The therapeutic potential of the cerebellum in schizophrenia

Krystal L Parker, Nandakumar S Narayanan, Nancy C Andreasen, Krystal L Parker, Nandakumar S Narayanan, Nancy C Andreasen

Abstract

The cognitive role of the cerebellum is critically tied to its distributed connections throughout the brain. Accumulating evidence from anatomical, structural and functional imaging, and lesion studies advocate a cognitive network involving indirect connections between the cerebellum and non-motor areas in the prefrontal cortex. Cerebellar stimulation dynamically influences activity in several regions of the frontal cortex and effectively improves cognition in schizophrenia. In this manuscript, we summarize current literature on the cingulocerebellar circuit and we introduce a method to interrogate this circuit combining opotogenetics, neuropharmacology, and electrophysiology in awake-behaving animals while minimizing incidental stimulation of neighboring cerebellar nuclei. We propose the novel hypothesis that optogenetic cerebellar stimulation can restore aberrant frontal activity and rescue impaired cognition in schizophrenia. We focus on how a known cognitive region in the frontal cortex, the anterior cingulate, is influenced by the cerebellum. This circuit is of particular interest because it has been confirmed using tracing studies, neuroimaging reveals its role in cognitive tasks, it is conserved from rodents to humans, and diseases such as schizophrenia and autism appear in its aberrancy. Novel tract tracing results presented here provide support for how these two areas communicate. The primary pathway involves a disynaptic connection between the cerebellar dentate nuclei (DN) and the anterior cingulate cortex. Secondarily, the pathway from cerebellar fastigial nuclei (FN) to the ventral tegmental area, which supplies dopamine to the prefrontal cortex, may play a role as schizophrenia characteristically involves dopamine deficiencies. We hope that the hypothesis described here will inspire new therapeutic strategies targeting currently untreatable cognitive impairments in schizophrenia.

Keywords: anterior cingulate; cerebellum; cognitive symptoms; optogenetic stimulation; schizophrenia.

Figures

Figure 1
Figure 1
During positron emissions tomography (PET) imaging of a task typically thought to be cerebellum dependent, eyeblink conditioning, hypofunction was revealed in the cingulocerebellar circuit. A double subtraction method where the baseline pseudoconditioning phase of unpaired tones and airpuffs was first subtracted and then the rCBF for patients with schizophrenia was subtracted from that of controls, show negative peaks indicating patients with schizophrenia have less rCBF than controls. This representative image shows hypofunction of the anterior cingulate (Talairach coordinates: −1, 30, 14) and cerebellar lobules IV/V, and IX (Talairach coordinates: −3, −67, −17) in patients with schizophrenia in comparison to healthy controls. For each illustration there are three orthogonal views per row with transaxial on the top, sagittal in the middle, and coronal on the bottom. Green crosshairs are used to show the location of the slice. Images follow radiological convention and show location as if facing the patient where the left side of the image represents the patient’s right side. The statistical maps of the PET, showing the regions where the two groups differed significantly at the 0.005 level, are superimposed on a composite magnetic resonance image (MRI) derived by averaging the MR scans from the subjects. Regions in red/yellow tones indicate positive peaks (greater activation in patients than in controls) and regions with blue/purple indicate negative peaks (less activity in patients than controls). The statistical results are portrayed using the value of the associated t-statistic, which is shown on the color bar on the right. The images are referred to as “t maps” showing all voxels in the image which exceed a display threshold.
Figure 2
Figure 2
Fronto-ponto-cerebellar tractography reconstructed on a 3D T1- weighted image (Kamali et al., 2010).
Figure 3
Figure 3
Proposed efferent cingulocerellar circuitry. (A) Schematic representation of the efferent cerebellar projections enabling cerebellar access to the medial prefrontal cortex/anterior cingulate via the ventrolateral thalamus and VTA. Two efferent pathways are thought to connect the cerebellum and prefrontal cortex (1) Cerebellar projections originating from dentate (DN) or fastigial nuclei (FN) to the contralateral thalamus and anterior cingulate cortex; and (2) Cerebellar projections originating from DN or FN to the contralateral ventral tegmental area (VTA) which send dopaminergic projections to the anterior cingulate cortex. The afferent pathways from the anterior cingulate back to the cerebellum via the pontine nuclei (PN) and inferior olive (IO). (B) Our tract tracing data following anterograde tracer (green) in the right dentate nuclei and retrograde tracer (red) in the contralateral (left) medial prefrontal cortex revealed tracer colocalization of both red and green beads on a single contralateral ventrolateral thalamic (VLTh) neuron (B).
Figure 4
Figure 4
Schematic representation of the cingulocerebellar pathways allowing the cerebellum access to the prefrontal cortex. We propose using optogenetic stimulation of cerebellar projection neurons in the thalamus to recover activity in aberrant prefrontal neuronal ensembles in schizophrenia. Channelrhodopsin, a light-activated channel, can be infused into cerebellar neurons rendering cerebellar projections photoexcitable. Stimulating thalamic (or VTA) optical fibers can selectively stimulate the cerebellar neuronal projections to the anterior cingulate while not affecting other cerebellar neuronal populations. This optogenetic paradigm can be used in animals exhibiting phenotypes of schizophrenia and other neuropsychiatric illnesses in combination with elementary cognitive tasks impaired in schizophrenia to recover cognitive function and probe the cingluocerebellar circuit.

