Increased brain connectivity and activation after cognitive rehabilitation in Parkinson's disease: a randomized controlled trial

María Díez-Cirarda, Natalia Ojeda, Javier Peña, Alberto Cabrera-Zubizarreta, Olaia Lucas-Jiménez, Juan Carlos Gómez-Esteban, Maria Ángeles Gómez-Beldarrain, Naroa Ibarretxe-Bilbao, María Díez-Cirarda, Natalia Ojeda, Javier Peña, Alberto Cabrera-Zubizarreta, Olaia Lucas-Jiménez, Juan Carlos Gómez-Esteban, Maria Ángeles Gómez-Beldarrain, Naroa Ibarretxe-Bilbao

Abstract

Cognitive rehabilitation programs have demonstrated efficacy in improving cognitive functions in Parkinson's disease (PD), but little is known about cerebral changes associated with an integrative cognitive rehabilitation in PD. To assess structural and functional cerebral changes in PD patients, after attending a three-month integrative cognitive rehabilitation program (REHACOP). Forty-four PD patients were randomly divided into REHACOP group (cognitive rehabilitation) and a control group (occupational therapy). T1-weighted, diffusion weighted and functional magnetic resonance images (fMRI) during resting-state and during a memory paradigm (with learning and recognition tasks) were acquired at pre-treatment and post-treatment. Cerebral changes were assessed with repeated measures ANOVA 2 × 2 for group x time interaction. During resting-state fMRI, the REHACOP group showed significantly increased brain connectivity between the left inferior temporal lobe and the bilateral dorsolateral prefrontal cortex compared to the control group. Moreover, during the recognition fMRI task, the REHACOP group showed significantly increased brain activation in the left middle temporal area compared to the control group. During the learning fMRI task, the REHACOP group showed increased brain activation in the left inferior frontal lobe at post-treatment compared to pre-treatment. No significant structural changes were found between pre- and post-treatment. Finally, the REHACOP group showed significant and positive correlations between the brain connectivity and activation and the cognitive performance at post-treatment. This randomized controlled trial suggests that an integrative cognitive rehabilitation program can produce significant functional cerebral changes in PD patients and adds evidence to the efficacy of cognitive rehabilitation programs in the therapeutic approach for PD.

Keywords: Brain activation; Brain connectivity; Cerebral changes; Parkinson’s disease; Plasticity; Randomized controlled trial.

Conflict of interest statement

Funding

This study was supported by the Department of Health of the Basque Government [2011111117 to Dr. Naroa Ibarretxe-Bilbao] and the Spanish Ministry of Economy and Competitiveness [PSI2012–32441 to Dr. Naroa Ibarretxe-Bilbao].

Conflict of interest statement

N.O. and J.P. are co-authors and copyright holders of the REHACOP cognitive rehabilitation program, published by Parima Digital, S.L. (Bilbao, Spain). M.D.C., A.C.Z., O.L.J., J.C.G.E., M.A.G.B. and N.I.B. have no conflicts of interest to report.

Ethical approval and informed consent

The study protocol was approved by the Ethics Committee at the Health Department of the Basque Mental Health System in Spain and the Ethics Committee of the University of Deusto (approval Number: Psi-09/11–12). All subjects were volunteers and provided written informed consent prior to their participation in the study, in accordance with the Declaration of Helsinki of 1975, and the applicable revisions at the time of the investigation. All patients at the CG were provided with REHACOP rehabilitation once the trial finished.

