The Biological Basis of Schizophrenia
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Enter your email address below and we will send you your username. Back to table of contents. Previous article. Article No Access. The blocks represent different regions of the cerebral cortex, in which the Roman numerals indicate cortical layers and letters identify main types of neurons according to the key in the figure itself. Compared to these areas, the rest of the association cortex develops an intermediate density of lesions, whereas the primary cortices — both motor and sensory — develop the lowest density of neurofibrillary tangles Figure 2.
It is important to emphasize, however, that this notion is predicated primarily on the density of neurofibrillary tangles, whose distribution is felt by many to correlate best with the level of cognitive deterioration 35 — 37 , although it has been shown that primary sensory cortices have a high density of senile plaques 38 which is in fact much higher than that in medial temporal regions that are widely perceived as severely affected Apart from this gross overall topographic pattern, there is also a distinct laminar predilection in the distribution of the lesions Figure 1.
Such a pattern permits postulating that the disposition of the lesions explain the cortical dysfunction in terms of a disconnection resulting from the disruption of cortico-cortical connectivity 32 , 38 , as already discussed above and summarized in Figure 1.
The Biological Basis of Schizophrenia | SpringerLink
Therefore, as befits the complexity of the cerebral cortex, there is an intricate pattern of selective vulnerability vs. Figure 2. Many believe that schizophrenia and related disorders result from alterations in brain circuits Yet, this probably correct assumption lacks a concrete factual demonstration — hundreds of unverified neuropathological claims non-withstanding — and is in stark contrast with the relative wealth of information on the neuropathology of AD because virtually nothing claimed about histopathological observations in schizophrenia has survived efforts at independent verification or corroboration.
In fact, arguably the only widely accepted, consistent morphological alterations have been found by in vivo imaging, that consist in a reduction in gray matter, enlargement of the ventricles of the brain, and focal alterations in the white matter 42 — Be that as it may, it justifies the still vaguely articulated perception that schizophrenia is a disease of the cerebral cortex However, while the identification of a unique and consistent defect at any level — circuit, neural cell, or molecule — might facilitate enormously the rational design and development of treatments for any disease, nothing precludes the development and testing of novel agents for clinical syndromes — as opposed to diseases — which may be the best approach for schizophrenia.
The possibility that the seemingly logical focus thereafter on monoamine pathway-modifying pharmacological agents might have been inaccurate — from the pathophysiological perspective — does not negate the validity of searching for agents that maximize the benefits of chlorpromazine, while mitigating the potential for side effects. In the latter i. Be that as it may, for the purposes of the present discussion, suffice it to say that there is a consensus that, like AD, schizophrenia targets mainly the cerebral cortex Table 1 39 , 44 , 45 , Accordingly, as mentioned at the very beginning, this warrants not only comparing these disorders both in terms of similarities and differences, but also in terms of the nosological dilemmas they present.
In that latter sense alone, the difference amounts to millions every year, of whatever national currency is considered in terms of expenditures in health care. Table 1. We have recently postulated 56 that these sets of opposing factors operate over decades — primarily i. To the best of our knowledge, it has not been proposed before that schizophrenia results from targeting the 4EC, yet there seems to be no reason precluding such a possibility, which, of course, needs to be assessed scientifically.
The latter will obviously necessitate experimental evaluation, which is barely underway. Given the ongoing dramatic changes in the distinction between neurons and glial cells in the brain, the above proposal that 4EC are pivotally involved in AD and schizophrenia defies the former notion that the targeted element s can be conceptualized simplistically as neurons vs. In fact, considering the still unresolved nature of 4EC as precursors or variants of oligodendrocytes, their near-neuronal attributes e.
Even if the present proposal about the predominant targeting of 4EC in AD does not survive experimental testing, it casts doubt on the ability to postulate targeting mechanisms based exclusively on neuronal vs. Thus, it is also possible that it is not specific cell types, but key attributes shared between neuronal and non-neuronal cells that are targeted early on in the disease process, if this process attacks first — or in any way selectively — neural cells.