References

    1. Abi-Dargham A., Mawlawi O., Lombardo I., Gil R., Martinez D., Huang Y., et al. (2002). Prefrontal dopamine D1 receptors and working memory in schizophrenia. J. Neurosci. 22, 3708–3719
    1. Adams R., David A. S. (2007). Patterns of anterior cingulate activation in schizophrenia: a selective review. Neuropsychiatr. Dis. Treat. 3, 87–101 10.2147/nedt.2007.3.1.87
    1. Akshoomoff N. A., Courchesne E. (1992). A new role for the cerebellum in cognitive operations. Behav. Neurosci. 106, 731–738 10.1037/0735-7044.106.5.731
    1. Alphs L. (2006). An industry perspective on the NIMH consensus statement on negative symptoms. Schizophr. Bull. 32, 225–230 10.1093/schbul/sbj056
    1. Andreasen N. C., Arndt S., Swayze V., 2nd, Cizadlo T., Flaum M., O’Leary D., et al. (1994). Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. Science 266, 294–298 10.1126/science.7939669
    1. Andreasen N. C., O’Leary D. S., Arndt S., Cizadlo T., Rezai K., Watkins G. L., et al. (1995a). I. PET studies of memory: novel and practiced free recall of complex narratives. Neuroimage 2, 284–295 10.1006/nimg.1995.1036
    1. Andreasen N. C., O’Leary D. S., Cizadlo T., Arndt S., Rezai K., Watkins G. L., et al. (1995b). II. PET studies of memory: novel versus practiced free recall of word lists. Neuroimage 2, 296–305 10.1006/nimg.1995.1037
    1. Andreasen N. C., O’Leary D. S., Flaum M., Nopoulos P., Watkins G. L., Boles Ponto L. L., et al. (1997). Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet 349, 1730–1734 10.1016/s0140-6736(96)08258-x
    1. Andreasen N. C., O’Leary D. S., Paradiso S., Cizadlo T., Arndt S., Watkins G. L., et al. (1999). The cerebellum plays a role in conscious episodic memory retrieval. Hum. Brain Mapp. 8, 226–234 10.1002/(sici)1097-0193(1999)8:4<226::aid-hbm6>;2-4
    1. Andreasen N. C., Olsen S. (1982). Negative v positive schizophrenia: definition and validation. Arch. Gen. Psychiatry 39, 789–794 10.1001/archpsyc.1982.04290070025006
    1. Andreasen N. C., Paradiso S., O’Leary D. S. (1998). “Cognitive Dysmetria” as an integrative theory of schizophrenia. Schizophr. Bull. 24, 203–218 10.1093/oxfordjournals.schbul.a033321
    1. Andreasen N. C., Pierson R. (2008). The role of the cerebellum in schizophrenia. Biol. Psychiatry 64, 81–88 10.1016/j.biopsych.2008.01.003
    1. Anticevic A., Cole M. W., Repovs G., Savic A., Driesen N. R., Yang G., et al. (2013). Connectivity, pharmacology and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia. Front. Psychiatry 4:169 10.3389/fpsyt.2013.00169
    1. Artiges E., Salamé P., Recasens C., Poline J. B., Attar-Levy D., De La Raillère A., et al. (2000). Working memory control in patients with schizophrenia: a PET study during a random number generation task. Am. J. Psychiatry 157, 1517–1519 10.1176/appi.ajp.157.9.1517
    1. Bijsterbosch J. D., Lee K.-H., Hunter M. D., Tsoi D. T., Lankappa S., Wilkinson I. D., et al. (2011). The role of the cerebellum in sub- and supraliminal error correction during sensorimotor synchronization: evidence from fMRI and TMS. J. Cogn. Neurosci. 23, 1100–1112 10.1162/jocn.2010.21506
    1. Boehringer A., Macher K., Dukart J., Villringer A., Pleger B. (2013). Cerebellar transcranial direct current stimulation modulates verbal working memory. Brain Stimul. 6, 649–653 10.1016/j.brs.2012.10.001
    1. Bolbecker A. R., Mehta C. S., Edwards C. R., Steinmetz J. E., O’Donnell B. F., Hetrick W. P. (2009). Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia. Schizophr. Res. 111, 182–191 10.1016/j.schres.2009.03.016
    1. Bonnot O., de Montalembert M., Kermarrec S., Botbol M., Walter M., Coulon N. (2011). Are impairments of time perception in schizophrenia a neglected phenomenon? J. Physiol. Paris 105, 164–169 10.1016/j.jphysparis.2011.07.006
    1. Bostan A. C., Dum R. P., Strick P. L. (2010). The basal ganglia communicate with the cerebellum. Proc. Natl. Acad. Sci. U S A 107, 8452–8456 10.1073/pnas.1000496107
    1. Bostan A. C., Dum R. P., Strick P. L. (2013). Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn. Sci. 17, 241–254 10.1016/j.tics.2013.03.003
