Abstract
Optokinetic eye movements are crucial for keeping a stable image on the retina during movements of the head. These eye movements can be differentiated into a cortically generated response (optokinetic look nystagmus) and the highly reflexive optokinetic stare nystagmus, which is controlled by circuits in the brainstem and cerebellum. The contributions of these infratentorial networks and their functional connectivity with the cortical eye fields are still poorly understood in humans. To map ocular motor centres in the cerebellum and brainstem, we studied stare nystagmus using small-field optokinetic stimuli in the horizontal and vertical directions in 22 healthy subjects. We were able to differentiate ocular motor areas of the pontine brainstem and midbrain in vivo for the first time. Direction and velocity-dependent activations were found in the pontine brainstem (nucleus reticularis, tegmenti pontis, and paramedian pontine reticular formation), the uvula, flocculus, and cerebellar tonsils. The ocular motor vermis, on the other hand, responded to constant and accelerating velocity stimulation. Moreover, deactivation patterns depict a governing role for the cerebellar tonsils in ocular motor control. Functional connectivity results of these hubs reveal the close integration of cortico-cerebellar ocular motor and vestibular networks in humans. Adding to the cortical concept of a right-hemispheric predominance for visual-spatial processing, we found a complementary left-sided cerebellar dominance for our ocular motor task. A deeper understanding of the role of the cerebellum and especially the cerebellar tonsils for eye movement control in a clinical context seems vitally important and is now feasible with functional neuroimaging.
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References
Afshar F, Watkins ES, Yap JC (1978) Stereotaxic atlas of the human brainstem and cerebellar nuclei: a variability study. vol Bd. 17. Raven Press
Ashburner J (2007) A fast diffeomorphic image registration algorithm NeuroImage 38:95–113. doi:10.1016/j.neuroimage.2007.07.007
Barmack NH, Pettorossi VE (1985) Effects of unilateral lesions of the flocculus on optokinetic and vestibuloocular reflexes of the rabbit. J Neurophysiol 53:481–496
Bense S et al (2006a) Direction-dependent visual cortex activation during horizontal optokinetic stimulation (fMRI study). Hum Brain Mapp 27:296–305. doi:10.1002/hbm.20185
Bense S et al (2006b) Brainstem and cerebellar fMRI-activation during horizontal and vertical optokinetic stimulation experimental brain research 174:312–323
Boileau I, Beauregar M, Beuter A, Breault C, Lecours AR (2002) Optokinetic stimulation and the egocentred midsagittal plane: an fMRI study. NeuroReport 13:61–65
Brandt T, Bartenstein P, Janek A, Dieterich M (1998) Reciprocal inhibitory visual-vestibular interaction. Visual motion stimulation deactivates the parieto-insular vestibular cortex. Brain J Neurol 121(Pt 9):1749–1758
Bremmer F, Klam F, Duhamel JR, Ben Hamed S, Graf W (2002) Visual-vestibular interactive responses in the macaque ventral intraparietal area (VIP). Eur J Neurosci 16:1569–1586
Buttner U, Buttner-Ennever JA, Henn V (1977) Vertical eye movement related unit activity in the rostral mesencephalic reticular formation of the alert monkey. Brain Res 130:239–252
Buttner-Ennever JA (2007) Anatomy of the oculomotor system. Dev Ophthalmol 40:1–14. doi:10.1159/0000100345
Chao-Gan Y, Yu-Feng Z (2010) DPARSF: a MATLAB toolbox for “Pipeline” data analysis of resting-state fMRI. Front Syst Neurosci 4:13. doi:10.3389/fnsys.2010.00013
Chapman LJ, Chapman JP (1987) The measurement of handedness. Brain Cogn 6:175–183
Cohen B, Matsuo V, Raphan T (1977) Quantitative analysis of the velocity characteristics of optokinetic nystagmus and optokinetic after-nystagmus. J Physiol 270:321–344
