Discussion
For centuries, diagnostic models of medical diseases have paused in one particular phase of understanding; that is clinically significant signs and symptoms, it was not until the 19th century that other phases were established, psychiatric disorders represented no exception, but due to their uniqueness, and the complex etiological factors contributing into their development, it was not until the late fifth decade of the 20th century that the Psychiatric disorders followed the tracks of medicine (Kugaya A et al, 2000).
In psychiatry, as well in medicine in general, the most accepted model of a disorder follows four phases of development; Phase 1, where the diagnosis represents a clinically significant key symptom or sign. Its presence or absence makes the diagnosis. Phase 2., the diagnosis represents a syndromatic clinical picture with known natural history. Phase 3. The diagnosis represents known cell pathology. Clinicians/researchers detect the associated pathophysiology and pathochemistry of the disorder which also deepens the understanding of normal physiology and biochemistry and lastly Phase 4., The diagnosis represents known origin. Currently, the research of schizophrenia is mainly focused at Phase 3 i.e. to detect Neuropathological and neurochemical correlates of Schizophrenia at different stages of Symptomatology and Treatment aiming to reach phase four (Othmer et al, 1998).
Among the most common methods to detect such changes are the neuroimaging techniques. Neuroimaging in schizophrenia has been fully discussed and presented in chapter one. As stated, currently, there are three modalities that are in clinical use and has efficacy for the mental health practitioner i.e. computerized tomography (CT), MRI, and various types of perfusion studies, typically examining regional cerebral blood flow (rCBF) (Kishimoto et al. 1998). The future of this type of imaging has been discussed in chapter three. For the purposes of this study, we focus almost exclusively perfusion studies
Measurable Parameters of Brain Function
There is no single parameter that completely or even best describes the functional status of the brain. Any measurement of brain activity subsumes a complex set of physiological and biochemical phenomena subserving diverse neuronal activities, such as cellular homeostasis, neuronal excitation and inhibition, maintenance of membrane potentials, and even plastic change at the cellular or subcellular level. The choice of which parameter to measure in a given study of schizophrenia must be largely guided by the particular research question to be asked. The most common parameters of general neuronal function are rCBF and the local cerebral metabolic rate of glucose. An exciting and relatively newer approach is to measure the functional activity of components of various specific neuropathological systems. Regional cerebral blood flow is also attractive to the field of psychiatry because it provides direct measurements of the brain and thereby bypasses the limitations of peripheral measures (e.g., concentrations of plasma hormones or urinary metabolites), which generate only indirect assessments of central nervous system function (Serra-Mestres J etal. 2000).
The ideal functional brain imaging technique for studying schizophrenia would have a number of special features. It would be noninvasive to avoid creating extraneous cognitive sets (that is, those not of primary interest, such as anxiety or discomfort) that might be reflected in the physiological data and thus contaminate the cerebral physiological landscape being investigated. It should be procedurally easy for patients who might not be able to cooperate with long, invasive procedures and with motor restraint or other discomforts (Houston AS et al., 1998).
The Study Concepts
The complexity of human nervous system and its information processing pathways is still partly understood. The necessity to correlate psychiatric symptoms and psychopathology to neuroimaging modalities is obvious, especially when introducing a new technology into diagnostic work up (George et al, 1998). Based on the pervious Principles, This study was conducted aiming to contribute in answering the following questions:
1. What are the alterations in regional cerebral blood flow of schizophrenic patients compared to healthy volunteers.
2. Is there any detectable relation between alterations in regional cerebral blood flow and cluster of symptoms and signs of schizophrenia.
3.What is the effect of treatment on regional cerebral blood flow
The Study Proper
We proceeded the study proper with a pilot study for nearly one year, Our aim were to determine the size and method of selection of the sample and to assess the reliability of clinical diagnoses using different Tools used. This was very useful as it was found that the number of patients who fulfilled the inclusion criteria and attended out patient clinics monthly was between 8-11 patients. The total number of patients seen through the period of pilot study was 119 patients and only 25 of them were admitted.
