Could Stress Cause Psychosis in Individuals Vulnerable to Schizophrenia?

Corcoran, Cheryl; Mujica‐Parodi, Lilianne R.; Yale, Scott; Leitman, David I.; Malaspina, Dolores

doi:10.1017/s1092852900022240

Cited by 43 publications

(32 citation statements)

References 111 publications

(89 reference statements)

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“…It has been observed that this ''vulnerability,'' or lack of inhibition in the threat detection mechanism , manifests itself as an overt illness only under the impact of stress factors (Ventura et al, 1989), so that schizophrenic disturbances eventually result as an overlap of environmental stress onto the individual's premorbid personality component. Advances in understanding the neurobiology of the stress cascade (Wik et al, 1986;Tandon et al, 1991;McEwen, 2004) led to a plausible model by which this vulnerability occurs through neurotoxic effects on the hippocampus, involving synaptic remodeling (Corcoran et al, 2002;Kim and Kim, 2007;Weinberger and McClure, 2002).…”

Section: Schizophrenia and The Limbic Dysregulation Hypothesismentioning

confidence: 99%

“…The central amygdala (CE) forms the main excitatory component of the arousal response (Davis and Whalen, 2001). The primary inhibitory pathways are the medial PFC (Baxter et al, 2000;Blair et al, 2005;Phelps et al, 2004;Rosenkranz et al, 2003) and the hippocampus (Corcoran et al, 2002;Sotres-Bayon et al, 2004). Outputs from the limbic system, via the hypothalamus, provide inputs for the endocrine and autonomic nervous systems.…”

Section: Schizophrenia and The Limbic Dysregulation Hypothesismentioning

confidence: 99%

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Schizophrenia—a parameters’ game?

Rǎdulescu

2008

Journal of Theoretical Biology

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Section: Schizophrenia and The Limbic Dysregulation Hypothesismentioning

confidence: 99%

Section: Schizophrenia and The Limbic Dysregulation Hypothesismentioning

confidence: 99%

Schizophrenia—a parameters’ game?

Rǎdulescu

2008

Journal of Theoretical Biology

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“…Deficits in working memory, associated with prefrontal cortical dysfunction, are a hallmark of several neuropsychiatric disorders, including depression, Parkinson's disease, and schizophrenia (Lewis et al, 2004;Monchi et al, 2004;Rogers et al, 2004;Shad et al, 2004). Both stress and hypersecretion of corticosteroids have been causally implicated in depression and schizophrenia (Altamura et al, 1999;Corcoran et al, 2002;Barden, 2004;Ryan et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors

Cerqueira¹,

Pêgo²,

Taipa³

et al. 2005

J. Neurosci.

259

195

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Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 g/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

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“…Yet, even with the use of clinical ratings [8] , establishing precisely the severity of delusions and hallucinations is difficult, due to each particular individual's history and circumstances. In fact, some recent hypotheses suggest that psychotic symptoms are only an 'epiphenomenon' of the core pathophysiology [9] , and hence altogether unreliable for making diagnosis and treatment decisions. Herein lies the strength of a quantitative biological measure.…”

Section: Introductionmentioning

confidence: 99%

A Systems Approach to Prefrontal-Limbic Dysregulation in Schizophrenia

Rǎdulescu

Mujica‐Parodi²

2008

Neuropsychobiology

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Introduction: Using a prefrontal-limbic dysregulation model for schizophrenia, we tested whether a dynamic control systems approach in conjunction with neuroimaging might increase detection sensitivity in characterizing the illness. Our analyses were modeled upon diagnostic tests for other dysregulatory diseases, such as diabetes, in which trajectories for the excitatory and inhibitory components of the negative feedback loops that reestablish homeostasis are measured after system perturbation. We hypothesized that these components would show distinct coupling dynamics within the patient population, as compared to healthy controls, and that these coupling dynamics could be quantified statistically using cross-correlations between excitatory and inhibitory time series using fMRI. Methods: As our perturbation, we activated neural regions associated with the emotional arousal response, using affect-valent facial stimuli presented to 11 schizophrenic patients (all under psychotropic medication) and 65 healthy controls (including 11 individuals age- and sex-matched to the patients) during fMRI scanning. We first performed a random-effects analysis of the fMRI data to identify activated regions. Those regions were then analyzed for group differences, using both standard analyses with respect to the time series peaks, as well as a dynamic analysis that looked at cross-correlations between excitatory and inhibitory time series and group differences over the entire time series. Results: Patients and controls showed significant differences in signal dynamics between excitatory and inhibitory components of the negative feedback loop that controls emotional arousal, specifically between the right amygdala and Brodmann area 9 (BA9), when viewing angry facial expressions (p = 0.002). Further analyses were performed with respect to activation amplitudes for these areas in response to angry faces, both over the entire time series as well as for each time point along the time series. While the amygdala responses were not significantly different between groups, patients showed significantly lower BA9 activation during the beginning of the response (0.000 ≤ p ≤ 0.021) and significantly higher BA9 activation towards the end of the response (0.008 ≤ p ≤ 0.025), suggesting longer time-lags between patients’ excitatory responses and the inhibitory activation that modulates it. Conclusions: Our results capture a significant dysregulation between the excitatory (amygdala) and inhibitory (prefrontal) limbic regions in medicated schizophrenic patients versus healthy controls. They suggest that, analogously to diagnostic tests used in other physiological diseases, quantifying dysregulation using a control systems approach may provide an appropriate model to investigate further in developing presymptomatic neurobiological assessments of risk, or illness severity in symptomatic patients.

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Could Stress Cause Psychosis in Individuals Vulnerable to Schizophrenia?

Cited by 43 publications

References 111 publications

Schizophrenia—a parameters’ game?

Schizophrenia—a parameters’ game?

Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors

A Systems Approach to Prefrontal-Limbic Dysregulation in Schizophrenia

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