Figures

Fig. 1
Fig. 1
CONSORT Flow Diagram. CONSORT = Consolidated Standards of Reporting Trials; MRI = Magnetic Resonance Imaging
Fig. 2
Fig. 2
Resting-state brain connectivity fMRI changes (interaction level group x time). Seed (black point) = the left inferior temporal lobe (BA20L; x = −51; y = −23; z = −29); Targets (red points) = left and right dorsolateral prefrontal cortex (BA9L; x = −29; y = 41; z = 25) and (BA9R; x = 33; y = 42; z = 24). Lines represent increased connectivity between the seed and target at the interaction level (group x time), showing the REHACOP group increased brain connectivity at post-treatment compared to the CG. Graphic shows mean connectivity values during resting-state at pre-treatment and post-treatment for REHACOP group and CG. Results are shown at p < .05 FDR-corrected. A = Anterior; P = Posterior; I = Inferior; S = Superior; CG = Control Group
Fig. 3
Fig. 3
fMRI activation changes during Memory fMRI Paradigm. Areas of brain activation change are shown in red. Graphics show mean beta values while the learning and the recognition memory fMRI tasks at pre-treatment and post-treatment. Results are shown at p < .001-uncorrected. A = Anterior; P = Posterior; I = Inferior; S = Superior; CG = Control Group

