Single-Photon Emission Computed Tomography (SPECT) and Schizophrenia
As previously explained in chapter 2, SPECT is a tomographic technique that studies the emission of single photons from a radiotracer introduced into the body. The facet of the technique that renders it so potentially powerful is its ability to measure physiological changes underlying transient mental phenomena, also makes their application to psychiatric research complex. Since a subject's sensory input, cognitive and motor outputs, mental state, and the ambient conditions in the testing environment all have potential neurophysiological repercussions, they must be rigorously controlled.
SPECT has several advantages over other available methods for studing schizophrenia, particularly PET, it has the obvious advantages of a tomographic approach and better spatial resolution. Since single photon emitting isotopes have longer half-lives than do positron emitters,. For the same reason scans with the iodine 123 and technetium 99m radiopharmaceuticals can be performed many hours after the radiotracer, giving SPECT greater procedural flexibility than PET. The cost of SPECT is much far less than of other techniques also SPECT is less invasive than PET (Frey K. A.,2000).
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. The problem is greatest for photons of low energy, such as xenon 133. No completely satisfactory method for dealing with the issue has been found for SPECT scanning (Hendren RL, etal, 2000).
This again illustrates the problems inherent in making diagnosis from structural changes. The changes are subtle in many people affected with this illness and the structural changes are statistically significant for groups but not predictive of individuals. When broadly summarizing the findings of SPECT (Table 4 ), evaluating frontal metabolism in schizophrenia, With use of a variety of verbal, visual, and spatial tasks and their studies ranged broadly over many resting and activation studies. The variability of frontal metabolism is marked in the differences in test conditions, medication status, metabolic tracers, and other such factors, and therefore make it very difficult to derive conclusions (McClure RJ. etal, 1998).
Brain Functional Alterations in Schizophrenia
Alterations in global metabolism or cerebral blood flow
Reductions in blood flow and metabolism to the entire brain have been consistently demonstrated in primary degenerative dementias (in which there are also more severe localized functional decrements in temporoparietal and sometimes frontal regions) 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. Early studies using intracarotid techniques rarely found reduced flow, but the results of inhalation rCBF studies have been mixed. But more 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. 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).
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).
Table 4: Controlled Cortical Probe and SPECT Studies Evaluating Different regional Metabolism in Schizophrenia
Study Sample size Test conditions Medications status Resullts
Metab.   tracer
Kety et al, 1948 22 Resting,         sensory status not specified No antipsychotics, other medication not specified Nitrous oxide inhalation No         significant difference schizophrenic patients vs controls (only total         cerebral blood flow measurement possible)
Ingvar and Franzen, 1974, 1975, 1975 31 Resting         in quiet room with eyes blindfolded, older psychotic group had simple         picture test, low psychotic group had Raven's Progressive Matrices, 10         controls tested with auditory digit-span- backward-test, 9 controls         tested with Raven's Progressive Matrices 30/31 taking variable dosages of antipsychoties; all patients and         controls premedicated with 200 mg of phenobarbital and 0.75 mg of         atropine Intracarotid xenon 13, 32 probes/1 hemisphere only At  rest: no significant differences in frontal flow rates between schizophrenic patients and alcoholic controls, postcentral flow         significantly greater in older highly psychotic group than in alcoholic  controls, ratio of frontal to postcentral blood flow significantly less  in schizophrenic patients than in alcoholic controls, thus 'relative  hypofrontality'  With      cognitive activation: older highly psychotic group showed significantly  less frontal flow response than alcoholic controls (note that 2   different cognitive tasks were used), trend for lower flow response was  found in low psychotic group compared with controls (for identical         testing procedure, differences not significant)
Mathew et al 1981 6 Resting,         sensory status not specified All not taking medication Xenon 133 inhalation 16 probes/both hemispheres lower mean RCBF value for gray matter in         schizophrenic patients vs controls was significant only for R         hemisphere, no relative hypofrontality reported