Crossland WJ, Hu XJ, Rafols JA (1994) Morphological study of the rostral interstitial nucleus of the medial longitudinal fasciculus in the monkey, Macaca mulatta, by Nissl, Golgi, and computer reconstruction and rotation methods. J Comp Neurol 347:47–63. doi:10.1002/cne.903470105
de Jong BM, Shipp S, Skidmore B, Frackowiak RS, Zeki S (1994) The cerebral activity related to the visual perception of forward motion in depth. Brain J Neurol 117(Pt 5):1039–1054
de Schotten MT, Dell’Acqua F, Forkel SJ, Simmons A, Vergani F, Murphy DGM, Catani M (2011) A lateralized brain network for visuospatial attention. Nat Neurosci 14:1245–1246. doi:10.1038/nn.2905. http://www.nature.com/neuro/journal/v14/n10/abs/nn.2905.html (supplementary-information)
Devonshire IM, Papadakis NG, Port M, Berwick J, Kennerley AJ, Mayhew JE, Overton PG (2012) Neurovascular coupling is brain region-dependent. NeuroImage 59:1997–2006. doi:10.1016/j.neuroimage.2011.09.050
Diedrichsen J (2006) A spatially unbiased atlas template of the human cerebellum. NeuroImage 33:127–138. doi:10.1016/j.neuroimage.2006.05.056
Dieterich M, Bucher SF, Seelos KC, Brandt T (1998) Horizontal or vertical optokinetic stimulation activates visual motion-sensitive, ocular motor and vestibular cortex areas with right hemispheric dominance. An fMRI study. Brain J Neurol 121(Pt 8):1479–1495
Dieterich M, Bucher SF, Seelos KC, Brandt T (2000) Cerebellar activation during optokinetic stimulation and saccades. Neurology 54:148–155
Dieterich M, Bense S, Lutz S, Drzezga A, Stephan T, Bartenstein P, Brandt T (2003a) Dominance for vestibular cortical function in the non-dominant hemisphere. Cereb Cortex 13:994–1007
Dieterich M, Bense S, Stephan T, Yousry TA, Brandt T (2003b) fMRI signal increases and decreases in cortical areas during small-field optokinetic stimulation and central fixation. Exp Brain Res 148:117–127. doi:10.1007/s00221-002-1267-6
Dieterich M, Muller-Schunk S, Stephan T, Bense S, Seelos K, Yousry TA (2009) Functional magnetic resonance imaging activations of cortical eye fields during saccades, smooth pursuit, and optokinetic nystagmus. Ann N Y Acad Sci 1164:282–292. doi:10.1111/j.1749-6632.2008.03718.x
Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K (2005) A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. NeuroImage 25:1325–1335. doi:10.1016/j.neuroimage.2004.12.034
Faull OK, Jenkinson M, Clare S, Pattinson KTS (2015) Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI NeuroImage 113:356–364. doi:10.1016/j.neuroimage.2015.02.026
Friston KJ, Frith C, Turner R, Frackowiak RSJ (1995a) Characterizing evoked hemodynamics with fMRI NeuroImage 2:157–165
Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith C, Frackowiak RSJ (1995b) Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2:189–210
Furman JM, Becker JT (1989) Vestibular responses in Wernicke’s encephalopathy. Ann Neurol 26:669–674. doi:10.1002/ana.410260513
Galati G, Pappata S, Pantano P, Lenzi GL, Samson Y, Pizzamiglio L (1999) Cortical control of optokinetic nystagmus in humans: a positron emission tomography study. Exp Brain Res 126:149–159
Gaymard B, Rivaud S, Cassarini JF, Dubard T, Rancurel G, Agid Y, Pierrot-Deseilligny C (1998) Effects of anterior cingulate cortex lesions on ocular saccades in humans. Exp Brain Res 120:173–183
Gerrits N (1990) Vestibular nuclear complex. The human nervous system. Academic, Philadelphia, pp 863–888
Giaschi D et al (2003) Conscious visual abilities in a patient with early bilateral occipital damage. Dev Med Child Neurol 45:772–781
Glasauer S, Stephan T, Kalla R, Marti S, Straumann D (2009) Up-down asymmetry of cerebellar activation during vertical pursuit eye movements. Cerebellum (London, England) 8:385–388. doi:10.1007/s12311-009-0109-5
Hasegawa T, Kato I, Harada K, Ikarashi T, Yoshida M, Koike Y (1994) The effect of uvulonodular lesions on horizontal optokinetic nystagmus and optokinetic after-nystagmus in cats. Acta Otolaryngol Suppl 511:126–130