A lot of difficulties have been encountered during this study. Although schizophrenia is a rather common diagnosis for patients admitted at the institute of psychiatry, Ain Shams University. There was a great difficulty in finding cases fulfilling the strict criteria concerning diagnosis and the drug free period. As most of those patients admitted were already on medications. Eight patients were fulfilling the criteria but either they or their families refused to enter the study for fear of hazards of radiation during the procedure of SPECT.
Unlike other studies, Most of our patients did not show fear from the place. This can be attributed to the teamwork at radiotherapy department where the SPECT procedure was done who was extremely cooperative. It is rather remarkable that families of the patients where welcoming the study aiming for aiding the scientific work intending to reveal the neuropathological correlates to schizophrenia. It is worthy of notice that the study itself made both the patients and the families more compliant on medication, and less sensitive to the degree of stigma associated with schizophrenia.
The relationship between rCBF and schizophrenia is often studied by subtracting images obtained during a control condition from those obtained during an experimental condition. While the absence of this methodology could be seen as a major limitation of the present study, the authors feel that submitting actively ill psychotic schizophrenics to a cognitive task would raise interference levels between task performance and psychotic experiences, possibly masking the results and generally making analysis more difficult and less reliable (Sabri et al, 1997).
Also, it was difficult to find cooperative subjects to be the control and accepting to do the SPECT procedure as most of people knew little about SPECT and they had fear from radiation and malignancies especially the procedure will be done at radiotherapy and oncology department. Without the help of radiodiagnosis department it was very difficult to tolerate the cost of the SPECT procedure and so we limit our study to 20 patients.
Although the number of patients was only 20 patients, the sample size is considered large in comparison to previous similar studies, which were done in advanced countries as those illustrated on table (4), that showed that from 21 studies that used drug naive patients the minimum used 6 patients while the maximum study used 24 patients, the average was 14 patient per study.
Being a stratified sample, we managed to obtain equal number of male and female patients. An important findings is the non significant difference between male and female as regards PANSS scores and SPECT findings. This agrees with the results of which reported the same non significant sex difference (McClure RJ. etal, 1998). The results can be classified to results limited to Drug naive patients, results during the admission period and results by the end of admission.
Regional Cerebral Blood Flow Findings
During the study all of the selected cases showed various degree of hypoperfusion in their SPECT and none of the control showed any abnormality. These results agrees with the results of Kishimoto et al 1998. During the study of schizophrenic patients in the active phase of the disease yielded three major findings.
Alterations in global metabolism or cerebral blood flow
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. Recent review of studies across all methodological modalities found that although 70 percent were negative, 30 percent did find global reductions (Curtis VA etal, 2000). Some of the positive findings in the area may be accounted for by differences in patient populations or important methodological problems. Whether those factors can explain all of the positive findings is unclear, but the bulk of the available evidence indicates that if there is reduced global brain function in schizophrenia, the changes are not of the magnitude present in typical dementias, such as dementia of the Alzheimer's type. That is perhaps not surprising given that most neurological illnesses in which marked decreases in global brain function have been unequivocally demonstrated are characterized by either gross structural or physiological pathology and more gross neurological signs than have been demonstrated in schizophrenia (Steinberg JL etal, 1996). In our study The incidence of qualitative abnormal perfusion in different brain areas in patients immediately after admission ((table 10) showed affection for most parts of the brain, both the right temporal (table 13) 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 (Table 10). 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). Hypoperfusion in our sample is confined to only the superior frontal regions examined. 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).
Alterations in patterns of functional asymmetry
The notion that schizophrenia may involve disordered lateralization of brain activity has been explored for many years using a variety of methods. However, even among those studies that support the notion there is little agreement as to which hemisphere is implicated or whether the putative aberration may involve both hemispheres. Similarly, if there is an abnormality, it is unclear whether it consists of increased or decreased activity on the affected side or an increase in one side and a decrease on the other side. The existing functional brain imaging data gathered through our study (Tables 10-15) supports the decreased perfusion of the left hemisphere when compared to the right side (Higashima M etal. 2000).
Although generalized hypoperfusion was detected, there were significant differences between the two hemispheres showing more hypofronatality at left ROIs when compared to the right side. this could concides with the findings of Nohara et al (2000).
