1995). Statistical parametric maps in functional imaging: A general linear approach. Human Brain Mapping, 2, 189–210.

    Article  Google Scholar 

  • Gibbons, Z. C., Snowden, J. S., Thompson, J. C., Happé, F., Richardson, A., & Neary, D. (2007). Inferring thought and action in motor neurone disease. Neuropsychologia, 45, 1196–1207.

    Article  PubMed  CAS  Google Scholar 

  • Girardi, A., Macpherson, S. E., & Abrahams, S. (2011). Deficits in emotional and social cognition in amyotrophic lateral sclerosis. Neuropsychology, 25, 53–65.

    Article  PubMed  Google Scholar 

  • Goldstein, L. H., & Abrahams, S. (2013). Changes in cognition and behaviour in amyotrophic lateral sclerosis: Nature of impairment and implications for assessment. Lancet Neurology, 12, 368–380.

    Article  PubMed  Google Scholar 

  • Goldstein, L. H., Newsom-Davis, I. C., Bryant, V., Brammer, M., Leigh, P. N., & Simmons, A. (2011). Altered patterns of cortical activation in ALS patients during attention and cognitive response inhibition tasks. Journal of Neurology, 258, 2186–2198.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jelsone-Swain, L., Persad, C., Votruba, K. L., Weisenbach, S. L., Johnson, T., Gruis, K. L., et al. (2012). The relationship between depressive symptoms, disease state, and cognition in amyotrophic lateral sclerosis. Frontiers in Psychology, 3, 542.

  • Jelsone-Swain, L., Persad, C., Burkard, D., & Welsh, R. C. (2015). Action processing and mirror neuron function in patients with amyotrophic lateral sclerosis: An fMRI study. PloS One, 10, e0119862.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Johnstone, T., Ores Walsh, K. S., Greischar, L. L., Alexander, A. L., Fox, A. S., Davidson, R. J., et al. (2006). Motion correction and the use of motion covariates in multiple-subject fMRI analysis. Human Brain Mapping, 27, 779–788.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kasper, E., Schuster, C., Machts, J., Bittner, D., Vielhaber, S., Benecke, R., et al. (2015). Dysexecutive functioning in ALS patients and its clinical implications. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16, 160–171.

    Article  PubMed  CAS  Google Scholar 

  • Kassubek, J., Müller, H. P., Del Tredici, K., Brettschneider, J., Pinkhardt, E. H., Lulé, D., et al. (2014). Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain, 137, 1733–1740.

    Article  PubMed  Google Scholar 

  • Keller, J., Gorges, M., Horn, H. T., Aho-Özhan, H. E. A., Pinkhardt, E. H., Uttner, I., et al. (2015). Eye-tracking controlled cognitive function tests in patients with amyotrophic lateral sclerosis: A controlled proof-of-principle study. Journal of Neurology, 262, 1918–1926.

    Article  PubMed  CAS  Google Scholar 

  • Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., et al. (2011). Amyotrophic lateral sclerosis. Lancet, 377, 942–955.

    Article  PubMed  CAS  Google Scholar 

  • Konrad, C., Henningsen, H., Bremer, J., Mock, B., Deppe, M., Buchinger, C., et al. (2002). Pattern of cortical reorganization in amyotrophic lateral sclerosis: A functional magnetic resonance imaging study. Experimental Brain Research, 143, 51–56.

    Article  PubMed  Google Scholar 

  • Loose, M., Burkhardt, C., Aho-Özhan, H., Keller, J., Abdulla, S., Böhm, S., et al. (2016). Age and education-matched cut-off-scores for the revised German/Swiss-German version of ECAS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 17, 374–376.

    Article  PubMed  Google Scholar 

  • Ludolph, A., Drory, V., Hardiman, O., Nakano, I., Ravits, J., Robberecht, W., et al. (2015). A revision of the El Escorial criteria – 2015. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16, 291–292.

    Article  PubMed  Google Scholar 

  • Lulé, D., Diekmann, V., Anders, S., Kassubek, J., Kübler, A., Ludolph, A. C., et al. (2007). Brain responses to emotional stimuli in patients with amyotrophic lateral sclerosis (ALS). Journal of Neurology, 254, 519–527.

    Article  PubMed  Google Scholar 

  • Lulé, D., Burkhardt, C., Abdulla, S., Böhm, S., Kollewe, K., Uttner, I., et al. (2015). The Edinburgh cognitive and Behavioural amyotrophic lateral sclerosis screen: A cross-sectional comparison of established screening tools in a German-Swiss population. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16, 16–23.

    Article  PubMed  Google Scholar 

  • Maldjian, J. A., Laurienti, P. J., Kraft, R. A., & Burdette, J. H. (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage, 19, 1233–1239.

    Article  PubMed  Google Scholar 

  • Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 314, 130–133.

    Article  PubMed  CAS  Google Scholar 

  • Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proceedings of the National Academy of Sciences of the United States of America, 87, 9868–9872.

  • Phukan, J., Pender, N. P., & Hardiman, O. (2007). Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurology, 6, 994–1003.

    Article  PubMed  CAS  Google Scholar 

  • Phukan, J., Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., et al. (2012). The syndrome of cognitive impairment in amyotrophic lateral sclerosis: A population-based study. Journal of Neurology, Neurosurgery, and Psychiatry, 83, 102–108.

    Article  PubMed  Google Scholar 

  • Poldrack, R. A. (2007). Region of interest analysis for fMRI. Social Cognitive and Affective Neuroscience, 2, 67–70.

    Article  PubMed  PubMed Central  Google Scholar 

  • Poletti, B., Solca, F., Carelli, L., Madotto, F., Lafronzo, A., Faini, A., et al. (2016). The validation of the Italian Edinburgh cognitive and Behavioural ALS screen (ECAS). Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 17, 489–498.