Heinen SJ, Keller EL (1996) The function of the cerebellar uvula in monkey during optokinetic and pursuit eye movements: single-unit responses and lesion effects. Exp Brain Res 110:1–14
Hiramatsu T, Ohki M, Kitazawa H, Xiong G, Kitamura T, Yamada J, Nagao S (2008) Role of primate cerebellar lobulus petrosus of paraflocculus in smooth pursuit eye movement control revealed by chemical lesion. Neurosci Res 60:250–258. doi:10.1016/j.neures.2007.11.004
Horn AK, Buttner U, Buttner-Ennever JA (1999) Brainstem and cerebellar structures for eye movement generation. Adv Otorhinolaryngol 55:1–25
Hu D, Shen H, Zhou Z (2008) Functional asymmetry in the cerebellum: a brief review. Cerebellum (London, England) 7:304–313. doi:10.1007/s12311-008-0031-2
Igarashi M, Takeda N, Chae S (1992) Uvula-nodulus and gravity direction (a study on vertical optokinetic-oculomotor functions). Acta Astronaut 27:25–30
Ilg UJ, Hoffmann KP (1991) Responses of monkey nucleus of the optic tract neurons during pursuit and fixation. Neurosci Res 12:101–110
Ilg UJ, Hoffmann KP (1996) Responses of neurons of the nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic tract in the awake monkey. Eur J Neurosci 8:92–105
Kashou NH, Leguire LE, Roberts CJ, Fogt N, Smith MA, Rogers GL (2010) Instruction dependent activation during optokinetic nystagmus (OKN) stimulation: an FMRI study at 3T. Brain Res 1336:10–21. doi:10.1016/j.brainres.2010.04.017
Kheradmand A, Zee DS (2011) Cerebellum and ocular motor control. Front Neurol 2:53. doi:10.3389/fneur.2011.00053
Konen CS, Kleiser R, Seitz RJ, Bremmer F (2005) An fMRI study of optokinetic nystagmus and smooth-pursuit eye movements in humans. Exp Brain Res 165:203–216. doi:10.1007/s00221-005-2289-7
Kralj-Hans I, Baizer JS, Swales C, Glickstein M (2007) Independent roles for the dorsal paraflocculus and vermal lobule VII of the cerebellum in visuomotor coordination. Exp Brain Res 177:209–222. doi:10.1007/s00221-006-0661-x
Lee SH, Park SH, Kim JS, Kim HJ, Yunusov F, Zee DS (2014) Isolated unilateral infarction of the cerebellar tonsil: ocular motor findings. Ann Neurol 75:429–434
Leigh RJ, Zee DS (2006) The neurology of eye movements. Contemporary neurology series, 4th edn, vol 70. Oxford Univ Press, Oxford
Mustari MJ, Fuchs AF (1990) Discharge patterns of neurons in the pretectal nucleus of the optic tract (NOT) in the behaving primate. J Neurophysiol 64:77–90
Mustari MJ, Ono S, Das VE (2009) Signal processing and distribution in cortical-brainstem pathways for smooth pursuit eye movements. Ann N Y Acad Sci 1164:147–154. doi:10.1111/j.1749-6632.2009.03859.x
Nagao S, Kitamura T, Nakamura N, Hiramatsu T, Yamada J (1997) Location of efferent terminals of the primate flocculus and ventral paraflocculus revealed by anterograde axonal transport methods. Neurosci Res 27:257–269. doi:10.1016/S0168-0102(97)01160-7
Ohki M, Kitazawa H, Hiramatsu T, Kaga K, Kitamura T, Yamada J, Nagao S (2009) Role of primate cerebellar hemisphere in voluntary eye movement control revealed by lesion effects. J Neurophysiol 101:934–947. doi:10.1152/jn.90440.2009
Ono S, Mustari MJ (2009) Smooth pursuit-related information processing in frontal eye field neurons that project to the NRTP. Cereb Cortex 19:1186–1197. doi:10.1093/cercor/bhn166
Ono S, Das VE, Economides JR, Mustari MJ (2005) Modeling of smooth pursuit-related neuronal responses in the DLPN and NRTP of the rhesus macaque. J Neurophysiol 93:108–116. doi:10.1152/jn.00588.2004
Pierrot-Deseilligny C, Milea D, Muri RM (2004) Eye movement control by the cerebral cortex. Curr Opin Neurol 17:17–25
Poldrack RA, Fletcher PC, Henson RN, Worsley KJ, Brett M, Nichols TE (2008) Guidelines for reporting an fMRI study NeuroImage 40:409–414. doi:10.1016/j.neuroimage.2007.11.048
Robinson FR, Fuchs AF (2001) The role of the cerebellum in voluntary eye movements. Annu Rev Neurosci 24:981–1004. doi:10.1146/annurev.neuro.24.1.981
Schmahmann JD (2000) MRI atlas of the human cerebellum. Academic Press, San Diego