Although it cannot be ruled out that some patients with schizophrenia may have disordered lateralization in some brain areas during some conditions, there are few consistent findings, and further research is necessary to ascertain the role of functional laterality in schizophrenia (Zakzanis KK, etal, 2000).
Following therapy, the frontal lobe and parietal lobes remained as the most common sites for hypoperfusion followed by basel ganglia structures and lastly temporal lobe who the least affected.
Frontal Lobe Abnormalities
Ingvar and Franzen (1974) first showed frontal lobe hypoperfusion using SPECT in schizophrenia. Since then, several SPECT 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) studies have appeared in the literature. The findings have been somewhat variable, especially in regard to the existence of reduced frontal lobe perfusion in the resting state. However, in some studies, such hypofrontality has not been found. In some studies (Busatto et al, 1994), The variability in findings may be related to differences in patient populations, cognitive activation strategies, and methods of quantification. In some studies, the whole brain blood flow as the parameter for normalization has been used, whereas in others, the cerebellum has been used as the denominator in examining regional blood flow in specific hypothesized brain regions. Using the whole brain approach may be more specific, though less sensitive, in identifying abnormalities, such as hypofrontality (Lee SM et al, 1999).
The frontal lobes are responsible for many higher cognitive abilities, including executive, inhibitory, and motivational functions. In our study the most common site of lesions is the frontal lobe (Kamel etal, 1996) . This coincides with an umber of similar studies conducted in the past years (Nohara S et al, 2000; Higashima M etal, 2000).In our study 19 patients out of 20 (95%) showed frontal lobe abnormality in the form of bilateral superior frontal hypoperfusion.
In our study, it was difficult to show the prefrontal areas or the different frontal gyri and so our findings were localized globally to the superior and inferior frontal ROIs bilaterally.
Several investigators have suggested that schizophrenia is characterized by increased posterior cortical activity. Among the early studies of rCBF study of schizophrenia in the mid-1970s, several have suggested that the hypofrontal pattern represented a redistribution of flow with relatively lower flow to frontal areas and relatively higher flow to posterior cortex. In that study the patients who were the most indifferent, the most inactive, and the most autistic had the lowest frontal flows, whereas the most cognitively disturbed patients showed the highest postcentral rCBF. That finding suggested that schizophrenia includes a hypointentional component related to hypofrontality. Also it suggested that the decreased ratio of anterior to posterior metabolism found in schizophrenia was caused by increased posterior flow rather than by lower frontal flow (Kamel etal , 1996). However, later studies by the same investigators also demonstrated decreased frontal activity, and no other investigators have shown similar findings. Studies performed during a task that activates posterior cortical areas in normal subjects, a situation that might be expected to evoke posterior abnormalities in patients if present, failed to demonstrate any such changes. All those miscellaneous abnormalities remain, for the most part, sporadic findings and await further confirmation (Chen E etal, 2000).
In many studies, specific symptom domains and SPECT findings in schizophrenia have also been examined. Some have shown that regional blood flow shows specific and predicted correlations with negative and positive symptoms; reduced prefrontal blood flow was associated with negative symptoms. A direct demonstration between specific symptoms and blood flow alterations has been provided. Functional neuroimaging studies, such as SPECT, can elucidate the specific neural networks that may underlie discrete symptom clusters in schizophrenia (Serra-Mestres J et al, 2000). However during our study, no statistically significant correlations could be detected with any specific relations to the psychopathological correlates detected by PANSS.
How Prevalent is Hypofrontality in Schizophrenia?
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.
Some observations support the hypothesis that hypofrontality is a state dependent marker in schizophrenia, rather than a trait marker. On one hand, a trend to hyperfrontality has been observed in studies of actively psychotic schizophrenics. On the other hand, hypofrontality may disappear with psychopathological improvement, and appeared to remain stable over a period of 18 years in clinically unchanged schizophrenic individuals (Parellada E et al, 1998). These view points may provide an adequate framework for our data. Due to the active phase of the disease, hypofrontality is observed, as a strong finding. Therefore, the small hypofrontality observed is stable over the course of the disease.