    1. Bostan A. C., Strick P. L. (2010). The cerebellum and basal ganglia are interconnected. Neuropsychol. Rev. 20, 261–270 10.1007/s11065-010-9143-9
    1. Boyden E. S., Zhang F., Bamberg E., Nagel G., Deisseroth K. (2005). Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 10.1038/nn1525
    1. Bracha V., Zbarska S., Parker K., Carrel A., Zenitsky G., Bloedel J. R. (2009). The cerebellum and eye-blink conditioning: learning versus network performance hypotheses. Neuroscience 162, 787–796 10.1016/j.neuroscience.2008.12.042
    1. Brown S. M., Kieffaber P. D., Carroll C. A., Vohs J. L., Tracy J. A., Shekhar A., et al. (2005). Eyeblink conditioning deficits indicate timing and cerebellar abnormalities in schizophrenia. Brain Cogn. 58, 94–108 10.1016/j.bandc.2004.09.011
    1. Buhusi C. V., Meck W. H. (2005). What makes us tick? Functional and neural mechanisms of interval timing. Nat. Rev. Neurosci. 6, 755–765 10.1038/nrn1764
    1. Buschman T. J., Miller E. K. (2007). Top-down versus bottom-up control of attention in the prefrontal and posterior parietal cortices. Science 315, 1860–1862 10.1126/science.1138071
    1. Carper R. A., Courchesne E. (2000). Inverse correlation between frontal lobe and cerebellum sizes in children with autism. Brain 123(Pt. 4), 836–844 10.1093/brain/123.4.836
    1. Carroll C. A., O’Donnell B. F., Shekhar A., Hetrick W. P. (2009). Timing dysfunctions in schizophrenia as measured by a repetitive finger tapping task. Brain Cogn. 71, 345–353 10.1016/j.bandc.2009.06.009
    1. Carter C. S., Braver T. S., Barch D. M., Botvinick M. M., Noll D., Cohen J. D. (1998). Anterior cingulate cortex, error detection and the online monitoring of performance. Science 280, 747–749 10.1126/science.280.5364.747
    1. Carter C. S., MacDonald A. W., 3rd, Ross L. L., Stenger V. A. (2001). Anterior cingulate cortex activity and impaired self-monitoring of performance in patients with schizophrenia: an event-related fMRI study. Am. J. Psychiatry 158, 1423–1428 10.1176/appi.ajp.158.9.1423
    1. Cavanagh J. F., Cohen M. X., Allen J. J. B. (2009). Prelude to and resolution of an error: EEG phase synchrony reveals cognitive control dynamics during action monitoring. J. Neurosci. 29, 98–105 10.1523/jneurosci.4137-08.2009
    1. Chaki S., Hikichi H. (2011). Targeting of metabotropic glutamate receptors for the treatment of schizophrenia. Curr. Pharm. Des. 17, 94–102 10.2174/138161211795049570
    1. Chen H., Yang L., Xu Y., Wu G., Yao J., Zhang J., et al. (2014). Prefrontal control of cerebellum-dependent associative motor learning. Cerebellum 13, 64–78 10.1007/s12311-013-0517-4
    1. Condé F., Audinat E., Maire-Lepoivre E., Crépel F. (1990). Afferent connections of the medial frontal cortex of the rat. A study using retrograde transport of fluorescent dyes. I. Thalamic afferents. Brain Res. Bull. 24, 341–354 10.1016/0361-9230(90)90088-h
    1. Cooper I. S., Amin I., Riklan M., Waltz J. M., Poon T. P. (1976). Chronic cerebellar stimulation in epilepsy. Clinical and anatomical studies. Arch. Neurol. 33, 559–570 10.1001/archneur.1976.00500080037006
    1. Courchesne E., Mouton P. R., Calhoun M. E., Semendeferi K., Ahrens-Barbeau C., Hallet M. J., et al. (2011). Neuron number and size in prefrontal cortex of children with autism. JAMA 306, 2001–2010 10.1001/jama.2011.1638
    1. Courchesne E., Townsend J., Akshoomoff N. A., Saitoh O., Yeung-Courchesne R., Lincoln A. J., et al. (1994). Impairment in shifting attention in autistic and cerebellar patients. Behav. Neurosci. 108, 848–865 10.1037/0735-7044.108.5.848
    1. Crespo-Facorro B., Paradiso S., Andreasen N. C., O’Leary D. S., Watkins G. L., Boles Ponto L. L., et al. (1999). Recalling word lists reveals “cognitive dysmetria” in schizophrenia: a positron emission tomography study. Am. J. Psychiatry 156, 386–392
    1. Crespo-Facorro B., Wiser A. K., Andreasen N. C., O’Leary D. S., Watkins G. L., Boles Ponto L. L., et al. (2001). Neural basis of novel and well-learned recognition memory in schizophrenia: a positron emission tomography study. Hum. Brain Mapp. 12, 219–231 10.1002/1097-0193(200104)12:4<219::aid-hbm1017>;2-l
