title: Timing Tasks Synchronize Cerebellar and Frontal Ramping Activity and Theta Oscillations: Implications for Cerebellar Stimulation in Diseases of Impaired Cognition.
abstract: Timing is a fundamental and highly conserved mammalian capability, yet the underlying neural mechanisms are widely debated. Ramping activity of single neurons that gradually increase or decrease activity to encode the passage of time has been speculated to predict a behaviorally relevant temporal event. Cue-evoked low-frequency activity has also been implicated in temporal processing. Ramping activity and low-frequency oscillations occur throughout the brain and could indicate a network-based approach to timing. Temporal processing requires cognitive mechanisms of working memory, attention, and reasoning, which are dysfunctional in neuropsychiatric disease. Therefore, timing tasks could be used to probe cognition in animals with disease phenotypes. The medial frontal cortex and cerebellum are involved in cognition. Cerebellar stimulation has been shown to influence medial frontal activity and improve cognition in schizophrenia. However, the mechanism underlying the efficacy of cerebellar stimulation is unknown. Here, we discuss how timing tasks can be used to probe cerebellar interactions with the frontal cortex and the therapeutic potential of cerebellar stimulation. The goal of this theory and hypothesis manuscript is threefold. First, we will summarize evidence indicating that in addition to motor learning, timing tasks involve cognitive processes that are present within both the cerebellum and medial frontal cortex. Second, we propose methodologies to investigate the connections between these areas in patients with Parkinson's disease, autism, and schizophrenia. Lastly, we hypothesize that cerebellar transcranial stimulation may rescue medial frontal ramping activity, theta oscillations, and timing abnormalities, thereby restoring executive function in diseases of impaired cognition. This hypothesis could inspire the use of timing tasks as biomarkers for neuronal and cognitive abnormalities in neuropsychiatric disease and promote the therapeutic potential of the cerebellum in diseases of impaired cognition.
authors.affiliation: Department of Neurology, Carver College of Medicine, University of Iowa , Iowa City, IA , USA.
authors.forename: Krystal L
authors.initials: KL
authors.lastname: Parker
keywords: cerebellum; eyeblink conditioning; interval timing; prefrontal cortex; ramping activity; theta oscillations
references.citation: J Neurophysiol. 2012 Jan;107(1):50-64
references.pmid: 21957220
references.citation: Nat Neurosci. 2013 Dec;16(12):1888-95
references.pmid: 24141310
references.citation: J Neurosci. 2003 Jun 15;23(12):5342-53
references.pmid: 12832560
references.citation: Nature. 1997 Feb 13;385(6617):634-6
references.pmid: 9024661
references.citation: Behav Neurosci. 2000 Dec;114(6):1058-67
references.pmid: 11142638
references.citation: Learn Mem. 2003 Nov-Dec;10(6):427-55
references.pmid: 14657256
references.citation: Schizophr Res. 2013 Aug;148(1-3):24-8
references.pmid: 23768814
references.citation: Psychopharmacology (Berl). 2004 Jun;174(1):3-16
references.pmid: 15118803
references.citation: Nat Rev Neurosci. 2005 Oct;6(10):755-65
references.pmid: 16163383
references.citation: J Neurophysiol. 2004 Feb;91(2):719-27
references.pmid: 14573551
references.citation: Trends Cogn Sci. 2013 May;17(5):241-54
references.pmid: 23579055
references.citation: Exp Brain Res. 1988;73(1):167-80
references.pmid: 3208855
references.citation: J Physiol Paris. 2011 Dec;105(4-6):164-9
references.pmid: 21803155
references.citation: Basal Ganglia. 2015 Aug 1;5(2-3):51-55
references.pmid: 26251824
references.citation: Cerebellum. 2007;6(1):38-57
references.pmid: 17366265
references.citation: J Neurosci. 2006 Jan 25;26(4):1314-28
references.pmid: 16436619
references.citation: Schizophr Res. 2010 Dec;124(1-3):91-100
references.pmid: 20817483
references.citation: Cerebellum. 2012 Dec;11(4):946-56
references.pmid: 22430943
references.citation: Psychol Med. 2003 Oct;33(7):1249-61
references.pmid: 14580079
