Browsing by Author "O’Donnell, Brian F."

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    Altered cerebellar-cortical resting-state functional connectivity in cannabis users
    (Sage, 2021) Schnakenberg Martin, Ashley M.; Kim, Dae-Jin; Newman, Sharlene D.; Cheng, Hu; Hetrick, William P.; Mackie, Ken; O’Donnell, Brian F.; Psychiatry, School of Medicine
    Background: Cannabis use has been associated with abnormalities in cerebellar mediated motor and non-motor (i.e. cognition and personality) phenomena. Since the cerebellum is a region with high cannabinoid type 1 receptor density, these impairments may reflect alterations of signaling between the cerebellum and other brain regions. Aims: We hypothesized that cerebellar-cortical resting-state functional connectivity (rsFC) would be altered in cannabis users, relative to their non-using peers. It was also hypothesized that differences in rsFC would be associated with cannabis use features, such as age of initiation and lifetime use. Methods: Cerebellar-cortical and subcortical rsFCs were computed between 28 cerebellar lobules, defined by a spatially unbiased atlas template of the cerebellum, and individual voxels in the cerebral regions, in 41 regular cannabis users (20 female) and healthy non-using peers (N = 31; 18 female). We also investigated associations between rsFC and cannabis use features (e.g. lifetime cannabis use and age of initiation). Results: Cannabis users demonstrated hyperconnectivity between the anterior cerebellar regions (i.e. lobule I-IV) with the posterior cingulate cortex, and hypoconnectivity between the rest of the cerebellum (i.e. Crus I and II, lobule VIIb, VIIIa, VIIIb, IX, and X) and the cortex. No associations were observed between features of cannabis use and rsFC. Conclusions: Cannabis use was associated with altered patterns of rsFC from the cerebellum to the cerebral cortex which may have a downstream impact on behavior and cognition.
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    Auditory feature perception and auditory hallucinatory experiences in schizophrenia spectrum disorder
    (Springer, 2017-09-21) Schnakenberg Martin, Ashley M.; Bartolomeo, Lisa; Howell, Josselyn; Hetrick, William P.; Bolbecker, Amanda R.; Breier, Alan; Kidd, Gary; O’Donnell, Brian F.; Psychiatry, School of Medicine
    Schizophrenia spectrum disorder (SZ) is associated with deficits in auditory perception as well as auditory verbal hallucinations (AVH). However, the relationship between auditory feature perception and auditory verbal hallucinations (AVH), one of the most commonly occurring symptoms in psychosis, has not been well characterized. This study evaluated perception of a broad range of auditory features in SZ and to determine whether current AVHs relate to auditory feature perception. Auditory perception, including frequency, intensity, duration, pulse-train and temporal order discrimination, as well as an embedded tone task, was assessed in both AVH (n = 20) and non-AVH (n = 24) SZ individuals and in healthy controls (n = 29) with the Test of Basic Auditory Capabilities (TBAC). The Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) was used to assess the experience of auditory hallucinations in patients with SZ. Findings suggest that compared to controls, the SZ group had greater deficits on an array of auditory features, with non-AVH SZ individuals showing the most severe degree of abnormality. IQ and measures of cognitive processing were positively associated with performance on the TBAC for all SZ individuals, but not with the HPSVQ scores. These findings indicate that persons with SZ demonstrate impaired auditory perception for a broad range of features. It does not appear that impaired auditory perception is associated with recent auditory verbal hallucinations, but instead associated with the degree of intellectual impairment in SZ.
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    Bifactor Structure of the Schizotypal Personality Questionnaire Across the Schizotypy Spectrum
    (Guilford Press, 2021-08) Moussa-Tooks, Alexandra B.; Bailey, Allen J.; Bolbecker, Amanda R.; Viken, Richard J.; O’Donnell, Brian F.; Hetrick, William P.; Psychiatry, School of Medicine
    Despite widespread use in schizophrenia-spectrum research, uncertainty remains around an empirically supported and theoretically meaningful factor structure of the Schizotypal Personality Questionnaire (SPQ). Current identified structures are limited by reliance on exclusively nonclinical samples. The current study compared factor structures of the SPQ in a sample of 335 nonpsychiatric individuals, 292 schizotypy-spectrum individuals (schizophrenia, schizoaffective disorder, or schizotypal personality disorder), and the combined group (N = 627). Unidimensional, correlated, and hierarchical models were assessed in addition to a bifactor model, wherein subscales load simultaneously onto a general factor and a specific factor. The best-fitting model across samples was a two-specific factor bifactor model, consistent with the nine symptom dimensions of schizotypy as primarily a direct manifestation of a unitary construct. Such findings, for the first time demonstrated in a clinical sample, have broad implications for transdiagnostic approaches, including reifying schizotypy as a construct underlying diverse manifestations of phenomenology across a wide range of severity.
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    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 Medicine
    The 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.
