Concept of Single Photon  
Computed Tomography (SPECT) Technique
Historical Past and Essential Features
In 1890, Roy & Sherrington proposed, in a remarkable piece of foresight, that the chemical products of cerebral metabolism caused alterations in small cerebral arterial vessels so that its vascular supply can be varied locally in correspondence with local variations of functional activity, although Roy and Sherrington's proposal was not taken seriously until the second half of the twentieth century. Prior to that it was assumed that, unlike other tissues, brain did not require an increase in regional cerebral blood flow (rCBF) when particular local regions were doing work.
In 1945 researchers first demonstrated that average blood flow could be measured for the human brain as a whole by ascertaining the difference between arterial and venous concentrations of the inert tracer arriving and leaving the brain. Regional blood flow measurements by extracranial monitoring of the delivery and washout of radioisotopes of inert substances soon followed. In the 1960s a method for measuring the blood flow of many cortical regions in one hemisphere was developed. It involved the injection into the carotid artery of a saline solution of the inert radioisotope xenon 133 gas. Extracranial detectors were used to monitor the rates of arrival and disappearance of gamma rays from various cortical areas, which allowed the calculation of regional blood flow to each area. It was quickly noted that rCBF measurements carried out in that fashion, albeit invasive, were sensitive to functional activation of specific cortical areas. During the 1980s, the introduction of a completely noninvasive, atraumatic, and quick technique, in which xenon 133 gas was administered to the subject by inhalation and which was particularly well suited to studying psychotic persons.
The main functions of the brain include controlling motor activity, sensation and the storage, retrieval and processing of information. This activity is mediated by neurons. When activated, resting neurons undergo a very rapid change. Ion channels in the cell membrane open and allow entry of sodium ions. The resulting depolarization continues along the axon and causes the release of a neurotransmitter when it reaches the synapse. These processes use energy. The highest energy turnover occurs in brain regions having the highest density of synapses, where glucose metabolism is highest. Glucose metabolism requires oxygen and ATP, Oxygen is delivered through oxyhaemoglobin in arterial and capillary blood. The very rapid and localized increases in glucose metabolism which underlie increases in brain activity occur with rapid local changes in blood flow to meet the increased demand. This change in rCBF forms the basis of much SPECT and PET imaging. Rapid haemodynamic response at the capillary level is probably mediated by nitric oxide acting on precapillary vessels (Keshavan MS etal, 1999).
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 (Santosh PJ., 2000).
SPECT employs isotopes that decay by electron capture or g-emission or both, including both 123-iodine (123I) and the long-lived metastable nuclide 99m-technetium (99mTc). No comparable theoretical limit on spatial resolution exists for SPECT because the site of g-emission and the site of radioactive decay are synonymous. The emission of only a single photon fundamentally distinguishes SPECT and necessitates an intrinsically approach to ascertaining the origin of a decay event and therefore of camera design. Specifically, SPECT utilizes a method know as collimation (Figure. 8).
Figure 8: Image reconstruction from back projection in SPECT
uses a collimator placed between the object and the crystal detector.
In a manner analogous to the effects of a polarizing filter for visible light, a collimator is a physical filter that permits only g-rays of a specific spatial trajectory to reach the SPECT scanner's detector. Most commonly, a collimator is a lead structure that is interposed between the subject and the radiation detector. The collimator contains many holes of sufficiently long and narrow dimension so that only photons of a parallel trajectory are allowed through. In contrast to parallel photons, g-rays that deviate slightly are absorbed by the lead and go undetected. Different collimators (e.g., parallel, fan-beam, and cone-beam) have holes of differing orientations (e.g., perpendicular to the detector, focused in twodimensions, and focused in three dimensions, respectively). Given a known geometric configuration for the specific collimator's holes, the original path of a detected photon is linearly extrapolated. Collimation is less efficient than coincidence detection because many potentially informative photons are lost. However, the sensitivity of SPECT has been largely enhanced by advances in collimator design and an increase in the number of detectors surrounding the body; SPECT is now sufficiently sensitive for routine use in nearly all the same applications as PET (Innis R B,1998).
The first ECT (Emission Computed Tomography) device was the MARK-IV developed by Edwards and Kuhl (1963). The MARK IV consisted of several banks of sodium iodide (NaI) photon detectors arranged in a rectangular shape around the patient's head. The first commercial Single Photon-ECT or SPECT imaging device was similar in design to the MARK IV but had 32 photon detectors and was called the Tomomatic-32. Many research systems which eventually became clinical standards were also developed in the early to mid 1970s (fig 9) (Jaszczak R.J. et al, 1977).