    1. Dembrow N. C., Chitwood R. A., Johnston D. (2010). Projection-specific neuromodulation of medial prefrontal cortex neurons. J. Neurosci. 30, 16922–16937 10.1523/jneurosci.3644-10.2010
    1. Demirtas-Tatlidede A., Freitas C., Cromer J. R., Safar L., Ongur D., Stone W. S., et al. (2010). Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr. Res. 124, 91–100 10.1016/j.schres.2010.08.015
    1. Demirtas-Tatlidede A., Vahabzadeh-Hagh A. M., Pascual-Leone A. (2013). Can noninvasive brain stimulation enhance cognition in neuropsychiatric disorders? Neuropharmacology 64, 566–578 10.1016/j.neuropharm.2012.06.020
    1. Deutch A. Y. (1993). Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson’s disease. J. Neural Transm. Gen. Sect. 91, 197–221 10.1007/bf01245232
    1. Devinsky O., Morrell M. J., Vogt B. A. (1995). Contributions of anterior cingulate cortex to behaviour. Brain 118(Pt. 1), 279–306 10.1093/brain/118.1.279
    1. Elvevåg B., McCormack T., Gilbert A., Brown G. D. A., Weinberger D. R., Goldberg T. E. (2003). Duration judgements in patients with schizophrenia. Psychol. Med. 33, 1249–1261 10.1017/s0033291703008122
    1. Fierro B., Palermo A., Puma A., Francolini M., Panetta M. L., Daniele O., et al. (2007). Role of the cerebellum in time perception: a TMS study in normal subjects. J. Neurol. Sci. 263, 107–112 10.1016/j.jns.2007.06.033
    1. Fiez J. A., Petersen S. E., Cheney M. K., Raichle M. E. (1992). Impaired non-motor learning and error detection associated with cerebellar damage. A single case study. Brain 115(Pt. 1), 155–178 10.1093/brain/115.1.155
    1. Flashman L. A., Flaum M., Gupta S., Andreasen N. C. (1996). Soft signs and neuropsychological performance in schizophrenia. Am. J. Psychiatry 153, 526–532
    1. Fornito A., Yücel M., Dean B., Wood S. J., Pantelis C. (2009). Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: bridging the gap between neuroimaging and neuropathology. Schizophr. Bull. 35, 973–993 10.1093/schbul/sbn025
    1. Forsyth J. K., Bolbecker A. R., Mehta C. S., Klaunig M. J., Steinmetz J. E., O’Donnell B. F., et al. (2012). Cerebellar-dependent eyeblink conditioning deficits in schizophrenia spectrum disorders. Schizophr. Bull. 38, 751–759 10.1093/schbul/sbQ128
    1. Gasquoine P. G. (2013). Localization of function in anterior cingulate cortex: from psychosurgery to functional neuroimaging. Neurosci. Biobehav. Rev. 37, 340–348 10.1016/j.neubiorev.2013.01.002
    1. Glahn D. C., Laird A. R., Ellison-Wright I., Thelen S. M., Robinson J. L., Lancaster J. L., et al. (2008). Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biol. Psychiatry 64, 774–781 10.1016/j.biopsych.2008.03.031
    1. Glickstein M., May J. G., 3rd, Mercier B. E. (1985). Corticopontine projection in the macaque: the distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J. Comp. Neurol. 235, 343–359 10.1002/cne.902350306
    1. Goldman-Rakic P. S., Castner S. A., Svensson T. H., Siever L. J., Williams G. V. (2004). Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 174, 3–16 10.1007/s00213-004-1793-y
    1. Gottwald B., Wilde B., Mihajlovic Z., Mehdorn H. M. (2004). Evidence for distinct cognitive deficits after focal cerebellar lesions. J. Neurol. Neurosurg. Psychiatry 75, 1524–1531 10.1136/jnnp.2003.018093
    1. Grafman J., Litvan I., Massaquoi S., Stewart M., Sirigu A., Hallett M. (1992). Cognitive planning deficit in patients with cerebellar atrophy. Neurology 42, 1493–1496 10.1212/wnl.42.8.1493
    1. Grimaldi G., Argyropoulos G. P., Boehringer A., Celnik P., Edwards M. J., Ferrucci R., et al. (2014). Non-invasive cerebellar stimulation-a consensus paper. Cerebellum 13, 121–138 10.1007/s12311-013-0514-7
    1. Grimaldi G., Manto M. (2012). Topography of cerebellar deficits in humans. Cerebellum 11, 336–351 10.1007/s12311-011-0247-4
    1. Groiss S. J., Ugawa Y. (2013). “Chapter 51—Cerebellum,” in Handbook of Clinical Neurology. Brain Stimulation, eds Lozano A. M., Hallett M. (Elsevier; ), 643–653 Available online at: Accessed on February 21 2014.
