Item-specific overlap between hallucinatory experiences and cognition in the general population: A three-step multivariate analysis of international multi-site data

Hallucinatory experiences (HEs) can be pronounced in psychosis, but similar experiences also occur in nonclinical populations. Cognitive mechanisms hypothesized to underpin HEs include dysfunctional source monitoring, heightened signal detection, and impaired attentional processes. Using data from an international multisite study on non-clinical participants (N = 419), we described the overlap between two sets of variables - one measuring cognition and the other HEs - at the level of individual items. We used a three-step method to extract and examine item-specific signal, which is typically obscured when summary scores are analyzed using traditional methodologies. The three-step method involved: (1) constraining variance in cognition variables to that which is predictable from HE variables, followed by dimension reduction, (2) determining reliable HE items using split-halves and permutation tests, and (3) selecting cognition items for interpretation using a leave-one-out procedure followed by repetition of Steps 1 and 2. The results showed that the overlap between HEs and cognition variables can be conceptualized as bi-dimensional, with two distinct mechanisms emerging as candidates for separate pathways to the development of HEs: HEs involving perceptual distortions on one hand (including voices), underpinned by a low threshold for signal detection in cognition, and HEs involving sensory overload on the other hand, underpinned by reduced laterality in cognition. We propose that these two dimensions of HEs involving distortions/liberal signal detection, and sensation overload/reduced laterality may map onto psychosis-spectrum and dissociation-spectrum anomalous experiences, respectively

Motherhood and ovarian hormones influence hippocampus-dependent cognition and neurogenesis later in life

Age-related cognitive decline in women may be influenced by hormonal experiences over the lifespan including parity (pregnancy and motherhood) and menopause. Previous research implicates hippocampal neurogenesis in spatial learning and age-related cognitive decline and indicates that different regions of the hippocampus (dorsal and ventral) may contribute differentially to spatial working and reference memory. Therefore, the current study investigates influences of parity and ovarian hormones on hippocampus-dependent spatial working and reference memory and neurogenesis during middle age. Multiparous and nulliparous middle-aged rats were either ovariectomized or received sham surgery and were injected with the DNA synthesis marker bromodeoxyuridine (BrdU). Rats were trained on working/reference (hidden platform moved every two days) and reference (hidden platform was stationary) memory versions of the Morris water maze on days 12-21 after BrdU injection. On day 22 rats were given a probe trial to assess memory retention. Multiparous rats had enhanced early working/reference memory acquisition compared to nulliparous rats and this was more prominent in ovariectomized rats. In contrast, nulliparous females had better reference memory acquisition compared to multiparous rats and had enhanced spatial reference memory during the probe trial. Multiparous females had a larger ventral dentate gyrus and greater density of immature neurons compared to nulliparous females, whereas nulliparous females had greater density of older BrdU-labelled cells in the dentate gyrus compared to multiparous females. Depending on ovarian hormone status and parity, neurogenesis in the dorsal dentate gyrus correlated with measures of spatial reference learning, whereas neurogenesis in the ventral dentate gyrus correlated with spatial working/reference performance. Overall, results indicate multiparous rats have better spatial working memory performance whereas nulliparous rats have enhanced reference performance. These results may reflect differences in neuroplasticity (with multiparous rats having more immature neurons and nulliparous rats having greater survival of new neurons) and/or stress resilience differences between the parous groups. Importantly, the influence of parity on spatial working and reference memory and acquisition was modified by ovarian hormone status. These results also suggest that the role of new neurons in cognition may be moderated by parity and ovarian status in middle age.Arts, Faculty ofPsychology, Department ofGraduat

Spatiotemporal fMRI-CPCA : a new method for comparing resting state to task-based brain networks in clinical and non-clinical samples

Recent decades of neuroimaging have witnessed a rapid increase in network-based research, reflecting the understanding that cognition arises from the interacting activity of multiple large-scale brain networks. However, research has increasingly prioritized studying how activity in resting state (RS) networks relate to cognition, rather than using task-based experimentation to observe the networks supporting cognitive processes. A central assumption of this approach is that task-based activity constitutes a ‘rebalancing’ of RS networks for task conditions. However, no research to date has adequately tested this assumption by evaluating RS and other network sets on their ability to explain task-related BOLD signal. In this dissertation, we introduce a novel method, Spatiotemporal fMRI-CPCA, and demonstrate its utility in characterizing the successes, and shortcomings, of different network models in accounting for the variance and spatiotemporal features of brain networks predictable from task timing. Through a series of quality assurance analyses, we validate the Spatiotemporal fMRI-CPCA method and illustrate the metrics by which network model performance can be evaluated. In order to establish a ‘ground truth’ against which network models could be evaluated, we measured and characterized the data-driven brain networks supporting verbal paired associates learning. Then, we employed Spatiotemporal fMRI-CPCA to examine how well two popular RS network models, and one network model using spatial templates derived from past observations of task-based networks, accounted for these data-driven networks. Overall, our results indicated advantages of the task-derived network model relative to both RS network models in capturing task-specific variance in BOLD signal, and in predicting key spatial and hemodynamic characteristics of the task-based networks. The advantages of the task-derived-templates model also extended to better accuracy characterizing differences in network activation between patients with schizophrenia and healthy controls. We discuss the implications of these findings for efforts to study the neural basis of cognition, and cognitive disorder, through observation of resting state networks.Arts, Faculty ofPsychology, Department ofGraduat

