According to the National Institute of Mental Health, nearly 20% of the US population may suffer from a diagnosable mental illness in any given six month period (1991). Obviously the issue of mental health warrants close scrutiny, as such illness can translate into lost work days and lost dollars. From a health care perspective, many of those suffering can be relieved of their symptoms and return to normal life, so to speak. Schizophrenia, however represents one of the more disabling illnesses whose prognosis for the patient looks poor.
Affecting nearly two million Americans, "schizophrenia" probably represents a grouping of many types of resembling illnesses (NIMH, 1991). Typically, the patient exhibits prodromal signs such as social isolation and withdrawal, role impairment, eccentric behavior, decreased affect, and disregard for personal hygiene. These then generally give way to intermittent psychotic episodes with intervening, sometimes long negative symptom periods. The so called positive symptoms of schizophrenia include disordered thinking and memory; the patient may display incoherent speech and rapid shifting to unrelated ideas. Delusions and false or bizarre beliefs, hallucinations, and perceptual difficulties also comprise the symptomology. Schizophrenic persons usually have an absence of feeling, a sense of remoteness and inappropriate reactions. Even more difficult to treat (Kandel) are the negative signs of poverty of speech, poor attention span, blunt affect, and lack of motivation. To date, well-targeted epidemiological studies of severe mental illness that determine prevalence and variations in rates, which in turn help identify risk factors, are lacking. Currently, it appears that the while the illness occurs equally among members of various ethnic and racial groups, the incidence among the poor is nearly eight times higher than that of the highest socioeconomic group. The poverty could possibly result from the difficulty persons face in holding a job and maintaining a decent living (schizophrenia is common among the long-term homeless). However environmental factors may well play a pivotal role in increasing a biological risk (NIMH, 1991).
The nature/nurture question arguably complicates all discussion of mental illness. Certainly psychosocial factors ("stressors") could influence coping mechanisms and age and degree of onset, even in the most severe cases, however in the case of schizophrenia a large body of research implicates an organic etiology for the illness. By what mechanism could an organic defect cause schizophrenic symptomology? Krieckhaus, Donahoe, and Morgan (1992) hypothesized dopamine hyperactivity in paranoid schizophrenia to present one such mechanism. They cite evidence that dopamine (DA) agonists can cause delusional symptoms in both normal and schizophrenic persons. Furthermore, DA D2 receptor blockers can depress the positive symptoms of paranoid schizophrenia. The negative symptoms, which could stem from prefrontal defects, don’t respond nearly as well. It turns out that the CA1 area of the hippocampus is particularly endowed with D2 receptors, while the prefrontal region relies more on D1 receptors, inferring that the CA1 region is indeed the defect locus .
Normally, CA1 pyramidal cells send out diffuse reinforcement signals via the inferior temporal cortex that lead to fixation of belief in the parietal-temporal-occipital cortex (PTO). The PTO neurons comprise something of a neural net that receives internal and external inputs. These influence voluntary, deliberate behavior via area 7, which in turn steers area 4, the origin of voluntary (pyramidal) motor movement. The connections most often made (and thus strengthened) will govern, and these presumably
recognize accurate conditions in the external environment. Too strong of a
signal or one given at an inappropriate time could strengthen inaccurate connections, ones that frequently don’t receive as much attention. Thus, hyperactive CA1 neurons through DA could reinforce fantasies and trivia and cause the delusions and hallucinations of paranoid schizophrenia. (Of course, the premorbid patterns would have an effect.) (Krieckhaus, Donhoe, Morgan, 1992).
When does the system go awry in schizophrenia? Unlike Parkinsonism or Huntington’s, both chronic and progressive diseases, increasing evidence points to a defective neurodevelopmental process. Brain imaging techniques have exposed a variety of structural abnormalities in persons suffering from schizophrenia, and Weinberger’s monozygotic twin studies suggest that the structural differences seen in the affected twin were likely the result of developmental defects and not genetics (Kandel). Brains of schizophrenics have shown enlarged lateral ventricles (Nasralleh, 1993) that are associated with prominent prodromal symptoms (Wright, Gill, and Murray, 1993; Randel). They also have exhibited enlarged third ventricles (Nasralleh, 1993; Wright, Gill, and Murray, 1993; Kandel), present at the onset of illness and associated with both obstetric complications (see below) and prodromal symptoms (Nasralleh, 1993). Also demonstrated were hypoplasia of medial/limbic temporal structures, especially the hippocampus, and again present at the onset (Nasralleh, 1993), reduction of cortical size (Wright, Gill, and Murray, 1993; Naaralleh, 1993; Kandel), an increase in lenticular nucleus size, cerebellar vermal dysplasia, and decreased N-acetyl aspartate in the hippocampus and amygdala. Interestingly, a family history of schizophrenia seems related to occurrence of these abnormalities, hinting to an interplay between the genetic control of neurodevelopment and the manifestation of schizophrenia (Nasralleh, 1993)-
Schizophrenic patients have experienced more than their fair share of perinatal and obstetric complications (Nasralleh, 1993; Kandel). While not likely a cause in themselves, it may be that a high risk for schizophrenia correlates with a high risk for a complication(s), i.e. occur as a "symptom" of disease. (Naeralleh, 1993) Schizophrenics also show a greater likelihood of birth during the winter and spring months (Wright, Gill, and Murray, 1993). This seasonality is discussed below.
