Schizophrenia: a disease of interhemispheric processes at forebrain and brainstem levels?

The evidence is convincing that each human cerebral hemisphere is capable of human mental activity. This being so, every normal human thought and action demands either a consensus between the two hemispheres, or a dominance of one over the other, in any event integrated into a unity of conscious mentation. How this is achieved remains wholly mysterious, but anatomical and behavioral data suggest that the two hemispheres, and their respective bilateral, anatomical-functional components, maintain a dynamic equilibrium through neural competition. While the forebrain commissures must contribute substantially to this competitive process, it is emphasized in this review that the serotonergic raphé nuclei of pons and mesencephalon are also participants in interhemispheric events. Each side of the raphé projects heavily to both sides of the forebrain, and each is in receipt of bilateral input from the forebrain and the habenulo-interpeduncular system. A multifarious loop thus exists between the two hemispheres, comprised of both forebrain commissural and brainstem paths. There are many reasons for believing that perturbation of this loop, by a variety of pathogenic agents or processes, probably including severe mental stress in susceptible individuals, underlies the extraordinarily diverse symptomatology of schizophrenia. Abnormality of features reflecting interhemispheric processes is common in schizophrenic patients; and the 'first rank' symptoms of delusions or hallucinations are prototypical of what might be expected were the two hemispheres unable to integrate their potentially independent thoughts. Furthermore, additional evidence suggests that the disorder lies within, or is focused primarily through, the raphé serotonergic system, that plays such a fundamental role in consciousness, in dreaming, in response to psychotomimetic drugs, and probably in movement, and even the trophic state of the neocortex. This system is also well situated to control the dopaminergic neurons of the ventral tegmental area, thus relating to the prominence of dopaminergic features in schizophrenia; and the lipofuscin loading and intimate relation with blood vessels and ependyma may make neurons of the raphé uniquely vulnerable to deleterious agents.