    1. Grube M., Lee K.-H., Griffiths T. D., Barker A. T., Woodruff P. W. (2010). Transcranial magnetic theta-burst stimulation of the human cerebellum distinguishes absolute, duration-based from relative, beat-based perception of subsecond time intervals. Front. Psychol. 1:171 10.3389/fpsyg.2010.00171
    1. Gupta S., Andreasen N. C., Arndt S., Flaum M., Schultz S. K., Hubbard W. C., et al. (1995). Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. Am. J. Psychiatry 152, 191–196
    1. Hadley J. A., Nenert R., Kraguljac N. V., Bolding M. S., White D. M., Skidmore F. M., et al. (2014). Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia. Neuropsychopharmacology 39, 1020–1030 10.1038/npp.2013.305
    1. Hanaie R., Mohri I., Kagitani-Shimono K., Tachibana M., Azuma J., Matsuzaki J., et al. (2013). Altered microstructural connectivity of the superior cerebellar peduncle is related to motor dysfunction in children with autistic spectrum disorders. Cerebellum 12, 645–656 10.1007/s12311-013-0475-x
    1. Heck D. H., Howell J. W. (2013). Prefrontal cortical-cerebellar interaction deficits in autism spectrum disorders. Autism S4:001. 10.4172/2165-7890.S4-001
    1. Honey G. D., Pomarol-Clotet E., Corlett P. R., Honey R. A. E., McKenna P. J., Bullmore E. T., et al. (2005). Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function. Brain 128, 2597–2611 10.1093/brain/awh632
    1. Hsu M. M., Shyu B. C. (1997). Electrophysiological study of the connection between medial thalamus and anterior cingulate cortex in the rat. Neuroreport 8, 2701–2707 10.1097/00001756-199708180-00013
    1. Ivry R. B., Spencer R. M. (2004). Evaluating the role of the cerebellum in temporal processing: beware of the null hypothesis. Brain 127, E13–E14 10.1093/brain/awh227
    1. Jones C., Watson D., Fone K. (2011). Animal models of schizophrenia. Br. J. Pharmacol. 164, 1162–1194 10.1111/j.1476-5381.2011.01386.x
    1. Kamali A., Kramer L. A., Frye R. E., Butler I. J., Hasan K. M. (2010). Diffusion tensor tractography of the human brain cortico-ponto-cerebellar pathways: a quantitative preliminary study. J. Magn. Reson. Imaging 32, 809–817 10.1002/jmri.22330
    1. Klein J., Hadar R., Götz T., Männer A., Eberhardt C., Baldassarri J., et al. (2013). Mapping brain regions in which deep brain stimulation affects schizophrenia-like behavior in two rat models of schizophrenia. Brain Stimul. 6, 490–499 10.1016/j.brs.2012.09.004
    1. Koch G., Oliveri M., Torriero S., Salerno S., Lo Gerfo E., Caltagirone C. (2007). Repetitive TMS of cerebellum interferes with millisecond time processing. Exp. Brain Res. 179, 291–299 10.1007/s00221-006-0791-1
    1. Koziol L. F., Budding D., Andreasen N., D’Arrigo S., Bulgheroni S., Imamizu H., et al. (2013). Consensus paper: the cerebellum’s role in movement and cognition. Cerebellum 13, 151–177 10.1007/s12311-013-0511-x
    1. Kuepper R., Skinbjerg M., Abi-Dargham A. (2012). The dopamine dysfunction in schizophrenia revisited: new insights into topography and course. Handb. Exp. Pharmacol. 212, 1–26 10.1007/978-3-642-25761-2_1
    1. Kühn S., Romanowski A., Schubert F., Gallinat J. (2012). Reduction of cerebellar grey matter in Crus I and II in schizophrenia. Brain Struct. Funct. 217, 523–529 10.1007/s00429-011-0365-2
    1. Legg C. R., Mercier B., Glickstein M. (1989). Corticopontine projection in the rat: the distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J. Comp. Neurol. 286, 427–441 10.1002/cne.902860403
    1. Leiner H. C., Leiner A. L., Dow R. S. (1994). The underestimated cerebellum. Hum. Brain Mapp. 2, 244–254 10.1002/hbm.460020406
    1. Magnotta V. A., Adix M. L., Caprahan A., Lim K., Gollub R., Andreasen N. C. (2008). Investigating connectivity between the cerebellum and thalamus in schizophrenia using diffusion tensor tractography: a pilot study. Psychiatry Res. 163, 193–200 10.1016/j.pscychresns.2007.10.005
    1. McCormick L., Decker L., Nopoulos P., Ho B.-C., Andreasen N. (2005). Effects of atypical and typical neuroleptics on anterior cingulate volume in schizophrenia. Schizophr. Res. 80, 73–84 10.1016/j.schres.2005.06.022
    1. Meyer-Lindenberg A., Poline J. B., Kohn P. D., Holt J. L., Egan M. F., Weinberger D. R., et al. (2001). Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am. J. Psychiatry 158, 1809–1817 10.1176/appi.ajp.158.11.1809
    1. Middleton F. A., Strick P. L. (2001). Cerebellar projections to the prefrontal cortex of the primate. J. Neurosci. 21, 700–712