Additional evidence for the neurodevelopment defect lies in the lack of gliosis (Wright, Gill, and Murray, 1993; Nasralleh, 1993) which occurs in other progressive, degenerative diseases, the appearance of physical abnormalities such as skeletal growth defects, and the presence of premorbid" dysfunction during childhood. Deakin, et. al. claim that a defect in the development of the basolateral circuit comprised of the orbital, cingulate, and polar temporal cortex and the amygdala may account for the "dyspraxia and dysgnosia for social communication" that often arises years before the first psychotic incident (cited Nasralleh, 1993)-
Post-mortem exams of persons with schizophrenia have also shown abnormalities in structure and histocytoarchitecture, largely in the hippocampal, parahippocampal, and entorhinal areas. To Nasralleh (1993) these suggest a "... disruption in one or more of the programmed neurodevelopmental processes of neuronal proliferation, migration, and differentiation as well as the important ‘subtractive’ processes of neuronal elimination, axonal, retraction and synaptic pruning..." (p.271). This could account for the wide variety seen in the natural history of schizophrenia.
The question then arises as to where the initial lesion occurs. A large body of literature on "adaptive plastic regenerative changes" proposes that an initial defect could lead to subsequent abnormal reinnervation and persistent dysfunction. Thus the gene-environment interaction could play a role in schizophrenia throughout life. To complicate matters more, as noted above, the problem could be with any number of processes. For example, perinatal hypoxia can lead to DA supersensitivity in rats and seriously affect the hippocampus, which is especially sensitive to lack of oxygen (Nasralleh, 1993). A fascinating proposal concerning cross-reactivity of maternal anti-bodies and the fetal tissue has received much attention lately and warrants greater consideration.
Numerous studies conducted on the relation of influenza infection and schizophrenia offer somewhat discordant evidence. It does seem, however, that exposure of the mother to the virus during the second trimester correlates to higher risk for schizophrenia. Variance in the occurrence population and even among monozygotic twins presents a problem in explaining the mechanism of action, since the first suggests a genetic component, while the second suggests a strong environmental component. Wright , Gill, and Murray (1993) suggest that direct fetal infection is unlikely, since the influenza virus does not cross the placenta (which discredits Naaralleh’s suggestion that influenza neuraminidase might be a causative factor). However, maternal IgG antibodies can enter into the fetal bloodstream. Supposing the mother was predisposed to produce a vigorous anti-viral response through differing HLA antigen frequency (hence a role for genetics), the resultant antibodies could travel across the undeveloped fetal blood-brain barrier and cause tissue damage. Specifically, they could disrupt cell adhesion molecules and the process of neuronal migration. Twins, while sharing the same genetics and environment could conceivably acquire variant "doses" through such events as twin transfusion syndrome (Wright, Gill, and Murray, 1993).
No doubt the area of schizophrenic research holds rich possibilities. Suppose an etiology, of which there are likely many, could be elucidated, the potential for early identification of risk factors and intervention arises. As current schizophrenia treatment lacks anything near universal effectiveness and holds serious side effects in store for the patient, prevention may be key.
References:
Kandel, Eric R. Disorders of Thought: Schizophrenia. pp. 854-868.
Krieckhaus, E. E., Donahoe, John W., Morgan, Maria A. Paranoid Schizophrenia May be Caused by Dopamine Hyperactivity of CA1 Hippocampus. Biological Psychiatry. Vol. 31, 1992: pp. 560--570.
Nasralleh, Henry A. Neurodevelopmental Pathogenesis of Schizophrenia. Psychiatric Clinics of North America. Vol. 16, no 2, June, 1993: pp. 271-279.
National Institute of Mental Health. Caring for People With Severe Mental Disorders: A National Plan of Research to Improve Services. DHHS Pub. No. (ADM)91-1762. Washington, D.C.: Supt. of Docs., U.S. Govt. Print. Off., 1991.
Wright, Padraig, Gill, Michael, Murray, Robin M. Schizophrenia: Genetics and the Maternal Immune Response to Viral Infection. American Journal of Medical Genetics (Neuropsvchiatric Genetics, Vol. 48, 1993: pp. 40-46.