• Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Implications of normal brain development for the pathogenesis of schizophrenia

Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6).

The organization of projections from the cholinergic neurons of the basal forebrain to neocortex and associated structures was investigated in the rhesus monkey with the help of horseradish peroxidase transport, acetyl-cholinesterase histochemistry, and choline acetyltransferase immunohis-tochemistry. Four groups of neurons contained cholinergic perikarya and were designated as Chl-Ch4. The Ch1 group corresponds to the medial septal nucleus; about 10% of its neurons are cholinergic, and it provides a substantial projection to the hippocampus. The Ch2 group corresponds to the vertical nucleus of the diagonal band; at least 70% of its neurons are cholinergic, and it is the major source of innervation that the hippocampus and hypothalamus receive from the Chl-Ch4 complex. The Ch3 group most closely corresponds to the horizontal nucleus of the diagonal band; only 1% of its neurons can definitely be shown to be cholinergic, and it is the major source of Chl-Ch4 projections to the olfactory bulb. The Ch4 group most closely corresponds to the nucleus basalis of Meynert; at least 90% of its neurons are cholinergic, and it has projections to widespread areas of cortex and to the amygdala. In fact, the Ch4 group provides the single major source of cholinergic innervation for the entire cortical surface. In this respect, it is analogous to the raphe nuclei and to the nucleus locus coeruleus, which constitute the major sources of widespread cortical serotonergic and nor-adrenergic innervation, respectively.



The extensive Ch4 group can be divided into several subdivisions. Each subdivision has a preferential set of targets for its projections even though the connection patterns contain considerable overlap. The anteromedial subdivision of Ch4 is the major source of cholinergic projections to areas on the medial aspect of the cerebral hemispheres; the anterolateral Ch4 sub-division is the major source of cholinergic projections to frontoparietal op-ercular areas and to the amygdala; the intermediate Ch4 subdivision pro-vides the major cholinergic input for a variety of dorsal prefrontal, insular, posterior parietal, inferotemporal, and peristriate areas; and the posterior subdivision of Ch4 provides the major cholinergic innervation of superior temporal and immediately adjacent areas.



The basal forebrain in the human contains a cytoarchitechture analogous to that of the monkey. The Ch4 group (nucleus basalis) of the human is very extensive and can be subdivided into the same components that were identfied in the monkey brain. Pathological changes in Ch4 neurons have been described in a variety of human disease. In Alzheimer's disease, the relatively selective depression of neocortical cholinergic innervation may be closely associated with the neuronal loss in Ch4, which has also been described inthis condition.



In the rhesus monkey, all types of cortical areas receive substantial projections from the hippocampus. Virtually all of this hypothalamic input into neocortex arises from acetylcholinesterase-rich neurons which lack choline acetyltransferase. The hypothalamocortical pathway is therefore acetylcholinesterase-rich but not cholinergic.

Cholinergic innervation of cortex by the basal forebrain : cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey

Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.

/pdf/the-neuropathology-of-schizophrenia-a-critical-review-of-the-1zxk39qd1v.pdf

The neuropathology of schizophrenia. A critical review of the data and their interpretation.

New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata.

• Morphometric study of Clarke's nucleus in 12 cases of sporadic amyotrophic lateral sclerosis and 12 normal control subjects showed an average 36% reduction in the neuronal population in the disease group, with involvement in each case. Histopathologic findings of cell degeneration were definite but less noticeable than in the ventral horns. The process seems likely to be similar to that affecting motor neurons but is less advanced at the time of death.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=neur&articleId=580548&pdfFileName=archneur_39_3_006.pdf

Regular involvement of Clarke's nucleus in sporadic amyotrophic lateral sclerosis.

The nucleus of the ansa peduncularis in the substantia innominata frequently contains degenerating neurons in patients with Huntington's disease, Alzheimer's disease, schizophrenia, and possibly other neurological and neuropsychiatric conditions. A large number of the degenerating cells are found only exceptionally in neurologically normal patients who are without mental symptoms, and the significance of the lesion may be related to quantitative factors, analogous to granulovacuolar degeneration of the hippocampus. The cells show massive distention with solvent-extractable lipid-pigment vacuolar droplet material that imparts a distinctive light and electron microscopic appearance.

Lesions of the Nucleus Ansae Peduncularis in Neuropsychiatric Disease

•ue from L-4 sL-4cord, dorsal root ganglia, sural nerve, and intramusintramusbrcularthe gastrocnemius was obtained during 35 random autopsies, embedded in paraffin, and stained with PAS and Holmes Alcian blue and studied for the incidence and distribution of corpora amylacea (CA). Intraaxonal CA in spinal grey matter were commonly found, but the incidence in root ganglia, sural, and intramuscular nerve was low. Clinicallygnificant intraneuronal spinal grey CA were found in six of eight men past the age of 60 years. Corpora amylacea in spinal white matter were most common in the region of posterior root entry.

https://jamanetwork.com/journals/neur/articlepdf/576298/archneur_35_2_008.pdf

Corpora amylacea of the lumbar spinal cord and peripheral nervous system.

• A metastatic seminoma of the right temporal fossa, with facial pain, extraocular paresis, otitis, and abdominal symptoms, was found in a 34-year-old man one year after orchidectomy for a primary testicular tumor that had been treated by surgery and radiotherapy. This is an unusual intracranial metastatic tumor that merits active treatment.

Paul Averback

Papers

Regular involvement of Clarke's nucleus in sporadic amyotrophic lateral sclerosis.

Lesions of the Nucleus Ansae Peduncularis in Neuropsychiatric Disease

Corpora amylacea of the lumbar spinal cord and peripheral nervous system.

Metastatic intracranial seminoma.