Mathew et al 1982 23 Resting,         sensory status not specified 13 medicated, 9 not taking medication for 1 wk, 1 unknown Xenon 133 inhalation 16 probes/both hemispheres mean         blood flow in both hemispheres and in most brain regions studied was         significantly lower in schizophrenic patients vs normal controls, no         relative hypofrontality reported
Ariel et al, 1983 29 Resting, sensory status not specified 22 medicated Xenon 133 inhalatior 16 probes/both hemispheres Relative hypofrontality in 1 hemisphere of schizophrenic patients
Gur et al, 1983 15 Resting,         eyes open, verbal analogy test and spatial task All Medicated Xenon 133 inhalation, 16 probes/both hemispheres At         rest: increased frontal flow in both schizophrenic patients and controls
With         cognitive activation: schizophrenic patients had significantly less         changein left hemispheric flow for verbal analogy test than controls but         a greater left hemispheric increase for the spatial task
Gur et al, 1985 19 5 not taking medication for 1 y, 3 not taking medication for 2 mo, 8         not taking medication for 7 d, 3 drug naive Xenon 133 inhalation, 16 probes/both hemispheres No         hypofrontality noted
Resting,         eyes open, ears unoccluded; activation with verbal analogy test and         spatial task
Devous et a], 1985 34 Resting All not taking         medication for 7 d Xenon 133         inhalation with SPECT Hypofrontality noted
19 Activation with WCS All not taking         medication for 7 d Xenon 133         inhalation with SPECT Decreased frontal flow during activation         relative to resting state in schizophrenic patients
Kurachi         et al, 1985 16 Resting:         eyes covered All         taking medication Xenon         133 inhalation, 16 probes/both hemispheres Relative         hypofrontality noted
Resting, eyes covered (RCBF measured at admission, at 1, 2, 4 wk, and at   discharge)
Warkentin et 16 Not specified Xenon 133 inhalation, 32 probes/both hemispheres No         significant relative hypofrontality at admission, R frontal flow         significantly decreased with medication
al, 1985
Berman et al, 1988 24 Resting, eyes closed; activation with WCS and number- matching task All taking medication Xenon 133 inhalation, 32 probes/both         hemispheres Relative decreased prefrontal flow noted at rest, neither absolute         nor relative prefrontal flow noted with number-matching task, relative         prefrontal flow decreased signficantly during WCS
18 2         visual contionius performance task All not taking medication for 4 wk Xenon 133 inhalation, 32 probes/both hemispheres No         differences in frontal activation noted with either task in patients vs         controls
Chabrol et al, 1986 10 Resting,         sensory status not specified All drug naive Xenon 133 inhalation, 32 probes/both hemispheres Relative         hypofrontality noted
Guenther et al, 1986 16 Resting,         sensory status not specified; motor activation of dominant R hand 12 drug naive, 4 drug Xenon 133 inhalation with SPECT Relative         hypofrontality noted
washout for 1 wk
Weinberger         et al, 1986 20 Resting,         eyes closed; activation with WCS and number- matching task All         not taking medication for 4-6 wk Xenon         133 inhalation, 32 probes/both hemispheres Relative         decreased prefrontal flow noted
at         rest, neither absolute nor relative prefrontal flow noted with         number-matching task, relative prefontal flow decreased significantly         during WCS
Geraud et al, 1987 51 Resting,         eyes closed 13 not treated,
         29 taking neuroleptics,
         9 completed a washout period for oral medication for 1 5 d and depot         medication for 45 d		 Xenon 133 inhalation, 32 probes/both hemispheres Relative         hypofrontality noted
Berman et al, 1988 24 Resting,         eyes closed; activation with Raven's Progressive Matrices and         symbols-matching task All off medication for >4 wk Xenon 133 inhalation, 32 probes/both hemispheres No         hypofrontality noted
Dousse et al, 1988 27 Resting,         eyes closed 12 taking medication for <10 d, 12 taking medication for 11-60 d,         3 drug naive Xenon 133 inhalation, 26 probes/both hemispheres No         hypofrontality noted
Mathew et al, 1988 108 Resting,         sensory status not specified 46 not taking medication for 2 wk, 62 medicated Xenon 133 inhalation, 32 probes/both hemispheres Relative         hypofrontality noted