Is Hypofrontality in Schizophrenia an Effect of Medication?
During our study all of the selected group did not receive medications for the past six months, this is on of the longest washout periods ever reported in similar studies and the results obtained were similar to studies reporting either no change in values or parameters of relative or absolute prefrontal activity. There are little convincing data to support antipsychotic treatment as a major factor in hypofrontality. However, further work, including longitudinal studies and examinations of more patients early in their course, will be necessary to resolve the question definitively.
Temporal Lobe Findings
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 Antispychotics, 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).
In addition to the results of studies addressing major hypotheses several other findings have been reported. For the most part they represent the results of single reports that have not been replicated. For example, A very recent study found significant left hypoperfusion of temporal lobes relative to right side (Ambrus E, 1999)..
After treatment, a significantly increased rCBF was observed in the left thalamus (possibly due to neuroleptic action on dopamine receptors in this area).
Parietal Lobe Abnormalities
During our study, There were highly significant hypoperfusion and metabolism 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, this coincides with several findings suggesting Correlation between negative symptoms left parietal rCBF. After neuroleptic treatment (and reduction of positive symptoms), only negative symptoms correlated with parietal lobe hypoperfusion (Sabri O et al, 1997).
Basal Ganglia Abnormalities
Delusions and delusional ideation are the most characteristic diagnostic feature of schizophrenia. Affected individuals are unable to evaluate the adequacy of thoughts or perceptions, and this leads to incorrect inferences about external reality. Thus perceptual and judgement disturbances are involved in delusional ideation. Physiologically, limbic systems process information by evaluating external stimuli, delusions may be associated with hypoactivity in a crucial element of the limbic system. such as the anterior cingulate cortex. This is not surprising. since it is known from anatomical studies that the limbic cortex is connected to the dorsolateral prefrontal cortex (DLPFC) by afferent projections.
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. Other investigators have suggested that striatal glucose metabolism is increased in schizophrenia, and one study reported that the ratio of cortical to subcortical (primarily basal ganglia) glucose metabolism was reduced in schizophrenia. However, the weight of the evidence suggests that the phenomenon is related to antipsychotic treatment.
During the study, there were highly significant hypoperfusion basal ganglia perfusion and metabolism, which remained following treatment with no apparent statistically significant change
Psycopathological correlates of the study
To approach our study we first need to highlight the disorder of which we will focus our study to. As pointed out by Berner and Kieffer (1986), all attempts to define schizophrenia ultimately refer either to Kraepelin (1913), Bleuler (1911), or Schncider (1939), who agreed on an organic or endogenous underlying pathological impairment. Indeed, schizophrenia is the 'functional' disorder closest to the organic mental disorders, a view also was accepted by Jaspers (1923) and reflected in his hierarchical principle. This principle is followed by ICD-10 and therefore also in this compendium.
In ICD-10 the Schneiderian first rank symptoms have been included because these systems prefer reliability to validity. The predictive validity of schizophrenia in relation to response to neuroleptics was considered by Crow (1980) when he introduced the concept of negative and positive symptoms into schizophrenia. Crow (1980) separated two types of schizophrenia: Type 1 patients had a good response to neuroleptics and were characterized by positive symptoms and no dementia, whereas type 2 patients had poor response to neuroleptics and were characterized by negative symptoms and dementia.
Bleuler (1924) suggested the basic symptoms can be considered as negative symptoms and the accessory symptoms consequently as positive symptoms). Within the context of theories of psychopathology, the negative and positive symptoms seem easy to understand. Thus, negative symptoms are delayed development or even no development of certain normal mental functions, of which the anhedonia is most fundamental.
Pathological psychology deals with disturbed expression of normal mental functions, and hedonia is one of the most fundamental attributes of man as a social creature (the in stinctual drive of life satisfaction in interpersonal relations). The negative symptoms can be subdivided into emotional withdrawal, disturbances of verbal communication (conceptual disorganization, loosening of associations) and of nonverbal communication (autism). In the more severe cases the negative symptoms are the deterioration into dementia.