Similar considerations apply to schizophrenia, in which, as stated in the preceding section, the characterization of the possible participation of 4EC has barely begun solely by stating the possibility of such a mechanism. If the 4EC hypothesis is correct, it would open an essentially unexplored avenue for research and treatment development that could have a powerful effect in overcoming the IG.
However, markers with proven diagnostic value do not presently include indicators of inflammation, macroglial alterations, and, much less, 4EC involvement, although there are numerous reports suggesting — but not proving — that the former may also be of diagnostic value 69 — Given the probable multifactorial nature of sADs 54 , it is likely that an array of markers addressing different mechanisms involved in the condition may help to: 1 increase the sensitivity and specificity of the tests under development, 2 discern subtypes of patients in which different mechanisms mediate a similar cognitive impairment syndrome, and 3 predict and monitor the response to various alternative mechanism-selective treatments.
The Biological Basis of Schizophrenia
Therefore, whether the hypothetical 4EC mechanism proposed here is universal, or unique to certain groups of patients, research aimed at testing this hypothesis may lead to the implementation of assays for 4EC involvement by cerebrospinal fluid analysis, or blood-borne indicators of 4EC involvement, or in vivo imaging assessment of such involvement with ligands for 4EC — or a combination of these — as well as a more refined histopathological assessment for patients with Mild Cognitive Impairment and dementia postmortem.
The above considerations are relevant also to our recent assessment of the intersection of the epidemics of dementia and diabetes, since this is one additional situation in which the elucidation of the targeted vs. Very similar considerations apply to schizophrenia, given the equivalent lack of biomarkers both to make the diagnosis unencumbered by clinical observations, as well as to measure the efficacy of the treatments and to determine whether they impact the long-term prognosis of individual patients 45 , This dilemma includes, but is not limited to the high prevalence of metabolic syndrome and diabetes associated with the use of antidepressants and antipsychotics in schizophrenia 76 , which, like in AD 74 , probably interact with the original mechanisms responsible for brain dysfunction and is quite likely to influence the well-documented tendency for patients with schizophrenia to continue to deteriorate cognitively, and certainly prematurely, even now that their long-term survival has improved with better treatment It has not escaped our attention that casting hypotheses on the primary targeting mechanisms causing AD and schizophrenia in terms of one or another cell type — or cellular component, such as synapses — may be narrow-minded and ultimately inadequate.
This challenge is in fact compounded by the 4EC hypothesis, since 4EC share properties with several neural cell types. However, it would seem that casting such a hypothesis in terms of a putative primary involvement of 4EC is scientifically testable, and provides a heuristically useful counterbalance to the presently massive — if appropriate — attention to the suspected role of microglia in the early mechanisms mediating AD and schizophrenia 54 , 66 , 67 , None of the above hypothetical scenarios are contradictory or incompatible with the eventual i.
Such secondary events include also inflammation and the intra- and extra-cellular accumulation of pathological forms of amyloid and tau proteins in AD, since it is unknown whether this occurs in schizophrenia , regardless of whether these are cast as disease-compounding, or ultimately ineffective or counterproductive attempts at cellular and molecular defense. It is important to remark that future research in both schizophrenia and AD is likely to benefit from substantial refinements in non-pharmacological treatments available today, which are unfortunately poorly standardized at present, and, therefore, not regimented into accepted treatments covered by virtually all forms of health insurance.
Perhaps the best example of such a need is physical exercise, for which there is a growing body of literature indicating clearcut benefits not only in mild cognitive impairment and AD 84 , but also in schizophrenia These interventions appear to synergistically improve the condition of patients with both conditions AD and schizophrenia , in addition to pharmacological agents. This approach should ideally be part and parcel of the ongoing re-examination of the field of neurodegenerative and neuropsychiatric disorders, which has as a common theme the dire need to reinvigorate the intellectual framework to establish causality, etiologies, and pathophysiology in an integrative, multidisciplinary fashion, beyond the molecular level alone 20 , 21 , The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Work by the authors on this topic was supported by the Brain-Mind Project, Inc. Pick A. Ueber primare chronische Demenz so. Dementia praecox im jugendlichen Alter. Prager Med Wochenschr 16 —5. Kuhn R.
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Evidence That Schizophrenia is a Brain Disease
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