Weinberger et al, 1986 16 Resting,         eyes closed; activation WCS and number-matching task All not taking medication for at least 4 wk Xenon 133 inhalation, 32 probes/both hemispheres At         rest, data not reported; neither absolute nor relative prefrontal flow         noted with number- matching task,
relative         prefrontal flow decreased significantly during WCS
Bajc et al, 1989 28 Resting,         sensory status not specified 20 medicated for <2 wk, 8 medicated long term 99mTc-HMPAO SPECT No         hypofrontality noted
Cohen et al, 1989 10 Resting,         eyes open All medicated long term Iodine 123 IMP SPECT No         hypofrontality noted
Erbas et al, 1990 20 Resting,         eyes closed All medicated 99m Tc-HMPAO SPECT lower         frontal hypofrontality noted
Paulman et al, 1990 40 Resting,         eyes open 20 medicated, 20 not taking medication for 7-14 d Xenon 133 inhalation with SPECT Relative         hypofrontality noted
Sagawa et al, 1990 53 Resting,         eyes closed All medicated Xenon 133 inhalation with SPECT Hypofrontality         noted
Warkentin etal, 1990 17 7 medicated, 6 not' taking medication for 3-12 mo, 4 drug naive Xenon 133 inhalation, 32 probes/both hemispheres No         hypofrontality noted at admission, significant 1 hemisphere         hypofrontality noted between 1 wk and discharge
Resting,         eyes closed; (rCBF measured at admission, at 1 wk, and at discharge in         subgroup of 1 0 unmedicated patients)
Wood         and flowers, 1990 18 Activation         with 2 trials of auditory probe recognition memory task, eyes closed All         not taking medication for > 10 days Xenon         133 inhalation, 16 probes/both hemispheres Relative         hypofrontality as a result of greater anxiety on second recognition         trial after presumed habituation
Bajc et al (1989) 28 28 medicated SCZ and 11 HCN; studied at rest 99mTc-HMPAO SPECT Hypoperfusion         in several brain regions in chronic and negative symptom patients
Musalek et al (1989) 28 28 psychotic patients 99mTc-HMPAO SPECT Hyperactivity         in basal regions
Erbas et al (1990) 20 20 medicated SCZ and 11 HCN 99mTc-HMPAO SPECT Hypofrontality         seen
Kawasaki et al [         (1992; 1993; 1996) 10 10 medicated and SCZ and 10 HCN; at rest; on         activation with WCST; and last study with 38 medicated SCZ 99mTc-HMPAO SPECT Hyperactivity in left basal ganglia and left hippocampus; left         hypofrontality only on activation; right medial prefrontal hyperactivity         in both conditions
Lewis et al (1992) 25 25 SCZ and 25 HCN during Chicago Word Fluence Test 99mTc-HMPAO SPECT Hyperactivity         in caudate thalamus and left posterior cortical regions, and         hypoactivity in left frontal cortex
Ebmeier et al] (1993) 20 20 unmedicated SCZ and 20 HCN 99mTc-HMPAO SPECT Frontal         hyperactivity at rest
McGuire et al (1993) 12 12 male SCZ; during hallucinations and after remission 99mTc-HMPAO SPECT Hyperperfusion         in Broca's area during hallucinations
Busatto         et al (1994) 10 10         medicated SCZ and 10 HCN; at rest and during activation with a verbal         memory task 99mTc-HMPAO SPECT No         differences in perfusion between groups
Catafau et al (1994) Catafu et al (1994) 10 10 never treated SCZ and 8 HCN; studied at rest and on activation         with WCST 99mTc-HMPAO SPECT Frontal         hyperactivity and temporal hypoactivity at rest; relative hypofrontality         upon activation in SCZ
Gordon et al] (1994) 5 medicated and 5 unmedicated SCZ; studied at rest 99mTc-HMPAO SPECT No         differences seen
Rubin et al (1991; 1994) 43 43 medicated, 43 unmedicated, and SCZ 24 HCN 99mTc-HMPAO SPECT Hypofrontality         both at rest and on activation; hyperperfusion in striatum on activation
Vital et al (1995) 17 9 drug-naive SCZ, 8 medication-free SCZ, and 12 HCN 99mTc-HMPAO SPECT Hypofrontality         seen
Klemm et al (1996) 17 17 SCZ and 12 depressed patients 99mTc-HMPAO SPECT Temporal         lobe hypoperfusion correlated with positive symptoms
Erkwoh et al (1997) 24 24 drug-naive SCZ 99mTc-HMPAO SPECT Different         correlations rCBF vs psychopathology, after treatment, only negative         symptoms correlated with hypoperfusion
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 concerning the question are relatively sparse and do little to resolve it. A number of xenon 133 resting rCBF studies do not support the notion of altered laterality in schizophrenia. However, two studies performed during cognitive activation specifically designed to explore laterality in schizophrenia suggested that there is left hemisphere over activity. Very few SPECT reports of altered lateralization have been published, but left hemisphere overactivation and increased left temporal metabolism, with particular focus on the hippocampus and parahippocampal areas, have been reported (Ceballos C, etal, 1997).
