Neurodynamics of Abnormalities in Cerebral Metabolism and Structure in Schizophrenia

Abstract

Much evidence points to the importance of intrauterine events in the etiology of schizophrenia and suggests a complex interplay between dysfunctional and intact neurons in the pathophysiology of the disorder. This article contrasts what is known of the topographies of metabolic and structural brain abnormalities in schizophrenia at differing stages of the illness. From these contrasts, a schema is elaborated by which subtle neurodevelopmental perturbation in early to middle gestation might give rise to functional and structural abnormalities that ultimately release the diagnostic symptoms of schizophrenia. An interaction between those mechanisms mediating the expression of psychosis and the initially subtle stages of normal aging is posited to act on the substrate of a brain that is already developmentally compromised. Such a process might masquerade as "progression" in the absence of any active disease directly attributable to the original etiological event.

A prospective study of offspring of women with psychosis: visual dysfunction in early childhood predicts schizophrenia‐spectrum disorders in adulthood

“…Visual dysfunctions in childhood may well negatively influence the development of visual perception and cognitive function (2, 3). These diverse deviations are also similar in some respects to those frequently found in patients with schizophrenia (6–11).…”

A prospective study of offspring of women with psychosis: visual dysfunction in early childhood predicts schizophrenia‐spectrum disorders in adulthood

“…Visual dysfunctions in childhood may well negatively influence the development of visual perception and cognitive function (2, 3). These diverse deviations are also similar in some respects to those frequently found in patients with schizophrenia (6–11).…”

Gender specificity of geographical variation in morbid risk for schizophrenia in rural Ireland

“…Irrespective of these considerations, the present findings suggest an additional example of why (1,3,4,6,7,30) sexual dimorphism, and those diverse factors by which such processes are regulated, are acquiring renewed significance for the epidemiology and etiopathology of schizophrenia.…”

Cognitive dysfunction in chronic schizophrenia followed prospectively over 10 years and its longitudinal relationship to the emergence of tardive dyskinesia

“…While a static encephalopathy is readily compatible with contemporary perspectives of schizophrenia as a neurodevelopmental disorder (Waddington, 1993 a), it must be emphasized that a progressive element to schizophrenia would not in itself contradict such a perspective; neurodevelopmental origin(s) and adult disease progression are not mutually exclusive, and may be sequential phases of one longitudinal process or separate dimensions of the same pathology (Waddington, 19936;Waddington et al 1995 a). The overall rate of decline in cognitive function encountered in the present patient population, while both greater and more fundamental than would be otherwise expected, is considerably less than is found for major neurodegenerative processes such as Alzheimer's disease (Stern et al 1994); this would complement neuropathological and post mortem neurochemical evidence that the marked cognitive deficits found in many older patients with schizophrenia do not occur in association with degenerative changes such as those found in dementia of Alzheimer or other type (Casanova et al 1992;Purohit et al 1993;Haroutunian et al 1994).…”

“…Alternatively, long-term treatment could disturb a unitary cerebral system that is already dysfunctional as an integral part of the pathophysiology of the illness itself: the result could also be the emergence of greater cognitive dysfunction and of orofacial dyskinesia, but with primacy attached to an interaction between neuroleptics and a specific substrate of the illness; vulnerability to orofacial dyskinesia would then depend more upon individual illness-related factors (see also Owens et al 1982;Rogers, 1985;Waddington, 1989;Fenton et al 1994;Waddington et al 1995*). Multiple lines of evidence point to dysfunction in cortico-striato-pallido-thalamic systems in schizophrenia (Waddington, 19936), and such a network would be a possible candidate for a substrate to the alternative schema considered above; long-term treatment with neuroleptic drugs might slowly induce further dysfunction in this and possibly related systems, the various striato-pallidal components of which might subserve differentially the emergence of involuntary orofacial v. limb-trunkal movements.…”

A prospective study of offspring of women with psychosis: visual dysfunction in early childhood predicts schizophrenia‐spectrum disorders in adulthood

“…Visual dysfunctions in childhood may well negatively influence the development of visual perception and cognitive function (2, 3). These diverse deviations are also similar in some respects to those frequently found in patients with schizophrenia (6–11).…”

Gender specificity of geographical variation in morbid risk for schizophrenia in rural Ireland

“…Irrespective of these considerations, the present findings suggest an additional example of why (1,3,4,6,7,30) sexual dimorphism, and those diverse factors by which such processes are regulated, are acquiring renewed significance for the epidemiology and etiopathology of schizophrenia.…”

Cognitive dysfunction in chronic schizophrenia followed prospectively over 10 years and its longitudinal relationship to the emergence of tardive dyskinesia

