Summary
Schizophrenia is increasingly believed to be based in organic conditions primarily affecting the CNS. Abnormalities all suggest a link between schizophrenia and CNS pathology. More compelling evidence is offered by neuropsychological, neuroradiological, and neurophysiological studies. Although no single pathognomonicneurostructural or neurophysiological abnormality has yet been delineated in schizophrenia, certain cerebral concomitants of the illness have been demonstrated in a consistent fashion. Increasingly, it appears that cerebral dysfunction of a system of interconnected cortical and subcortical brain regions may be present to a lesser or greater degree and may produce more or less psychopathology in individual patients (Bogerts B, 1999).
Currently, there are three main modalities which are currently used in brain-imaging techniques in Psychiatry and hence in schizophrenia : computerized tomography (CT), Magnetic Resonance Imaging and various types of perfusion studies, typically examining regional cerebral blood flow (rCBF).
In 1990, Raz & Raz summarized much of the CT imaging (1993 studies) with a metanalysis. The most defensible observations appear to be the following: there are structural changes in the brains of schizophrenics that appear to affect frontal and temporal lobes more than posterior brain, and the left is generally more implicated than the right. (Zakzanis KK et al, 2000).
Studies of MRI scans were searched for signs of early developmental anomaly, and the scans did not differ from normal in this regard. MRI has also been used extensively to replicate the finding of ventricular enlargement in both acute (DeLisi LE, et al,1991) as well as chronic schizophrenics (Gur RE, et al, 1994).
Recent well-controlled representative studies of these findings illustrate structural changes. Turetsky et al (1995) obtained quantitative MRI studies to examine specifically the left-frontal and the temporal-lobe CSF volumes. Abnormal brain asymmetry was reported with reduced volume in both left and right frontal lobes. In the subjects who showed greater left parenchymal volume reduction with attendant CSF volume increase, an increased number of negative symptoms were reported. This led to conclusions that there are selected structural deficits in schizophrenia rather than the diffusely undifferentiated CNS abnormalities that are inferred by a preponderance of studies that did not specifically look for volumes. This also suggests that the negative symptoms are more associated with temporal-lobe rather than frontal-lobe abnormality. This was reported as consistent with suggestions of temporolimbic prefrontal network abnormality in schizophrenia (Henn FA, Braus DF, 1999).
In vivo Magnetic Resonance Spectroscopy, a technique pioneered by Ackerman et al (1980). 31P and 1H are the nuclei most commonly utilized for in vivo studies. Over the past few years, phosphorus (31 P) and proton (1 H) MRS have been used to study schizophrenia. 31P MRS is particularly well suited to investigate neurodevelopmental aspects of the pathophysiology of schizophrenia. Many neurodevelopmental events involve either the formation of membranes, such as the proliferation of dendritic spines in synaptic development, or the degradation of membranes, such as synaptic pruning. 31P MRS measures concentrations of metabolites implicated in membrane synthesis and degradation and in high-energy phosphate levels that reflect the energy metabolism associated with these and other processes. 1H-MRS can provide measures of energy metabolism, neurotransmitter levels, and neuronal integrity. Because the MRS sensitivity and concentration of 1H nuclei in the brain are greater than 31P nuclei, 1H MRS can examine a smaller brain volume (approximately 1 cm3 ) than 31P MRS (approximately 15 cm3 ).
Functional Magnetic Resonance Imaging is a recent technique to measure CBF noninvasively by use of existing MR scanners (Kwong KK et al, 1992). This technique is reported to detect deoxyhemogolobin as an endogenous paramagnetic contrast agent compared with oxyhemoglobin, which is not paramagnetic (Ogawa S, et al, 1990). Patients with Schizophrenia show specificdeficits in language processing, which are classically considereda cardinal feature of the illness. Functional MRI has begun toreveal the neural dysfunction underlying these deficits (Curtis VA, et al, 1998). It was found that patients performing a language task showed a broadlysimilar pattern of neural activation, though with an attenuatedpower of response, compared with controls (Honey GD, et al, 1998). However, we observedspecific regions of hypoactivity in the frontotemporal cortex. These may be related to deficits in language processingthat can be observed at a cognitive level.
With regards to perfusion studies, the most common acronym given to such studies is single photon emission computed tomography (SPECT). In such images, the resolution is never as exquisite or detailed as that obtained by CT or MRI, but the technique does allow the detection of injected radiopharmaceuticals and their perfusion into different regional brain areas. The study is done while the patient is at rest. Having the patient at rest implies that metabolic activity should be uniform across the brain when homologous sites are compared. If there is a problem with the even perfusion of a particular brain region, it should either show up as an asymmetry or show up as a change from what would be considered a normal baseline activity level.