The psychological pathology deals with symptoms appearing -de novo- as manifestation of a disease process. The positive symptoms are unique disease symptoms of psychotic illness (hallucinations and delusions). In relation to validity the positive symptoms respond to neuroleptics (dopamine hyperactivity in the brain) while negative symptoms might respond to serotonin (Bech 1992).
Crow (1980) used a dimensional approach to negative versus positive symptoms of schizophrenia, whereas Andreasen and Olsen (1982) referred to negative and positive categories or subtypes of schizophrenia. Andreasen (1981, 1982) constructed the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS). The apathetic factor of AMDP can be considered as a negative syndrome of AMDP (Pieztker et al. 1983). Another scale for measuring positive and negative symptoms of schizophrenia is the Bonn Scale for the Assessment of Basic Symptoms of Schizophrenia (Gross et al. 1987).
A most interesting approach from the point of view of rating scales is the Positive and Negative Syndrome Scale (Kay et al. 1988) which rnodifies the BPRS to include more negative symptoms (Table 33). This scale consists of 30 items (Table 34), 7 of which cover the negative syndrome of schizophrenia, another 7 the positive syndrome, and the remaining 16 a general psychopathological subscale. Of the 30 items in the PANSS, 18 are from the BPRS, and 12 are new items. In contrast to the original BPRS (Overall and Gorham 1962), the PANSS provides strict item definition; however, it follows the original version in having a 0-6 calibration for each item.
PANSS scores of Patients immediately after Admission (Table 9) showed a very high above average (markedly significant) according to the interpretive guidelines for PANSS score, also the same applied to the scores of Positive, negative and general psychopathology subscales. After a mean duration of treatment of 71.4 days PANSS total score regressed, but still showing an above average (significant) according to the interpretive guidelines for PANSS score, also the same applies to the scores of negative syndrome and general psychopathology which also regressed, regarding positive syndrome it regressed giving a statistically significant value indicating improvement. The PANSS scores were used as Factor analysis to detect loading on different dimensions. But they were negatively correlated with all region of areas included.
As found in our analysis of reversible symptoms, Positive symptoms show loadings on separate dimensions, there where 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. As is shown in Table (18), negative symptoms were not affected by neuroleptic treatment.
Table (33)
Psychometric Description PANSS Scale for schizophrenia
Type Symptom   subscale
Content   validity Negative   and positive dimensions of schizophrenia. Item distribution according to the   components
Administration Interviewer   scale to be used by skilled observers (goal directed interview).
Time   frame For   each item it is indicated whether the assessment is observation at interview   alone, or whether the basis for rating also includes reports from others,   e.g. family (only item G16 in PANSS is solely based on reports).
Item   selection The   PANSS includes BPRS. The innovation is the negative syndrome
Item   calibration scale   definition 0-7
Number   of items The   negative syndrome scale contains items (NI-N7), the positive syndrome scale   contains items (P1-P7), and the General psychopathology (G1-G16)
Content   validity The   PANSS subscales of negative and positive syndromes have been factor analysed   (Key et al., 1991). The first factor was the negative scale and the second   factor the positive syndrome. Rasch analysis has not yet been performed   (Andersen et al. 1 989).
Interobserver   reliability The   PANSS has adequate reliability (Key et al. 1987)
Table (34)
PANSS: negative, positive, and general psychopathological subscales
N1 Blunted affect
N2 Emotional withdrawal
N3 Poor rapport
N4 Passive social withdrawal
N5 Difficulty in abstract thinking
N6 Lack of spontaneity and flow of conversation
N7 Stereotyped thinking
P1 Delusions
P2 Conceptual disorganisation
P3 Hallucinatory behaviour
P4 Excitement
P5 Grandiosity
P6 Suspiciousness
P7 Hostility
G1 Somatic concern
G2 Anxiety
G3 Guilt feelings
G4 Tension
G5 Mannerism and posturing
G6 Depression
G7 Motor retardation
G8 Uncooperativeness
G9 Unusual thought content
G10 Disorientation
G11 Poor attention
G12 Lack of judgment and insight
G13 Disturbance of volition
G14 Poor impulse control
G15 Preoccupation
G16 Active social avoidance
Data Following the 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 risperidone and changes in relative cortical perfusion. As discussed by Gray et al. (1991), neuroleptics seem to act on the positive dimension alone. This dimension therefore has a predictive validity from a neuropsychopharmacological point of view (Laruelle M, 2000: Chen Ry etal, 2000 ; Erkwoh R etal, 1999).