Figure 9: An early SPECT image of Brain (Ingvar DH, 1973)
Early applications resulted in diagnostically unusable images, and the technique was not widely accepted (Jaszczak R.J., 1988). It was not until methods developed during the introduction of x-ray CT by Hounsfield (1973) and Cormak (1963) were applied to nuclear medicine ECT that this imaging modality began to gain attention in the medical imaging community. Image reconstruction algorithms invented for x-ray CT had to be modified for ECT to take into account effects of photon attenuation and scatter within the body and limited mechanical and electrical detector response When this was accomplished, image reconstruction techniques, such as filtered back projection (FBP), produced ECT images which for the first time allowed qualitative and quantitative image analysis and clinical use.
Unlike other imaging modalities such as magnetic resonance imaging (MRI), or x-ray, an SPECT image gives a picture of organ function, not strict anatomy. This is because, for example, SPECT involves the detection of gamma rays emitted singly from radioactive atoms. A radiopharmaceutical is a protein or an organic molecule which has a radionuclide attached to it. The proteins and organic molecules are selected based on their use or absorption properties within the human body. Thus, in a general sense, a brain will absorb or uptake a certain amount of radiopharmaceutical, which appears as a bright area in a SPECT image. Abnormally high or low physiological uptake of a radiopharmaceutical will appear as an unusually bright or dark area on a SPECT scan and will raise suspicions about the presence of a diseased state (Yurgelun-Todd DA etal, 1999).
The essential difference of SPECT from PET is that the isotopes used in the tracers emit single photons. This means that the localization of the source of each detected photon is a more complicated, less exact process. Both the energy and the trajectory of individual photons are taken into account in calculating the source. Collimators mean that SPECT can have good spatial resolution but at the expense of sensitivity. Sensitivity in this context is the fraction of all photon emissions which result in a recorded event. Estimates of the effect of attenuation by intervening tissues are done mathematically (attenuation correction). With PET, absolute quantitation of RCBF can be made if arterial concentrations of radiotracer are known. This is not possible with SPECT, where measures are given in terms of relative RCBF, in which the region of interest is compared with some neutral reference area (perhaps the cerebellum or visual cortex) or else to the mean of the whole-brain RCBF value.
Most SPECT systems available in clinical practice are of the type known as rotating gamma cameras. These are well suited for clinical nuclear medicine uses in the body as a whole, but their limited resolution, which also depends on the distance from the detector, precludes their wide use in brain research. So-called 'head-dedicated' systems have a circular array of detectors with focused collimators and can only be used for brain imaging. These can give high-resolution images, with spatial resolutions approaching those with PET.
SPECT uses isotopes with longer half-lives than those for PET. Xenon 5 days, 99technetium 6h and 12iodine 13h. Unlike the PET isotopes of carbon, oxygen and nitrogen, these are much less biologically relevant elements. Considerable radiochemical expertise is needed to design molecules which will carry these isotopes across the blood-brain barrier. The exception is 33xenon RCBF imaging, which is an inhalation technique and capable of giving 'dynamic' SPECT images, due to the rapid washout of this isotope. However, resolution with the 133xenon technique is poor. Radiotracer molecules designed to cross the blood-brain barrier quickly and in proportion to blood flow include 123iodine-iodoamphetamine and more recently 99technetium-hexamethylpro-pyleneaminoxime (99technerium-HMPAO or Exemetazine). With the latter compound, the HMPAO carries the 99technetium atom across the blood-brain barrier on first pass. It is taken up intracellularly and the change in pH makes it hydrophilic. This means it is trapped within the cells and remains in a stable distribution directly related to RCBF for several hours., This gives a snapshot image of RCBF as it exists during the 3 or 4 min window after intravenous injection (Kugaya A etal, 2000).