Sex, hormones, and neurogenesis in the hippocampus : Hormonal modulation of neurogenesis and potential functional implications

The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurons in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely surprising as the physiology of males and females is different, with the most notable difference that the females gestate and nurse the offspring. Furthermore, reproductive experience (pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus in females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex and experience-dependent way. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression and this review provides early evidence of the functional links between hormonal modulation of neurogenesis to regulate cognition and stress.Arts, Faculty ofOther UBCPsychology, Department ofReviewedFacultyPostdoctora

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history

Menopause is associated with cognitive decline, and hormone therapies (HT) may improve cognition depending on type, and timing of HT. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin six months later, and all rats were trained in the Morris water maze. Premarin improved spatial learning and memory in nulliparous rats, but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor (TNF) α and the CXC chemokine ligand 1 (CXCL1) in nulliparous, but not primiparous, trained rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.Arts, Faculty ofMedicine, Faculty ofPsychology, Department ofReviewedFacultyResearcherPostdoctoralGraduat

Real-Time Symptom Capture of Hallucinations in Schizophrenia with fMRI: Absence of Duration-Dependent Activity

Background: While advances in the field of functional magnetic resonance imaging (fMRI) provide new opportunities to study brain networks underlying the experience of hallucinations in psychosis, there are methodological challenges unique to symptom-capture studies. Study Design: We extracted brain networks activated during hallucination-capture for schizophrenia patients when fMRI data collected from two sites was merged (combined N = 27). A multidimensional analysis technique was applied, which would allow separation of brain networks involved in the hallucinatory experience itself from those involved in the motor response of indicating the beginning and end of the perceived hallucinatory experience. To avoid reverse inference when attributing a function (e.g., a hallucination) to anatomical regions, it was required that longer hallucinatory experiences produce extended brain responses relative to shorter. Study Results: For radio-speech sound files, an auditory perception brain network emerged, and displayed speech-duration-dependent hemodynamic responses (HDRs). However, in the hallucination-capture blocks, no network showed hallucination-duration-dependent HDRs, but a retrieved network that was anatomically classified as motor response emerged. Conclusions: During symptom capture of hallucinations during fMRI, no HDR showed duration dependence, but a brain network anatomically matching the motor response network was retrieved. Previous reports on brain networks detected by fMRI during hallucination capture are reviewed in this context; namely, that the brain networks interpreted as involved in hallucinations may in fact be involved only in the motor response indicating the onset of the hallucination

Item-specific overlap between hallucinatory experiences and cognition in the general population: A three-step multivariate analysis of international multi-site data

Hallucinatory experiences (HEs) can be pronounced in psychosis, but similar experiences also occur in nonclinical populations. Cognitive mechanisms hypothesized to underpin HEs include dysfunctional source monitoring, heightened signal detection, and impaired attentional processes. Using data from an international multisite study on non-clinical participants (N = 419), we described the overlap between two sets of variables - one measuring cognition and the other HEs - at the level of individual items. We used a three-step method to extract and examine item-specific signal, which is typically obscured when summary scores are analyzed using traditional methodologies. The three-step method involved: (1) constraining variance in cognition variables to that which is predictable from HE variables, followed by dimension reduction, (2) determining reliable HE items using split-halves and permutation tests, and (3) selecting cognition items for interpretation using a leave-one-out procedure followed by repetition of Steps 1 and 2. The results showed that the overlap between HEs and cognition variables can be conceptualized as bi-dimensional, with two distinct mechanisms emerging as candidates for separate pathways to the development of HEs: HEs involving perceptual distortions on one hand (including voices), underpinned by a low threshold for signal detection in cognition, and HEs involving sensory overload on the other hand, underpinned by reduced laterality in cognition. We propose that these two dimensions of HEs involving distortions/liberal signal detection, and sensation overload/reduced laterality may map onto psychosis-spectrum and dissociation-spectrum anomalous experiences, respectively