references.citation: Exp Brain Res. 1985;60(1):87-98
references.pmid: 4043285
references.citation: Neuropharmacology. 1998 Apr-May;37(4-5):471-80
references.pmid: 9704988
references.citation: Front Syst Neurosci. 2014 Feb 04;8:4
references.pmid: 24550789
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):480-5
references.pmid: 24367075
references.citation: J Neurosci. 2004 Mar 31;24(13):3295-303
references.pmid: 15056709
references.citation: J Autism Dev Disord. 2015 Feb;45(2):376-94
references.pmid: 23942847
references.citation: Neuroimage. 2006 Dec;33(4):1227-31
references.pmid: 17023183
references.citation: Eur J Neurosci. 2015 Jun;41(12):1524-37
references.pmid: 25892211
references.citation: Neuron. 2009 Jan 15;61(1):126-39
references.pmid: 19146818
references.citation: Synapse. 2008 Jul;62(7):544-50
references.pmid: 18435424
references.citation: Curr Opin Neurobiol. 2004 Apr;14(2):225-32
references.pmid: 15082329
references.citation: Brain Cogn. 2005 Jun;58(1):94-108
references.pmid: 15878730
references.citation: Front Syst Neurosci. 2014 Sep 15;8:163
references.pmid: 25309350
references.citation: Cerebellum. 2014 Feb;13(1):64-78
references.pmid: 24013852
references.citation: J Neurosci. 2013 Aug 21;33(34):13834-47
references.pmid: 23966703
references.citation: Neuropsychologia. 1996 Sep;34(9):863-71
references.pmid: 8822733
references.citation: J Neurosci. 2003 Oct 29;23(30):9897-905
references.pmid: 14586019
references.citation: Neuron. 2015 Apr 8;86(1):106-39
references.pmid: 25856490
references.citation: Arch Neurol. 1976 Aug;33(8):559-70
references.pmid: 821458
references.citation: Front Hum Neurosci. 2015 Jun 12;9:331
references.pmid: 26124714
references.citation: J Neurosci. 2014 Dec 10;34(50):16774-83
references.pmid: 25505330
references.citation: Schizophr Bull. 2012 Jun;38(4):751-9
references.pmid: 21148238
references.citation: Trends Neurosci. 2008 Feb;31(2):105-12
references.pmid: 18199490
references.citation: Synapse. 2011 Nov;65(11):1204-12
references.pmid: 21638338
references.citation: J Neurophysiol. 2015 Aug;114(2):1310-20
references.pmid: 26133799
references.citation: Neurobiol Learn Mem. 2012 Mar;97(3):277-88
references.pmid: 22387661
references.citation: J Neurosci. 2013 Jun 26;33(26):10910-4
references.pmid: 23804110
references.citation: Neurosci Res. 1985 Feb;2(3):157-80
references.pmid: 2991825
references.citation: J Neurosci. 1984 Nov;4(11):2811-22
references.pmid: 6502205
references.citation: Schizophr Bull. 1998;24(2):203-18
references.pmid: 9613621
references.citation: Neurosci Lett. 2003 Jan 16;336(2):73-6
references.pmid: 12499043
references.citation: Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):9448-53
references.pmid: 26124116
references.citation: Schizophr Res. 2009 Jun;111(1-3):182-91
references.pmid: 19351577
references.citation: Arch Gen Psychiatry. 1986 Feb;43(2):114-24
references.pmid: 3947207
references.citation: Proc Natl Acad Sci U S A. 1982 Apr;79(8):2731-5
references.pmid: 6953427
references.citation: Psychiatry Res. 2013 Dec 30;214(3):402-9
references.pmid: 24090512
references.citation: Brain Res. 1985 Dec 2;348(2):249-60
references.pmid: 4075084
references.citation: Neuropharmacology. 2012 Mar;62(3):1175-81
references.pmid: 21530549
references.citation: Trends Cogn Sci. 1998 Sep 1;2(9):362-71
references.pmid: 21227233
references.citation: Front Integr Neurosci. 2009 Aug 11;3:18
references.pmid: 19738932
references.citation: Cerebellum. 2014 Feb;13(1):121-38
references.pmid: 23943521
references.citation: J Neurophysiol. 2009 Jun;101(6):2859-71
references.pmid: 19339463
references.citation: Front Integr Neurosci. 2013 Oct 31;7:75
references.pmid: 24198770
references.citation: Annu Rev Neurosci. 2009;32:413-34
references.pmid: 19555291
references.citation: Cerebellum. 2013 Aug;12(4):547-56
references.pmid: 23436049
references.citation: J Neurosci. 1996 Jun 15;16(12):4032-40
references.pmid: 8656296
references.citation: Neurobiol Learn Mem. 1998 Mar;69(2):147-62
references.pmid: 9619994
references.citation: Prog Brain Res. 2004;143:331-9
references.pmid: 14653177
references.citation: J Neurosci. 2011 Mar 16;31(11):4051-62
references.pmid: 21411647