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    Differential Cognitive Performance in Females and Males with Regular Cannabis Use
    (Cambridge University Press, 2021) Schnakenberg Martin, Ashley M.; D’Souza, Deepak Cyril; Newman, Sharlene D.; Hetrick, William P.; O’Donnell, Brian F.; Psychiatry, School of Medicine
    Objectives: Preclinical and clinical studies suggest that males and females may be differentially affected by cannabis use. This study evaluated the interaction of cannabis use and biological sex on cognition, and the association between observed cognitive deficits and features of cannabis use. Methods: Cognitive measures were assessed in those with regular, ongoing, cannabis use (N = 40; 22 female) and non-using peers (N = 40; 23 female). Intelligence, psychomotor speed, and verbal working memory were measured with the Wechsler Abbreviated Scale of Intelligence, Digit Symbol Test, and Digit Span and Hopkins Verbal Learning Test, respectively. Associations between cognitive measures and cannabis use features (e.g., lifetime cannabis use, age of initiation, time since last use of cannabis, recent high-concentration tetrahydrocannabinoid exposure) were also evaluated. Results: No main effects of group were observed across measures. Significant interactions between group and biological sex were observed on measures of intelligence, psychomotor speed, and verbal learning, with greatest group differences observed between males with and without regular cannabis use. Psychomotor performance was negatively correlated with lifetime cannabis exposure. Female and male cannabis use groups did not differ in features of cannabis use. Conclusions: Findings suggest that biological sex influences the relationship between cannabis and cognition, with males potentially being more vulnerable to the neurocognitive deficits related to cannabis use.
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    Impaired Cerebellar-Dependent Eyeblink Conditioning in First-Degree Relatives of Individuals With Schizophrenia
    (Oxford University Press, 2014-09) Bolbecker, Amanda R.; Kent, Jerillyn S.; Petersen, Isaac T.; Klaunig, Mallory J.; Forsyth, Jennifer K.; Howell, Josselyn M.; Westfall, Daniel R.; O’Donnell, Brian F.; Hetrick, William P.; Department of Psychiatry, IU School of Medicine
    Consistent with reports of cerebellar structural, functional, and neurochemical anomalies in schizophrenia, robust cerebellar-dependent delay eyeblink conditioning (dEBC) deficits have been observed in the disorder. Impaired dEBC is also present in schizotypal personality disorder, an intermediate phenotype of schizophrenia. The present work sought to determine whether dEBC deficits exist in nonpsychotic first-degree relatives of individuals with schizophrenia. A single-cue tone dEBC paradigm consisting of 10 blocks with 10 trials each (9 paired and 1 unpaired trials) was used to examine the functional integrity of cerebellar circuitry in schizophrenia participants, individuals with a first-degree relative diagnosed with schizophrenia, and healthy controls with no first-degree relatives diagnosed with schizophrenia. The conditioned stimulus (a 400ms tone) coterminated with the unconditioned stimulus (a 50ms air puff to the left eye) on paired trials. One relative and 2 healthy controls were removed from further analysis due to declining conditioned response rates, leaving 18 schizophrenia participants, 17 first-degree relatives, and 16 healthy controls. Electromyographic data were subsequently analyzed using growth curve models in hierarchical linear regression. Acquisition of dEBC conditioned responses was significantly impaired in schizophrenia and first-degree relative groups compared with controls. This finding that cerebellar-mediated associative learning deficits are present in first-degree relatives of individuals with schizophrenia provides evidence that dEBC abnormalities in schizophrenia may not be due to medication or course of illness effects. Instead, the present results are consistent with models of schizophrenia positing cerebellar-cortical circuit abnormalities and suggest that cerebellar abnormalities represent a risk marker for the disorder.
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    Impaired Effective Connectivity During a Cerebellar-Mediated Sensorimotor Synchronization Task in Schizophrenia
    (Oxford University Press, 2019-04) Moussa-Tooks, Alexandra B.; Kim, Dae-Jin; Bartolomeo, Lisa A.; Purcell, John R.; Bolbecker, Amanda R.; Newman, Sharlene D.; O’Donnell, Brian F.; Hetrick, William P.; Psychiatry, School of Medicine
    Prominent conceptual models characterize schizophrenia as a dysconnectivity syndrome, with recent research focusing on the contributions of the cerebellum in this framework. The present study examined the role of the cerebellum and its effective connectivity to the cerebrum during sensorimotor synchronization in schizophrenia. Specifically, the role of the cerebellum in temporally coordinating cerebral motor activity was examined through path analysis. Thirty-one individuals diagnosed with schizophrenia and 40 healthy controls completed a finger-tapping fMRI task including tone-paced synchronization and self-paced continuation tapping at a 500 ms intertap interval (ITI). Behavioral data revealed shorter and more variable ITIs during self-paced continuation, greater clock (vs motor) variance, and greater force of tapping in the schizophrenia group. In a whole-brain analysis, groups showed robust activation of the cerebellum during self-paced continuation but not during tone-paced synchronization. However, effective connectivity analysis revealed decreased connectivity in individuals with schizophrenia between the cerebellum and primary motor cortex but increased connectivity between cerebellum and thalamus during self-paced continuation compared with healthy controls. These findings in schizophrenia indicate diminished temporal coordination of cerebral motor activity by cerebellum during the continuation tapping portion of sensorimotor synchronization. Taken together with the behavioral finding of greater temporal variability in schizophrenia, these effective connectivity results are consistent with structural and temporal models of dysconnectivity in the disorder.