Schmahmann JD, Doyon J, Toga AW, Petrides M, Evans AC (2000) MRI Atlas of the human cerebellum. Academic Press, San Diego
Schraa-Tam CK, van der Lugt A, Smits M, Frens MA, van Broekhoven PC, van der Geest JN (2008) fMRI of optokinetic eye movements with and without a contribution of smooth pursuit. J Neuroimaging Off J Am Soc Neuroimaging 18:158–167. doi:10.1111/j.1552-6569.2007.00204.x
Shojaku H, Grudt TJ, Barmack NH (1990) Vestibular and visual signals in the ventral paraflocculus of the cerebellum in rabbits. Neurosci Lett 108:99–104. doi:10.1016/0304-3940(90)90713-J
Smith AT, Wall MB, Thilo KV (2012) Vestibular inputs to human motion-sensitive visual cortex. Cereb Cortex 22:1068–1077. doi:10.1093/cercor/bhr179
Song XW et al (2011) REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PLoS One 6:e25031. doi:10.1371/journal.pone.0025031
Straube A, Scheuerer W, Eggert T (1997) Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye movements in humans. Ann Neurol 42:891–898. doi:10.1002/ana.410420611
Takeichi N, Kaneko CR, Fuchs AF (2005) Discharge of monkey nucleus reticularis tegmenti pontis neurons changes during saccade adaptation. J Neurophysiol 94:1938–1951. doi:10.1152/jn.00113.2005
Tan HS, Collewijn H, Van der Steen J (1992) Optokinetic nystagmus in the rabbit and its modulation by bilateral microinjection of carbachol in the cerebellar flocculus. Exp Brain Res 90:456–468
Thielert CD, Thier P (1993) Patterns of projections from the pontine nuclei and the nucleus reticularis tegmenti pontis to the posterior vermis in the rhesus monkey: a study using retrograde tracers. J Comp Neurol 337:113–126. doi:10.1002/cne.903370108
Vahedi K, Rivaud S, Amarenco P, Pierrot-Deseilligny C (1995) Horizontal eye movement disorders after posterior vermis infarctions. J Neurol Neurosurg Psychiatry 58:91–94
Voogd J, Barmack NH (2006) Oculomotor cerebellum. Prog Brain Res 151:231–268. doi:10.1016/s0079-6123(05)51008-2
Voogd J, Schraa-Tam CK, van der Geest JN, De Zeeuw CI (2012) Visuomotor cerebellum in human and nonhuman primates. Cerebellum (London, England) 11:392–410. doi:10.1007/s12311-010-0204-7
Waespe W, Cohen B (1983) Flocculectomy and unit activity in the vestibular nuclei during visual–vestibular interactions. Exp Brain Res 51:23–35
Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC (1996) A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 4:58–73. doi:10.1002/(SICI)1097-0193(1996)4:1<58:AID-HBM4>3.0.CO;2-O
Xiong G, Nagao S (2002) The lobulus petrosus of the paraflocculus relays cortical visual inputs to the posterior interposed and lateral cerebellar nuclei: an anterograde and retrograde tracing study in the monkey. Exp Brain Res 147:252–263. doi:10.1007/s00221-002-1241-3
Yakushin SB, Gizzi M, Reisine H, Raphan T, Buttner-Ennever J, Cohen B (2000) Functions of the nucleus of the optic tract (NOT). II. Control of ocular pursuit. Exp Brain Res 131:433–447
Zee DS, Yamazaki A, Butler PH, Gucer G (1981) Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 46:878–899
Zhang Y, Partsalis AM, Highstein SM (1993) Properties of superior vestibular nucleus neurons projecting to the cerebellar flocculus in the squirrel monkey. J Neurophysiol 69:642–645
zu Eulenburg P, Caspers S, Roski C, Eickhoff SB (2012) Meta-analytical definition and functional connectivity of the human vestibular cortex. NeuroImage 60:162–169. doi:10.1016/j.neuroimage.2011.12.032
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The authors would like to thank Wibke Mueller-Forell and Sabine Esser for the profound support throughout this project.
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Ruehl, R.M., Hinkel, C., Bauermann, T. et al. Delineating function and connectivity of optokinetic hubs in the cerebellum and the brainstem. Brain Struct Funct 222, 4163–4185 (2017). https://doi.org/10.1007/s00429-017-1461-8
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DOI: https://doi.org/10.1007/s00429-017-1461-8