Abstract
Purpose
The etiology of constipation in Parkinson’s disease is largely unknown. The aim of this study was to explore changes in regional neural activity and functional connections associated with constipation in a large cohort of individuals with Parkinson’s disease.
Methods
We prospectively recruited 106 patients with Parkinson’s disease with constipation and 73 patients with Parkinson’s disease without constipation. We used resting-state functional magnetic resonance imaging for the first time to measure differences in regional neural activity and functional connections between the two patient groups.
Results
Patients with constipation showed significantly higher amplitude of low-frequency fluctuation than patients without constipation in the right dorsal pons extending into the cerebellum and in the right insula. The two types of patients also showed substantial differences in functional connections linking the superior temporal gyrus, particularly the right superior temporal gyrus, with multiple brain regions.
Conclusion
Regional neural activity and functional connectivity in the brain differ substantially between patients with Parkinson’s disease with or without constipation. These findings provide a foundation for understanding the pathophysiology of constipation in Parkinson’s disease and for identifying therapeutic targets.
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Data availability
Anonymized data that were analyzed in this report are available upon request from the corresponding authors.
References
Knudsen K, Krogh K, Ostergaard K, Borghammer P (2017) Constipation in parkinson’s disease: subjective symptoms, objective markers, and new perspectives. Mov Disord 32(1):94–105
Rossi M, Merello M, Perez-Lloret S (2015) Management of constipation in Parkinson’s disease. Expert Opin Pharmacother 16(4):547–557
Borghammer P (2018) Is constipation in Parkinson’s disease caused by gut or brain pathology? Parkinsonism Relat Disord 55:6–7
Orimo S, Ghebremedhin E, Gelpi E (2018) Peripheral and central autonomic nervous system: does the sympathetic or parasympathetic nervous system bear the brunt of the pathology during the course of sporadic PD? Cell Tissue Res 373(1):267–286
Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P (2016) Pathological alpha-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol 79(6):940–949
Cerasa A, Koch G, Donzuso G, Mangone G, Morelli M, Brusa L, Stampanoni Bassi M, Ponzo V, Picazio S, Passamonti L, Salsone M, Augimeri A, Caltagirone C, Quattrone A (2015) A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias. Brain 138(Pt 2):414–427
Otomune H, Mihara M, Hattori N, Fujimoto H, Kajiyama Y, Konaka K, Mitani Y, Watanabe Y, Mochizuki H (2019) Involvement of cortical dysfunction in frequent falls in patients with Parkinson’s disease. Parkinsonism Relat Disord 64:169–174
Luo C, Chen Q, Song W, Chen K, Guo X, Yang J, Huang X, Gong Q, Shang HF (2014) Resting-state fMRI study on drug-naive patients with Parkinson’s disease and with depression. J Neurol Neurosurg Psychiatry 85(6):675–683
Chung SJ, Bae YJ, Jun S, Yoo HS, Kim SW, Lee YH, Sohn YH, Lee SK, Seong JK, Lee PH (2019) Dysautonomia is associated with structural and functional alterations in Parkinson disease. Neurology 92(13):e1456–e1467
Dayan E, Sklerov M, Browner N (2018) Disrupted hypothalamic functional connectivity in patients with PD and autonomic dysfunction. Neurology 90(23):e2051–e2058
Tessa C, Toschi N, Orsolini S, Valenza G, Lucetti C, Barbieri R, Diciotti S (2019) Central modulation of parasympathetic outflow is impaired in de novo Parkinson’s disease patients. PLOS ONE 14(1):e0210324
Zuo XN, Di Martino A, Kelly C, Shehzad ZE, Gee DG, Klein DF, Castellanos FX, Biswal BB, Milham MP (2010) The oscillating brain: complex and reliable. Neuroimage 49(2):1432–1445
Gorges M, Muller HP, Lule D, Ludolph AC, Pinkhardt EH, Kassubek J (2013) Functional connectivity within the default mode network is associated with saccadic accuracy in Parkinson’s disease: a resting-state FMRI and videooculographic study. Brain Connect 3(3):265–272
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30(12):1591–1601
Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, Brown RG, Koller W, Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ, Olanow CW (2006) International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord 21(7):916–923
Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE (2010) Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 25(15):2649–2653
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N, U. R. T. F. Movement Disorder Society (2008) Movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23(15):2129–70
Whitfield-Gabrieli S, Nieto-Castanon A (2012) Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2(3):125–141
Yan CG, Wang XD, Zuo XN, Zang YF (2016) DPABI: data processing & analysis for (resting-state) brain imaging. Neuroinformatics 14(3):339–351
Sklerov M, Dayan E, Browner N (2019) Functional neuroimaging of the central autonomic network: recent developments and clinical implications. Clin Auton Res 29(6):555–566
Sakakibara R (2021) Gastrointestinal dysfunction in movement disorders. Neurol Sci 42(4):1355–1365
Nakamori H, Naitou K, Horii Y, Shimaoka H, Horii K, Sakai H, Yamada A, Furue H, Shiina T, Shimizu Y (2019) Roles of the noradrenergic nucleus locus coeruleus and dopaminergic nucleus A11 region as supraspinal defecation centers in rats. Am J Physiol Gastrointest Liver Physiol 317(4):G545–G555