References

    1. Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, et al. Mild cognitive impairment in parkinson disease: a multicenter pooled analysis. Neurology. 2010;75(12):1062–1069. doi: 10.1212/WNL.0b013e3181f39d0e.
    1. American Psychiatric Association. (2003). Apa (2000). Diagnostic and Statistical Manual of Mental Disorders DSM (4th Ed., Text Revision),
    1. Ashburner J, Barnes G, Chen C, Daunizeau J, Flandin G, Friston K, et al. SPM8 manual. Institute of Neurology: Functional Imaging Laboratory; 2012.
    1. Bahar-Fuchs A, Clare L, Woods B. Cognitive training and cognitive rehabilitation for persons with mild to moderate dementia of the alzheimer’s or vascular type: a review. Alzheimer's Research & Therapy. 2013;5(4):35. doi: 10.1186/alzrt189.
    1. Belleville S, Clement F, Mellah S, Gilbert B, Fontaine F, Gauthier S. Training-related brain plasticity in subjects at risk of developing alzheimer's disease. Brain: A Journal of Neurology. 2011;134(Pt 6):1623–1634. doi: 10.1093/brain/awr037.
    1. Biundo R, Calabrese M, Weis L, Facchini S, Ricchieri G, Gallo P, Antonini A. Anatomical correlates of cognitive functions in early parkinson's disease patients. PloS One. 2013;8(5):e64222. doi: 10.1371/journal.pone.0064222.
    1. Cabeza R, Nyberg L. Imaging cognition II: an empirical review of 275 PET and fMRI studies. Journal of Cognitive Neuroscience. 2000;12(1):1–47. doi: 10.1162/08989290051137585.
    1. Cerasa A, Gioia MC, Salsone M, Donzuso G, Chiriaco C, Realmuto S, et al. Neurofunctional correlates of attention rehabilitation in parkinson’s disease: an explorative study. Neurological Sciences. 2014;35(8):1173–1180. doi: 10.1007/s10072-014-1666-z.
    1. Chiaravalloti ND, Wylie G, Leavitt V, DeLuca J. Increased cerebral activation after behavioral treatment for memory deficits in MS. Journal of Neurology. 2012;259(7):1337–1346. doi: 10.1007/s00415-011-6353-x.
    1. Chiaravalloti ND, Ibarretxe-Bilbao N, DeLuca J, Rusu O, Pena J, García-Gorostiaga I, Ojeda N. The source of the memory impairment in parkinson's disease: acquisition versus retrieval. Movement Disorders. 2014;29(6):765–771. doi: 10.1002/mds.25842.
    1. Christopher L, Strafella AP. Neuroimaging of brain changes associated with cognitive impairment in parkinson's disease. Journal of Neuropsychology. 2013;7(2):225–240. doi: 10.1111/jnp.12015.
    1. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis: I. Segmentation and surface reconstruction. NeuroImage. 1999;9(2):179–194. doi: 10.1006/nimg.1998.0395.
    1. Demirakca, T., Cardinale, V., Dehn, S., Ruf, M., & Ende, G. (2015). The exercising brain: Changes in functional connectivity induced by an integrated multimodal cognitive and whole-body coordination training. Neural Plasticity, 2016 doi:10.1155/2016/8240894
    1. Destrieux C, Fischl B, Dale A, Halgren E. Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. NeuroImage. 2010;53(1):1–15. doi: 10.1016/j.neuroimage.2010.06.010.
    1. Díez-Cirarda M, Ojeda N, Peña J, Cabrera-Zubizarreta A, Gómez-Beldarrain MÁ, Gómez-Esteban JC, Ibarretxe-Bilbao N. Neuroanatomical correlates of theory of mind deficit in parkinson’s disease: a multimodal imaging study. PloS One. 2015;10(11):e0142234. doi: 10.1371/journal.pone.0142234.
    1. Douaud G, Smith S, Jenkinson M, Behrens T, Johansen-Berg H, Vickers J, et al. Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain: A Journal of Neurology. 2007;130(Pt 9):2375–2386. doi: 10.1093/brain/awm184.
    1. Draganski B, Gaser C, Kempermann G, Kuhn HG, Winkler J, Buchel C, May A. Temporal and spatial dynamics of brain structure changes during extensive learning. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2006;26(23):6314–6317. doi: 10.1523/JNEUROSCI.4628-05.2006.
    1. Eack SM, Hogarty GE, Cho RY, Prasad KM, Greenwald DP, Hogarty SS, Keshavan MS. Neuroprotective effects of cognitive enhancement therapy against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial. Archives of General Psychiatry. 2010;67(7):674–682. doi: 10.1001/archgenpsychiatry.2010.63.
    1. Efron B, Tibshirani RJ. An introduction to the bootstrap CRC press. 1994.