“…While a static encephalopathy is readily compatible with contemporary perspectives of schizophrenia as a neurodevelopmental disorder (Waddington, 1993 a), it must be emphasized that a progressive element to schizophrenia would not in itself contradict such a perspective; neurodevelopmental origin(s) and adult disease progression are not mutually exclusive, and may be sequential phases of one longitudinal process or separate dimensions of the same pathology (Waddington, 19936;Waddington et al 1995 a). The overall rate of decline in cognitive function encountered in the present patient population, while both greater and more fundamental than would be otherwise expected, is considerably less than is found for major neurodegenerative processes such as Alzheimer's disease (Stern et al 1994); this would complement neuropathological and post mortem neurochemical evidence that the marked cognitive deficits found in many older patients with schizophrenia do not occur in association with degenerative changes such as those found in dementia of Alzheimer or other type (Casanova et al 1992;Purohit et al 1993;Haroutunian et al 1994).…”

“…Alternatively, long-term treatment could disturb a unitary cerebral system that is already dysfunctional as an integral part of the pathophysiology of the illness itself: the result could also be the emergence of greater cognitive dysfunction and of orofacial dyskinesia, but with primacy attached to an interaction between neuroleptics and a specific substrate of the illness; vulnerability to orofacial dyskinesia would then depend more upon individual illness-related factors (see also Owens et al 1982;Rogers, 1985;Waddington, 1989;Fenton et al 1994;Waddington et al 1995*). Multiple lines of evidence point to dysfunction in cortico-striato-pallido-thalamic systems in schizophrenia (Waddington, 19936), and such a network would be a possible candidate for a substrate to the alternative schema considered above; long-term treatment with neuroleptic drugs might slowly induce further dysfunction in this and possibly related systems, the various striato-pallidal components of which might subserve differentially the emergence of involuntary orofacial v. limb-trunkal movements.…”

A prospective study of offspring of women with psychosis: visual dysfunction in early childhood predicts schizophrenia‐spectrum disorders in adulthood

“…Visual dysfunctions in childhood may well negatively influence the development of visual perception and cognitive function (2, 3). These diverse deviations are also similar in some respects to those frequently found in patients with schizophrenia (6–11).…”

Gender specificity of geographical variation in morbid risk for schizophrenia in rural Ireland

“…Irrespective of these considerations, the present findings suggest an additional example of why (1,3,4,6,7,30) sexual dimorphism, and those diverse factors by which such processes are regulated, are acquiring renewed significance for the epidemiology and etiopathology of schizophrenia.…”

Cognitive dysfunction in chronic schizophrenia followed prospectively over 10 years and its longitudinal relationship to the emergence of tardive dyskinesia

“…While a static encephalopathy is readily compatible with contemporary perspectives of schizophrenia as a neurodevelopmental disorder (Waddington, 1993 a), it must be emphasized that a progressive element to schizophrenia would not in itself contradict such a perspective; neurodevelopmental origin(s) and adult disease progression are not mutually exclusive, and may be sequential phases of one longitudinal process or separate dimensions of the same pathology (Waddington, 19936;Waddington et al 1995 a). The overall rate of decline in cognitive function encountered in the present patient population, while both greater and more fundamental than would be otherwise expected, is considerably less than is found for major neurodegenerative processes such as Alzheimer's disease (Stern et al 1994); this would complement neuropathological and post mortem neurochemical evidence that the marked cognitive deficits found in many older patients with schizophrenia do not occur in association with degenerative changes such as those found in dementia of Alzheimer or other type (Casanova et al 1992;Purohit et al 1993;Haroutunian et al 1994).…”

“…Alternatively, long-term treatment could disturb a unitary cerebral system that is already dysfunctional as an integral part of the pathophysiology of the illness itself: the result could also be the emergence of greater cognitive dysfunction and of orofacial dyskinesia, but with primacy attached to an interaction between neuroleptics and a specific substrate of the illness; vulnerability to orofacial dyskinesia would then depend more upon individual illness-related factors (see also Owens et al 1982;Rogers, 1985;Waddington, 1989;Fenton et al 1994;Waddington et al 1995*). Multiple lines of evidence point to dysfunction in cortico-striato-pallido-thalamic systems in schizophrenia (Waddington, 19936), and such a network would be a possible candidate for a substrate to the alternative schema considered above; long-term treatment with neuroleptic drugs might slowly induce further dysfunction in this and possibly related systems, the various striato-pallidal components of which might subserve differentially the emergence of involuntary orofacial v. limb-trunkal movements.…”