Structural pathology underlying neuroendocrine dysfunction in schizophrenia.

Polydipsic hyponatremic schizophrenic (PHS) patients exhibit altered neuroendocrine activity that has been linked to their life-threatening water imbalance, as well as to impaired function and reduced volume of the anterior hippocampus. Polydipsic patients without hyponatremia (polydipsic normonatremic schizophrenics: PNS) exhibit similar, albeit less marked, changes in neuroendocrine activity and anterior hippocampal function, but not reduced anterior hippocampal volume. Indeed, reduced anterior hippocampal volume is seen in patients with normal water balance (nonpolydipsic normonatremic schizophrenics: NNS) whose neuroendocrine activity and anterior hippocampal function differ markedly from those with polydipsia. In an effort to reconcile these findings we measured hippocampal, amygdala and 3rd ventricle shapes in 26 schizophrenic patients (10 PNS, 7 PHS, 9 NNS) and 12 healthy controls matched for age and gender. Bilateral inward deformations were localized to the anterior lateral hippocampal surface (part of a neurocircuit which modulates neuroendocrine responses to psychological stimuli) in PHS and to a lesser extent in PNS, while deformations in NNS were restricted to the medial surface. Proportional deformations of the right medial amygdala, a key segment of this neurocircuit, were seen in both polydipsic groups, and correlated with the volume of the 3rd ventricle, which lies adjacent to the neuroendocrine nuclei. Finally, these structural findings were most marked in those with impaired hippocampal-mediated stress responses. These results reconcile previously conflicting data, and support the view that anterior lateral hippocampal pathology disrupts neuroendocrine function in polydipsic patients with and without hyponatremia. The relationship of these findings to the underlying mental illness remains to be established.

Neuropsychological impairment in patients with schizophrenia and evidence of hyponatremia and polydipsia.

Patients with schizophrenia and water imbalance may represent a subset of patients with distinct pathophysiological abnormalities and susceptibility to cognitive impairment. Specifically, patients with polydipsia and hyponatremia have been shown to have smaller anterior hippocampal volumes, which are also associated with various impairments in neuroendocrine function. To determine whether abnormalities in patients with water imbalance extend to the cognitive realm, the present study evaluated neuropsychological functioning in three groups of patients with schizophrenia: polydipsic hyponatremic, polydipsic normonatremic, and nonpolydipsic normonatremic. Participants were administered cognitive tests assessing intelligence, attention, learning/memory (verbal, nonverbal, emotional), and facial discrimination. Hyponatremic patients showed poorer overall neuropsychological functioning relative to all other patients, and polydipsic normonatremic patients performed intermediate to the other two groups. Results indicate that patients with schizophrenia and polydipsia, and particularly those with hyponatremia, show prominent cognitive deficits relative to patients without water imbalance. The clinical, neuroendocrine, and cognitive abnormalities in these patients may arise from pathology within the anterior hippocampus and associated prefrontal/limbic brain regions.

FMRI indices of auditory attention in schizophrenia.

The present study sought to identify abnormalities in activation in several brain regions in response to an auditory attention task in patients with schizophrenia. Ten patients and twenty healthy control participants were examined using Functional Magnetic Resonance Imaging (FMRI) measures acquired during an auditory attention task. Region of interest analyses of activation of targeted regions implicated in attention included: anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus, parahippocampal gyrus (PHG), and superior temporal gyrus (STG). The results indicated over-activation in patients with schizophrenia. While the control group showed notable coherence in activation within and across hemispheres the schizophrenia group showed relatively less coherence overall that was only present in the right hemisphere. These findings suggest that patients with schizophrenia show both an over-engagement of brain regions during attention task as well as a lack of communication among neural regions involved.

Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits.

Polydipsic hyponatremic schizophrenic patients (PHS) exhibit enhanced plasma arginine vasopressin (pAVP) and hypothalamic pituitary adrenal (HPA) axis responses to stress that appear attributable to anterior hippocampal dysfunction. Neuroanatomic and electrophysiologic studies indicate oxytocin activity in PHS patients should also be affected. Furthermore, oxytocin normally diminishes HPA responses to stress and facilitates cognitive and behavioral functions impaired in schizophrenia, suggesting that diminished oxytocin activity could contribute to this subsets' neuropsychiatric disorder. In the present study, we measured plasma oxytocin levels at intervals before and after stress induction in six polydipsic hyponatremic (PHS), four polydipsic normonatremic (PNS), five nonpolydipsic normonatremic schizophrenic (NNS) patients and seven healthy controls. Most of these subjects also completed studies measuring their medial temporal lobe volumes, their hippocampal-mediated HPA feedback and their ability to discriminate different facial emotions (an oxytocin-sensitive measure which is markedly impaired in schizophrenia). Results demonstrated that 1) plasma oxytocin levels were lower (p=.006) in hyponatremic patients relative to the other three groups, whose levels were similar and did not change. Oxytocin levels across all subjects were 2) inversely correlated with anterior hippocampal (p=.004) (but not posterior hippocampal or amygdala volumes), and 3) directly correlated with the integrity of hippocampal-mediated HPA feedback (p=.039). Finally, 4) oxytocin levels predicted schizophrenic patients' ability to correctly identify facial emotions (p=.004). These preliminary data provide further evidence that neuroendocrine dysfunction in PHS reflects anterior hippocampal pathology and contributes to a characteristic neuropsychiatric syndrome.

Noradrenergic antagonism of the P13 and N40 components of the rat auditory evoked potential.

RATIONALE: Two rat auditory evoked potential (AEP) components P13 and N40 are suggested as analogues to the human P50, which has abnormal suppression properties in schizophrenia. However, P50 likely reflects neural activity from several different brain areas. Studies examining each of these components in the rat model have proposed circuitry that involves alpha2 norepinephrine (NE) receptors, and different disruption effects are predicted depending on whether effects are presynaptic or postsynaptic. OBJECTIVES: The aim of this paper is to test differential effects of NE antagonism on disruption of normal P13 and N40 expression. MATERIALS AND METHODS: AEPs were recorded simultaneously in alert, freely moving rats using the alpha2 antagonist yohimbine. Amplitudes of P13 and N40 elicited by 500-ms interstimulus interval click pairs were measured after administration of a placebo and three doses of the yohimbine. RESULTS: A high dose of yohimbine yielded smaller P13 amplitudes to both clicks, consistent with presynaptic action. However, a moderate yohimbine dose yielded increased P13 amplitudes to both clicks. For N40, a moderate dose of yohimbine yielded increased amplitudes to the second stimulus, and a high dose restored normal suppression, which is consistent with previously reported findings. CONCLUSIONS: This study demonstrated that noradrenergic activity differentially affects P13 and N40 components. As P13 and N40 are each models of human P50, these findings highlight the complex circuitry that likely underlies P50. An appreciation for these complexities is critical for understanding the mechanisms of the P50 suppression deficit in schizophrenia, which may be influenced by both trait and state factors.