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    Investigating Cerebellar Neural Function in Schizophrenia Using Delay Eyeblink Conditioning: A Pilot fMRI Study
    (Elsevier, 2020) Kent, Jerillyn S.; Kim, Dae-Jin; Newman, Sharlene D.; Bolbecker, Amanda R.; O’Donnell, Brian F.; Hetrick, William P.; Psychiatry, School of Medicine
    There is accruing evidence of cerebellar abnormalities in individuals with schizophrenia as measured by performance on a variety of tasks believed to be dependent on cerebellar integrity, including delay eyeblink conditioning. There is also evidence of cerebellar dysfunction on a neural level in schizophrenia from both task-based and resting state neuroimaging studies, however few studies have examined cerebellar neural function while the cerebellum is directly recruited in individuals with schizophrenia. In the current pilot study, we examined neural activity during an explicitly cerebellar task in individuals with schizophrenia or schizoaffective disorder and non-psychiatric controls. Participants underwent delay eyeblink conditioning during fMRI. Results indicated eyeblink conditioning impairment in patients as evidenced by a group by time interaction for conditioned responses. A significant cluster of cerebellar activation was present in controls but not patients during the first half of conditioning; there were no significant differences in activation between groups. An ROI analysis focused on the cerebellum in patients revealed two significant clusters that were inversely associated with negative symptom severity. These results are broadly consistent with the theory of cognitive dysmetria, wherein cerebellar abnormalities are theorized to contribute to motor as well as cognitive and affective disturbances in schizophrenia.
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    Long-Term Aberrations To Cerebellar Endocannabinoids Induced By Early-Life Stress
    (Nature Research, 2020-04-29) Moussa-Tooks, Alexandra B.; Larson, Eric R.; Gimeno, Alex F.; Leishman, Emma; Bartolomeo, Lisa A.; Bradshaw, Heather B.; Green, John T.; O’Donnell, Brian F.; Mackie, Ken; Hetrick, William P.; Psychiatry, School of Medicine
    Emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling with studies on stress-induced endocannabinoid dysregulation focusing on cerebral changes that are temporally proximal to stressors. Little is known about temporally distal and sex-specific effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Following limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids, related lipids, and mRNA were assessed, and behavioral performance evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar interpositus nucleus in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Cerebellar interpositus transcriptomics revealed substantial sex effects, with minimal stress effects. Stress did impair novel object recognition in both sexes and social preference in females. Accordingly, the cerebellar endocannabinoid system exhibits robust sex-specific differences, malleable through early-life stress, suggesting the role of endocannabinoids and stress to sexual differentiation of the brain and cerebellar-related dysfunctions.
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    Neural evidence of switch processes during semantic and phonetic foraging in human memory
    (National Academy of Science, 2023) Lundin, Nancy B.; Brown, Joshua W.; Johns, Brendan T.; Jones, Michael N.; Purcell, John R.; Hetrick, William P.; O’Donnell, Brian F.; Todd, Peter M.; Psychiatry, School of Medicine
    Humans may retrieve words from memory by exploring and exploiting in "semantic space" similar to how nonhuman animals forage for resources in physical space. This has been studied using the verbal fluency test (VFT), in which participants generate words belonging to a semantic or phonetic category in a limited time. People produce bursts of related items during VFT, referred to as "clustering" and "switching." The strategic foraging model posits that cognitive search behavior is guided by a monitoring process which detects relevant declines in performance and then triggers the searcher to seek a new patch or cluster in memory after the current patch has been depleted. An alternative body of research proposes that this behavior can be explained by an undirected rather than strategic search process, such as random walks with or without random jumps to new parts of semantic space. This study contributes to this theoretical debate by testing for neural evidence of strategically timed switches during memory search. Thirty participants performed category and letter VFT during functional MRI. Responses were classified as cluster or switch events based on computational metrics of similarity and participant evaluations. Results showed greater hippocampal and posterior cerebellar activation during switching than clustering, even while controlling for interresponse times and linguistic distance. Furthermore, these regions exhibited ramping activity which increased during within-patch search leading up to switches. Findings support the strategic foraging model, clarifying how neural switch processes may guide memory search in a manner akin to foraging in patchy spatial environments.