    1. Eichenbaum H, Yonelinas AP, Ranganath C. The medial temporal lobe and recognition memory. Annual Review of Neuroscience. 2007;30:123–152. doi: 10.1146/annurev.neuro.30.051606.094328.
    1. Engvig A, Fjell AM, Westlye LT, Moberget T, Sundseth Ø, Larsen VA, Walhovd KB. Effects of memory training on cortical thickness in the elderly. NeuroImage. 2010;52(4):1667–1676. doi: 10.1016/j.neuroimage.2010.05.041.
    1. Filippi M, Riccitelli G, Mattioli F, Capra R, Stampatori C, Pagani E, et al. Multiple sclerosis: effects of cognitive rehabilitation on structural and functional MR imaging measures—an explorative study. Radiology. 2012;262(3):932–940. doi: 10.1148/radiol.11111299.
    1. Fischl B. FreeSurfer. NeuroImage. 2012;62(2):774–781. doi: 10.1016/j.neuroimage.2012.01.021.
    1. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis: II: inflation, flattening, and a surface-based coordinate system. NeuroImage. 1999;9(2):195–207. doi: 10.1006/nimg.1998.0396.
    1. Goldman JG, Litvan I. Mild cognitive impairment in parkinson's disease. Minerva Medica. 2011;102(6):441–459.
    1. Hindle JV, Petrelli A, Clare L, Kalbe E. Nonpharmacological enhancement of cognitive function in parkinson's disease: a systematic review. Movement Disorders. 2013;28(8):1034–1049. doi: 10.1002/mds.25377.
    1. Hoehn, M. M., & Yahr, M. D. (1998). Parkinsonism: Onset, progression, and mortality. 1967. Neurology, 50(2), 318–334. doi:10.1212/WNL.17.5.427
    1. Hojat M, Xu G. A visitor's guide to effect sizes–statistical significance versus practical (clinical) importance of research findings. Advances in Health Sciences Education. 2004;9(3):241–249. doi: 10.1023/B:AHSE.0000038173.00909.f6.
    1. Ibarretxe-Bilbao N, Junque C, Marti MJ, Tolosa E. Brain structural MRI correlates of cognitive dysfunctions in parkinson’s disease. Journal of the Neurological Sciences. 2011;310(1):70–74. doi: 10.1016/j.jns.2011.07.054.
    1. Ibarretxe-Bilbao N, Zarei M, Junque C, Marti MJ, Segura B, Vendrell P, et al. Dysfunctions of cerebral networks precede recognition memory deficits in early parkinson’s disease. NeuroImage. 2011;57(2):589–597. doi: 10.1016/j.neuroimage.2011.04.049.
    1. Jones DK, Cercignani M. Twenty-five pitfalls in the analysis of diffusion MRI data. NMR in Biomedicine. 2010;23(7):803–820. doi: 10.1002/nbm.1543.
    1. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. The Journal of Neuropsychiatry and Clinical Neurosciences. 2000;12(2):233–239. doi: 10.1176/jnp.12.2.233.
    1. Kelley WM, Miezin FM, McDermott KB, Buckner RL, Raichle ME, Cohen NJ, et al. Hemispheric specialization in human dorsal frontal cortex and medial temporal lobe for verbal and nonverbal memory encoding. Neuron. 1998;20(5):927–936. doi: 10.1016/S0896-6273(00)80474-2.
    1. Lancaster, J. L., Woldorff, M. G., Parsons, L. M., Liotti, M., Freitas, C. S., Rainey, L., et al. (2000). Automated Talairach atlas labels for functional brain mapping. Human brain mapping, 10(3), 120–131.
    1. Leavitt VM, Wylie GR, Girgis PA, DeLuca J, Chiaravalloti ND. Increased functional connectivity within memory networks following memory rehabilitation in multiple sclerosis. Brain Imaging and Behavior. 2014;8(3):394–402. doi: 10.1007/s11682-012-9183-2.
    1. Leung IH. Cognitive training in parkinson disease. Neurology. 2015;85:1–9. doi: 10.1212/WNL.0000000000002145.
    1. Lucas-Jiménez O, Díez-Cirarda M, Ojeda N, Peña J, Cabrera-Zubizarreta A, Ibarretxe-Bilbao N. Verbal memory in parkinson’s disease: a combined DTI and fMRI study. Journal of Parkinson’s Disease. 2015;5(4):793–804. doi: 10.3233/JPD-150623.
    1. Marsolek CJ, Kosslyn SM, Squire LR. Form-specific visual priming in the right cerebral hemisphere. Journal of Experimental Psychology. Learning, Memory, and Cognition. 1992;18(3):492. doi: 10.1037/0278-7393.18.3.492.
    1. Martinez-Martin P, Gil-Nagel A, Gracia LM, Gómez JB, Martínez-Sarriés J, Bermejo F. Unified parkinson's disease rating scale characteristics and structure. Movement Disorders. 1994;9(1):76–83. doi: 10.1002/mds.870090112.
    1. Mattay VS, Tessitore A, Callicott JH, Bertolino A, Goldberg TE, Chase TN, et al. Dopaminergic modulation of cortical function in patients with parkinson's disease. Annals of Neurology. 2002;51(2):156–164. doi: 10.1002/ana.10078.