Positron Emission Tomography is used in schizophrenia for assessment of CBF, glucose metabolic rate (GMR), and neuroreceptor functioning. One of the early findings in schizophrenia when PET was used, was a decreased uptake of 2-deoxyglucose in frontal lobes (Swanson CL Jr, et al, 1997). Most PET studies of laterality in schizophrenia patients (in the resting state) compared with control-group individuals have found increased metabolism or blood flow in the left temporal areas, suggesting that the left hemisphere is functionally overactive in schizophrenia,
In Chapter Two, we tried to clarify the Concept of Single Photon Emission Computed Tomography SPECT) Technique In Single Photon Emission Computed Tomography (SPECT) this biological process is studied by synthetically incorporating a radionuclide into a molecule of known physiological relevance. The so-called radiopharmaceutical is then administered to a patient either by inhalation, ingestion,or most commonly by intravenous injection. As radioactivity distributes within the subject, the radiotracer's uptake into the brain is measured over time and is used to obtain information about the physiological process of interest. Because of the high-energy (g-ray) emissions of the specific isotopes employed and the sensitivity and sophistication of the instruments used to detect them, the two-dimensional distribution of radioactivity within a brain slice may be inferred from information obtained outside the head. For this reason, SPECT are referred to as emission tomographic (from the Greek tomos for cut) technique. In contrast to more conventional radiographic methods, like a chest X-ray, where an external source of radiation merely casts a shadow of the body's organs and cavities onto a planar film, SPECT rely on more sophisticated principles to produce three-dimensional information. In order to understand this process, a basic understanding of the physics of photon emission is required (SantoshPJ., 2000).
In chapter three The extensive body of literature attempting to localize and characterize physiological brain dysfunction in schizophrenia detected by SPECT was reviewed.
First, a review of alterations in global metabolism of cerebral blood flow of 400 rCBF studies comparing laterality indexes in medication-free patients with schizophrenia and controls during 11 different cognitive conditions reflects the inconsistent findings in the literature and illustrates several problems encountered in that line of research. No consistent differences between patients and controls were found in the study, but several isolated differences could be demonstrated if a very liberal statistical approach (multiple univariate comparisons) were employed. There was one instance of greater left mean hemispheric rCBF in schizophrenia in the context of a right hemisphere preponderance in the normal subjects (during an attentional task), one instance of a greater degree of left prefrontal lateralization in the patients in the context of a lesser lateralization in the same direction in the normals (during a resting condition), and one instance of greater right temporal lobe activation in the patients in the context of normal left temporal lateralization (during an abstract reasoning task) (Zakzanis KK etal, 1998).
Second, A series of studies in which rCBF was measured during a number of different cognitive activation conditions, some linked to prefrontal cortex and others that were not, indicated that patients do have prefrontal cortical dysfunction, but that it may not become apparent unless the brain is called on to increase the level of physiological activity in the region. In those studies normal subjects increased prefrontal rCBF while performing a neuropsychological test linked to prefrontal cortex and requiring abstract reasoning, but neither medication-free nor antipsychotic treated patients showed the change (Chen RY, etal,2000).
Third, The majority of rCBF studies have been carried out in patients who were either receiving antipsychotic drugs at the time of the study or who had been previously treated and then withdrawn from antipsychotics for some time before the study. That, along with the fact that hypofrontality could not be demonstrated in several resting state SPECT studies of small numbers of patients who had never received medications, suggested to some investigators that antipsychotic treatment is responsible for hypofrontality in schizophrenia. However, a growing body of evidence refutes this notion.
Fourth, On of the most important questions to be answered in this study was Is hypofrontality a consistent characteristic of schizophrenia, or does it just affect a subgroup of patients who may have different pathophysiologies and etiologies underlying their illnesses? The approach of most studies has been to compare the mean value for a group of patients with schizophrenia with the mean value for an unrelated group of normal subjects. The results of such a comparison often confirm that, on the whole, patients have decreased parameters of frontal lobe function. However, there may be a great deal of overlap between the two groups, with only a minority of patient values actually falling beyond the lower limit of the normal values. One interpretation could be that hypofrontality is restricted to only a small subgroup of outliers. But since there is great variability in normal physiological values, and since what a given patient's potential value would have been if he or she did not have schizophrenia is not known, the true prevalence of hypofrontality in the schizophrenic population cannot be estimated (Erkwoh R etal, 1999).
Hypofrontality was the first functional abnormality to be shown in schizophrenia, and it remains the most frequently observed. However, data regarding the pathophysiologic mechanism of hypofrontality are just beginning to emerge.