When applying the pervious facts to our study, PANSS scores of Patients immediately after Admission (Table 9) showed a very high above average (markedly significant). After a mean duration of treatment of 71.4 days PANSS total score regressed, but the positive score regressed giving a statistically significant value. The PANSS scores were used as Factor analysis to detect loading on different dimensions. But they were no correlated with all region of areas included (Table 32).
As previously highlighted, 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
Critique of the Study
During the study we tried to demonstrate the effect of schizophrenia on alterations of regional cerebral blood flow and the effect of treatment, yet there remain a number of issues that should be taken into consideration and might have its implications on the obtained results.
First: There is a wealth of diverse functional abnormalities in schizophrenia, but there is also a lack of consensus about the findings. There may be a number of reasons for that dichotomy but chief among them are the difficulty of controlling the behavior of the subjects during the procedures and the complexity of interpreting functional abnormalities.
Second: Functional abnormalities of a specific brain area can result from a variety of pathological situations, including structural abnormalities in the area itself (intrinsic abnormalities) or in its afferent or efferent pathways, as well as neurochemical aberrations in any of those locations. Any single structural or neurochemical lesion can result in a variety of spatially disparate functional abnormalities, which, in turn, may lead to other functional problems downstream and which may become manifest under some conditions (for example, afferent input or physiological load), but not under others. Therefore, a given functional problem may actually be a reflection of distant pathology and may appear to be an inconsistent finding. Several examples of distant effects of lesions are well documented in the neurology literature. Perhaps the most commonly seen is the phenomenom of crossed-cerebellar diaschisis in which supratentorial lesions, such as infarction or tumor, can produce rCBF reductions in the contralateral cerebellar hemisphere. Those linked structural-functional abnormalities reflect anatomical connections between the affected areas. Cases in which the symptoms of patients with cerebrovascular disorders were related to functional changes distant from the structural infarct have also been reported. The reports clearly show that structural lesions can lead to differentiation or disconnection syndromes with distant physiological repercussions and associated clinical sequelae.
In schizophrenia, where no overt structural aberrations such as infarcts or tumors are apparent, the functional repercussions may be expected to be even subtler and more difficult to measure, but the same principles apply.
Third: A potential problem for some blood flow studies is the failure to take into account the subjects' arterial CO2 levels, which can alter blood flow. Many SPECT studies avoid the use of arterial lines and, therefore, report only relative values (for example, regional data expressed as a percentage of some global measure rather than absolute values). In those SPECT studies that do report absolute values an additional problem is the possibility that, since patients with schizophrenia may have relatively less brain tissue and enlarged CSF spaces as compared with normal controls, more values for CSF may be averaged in with values for tissue in those patients (the so-called partial-volume artifact), producing lower apparent tissue values (Bigliani V. etal, 1999).
There are also several disadvantages, including difficulties in the absolute quantitation of data obtained with any sort of tomographic imaging. Attenuation of radiation counts refers to the fact that since the energy of a photon is diminished as it travels through matter, which slows or even stops it, fewer photons originating in deep structures reach the extracranial detectors than do photons originating in superficial structures. That may produce artificially lower values for deep brain regions (such as the basal ganglia), which may be important in schizophrenia, and relatively higher values at the surface. No completely satisfactory method for dealing with the issue has been found for SPECT scanning.
Fourth: lastly SPECT concerns what so-called partial-volume effect. It results from the fact that when a structure that is smaller than the spatial resolution of the scanner is imaged, that structure only partially occupies the volume that the detectors see. That may result in an underestimation of the structure's activity level, and is a particularly serious confound for imaging the brain, in which there are numerous small structures with heterogeneous functions. The better the spatial resolution of the imaging system, the smaller will be the partial volume effect. The non-tomographic (two-dimensional) technique does not have that problem.
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