A report of over 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). The diversity of the findings highlights the state dependency of functional laterality and the need for careful control of state variables. Whether normal lateralization is to the left or to the right, and whether patients and controls differ, depends on what the subjects are doing during the scans and what region is examined. 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).
Metabolic hypofrontality
Several lines of converging evidence suggest that impaired frontal cortical function may play a role in schizophrenia. For example, clinical signs and symptoms of patients with gross frontal lobe lesions (including minor or soft neurological signs, disordered smooth-pursuit eye movements, impaired problem solving and abstract thinking, and such clinical features as bizarre behavior, poor social functioning, and inadequate hygiene) are also seen in schizophrenia. Studies of subhuman primates indicate a role for the prefrontal cortex (especially the dorsolateral aspect) in higher-order cognitive processes analogous to those impaired in schizophrenia (Parellada E etal, 1998).
Although those lines of reasoning are inferential more direct evidence for frontal cortical involvement in schizophrenia emerged from intracarotid rCBF studies in the 1970s. The early studies noted that patients with schizophrenia had relatively lower blood flow to frontal regions and relatively greater flow to postcentral regions. The patients who were most indifferent, most inactive, and showed the greatest degree of autistic disorder were the most hypofrontal (figure 11), whereas the most cognitively disturbed patients showed the highest postcentral rCBF. In addition to those observations it was noted that rCBF measurements could be made during cognitive activation. During a simple picture test normal subjects showed changes in rCBF whereas the more deteriorated patients did not.
Those pioneering research findings heralded the beginning of the modern era of functional brain imaging in psychiatry and refocused interest on the frontal lobes in schizophrenia. However, the intracarotid technique of xenon 133 administration was not well suited to clinical research. More recent attempts to confirm hypofrontality in schizophrenia using the noninvasive inhalation technique have met with inconsistent results. Possible explanations for the lack of consensus in the literature may include differences in instrumentation and methodology, differences in patient populations, and, most important, failure to control testing conditions adequately. Studies carried out during the resting state have proved variable. (Heckers S etal, 2000).
Fig (11)
Brain Tomographic series illustrating Hypofrontality
Is Hypofrontality in Schizophrenia Behaviorally Specific?
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. During tasks not specifically linked to prefrontal cortex, including simple matching tasks and paradigms involving attention and vigilance, hypofrontality was not as consistently and robustly observed. Attempts were made in the experiments to control nonspecific and state-dependent epiphenomenological factors that often confound interpretation of such studies. They included the use of a baseline activation measurement in addition to regionally specific cortical activation and the monitoring of peripheral indicators of autonomic arousal, such as pulse, blood pressure, and respiratory rate. The studies highlight the importance of controlling state factors in functional brain imaging studies (Chen RY, etal,2000).