In addition to the results of studies addressing major hypotheses several other findings have been reported. For example, A very recent study found significant left hypoperfusion of temporal lobes relative to right side (Ambrus E, 1999). Abnormal lateralization of temporal lobe blood found increased left globuspallidusrCBF relative to whole brain mean values in two groups of five drug-naive patients each as compared to 10 normal controls. Another study found decreased left lentiform nucleus glucose metabolism in medication-free patients, whereas yet another found decreased rCBF in the basal ganglia of patients.
The study concepts
We proceeded the study proper with a pilot study for nearly one year, Our where to determine the size and method of selection of the sample and to assess the reliability of clinical diagnoses using different Tools used. During the study all of the selected cases showed various degree of hypoperfusion in their SPECT and none of the control showed any abnormality.
As been discussed in chapter three, Reductions in blood flow and metabolism to the entire brain have been consistently demonstrated in primary degenerative dementias and, to a lesser extent, in normal aging. Although the question of whether schizophrenia presents a similar pathophysiological picture of globally reduced function is an important one, the data are less clear. In our study The Incidence of qualitative abnormal perfusion in different brain areas in patients immediately after admission showed affection for most parts of the brain, both the right temporal and the right parietal showed normal perfusion when compared to control subjects.
In terms of group difference pre-treatment data showed lower mean rCBF values than controls in superior frontal regions and parietal and left temporal regions as well as basal ganglia structures. So far as hypofrontality is concerned, there may be a parallel to the widespread opinion that hypofrontality is the most important but nevertheless inconsistent biological finding in resting-state chronic schizophrenia (Chen RY et al, 2000). The term (resting state) or (at rest) is correct for our study design in the sense of 'not performing an activation task. However, our patients exhibit a non-specific arousal rather than a resting state, which may reflect attempts to deal with psychotic experiences (i.e. processing information from internally generated sensory stimuli).
Following therapy, the frontal lobe and parietal lobes remained as the most common site for hypoperfusion followed Basel ganglia structures and lastly temporal lobe where the least effected.
Under-activity of the left temporal area was observed in the course of patient illness despite remission of the psychotic symptoms ( Chen RY, 2000). After response to Antipsychotics, the left temporal activity returned to a normal level. Our findings suggested that left temporal underactivity detected by SPECT together with clinical remission may indicate a better response to treatment. Left temporal rCBF at rest correlated with the Scale for the Assessment of Positive Symptoms total score. Thus, the results suggest, positive symptoms seem to be associated with left temporal cortex activity. (Parellada et aal, 1998)
After treatment, a significantly increased rCBF was observed in the left thalamus (possibly due to neuroleptic action on dopamine receptors in this area).
During our study, There were highly significant hypo perfusion left parietal lobe perfusion and metabolism, Following treatment, there were still a highly significant differences between the patient and control groups as regard left parietal lobe perfusion and metabolism.
During the study There were highly significant hypoperfusion basal ganglia perfusion and metabolism, this remained following treatment with no apparent statistically significant change
As found in our analysis of reversible symptoms, Positive symptoms show loadings on separate dimensions, there here markedly significant decrease in their scores following treatment. These findings reflect the psychopathological condition in schizophrenic patients who experience one type of phenomenon involving inappropriate and self-referenced judgments of reality independently from the other type, which is defined by disturbed and distorted perceptions of reality. Furthermore, this finding is consistent with that of a study of symptoms in acute schizophrenia. Negative symptoms were not affected by neuroleptic treatment.
Few studies have addressed the relationship between cortical activity and changes in psychiatric symptoms following treatment, We examined the possible relationship between changes in psychiatric symptoms. Following treatment, there were still a highly significant differences between the patient and control groups as regard superior frontal lobe, left parietal lobe and bilateral basal ganglia perfusion and metabolism perfusion and metabolism, and highly significant differences between the two groups.
Through the use of the present experimental design, We concluded that Schizophrenia is a more like to be a heterogonous syndrome rather than a continuum of symptoms, The frontal, left temporal, left parietal lobes and basal ganglia are the most vulnerable areas in demonstrating hypoperfusion, thus supporting the theory of circuits were more than theories suggesting localized and discrete lesions, The linkage of left- hemisphere hypofrontality to right-hemisphere hypofrontality function is interesting, since it displays a more prominent dysfunction in two different regions that are likely to be activated simultaneously at the same time by.
The study recommend further studies using symptom approach and regional brain activity to answer the question of whether disturbance of a specific brain region is confined only to a subgroup of patients. Dynamic SPECT studies using neuropsychological tasks to examine neuropsychological differences between the clusters of schizophrenic syndromes. Lastly, a further comparative study for the same group of patients for a longer duration of treatment and after remission of negative symptoms may be of a high value in understanding the response to neuroleptic medications.
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