    1. Nagano-Saito A, Washimi Y, Arahata Y, Kachi T, Lerch JP, Evans AC, et al. Cerebral atrophy and its relation to cognitive impairment in parkinson disease. Neurology. 2005;64(2):224–229. doi: 10.1212/01.WNL.0000149510.41793.50.
    1. Nombela C, Bustillo PJ, Castell PF, Sanchez L, Medina V, Herrero MT. Cognitive rehabilitation in parkinson’s disease: evidence from neuroimaging. Frontiers in Neurology. 2011;2:82. doi: 10.3389/fneur.2011.00082.
    1. Pena J, Ibarretxe-Bilbao N, Garcia-Gorostiaga I, Gomez-Beldarrain MA, Diez-Cirarda M, Ojeda N. Improving functional disability and cognition in parkinson disease: randomized controlled trial. Neurology. 2014;83(23):2167–2174. doi: 10.1212/WNL.0000000000001043.
    1. Penadés R, Pujol N, Catalán R, Massana G, Rametti G, García-Rizo C, et al. Brain effects of cognitive remediation therapy in schizophrenia: a structural and functional neuroimaging study. Biological Psychiatry. 2013;73(10):1015–1023. doi: 10.1016/j.biopsych.2013.01.017.
    1. Pereira JB, Junque C, Marti MJ, Ramirez-Ruiz B, Bartres-Faz D, Tolosa E. Structural brain correlates of verbal fluency in parkinson's disease. Neuroreport. 2009;20(8):741–744. doi: 10.1097/WNR.0b013e328329370b.
    1. Schwindt GC, Black SE. Functional imaging studies of episodic memory in alzheimer's disease: a quantitative meta-analysis. NeuroImage. 2009;45(1):181–190. doi: 10.1016/j.neuroimage.2008.11.024.
    1. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage. 2004;23:S208–S219. doi: 10.1016/j.neuroimage.2004.07.051.
    1. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, et al. Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. NeuroImage. 2006;31(4):1487–1505. doi: 10.1016/j.neuroimage.2006.02.024.
    1. Thalheimer, W., & Cook, S. (2002). How to calculate effect sizes from published research: A simplified methodology. Work-Learning Research, 1–9.
    1. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in parkinson's disease. Movement Disorders. 2010;25(15):2649–2653. doi: 10.1002/mds.23429.
    1. van Paasschen J, Clare L, Yuen KS, Woods RT, Evans SJ, Parkinson CH, et al. Cognitive rehabilitation changes memory-related brain activity in people with alzheimer disease. Neurorehabilitation and Neural Repair. 2013;27(5):448–459. doi: 10.1177/1545968312471902.
    1. Weissenbacher A, Kasess C, Gerstl F, Lanzenberger R, Moser E, Windischberger C. Correlations and anticorrelations in resting-state functional connectivity MRI: a quantitative comparison of preprocessing strategies. NeuroImage. 2009;47(4):1408–1416. doi: 10.1016/j.neuroimage.2009.05.005.
    1. Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connectivity. 2012;2(3):125–141. doi: 10.1089/brain.2012.0073.
    1. Whittington CJ, Podd J, Stewart-Williams S. Memory deficits in parkinson’s disease. Journal of Clinical and Experimental Neuropsychology. 2006;28(5):738–754. doi: 10.1080/13803390590954236.
    1. Wiesman, A. I., Heinrichs-Graham, E., McDermott, T. J., Santamaria, P. M., Gendelman, H. E., & Wilson, T. W. (2016). Quiet connections: reduced fronto-temporal connectivity in nondemented parkinson's disease during working memory encoding. Human Brain Mapping, doi:10.1002/hbm.23237
    1. Wolf DH, Gur RC, Valdez JN, Loughead J, Elliott MA, Gur RE, Ragland JD. Alterations of fronto-temporal connectivity during word encoding in schizophrenia. Psychiatry Research: Neuroimaging. 2007;154(3):221–232. doi: 10.1016/j.pscychresns.2006.11.008.
    1. Wykes T, Spaulding WD. Thinking about the future cognitive remediation therapy--what works and could we do better? Schizophrenia Bulletin. 2011;37(Suppl 2):S80–S90. doi: 10.1093/schbul/sbr064.
    1. Yarnall AJ, Breen DP, Duncan GW, Khoo TK, Coleman SY, Firbank MJ, ICICLE-PD Study Group. Characterizing mild cognitive impairment in incident parkinson disease: the ICICLE-PD study. Neurology. 2014;82(4):308–316. doi: 10.1212/WNL.0000000000000066.
    1. Yesavage JA, Sheikh JI. 9/geriatric depression scale (GDS) recent evidence and development of a shorter violence. Clinical Gerontologist. 1986;5(1–2):165–173. doi: 10.1300/J018v05n01_09.

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