    1. Minzenberg M. J., Laird A. R., Thelen S., Carter C. S., Glahn D. C. (2009). Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch. Gen. Psychiatry 66, 811–822 10.1001/archgenpsychiatry.2009.91
    1. Mitelman S. A., Newmark R. E., Torosjan Y., Chu K.-W., Brickman A. M., Haznedar M. M., et al. (2006). White matter fractional anisotropy and outcome in schizophrenia. Schizophr. Res. 87, 138–159 10.1016/j.schres.2006.06.016
    1. Mittleman G., Goldowitz D., Heck D. H., Blaha C. D. (2008). Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia. Synapse 62, 544–550 10.1002/syn.20525
    1. Moghaddam B., Javitt D. (2012). From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37, 4–15 10.1038/npp.2011.181
    1. Mouchet-Mages S., Rodrigo S., Cachia A., Mouaffak F., Olie J. P., Meder J. F., et al. (2011). Correlations of cerebello-thalamo-prefrontal structure and neurological soft signs in patients with first-episode psychosis. Acta Psychiatr. Scand. 123, 451–458 10.1111/j.1600-0447.2010.01667.x
    1. Narayanan N. S., Cavanagh J. F., Frank M. J., Laubach M. (2013). Common medial frontal mechanisms of adaptive control in humans and rodents. Nat. Neurosci. 16, 1888–1895 10.1038/nn.3549
    1. Narayanan N. S., Land B. B., Solder J. E., Deisseroth K., Dileone R. J. (2012). Prefrontal D1 dopamine signaling is required for temporal control. Proc. Natl. Acad. Sci. U S A 109, 20726–20731 10.1073/pnas.1211258109
    1. Narayanan N. S., Prabhakaran V., Bunge S. A., Christoff K., Fine E. M., Gabrieli J. D. E. (2005). The role of the prefrontal cortex in the maintenance of verbal working memory: an event-related FMRI analysis. Neuropsychology 19, 223–232 10.1037/0894-4105.19.2.223
    1. Nopoulos P. C., Ceilley J. W., Gailis E. A., Andreasen N. C. (1999). An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol. Psychiatry 46, 703–711 10.1016/s0006-3223(99)00093-1
    1. Oh J. S., Kubicki M., Rosenberger G., Bouix S., Levitt J. J., McCarley R. W., et al. (2009). Thalamo-frontal white matter alterations in chronic schizophrenia: a quantitative diffusion tractography study. Hum. Brain Mapp. 30, 3812–3825 10.1002/hbm.20809
    1. Okubo Y., Suhara T., Suzuki K., Kobayashi K., Inoue O., Terasaki O., et al. (1997). Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 385, 634–636 10.1038/385634a0
    1. Okugawa G., Nobuhara K., Sugimoto T., Kinoshita T. (2005). Diffusion tensor imaging study of the middle cerebellar peduncles in patients with schizophrenia. Cerebellum 4, 123–127 10.1080/14734220510007879
    1. Okugawa G., Sedvall G. C., Agartz I. (2003). Smaller cerebellar vermis but not hemisphere volumes in patients with chronic schizophrenia. Am. J. Psychiatry 160, 1614–1617 10.1176/appi.ajp.160.9.1614
    1. O’Leary D. S., Andreason N. C., Hurtig R. R., Hichwa R. D., Watkins G. L., Ponto L. L., et al. (1996). A positron emission tomography study of binaurally and dichotically presented stimuli: effects of level of language and directed attention. Brain Lang. 53, 20–39 10.1006/brln.1996.0034
    1. Oliveri M., Torriero S., Koch G., Salerno S., Petrosini L., Caltagirone C. (2007). The role of transcranial magnetic stimulation in the study of cerebellar cognitive function. Cerebellum 6, 95–101 10.1080/14734220701213421
    1. Olney J. W., Farber N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 998–1007 10.1001/archpsyc.1995.03950240016004
    1. Paradiso S., Crespo Facorro B., Andreasen N. C., O’Leary D. S., Watkins L. G., Boles Ponto L., et al. (1997). Brain activity assessed with PET during recall of word lists and narratives. Neuroreport 8, 3091–3096 10.1097/00001756-199709290-00017
    1. Parker K. L., Alberico S. L., Miller A. D., Narayanan N. S. (2013a). Prefrontal D1 dopamine signaling is necessary for temporal expectation during reaction time performance. Neuroscience 255, 246–254 10.1016/j.neuroscience.2013.09.057
    1. Parker K. L., Andreasen N. C., Liu D., Freeman J. H., O’Leary D. S. (2013b). Eyeblink conditioning in unmedicated schizophrenia patients: a positron emission tomography study. Psychiatry Res. 214, 402–409 10.1016/j.pscychresns.2013.07.006
    1. Parker K. L., Lamichhane D., Caetano M. S., Narayanan N. S. (2013c). Executive dysfunction in Parkinson’s disease and timing deficits. Front. Integr. Neurosci. 7:75 10.3389/fnint.2013.00075