As with rCBF studies the most consistent finding in schizophrenia to emerge from SPECT technology is decreased frontal lobe function. A recent reviewing  of functional brain imaging studies of schizophrenia found that over 60 percent were positive. However, of those studies that attempted to control behavior during the scans by having subjects perform a task that was in some way linked to the frontal lobe, 100 percent demonstrated hypofrontality (Toone BK, 2000).
The results suggest that the degree to which patients appear hypofrontal as compared with controls during a functional brain imaging study depends on whether they are engaged in an activity that in normal persons is associated with the activation of the prefrontal cortex. If true, that conjecture would have important implications for understanding the pathophysiological mechanism, and ultimately the neural specificity, of prefrontal failure in schizophrenia, and the observation may explain a number of the inconsistencies in the SPECT and rCBF literature. The fact that prefrontal cortical dysfunction in schizophrenia may be condition dependent is not inconsistent with the clinical picture of psychopathology that waxes and wanes under various circumstances (Laruelle M,2000).
Is Hypofrontality in Schizophrenia an Effect Of Medication?
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.
First, rCBF studies of young patients who had never received antipsychotics did find hypofrontality. That finding has been confirmed by two SPECT studies of antipsychotic-naive patients, most during a behavioral-cognitive task. Hypofrontality has also been observed in patients regardless of whether they are receiving or have been withdrawn from haloperidol but those results do not rule out the possibility of long-term effects of antipsychotic treatment on prefrontal physiology. However, a study of patients with Huntington's disease, some of whom had been chronically maintained on antipsychotic drugs, found no differences in prefrontal blood flow between such patients and those who were naive to antipsychotics (Erkwoh R, 1999). A study of eight pairs of monozygotic twins who were concordant for schizophrenia, but whose lifetime histories of antipsychotic drug intake differed greatly, found that in most pairs the twin who had been exposed to more antipsychotics was the more hyperfrontal of the pair during a prefrontally linked task (Blackwood DH,1999).
Finally, a number of studies have examined the metabolic or rCBF changes that occur when patients go from the unmedicated state to the medicated state. Those studies have reported either no change in values or an increase in 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.  
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).
RCBF studies of monozygotic twins discordant for schizophrenia shed light on the question. Assuming that the rCBF measurements for the well cotwin of a monozygotic pair may reflect the values that would have characterized the ill twin if he or she did not have schizophrenia, the former can be used as a genetically (as well as socioeconomically and environmentally) perfect control to determine the pathophysiological changes that have occurred in each patient. During a task linked to the frontal lobe the twin with schizophrenia was more hypofrontal than his or her well cotwin in every case. That would seem to suggest that if the experimental conditions are properly controlled, hypofrontality can be demonstrated in most, if not all, patients (Goldberg TE, 1995).
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.
The Pathophysiological Mechanism of Hypofrontality
A highly simplified scheme might consider three possible pathophysiological mechanisms for hypofrontality in schizophrenia--deefferentation of prefrontal cortex, deafferentation, and intrinsic prefrontal abnormality--operating either alone or in combination. Although it remains unproved as to which, if any, of the mechanisms may play a role in the behaviorally related pathophysiology of the prefrontal cortex in the illness, some clues are offered by the collective results of the functional and structural imaging literature (Higashima M. etal, 2000). 
Animal and human studies suggest a role for dopamine in the activation of prefrontal cortex and in prefrontally linked behaviors. One study demonstrated a direct correlation between CSF levels of the dopaminergic metabolite HVA and prefrontal rCBF during a prefrontal task in schizophrenia, and several groups have reported the reversal of hypofrontality with the administration of dopaminergic agonists (Minkowski K,1998).
There is also evidence for a link between prefrontal physiological hypoactivity and anatomical pathology in schizophrenia. One study observed a correlation between prefrontal rCBF during a prefrontal task and ventricular size on CT. The relationship was not observed during nonprefrontally specific tasks. Consistent with that finding is a   monozygotic twin study that found that in the affected twins the volume of the hippocampus (the structural variable that best differentiated the well from the ill twins) strongly predicted the degree of dorsolateral prefrontal activation during prefrontal cognition (the physiological variable that best differentiated the cotwins). The smaller the hippocampus, the less is the prefrontal activity, suggesting that there may be dysfunction of neocortical-limbic connectivity in schizophrenia. It is tempting to think that the anatomical, functional, and neurochemical alterations highlighted by those studies might be linked, but further work will be necessary to delineate the specifics of such a hypothesis (Goldberg TE etal, 1995).
