title: Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction.
abstract: Schizophrenia involves abnormalities in the medial frontal cortex that lead to cognitive deficits. Here we investigate a novel strategy to normalize medial frontal brain activity by stimulating cerebellar projections. We used an interval timing task to study elementary cognitive processing that requires both frontal and cerebellar networks that are disrupted in patients with schizophrenia. We report three novel findings. First, patients with schizophrenia had dysfunctional delta rhythms between 1-4 Hz in the medial frontal cortex. We explored cerebellar-frontal interactions in animal models and found that both frontal and cerebellar neurons were modulated during interval timing and had delta-frequency interactions. Finally, delta-frequency optogenetic stimulation of thalamic synaptic terminals of lateral cerebellar projection neurons rescued timing performance as well as medial frontal activity in a rodent model of schizophrenia-related frontal dysfunction. These data provide insight into how the cerebellum influences medial frontal networks and the role of the cerebellum in cognitive processing.
authors.affiliation: Department of Psychiatry, The University of Iowa, Iowa City, IA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Parker
authors.affiliation: Department of Neurology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Neurology, The University of Iowa, Iowa City, IA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Kelley
authors.affiliation: Department of Psychiatry, The University of Iowa, Iowa City, IA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Nessler
authors.affiliation: Institute of Personality and Social Research, University of California, Berkeley, Berkeley, CA, USA.
authors.forename: K-H
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Department of Psychology, The University of Iowa, Iowa City, IA, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Muller-Ewald
authors.affiliation: Department of Psychiatry, The University of Iowa, Iowa City, IA, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Andreasen
authors.affiliation: Department of Neurology, The University of Iowa, Iowa City, IA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Narayanan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology*; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D005260:Female; D005625:Frontal Lobe / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D012559:Schizophrenia / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D013788:Thalamus / Q000503:physiopathology; D065908:Transcranial Direct Current Stimulation / Q000379:methods