    1. Parker K. L., Zbarska S., Carrel A. J., Bracha V. (2009). Blocking GABAA neurotransmission in the interposed nuclei: effects on conditioned and unconditioned eyeblinks. Brain Res. 1292, 25–37 10.1016/j.brainres.2009.07.053
    1. Parnaudeau S., O’Neill P.-K., Bolkan S. S., Ward R. D., Abbas A. I., Roth B. L., et al. (2013). Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition. Neuron 77, 1151–1162 10.1016/j.neuron.2013.01.038
    1. Picton T. W., Stuss D. T., Alexander M. P., Shallice T., Binns M. A., Gillingham S. (2006). Effects of focal frontal lesions on response inhibition. Cereb. Cortex 17, 826–838 10.1093/cercor/bhk031
    1. Pierce K., Courchesne E. (2001). Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol. Psychiatry 49, 655–664 10.1016/s0006-3223(00)01008-8
    1. Pomarol-Clotet E., Canales-Rodríguez E. J., Salvador R., Sarró S., Gomar J. J., Vila F., et al. (2010). Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging. Mol. Psychiatry 15, 823–830 10.1038/mp.2009.146
    1. Prabhakaran V., Rypma B., Narayanan N. S., Meier T. B., Austin B. P., Nair V. A., et al. (2011). Capacity-speed relationships in prefrontal cortex. PLoS One 6:e27504 10.1371/journal.pone.0027504
    1. Ragland J. D., Laird A. R., Ranganath C., Blumenfeld R. S., Gonzales S. M., Glahn D. C. (2009). Prefrontal activation deficits during episodic memory in schizophrenia. Am. J. Psychiatry 166, 863–874 10.1176/appi.ajp.2009.08091307
    1. Rogers T. D., Dickson P. E., Heck D. H., Goldowitz D., Mittleman G., Blaha C. D. (2011). Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse 65, 1204–1212 10.1002/syn.20960
    1. Rogers T. D., Dickson P. E., McKimm E., Heck D. H., Goldowitz D., Blaha C. D., et al. (2013). Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder. Cerebellum 12, 547–556 10.1007/s12311-013-0462-2
    1. Saalmann Y. B., Kastner S. (2011). Cognitive and perceptual functions of the visual thalamus. Neuron 71, 209–223 10.1016/j.neuron.2011.06.027
    1. Salgado-Pineda P., Landin-Romero R., Fakra E., Delaveau P., Amann B. L., Blin O. (2014). Structural abnormalities in schizophrenia: further evidence on the key role of the anterior cingulate cortex. Neuropsychobiology 69, 52–58 10.1159/000356972
    1. Schmahmann J. D. (1998). Dysmetria of thought: clinical consequences of cerebellar dysfunction on cognition and affect. Trends Cogn. Sci. 2, 362–371 10.1016/s1364-6613(98)01218-2
    1. Schmahmann J. D. (2004). Disorders of the cerebellum: ataxia, dysmetria of thought and the cerebellar cognitive affective syndrome. J. Neuropsychiatry Clin. Neurosci. 16, 367–378 10.1176/appi.neuropsych.16.3.367
    1. Schmahmann J. D. (2010). The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis and its historical evolution from theory to therapy. Neuropsychol. Rev. 20, 236–260 10.1007/s11065-010-9142-x
    1. Schulz R., Wessel M. J., Zimerman M., Timmerman J., Gerloff C., Hummel F. C. (2014). White matter integrity of specific dentato-thalamo-cortical pathways is associated with learning gains in precise movement timing. Cereb. Cortex [Epub ahead of print]. 10.1093/cercor/bht356
    1. Schutter D. J. L. G., van Honk J., d’ Alfonso A. A. L., Peper J. S., Panksepp J. (2003). High frequency repetitive transcranial magnetic over the medial cerebellum induces a shift in the prefrontal electroencephalography gamma spectrum: a pilot study in humans. Neurosci. Lett. 336, 73–76 10.1016/s0304-3940(02)01077-7
    1. Seeman P. (1987). Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1, 133–152 10.1002/syn.890010203
    1. Shevelkin A. V., Ihenatu C., Pletnikov M. V. (2014). Pre-clinical models of neurodevelopmental disorders: focus on the cerebellum. Rev. Neurosci. 25, 177–194 10.1515/revneuro-2013-0049
    1. Siegel J. J., Kalmbach B., Chitwood R. A., Mauk M. D. (2012). Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning. J. Neurophysiol. 107, 50–64 10.1152/jn.00689.2011
    1. Sivaswamy L., Kumar A., Rajan D., Behen M., Muzik O., Chugani D., et al. (2010). A diffusion tensor imaging study of the cerebellar pathways in children with autism spectrum disorder. J. Child Neurol. 25, 1223–1231 10.1177/0883073809358765
    1. Snider R. S., Maiti A., Snider S. R. (1976). Cerebellar pathways to ventral midbrain and nigra. Exp. Neurol. 53, 714–728 10.1016/0014-4886(76)90150-3
    1. Stahl S. M., Buckley P. F. (2007). Negative symptoms of schizophrenia: a problem that will not go away. Acta Psychiatr. Scand. 115, 4–11 10.1111/j.1600-0447.2006.00947.x