Interpretation of physiological abnormalities can be complex. However, the wealth of information offered by brain imaging studies, particularly considered in conjunction with correlative data, provide important and heretofore unavailable clues. Future technological developments and new applications of the techniques will undoubtedly provide new insights.
Other regional changes
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). Abnormal lateralization of temporal lobe blood found increased left globus pallidus rCBF 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. 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.
Several investigators have suggested that schizophrenia is characterized by increased posterior cortical activity. The first rCBF study of schizophrenia in the mid-1970s 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 as well as a hypergnostic component related to an early FDG18 study performed while patients received mild forearm shock 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. However, later studies by the same investigators also demonstrated decreased frontal activity, and no other investigators have shown similar findings; in contrast an isolated report found a reversal of the pattern with relatively increased frontal and decreased posterior glucose metabolism in unmedicated patients during resting. Another study 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. Kawasaki et al (2000) have shown that regional blood flow as studied by SPECT shows specific and predicted correlations with negative and positive symptoms; reduced prefrontal blood flow was associated with negative symptoms, and reduced temporal lobe blood flow was associated with thought disorder. Similar findings have been observed by Ebmeier et al (1999)  and Klemm et al (1998) . A direct demonstration between specific symptoms and blood flow alterations has been provided by McGuire et al. They demonstrated that schizophrenia patients manifest hyperperfusion of the Broca's area during hallucinations as compared with the remitted state. Thus, functional neuroimaging studies, such as SPECT, can elucidate the specific neural networks that may underlie discrete symptom clusters in schizophrenia.
Understanding Functional Abnormalities In Schizophrenia
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.
Functional effects of distant lesions
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 and l-CMR-Glu 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.
Alterations in Neuroreceptors
The ability to examine neuroreceptors and other parameters of specific neurochemical function in vivo with SPECT represents one of the most exciting applications of functional brain imaging. Alterations in neuroreceptors in schizophrenia are suggested by the facts that (1) such alterations, particularly elevations of dopamine receptors in the striatum, have been found in postmortem studies; and (2) neurochemical therapeutic interventions, such as dopamine antagonists, remain the mainstay of treatment. The postmortem observations, however, have been complicated by potential artifacts having to do with receptor alterations after death, the effects of agonal events leading to death, and, to an even greater extent, the fact that most patients will have received extensive treatment with antipsychotic medication by the time of death. The last is a problem because it has been shown that the antipsychotics themselves produce an elevation of dopamine receptors in the striatum, making it difficult to conclude whether the observed increases in dopamine receptors are associated with the disease or are the effects of the antipsychotic medication  (Tamminga C, 1999).
Since SPECT studies have the potential to investigate patients while they are young and early in their course of illness, perhaps even before antipsychotic treatment, many of the problems can be circumvented, and a more meaningful assessment of receptor status may be obtained. Several studies have measured striatal D2 receptors in vivo in schizophrenia, with mixed results. Cerebral blood flow and D2 dopamine receptor binding in schizophrenics and controls are reviewed. Methodological influences on the validity of the data generated by these technologies include problems with measurement as well as clinical and anatomical heterogeneity. Work in these fields to date, however, has produced strong support for the role of D2 dopamine receptor blockade in antipsychotic efficacy. Neuroleptic-induced changes in regional brain metabolism over time have also been observed; however, the relationship between such actions and symptomatic change needs to be further clarified. Future studies on time-course of neuroleptic-associated changes in regional brain metabolism, blood flow and dopamine receptor binding in schizophrenics have the potential to provide greater insight into the relationship of these actions to symptomatic changes and drug-induced side-effects (Kugaya A. etal, 2000).
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