    Article  PubMed  Google Scholar 

  • Poujois, A., Schneider, F. C., Faillenot, I., Camdessanché, J. P., Vandenberghe, N., Thomas-Antérion, C., et al. (2013). Brain plasticity in the motor network is correlated with disease progression in amyotrophic lateral sclerosis. Human Brain Mapping, 34, 2391–2401.

    Article  PubMed  Google Scholar 

  • Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., et al. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain, 134, 2456–2477.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ringholz, G. M., Appel, S. H., Bradshaw, M., Cooke, N. A., Mosnik, D. M., & Schulz, P. E. (2005). Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology, 65, 586–590.

    Article  PubMed  CAS  Google Scholar 

  • Saxe, R., & Kanwisher, N. (2003). People thinking about thinking people: The role of the temporo-parietal junction in “theory of mind”. NeuroImage, 19, 1835–1842.

    Article  PubMed  CAS  Google Scholar 

  • Schoenfeld, M. A., Tempelmann, C., Gaul, C., Kühnel, G. R., Düzel, E., Hopf, J.-M., et al. (2005). Functional motor compensation in amyotrophic lateral sclerosis. Journal of Neurology, 252, 944–952.

    Article  PubMed  Google Scholar 

  • Sebastian, C. L., Fontaine, N. M. G., Bird, G., Blakemore, S.-J., De Brito, S. A., McCrory, E. J. P., et al. (2012). Neural processing associated with cognitive and affective theory of mind in adolescents and adults. Social Cognitive and Affective Neuroscience, 7, 53–63.

    Article  PubMed  Google Scholar 

  • Sripada, C. S., Angstadt, M., Banks, S., Nathan, P. J., Liberzon, I., & Phan, K. L. (2009). Functional neuroimaging of mentalizing during the trust game in social anxiety disorder. Neuroreport, 20, 984–989.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stark, C., & Squire, L. (2001). When zero is not zero: The problem of ambiguous baseline conditions in fMRI. Proceedings of the National Academy of Sciences of the United States of America, 98, 12760–12766.

  • Strong, M. J., Abrahams, S., Goldstein, L. H., Woolley, S., McLaughlin, P., Snowden, J., et al. (2017). Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, online first, DOI:10.1080/21678421.2016.1267768.

  • Tsermentseli, S., Leigh, P. N., & Goldstein, L. H. (2012). The anatomy of cognitive impairment in amyotrophic lateral sclerosis: More than frontal lobe dysfunction. Cortex, 48, 166–182.

    Article  PubMed  Google Scholar 

  • Tsujimoto, M., Senda, J., Ishihara, T., Niimi, Y., Kawai, Y., Atsuta, N., et al. (2011). Behavioral changes in early ALS correlate with voxel-based morphometry and diffusion tensor imaging. Journal of the Neurological Sciences, 307, 34–40.

    Article  PubMed  Google Scholar 

  • Uddin, L. Q., Iacobini, M., Lange, C., & Keenan, J. P. (2007). The self and social cognition: The role of cortical midline structures and mirror neurons. Trends in Cognitive Sciences, 11, 153–157.

  • Van der Hulst, E.-J., Bak, T. H., & Abrahams, S. (2015). Impaired affective and cognitive theory of mind and behavioural change in amyotrophic lateral sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 86, 1208–1215.

    Article  PubMed  Google Scholar 

  • Wagner, S., Sebastian, A., Lieb, K., Tüscher, O., & Tadic, A. (2014). A coordinate based ALE functional MRI meta-analysis of brain activation during verbal fluency tasks in healthy control subjects. BMC Neuroscience, 15, 19.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wilson, R. C., Takahashi, Y. K., Schoenbaum, G., & Niv, Y. (2014). Orbitofrontal cortex as a cognitive map of task space. Neuron, 81, 267–279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Witiuk, K., Fernandez-Ruiz, J., McKee, R., Alahyane, N., Coe, B. C., Melanson, M., et al. (2014). Cognitive deterioration and functional compensation in ALS measured with fMRI using an inhibitory task. Journal of Neuroscience, 34, 14260–14271.

    Article  PubMed  CAS  Google Scholar 

  • Zaitchik, D., Walker, C., Miller, S., LaViolette, P., Feczkoi, E., & Dickerson, B. C. (2010). Mental state attribution and the temporoparietal junction: An fMRI study comparing belief, emotion, and perception. Neuropsychologia, 48, 2528–2536.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zakzanis, K. K., Mraz, R., & Graham, S. J. (2005). An fMRI study of the Trail making test. Neuropsychologia, 43, 1878–1886.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Sonja Fuchs, Ines Schulthess (née Röll) and Jan Luitjens for their assistance with data collection as well as all those who participated in the study.

This is an EU Joint Programme – Neurodegenerative Disease Research (JPND; 01ED1405) project. The project is supported through the following organizations under the aegis of JPND – www.jpnd.eu, e.g. Germany, Bundesministerium für Bildung und Forschung (BMBF, FKZ), Sweden, Vetenskaprådet Sverige, and Poland, Narodowe Centrum Badan i Rozwoju (NCBR). This work was additionally supported by the BMBF (#01GM1103A).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dorothée Lulé.

Ethics declarations

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The experimental protocol was approved by the Ethics Committee of the University of Ulm (Statement No. 19/12).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Keller, J., Böhm, S., Aho-Özhan, H.E.A. et al. Functional reorganization during cognitive function tasks in patients with amyotrophic lateral sclerosis. Brain Imaging and Behavior 12, 771–784 (2018). https://doi.org/10.1007/s11682-017-9738-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-017-9738-3

Keywords

  • Amyotrophic lateral sclerosis
  • fMRI
  • Cognition
  • Executive function
  • Motor neuron disease