    1. Stoodley C. J., Schmahmann J. D. (2009). The cerebellum and language: evidence from patients with cerebellar degeneration. Brain Lang. 110, 149–153 10.1016/j.bandl.2009.07.006
    1. Strick P. L., Dum R. P., Fiez J. A. (2009). Cerebellum and nonmotor function. Annu. Rev. Neurosci. 32, 413–434 10.1146/annurev.neuro.31.060407.125606
    1. Sudarov A. (2013). Defining the role of cerebellar Purkinje cells in autism spectrum disorders. Cerebellum 12, 950–955 10.1007/s12311-013-0490-y
    1. Takayanagi M., Wentz J., Takayanagi Y., Schretlen D. J., Ceyhan E., Wang L., et al. (2013). Reduced anterior cingulate gray matter volume and thickness in subjects with deficit schizophrenia. Schizophr. Res. 150, 484–490 10.1016/j.schres.2013.07.036
    1. Tomlinson S. P., Davis N. J., Bracewell R. M. (2013). Brain stimulation studies of non-motor cerebellar function: a systematic review. Neurosci. Biobehav. Rev. 37, 766–789 10.1016/j.neubiorev.2013.03.001
    1. Tsubota T., Ohashi Y., Tamura K., Sato A., Miyashita Y. (2011). Optogenetic manipulation of cerebellar purkinje cell activity in vivo. PLoS One 6:e22400 10.1371/journal.pone.0022400
    1. Uylings H. B. M., Groenewegen H. J., Kolb B. (2003). Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17 10.1016/j.bbr.2003.09.028
    1. Vilensky J. A., Van Hoesen G. W. (1981). Corticopontine projections from the cingulate cortex in the rhesus monkey. Brain Res. 205, 391–395 10.1016/0006-8993(81)90348-6
    1. Vogt B. A., Hof P. R., Zilles K., Vogt L. J., Herold C., Palomero-Gallagher N. (2013). Cingulate area 32 homologies in mouse, rat, macaque and human: cytoarchitecture and receptor architecture. J. Comp. Neurol. 521, 4189–4204 10.1002/cne.23409
    1. Vogt B. A., Paxinos G. (2014). Cytoarchitecture of mouse and rat cingulate cortex with human homologies. Brain Struct. Funct. 219, 185–192 10.1007/s00429-012-0493-3
    1. Volz H.-P., Nenadic I., Gaser C., Rammsayer T., Häger F., Sauer H. (2001). Time estimation in schizophrenia: an fMRI study at adjusted levels of difficulty. Neuroreport 12, 313–316 10.1097/00001756-200102120-00026
    1. Walker E., Shaye J. (1982). Familial schizophrenia. A predictor of neuromotor and attentional abnormalities in schizophrenia. Arch. Gen. Psychiatry 39, 1153–1156 10.1001/archpsyc.1982.04290100027005
    1. Wassink T. H., Andreasen N. C., Nopoulos P., Flaum M. (1999). Cerebellar morphology as a predictor of symptom and psychosocial outcome in schizophrenia. Biol. Psychiatry 45, 41–48 10.1016/s0006-3223(98)00175-9
    1. Watson T. C., Becker N., Apps R., Jones M. W. (2014). Back to front: cerebellar connections and interactions with the prefrontal cortex. Front. Syst. Neurosci. 8:4 10.3389/fnsys.2014.00004
    1. Watson T. C., Jones M. W., Apps R. (2009). Electrophysiological mapping of novel prefrontal - cerebellar pathways. Front. Integr. Neurosci. 3:18 10.3389/neuro.07.018.2009
    1. Weinberger D. R., Berman K. F., Zec R. F. (1986). Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch. Gen. Psychiatry 43, 114–124 10.1001/archpsyc.1986.01800020020004
    1. Weinberger D. R., Kleinman J. E., Luchins D. J., Bigelow L. B., Wyatt R. J. (1980). Cerebellar pathology in schizophrenia: a controlled postmortem study. Am. J. Psychiatry 137, 359–361
    1. Weiss C., Disterhoft J. F. (1996). Eyeblink conditioning, motor control and the analysis of limbic-cerebellar interactions. Behav. Brain Sci. 19, 479–481 10.1017/s0140525x00081929
    1. White T., Nelson M., Lim K. O. (2008). Diffusion tensor imaging in psychiatric disorders. Top. Magn. Reson. Imaging 19, 97–109 10.1097/rmr.0b013e3181809f1e
    1. Williams S. M., Goldman-Rakic P. S. (1998). Widespread origin of the primate mesofrontal dopamine system. Cereb. Cortex 8, 321–345 10.1093/cercor/8.4.321
    1. Wiser A. K., Andreasen N. C., O’Leary D. S., Watkins G. L., Boles Ponto L. L., Hichwa R. D. (1998). Dysfunctional cortico-cerebellar circuits cause “cognitive dysmetria” in schizophrenia. Neuroreport 9, 1895–1899 10.1097/00001756-199806010-00042
    1. Wu T., Hallett M. (2013). The cerebellum in Parkinson’s disease. Brain 136, 696–709 10.1093/brain/aws360
    1. Yücel M., Pantelis C., Stuart G. W., Wood S. J., Maruff P., Velakoulis D., et al. (2002). Anterior cingulate activation during Stroop task performance: a PET to MRI coregistration study of individual patients with schizophrenia. Am. J. Psychiatry 159, 251–254 10.1176/appi.ajp.159.2.251

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren