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Item Cerebellar Activation Deficits in Schizophrenia During an Eyeblink Conditioning Task(Oxford University Press, 2021-08-28) Lundin, Nancy B.; Kim, Dae-Jin; Tullar, Rachel L.; Moussa-Tooks, Alexandra B.; Kent, Jerillyn S.; Newman, Sharlene D.; Purcell, John R.; Bolbecker, Amanda R.; O’Donnell, Brian F.; Hetrick, William P.; Psychiatry, School of MedicineThe cognitive dysmetria theory of psychotic disorders posits that cerebellar circuit abnormalities give rise to difficulties coordinating motor and cognitive functions. However, brain activation during cerebellar-mediated tasks is understudied in schizophrenia. Accordingly, this study examined whether individuals with schizophrenia have diminished neural activation compared to controls in key regions of the delay eyeblink conditioning (dEBC) cerebellar circuit (eg, lobule VI) and cerebellar regions associated with cognition (eg, Crus I). Participants with schizophrenia-spectrum disorders (n = 31) and healthy controls (n = 43) underwent dEBC during functional magnetic resonance imaging (fMRI). Images were normalized using the Spatially Unbiased Infratentorial Template (SUIT) of the cerebellum and brainstem. Activation contrasts of interest were "early" and "late" stages of paired tone and air puff trials minus unpaired trials. Preliminary whole brain analyses were conducted, followed by cerebellar-specific SUIT and region of interest (ROI) analyses of lobule VI and Crus I. Correlation analyses were conducted between cerebellar activation, neuropsychological test scores, and psychotic symptom scores. In controls, the largest clusters of cerebellar activation peaked in lobule VI during early dEBC and Crus I during late dEBC. The schizophrenia group showed robust cortical activation to unpaired trials but no significant conditioning-related cerebellar activation. Crus I ROI activation during late dEBC was greater in the control than schizophrenia group. Greater Crus I activation correlated with higher working memory scores in the full sample and lower positive psychotic symptom severity in schizophrenia. Findings indicate functional cerebellar abnormalities in schizophrenia which relate to psychotic symptoms, lending direct support to the cognitive dysmetria framework.Item Differential effects of two early life stress paradigms on cerebellar-dependent delay eyeblink conditioning(Elsevier, 2020-12) Moussa-Tooks, Alexandra B.; Hetrick, William P.; Green, John T.; Psychiatry, School of MedicineEarly life stress paradigms have become prominent in the animal literature to model atypical development. Currently, two models have prevailed within the literature: (1) limited bedding or nesting and (2) maternal separation or deprivation. Both models have produced aberrations spanning behavior and neural circuitry. Surprisingly, these two models have yet to be directly compared. The current study utilized delay eyeblink conditioning, an associative learning task with a well-defined cerebellar circuit, to compare the behavioral effects of standard limited bedding (postnatal day 2–9, n = 15) and maternal separation (60 min per day during postnatal day 2–14, n = 13) early life stress paradigms. Animals in all groups exhibited robust learning curves. Surprisingly, facilitated conditioning was observed in the maternal separation group. Rats that underwent limited bedding did not differ from the control or maternal separation groups on any conditioning measures. This study contributes to a clearer understanding of early life stress paradigms and the claims made about their mechanisms, which if better clarified can be properly leveraged to increase translational value.Item Polarity- and Intensity-Independent Modulation of Timing During Delay Eyeblink Conditioning Using Cerebellar Transcranial Direct Current Stimulation(SpringerLink, 2020-06) Mitroi, Jessica; Burroughs, Leah; Moussa-Tooks, Alexandra B.; Bolbecker, Amanda R.; Lundin, Nancy B.; O’Donnell, Brian F.; Hetrick, William P.; Psychiatry, School of MedicineDelay eyeblink conditioning (dEBC) is widely used to assess cerebellar-dependent associative motor learning, including precise timing processes. Transcranial direct current stimulation (tDCS), noninvasive brain stimulation used to indirectly excite and inhibit select brain regions, may be a promising tool for understanding how functional integrity of the cerebellum influences dEBC behavior. The aim of this study was to assess whether tDCS-induced inhibition (cathodal) and excitation (anodal) of the cerebellum differentially impact timing of dEBC. A standard 10-block dEBC paradigm was administered to 102 healthy participants. Participants were randomized to stimulation conditions in a double-blind, between-subjects sham-controlled design. Participants received 20-min active (anodal or cathodal) stimulation at 1.5 mA (n = 20 anodal, n = 22 cathodal) or 2 mA (n = 19 anodal, n = 21 cathodal) or sham stimulation (n = 20) concurrently with dEBC training. Stimulation intensity and polarity effects on percent conditioned responses (CRs) and CR peak and onset latency were examined using repeated-measures analyses of variance. Acquisition of CRs increased over time at a similar rate across sham and all active stimulation groups. CR peak and onset latencies were later, i.e., closer to air puff onset, in all active stimulation groups compared to the sham group. Thus, tDCS facilitated cerebellar-dependent timing of dEBC, irrespective of stimulation intensity and polarity. These findings highlight the feasibility of using tDCS to modify cerebellar-dependent functions and provide further support for cerebellar contributions to human eyeblink conditioning and for exploring therapeutic tDCS interventions for cerebellar dysfunction.