Tateno F, Sakakibara R, Kishi M, Tsuyusaki Y, Furukawa R, Yoshimatsu Y, Suzuki Y (2012) Brainstem stroke and increased anal tone. Low Urin Tract Symp 4(3):161–163
Abbott RD, Ross GW, Petrovitch H, Tanner CM, Davis DG, Masaki KH, Launer LJ, Curb JD, White LR (2007) Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord 22(11):1581–1586
King GW (1980) Topology of ascending brainstem projections to nucleus parabrachialis in the cat. J Comp Neurol 191(4):615–638
Voshart K, van der Kooy D (1981) The organization of the efferent projections of the parabrachial nucleus of the forebrain in the rat: a retrograde fluorescent double-labeling study. Brain Res 212(2):271–286
Eguchi K, Tadaki E, Simbulan D Jr, Kumazawa T (1987) Respiratory depression caused by either morphine microinjection or repetitive electrical stimulation in the region of the nucleus parabrachialis of cats. Pflugers Arch 409(4–5):367–373
Topolovec JC, Gati JS, Menon RS, Shoemaker JK, Cechetto DF (2004) Human cardiovascular and gustatory brainstem sites observed by functional magnetic resonance imaging. J Comp Neurol 471(4):446–461
Kimmerly DS, Morris BL, Floras JS (2013) Apnea-induced cortical BOLD-fMRI and peripheral sympathoneural firing response patterns of awake healthy humans. PLOS ONE 8(12):e82525
Frangos E, Komisaruk BR (2017) Access to vagal projections via cutaneous electrical stimulation of the neck: fMRI evidence in healthy humans. Brain Stimul 10(1):19–27
Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, Ziemssen T (2012) Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord 27(5):617–626
Orso B, Arnaldi D, Fama F, Girtler N, Brugnolo A, Doglione E, Filippi L, Massa F, Peira E, Bauckneht M, Morbelli S, Nobili F, Pardini M (2020) Anatomical and neurochemical bases of theory of mind in de novo Parkinson’s disease. Cortex 130:401–412
Alzahrani H, Antonini A, Venneri A (2016) Apathy in mild Parkinson’s disease: neuropsychological and neuroimaging evidence. J Parkinsons Dis 6(4):821–832
Lee SH, Kim SS, Tae WS, Lee SY, Lee KU, Jhoo J (2013) Brain volumetry in Parkinson’s disease with and without dementia: where are the differences? Acta Radiol 54(5):581–586
Li Y, Huang P, Guo T, Guan X, Gao T, Sheng W, Zhou C, Wu J, Song Z, Xuan M, Gu Q, Xu X, Yang Y, Zhang M (2020) Brain structural correlates of depressive symptoms in Parkinson’s disease patients at different disease stage. Psychiatry Res Neuroimag 296:111029
Ruan X, Li Y, Li E, **e F, Zhang G, Luo Z, Du Y, Jiang X, Li M, Wei X (2020) Impaired topographical organization of functional brain networks in Parkinson’s disease patients with freezing of gait. Front Aging Neurosci 12:580564
Macefield VG, Gandevia SC, Henderson LA (2006) Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory capacity apnea: a fMRI study. J Appl Physiol (1985) 100(1):266–73
Baker J, Paturel JR, Kimpinski K (2019) Cerebellar impairment during an orthostatic challenge in patients with neurogenic orthostatic hypotension. Clin Neurophysiol 130(1):189–195
Zhu Q, Cai W, Zheng J, Li G, Meng Q, Liu Q, Zhao J, von Deneen KM, Wang Y, Cui G, Duan S, Han Y, Wang H, Tian J, Zhang Y, Nie Y (2016) Distinct resting-state brain activity in patients with functional constipation. Neurosci Lett 632:141–146
Schmidt FM, Santos VL (2014) Prevalence of constipation in the general adult population: an integrative review. J Wound Ostomy Cont Nurs 41(1):70–6
Szewczyk-Krolikowski K, Tomlinson P, Nithi K, Wade-Martins R, Talbot K, Ben-Shlomo Y, Hu MT (2014) The influence of age and gender on motor and non-motor features of early Parkinson’s disease: initial findings from the Oxford parkinson disease center (OPDC) discovery cohort. Parkinsonism Relat Disord 20(1):99–105
Picillo M, Amboni M, Erro R, Longo K, Vitale C, Moccia M, Pierro A, Santangelo G, De Rosa A, De Michele G, Santoro L, Orefice G, Barone P, Pellecchia MT (2013) Gender differences in non-motor symptoms in early, drug naive Parkinson’s disease. J Neurol 260(11):2849–2855
Pagano G, Tan EE, Haider JM, Bautista A, Tagliati M (2015) Constipation is reduced by beta-blockers and increased by dopaminergic medications in Parkinson’s disease. Parkinsonism Relat Disord 21(2):120–125
Muller B, Larsen JP, Wentzel-Larsen T, Skeie GO, Tysnes OB, G. Parkwest Study (2011) Autonomic and sensory symptoms and signs in incident, untreated Parkinson’s disease: frequent but mild. Mov Disord 26(1):65–72
Pfeiffer RF (2020) Autonomic dysfunction in Parkinson’s Disease. Neurotherapeutics 17(4):1464–1479
Acknowledgements
We would like to thank all the patients in this study.
Funding
This study was supported by the Henan Province Science and Technology Development Plan (192102310085) and the Henan Province Medical Science and Technology Research Program (201701018).
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The authors declare that they do not have any conflicts of interest.
Ethical statement
This study was approved by the Ethics Committee of Henan Provincial People’s Hospital and conducted in accordance with the ethical standards in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants.
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Zheng, J.H., Sun, W.H., Ma, J.J. et al. Resting-state functional magnetic resonance imaging in patients with Parkinson’s disease with and without constipation: a prospective study. Clin Auton Res 32, 51–58 (2022). https://doi.org/10.1007/s10286-022-00851-8
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DOI: https://doi.org/10.1007/s10286-022-00851-8