Strategies for Functional Image Analysis
Image analysis becomes much more complex when between group designs are needed, for instance comparing subjects with a particular psychiatric disorder and matched healthy volunteers. Until recently, the image-analysis approach which has been used to compare groups has been the ?region of interest? technique. In this, each subjects image would be displayed on a visual display unit and a tracker ball or pen would be used to outline regions of interest. The mean activity for each region for the experimental subjects would then be compared with that for the controls. The main drawback with this technique is that it takes no account of structural brain differences which might exist between subjects. Using a human operator to decide the boundaries of regions of interest on the functional image requires the assumption that the operator knows where to place the boundaries. On a functional the inference that structural boundaries can be identified is obviously a circular one. There are two solutions to this problem. The first is to obtain structural imaging data as well as functional imaging data for each subject. Then, data-processing techniques can be used to 'co-register' the imaging data on a voxel-by-voxel basis, such that a superimposed map for each subject is obtained (Verhoeff NP, 1999). In The development of the first functional brain imaging technique that was used in humans was developed by a psychiatrist, Seymour Kety. Kety and his co-worker Schmidt developed a method using inhaled nitrous oxide for quantitative determination of cerebral blood flow. In 1948 they had already applied this to normal volunteers and patients with schizophrenia, including the effects of insulin and electroconvulsive treatment (Kety etal., 1948). These studies demonstrated that the global cerebral blood flow and oxygen consumption measured in schizophrenia was essentially normal, although they also pointed out that this did not preclude there being regional differences in blood flow. SPECT (or single-photon emission computed tomography (SPECT), the same technique) and PET rely on the same underlying principle: the introduction into the working brain of radioactive isotopes which are linked to particular tracers. These radiolabelled tracers cross the blood-brain barrier and emit gamma radiation whilst decaying. Depending on the property of the tracer, the concentration of this radioactivity will be related to the presence of particular receptors, to areas of altered glucose metabolism or to focal areas of increased blood flow. Gamma rays, or photons, are detected by gamma-ray detectors placed outside the head and a slice-by-slice image is constructed. The crucial difference between these two techniques lies in the properties of the two different types of isotopes used. SPECT uses as radioactive tracers isotopes which decay with the emission of single photons, such as iodine and technetiurn isotopes (Costa DC etal, 1999).
SPECT tracers with iodine or with technetium isotopes can be made in routine clinical nuclear medicine departments at relatively low cost. A long half-life means that administration of the tracer is not so urgent. As well as less flexibility because of the long half-life, the long half-life of SPECT isotopes has another important disadvantage in terms of relative safety. Gamma radiation will continue to be emitted for a significant time after the scanning session is completed, which is wasteful In terms of a scientific risk-benefit equation. The cumulative dose of radiation is potentially biologically more harmful with SPECT isotopes than with the short lived PET isotopes (Santosh PJ, 2000).
Image Reconstruction
The technique rely on the principle of computed tomography when translating information about photon paths into brain images. Briefly, computed tomography is basedon the premise that an appreciation of an object's two- or three-dimensional distribution in space may only be inferred by viewing it from multiple vantage points. Since information about a photon's direction, not depth, is known, views of photon trajectories from multiple angles around the entire head are required. In SPECT, such a set of measurements from a given angle or viewpoint is referred to as a projection. SPECT cameras usually rely on several (typically 2 to 4) detector ?heads? that rotate around the subject in synchrony, collecting data over 360 degrees (figure 10). A picture of the distribution of radioactivity within a given brain slice is then inferred by retracing or backprojecting the trajectories (typically thousands) of g-rays across the field of view for every imaging angle. Conceptually analogous to the simple childhood puzzle in which numbers in a square grid (e.g., 3/3) are inferred from their sums along each row, SPECT images require fast computer coprocessors and efficient mathematical algorithms (fast Fourier transformations) to handle the considerably larger matrices (e.g., 128 / 128 or 256 / 256 elements) of radiation density values and the correspondingly more intensive calculations. In this manner, individual radiation values (i.e., counts of detected events) are determined for each cell of the matrix (also known as a picture element or pixel), corresponding shades of color assigned, and an image of the distribution of radioactivity within the brain produced (Lass P, 1999).
Figure 10: A Gamma Camera
Despite its complexity and computational intensity, back projection is an imperfect process and introduces known artifacts into the images themselves. As the back projection algorithm retraces a photon's path, it cannot be sure of the actual point of decay. The algorithm is thus forced to assume an equal probability of radioactive decay and hence of radiation value for every point along the line of trajectory. Areas of the brain in which radioactivity is highly concentrated will stand out as many trajectoriesfrom multiple projections are superimposed and their probability values are summed. In the process, however, those areas containing no radioactivity now bear the statistical imprint of the algorithm's guess. Thus, small but finite values are ascribed to areas where none should exist. By increasing the density of spatial sampling through greater numbers of projections, the impact of these spurious values on image quantitation can be minimized but not eliminated. Therefore, a filter is still required to restore quantitative accuracy to images by "erasing" counts in those areas that should have none. Several filters have been developed in an effort to overcome these limitations, and these techniques remain the mainstay ofthe field of image reconstruction. Trade-offs exist with respect to the relative impact of filters on spatial resolution and noise amplification, and filter selection depends on the imaging context. Alternative reconstruction methods (e.g., restorative and iterative techniques) are the current focus of much research, and simple filtered back projection is likely to be superseded by more quantitatively accurate methods in the near future. Several physical factors affect the quantitative accuracy of SPECT images. Among these are the statistics of radioactive decay, photon scatter, limited spatial resolution, and partial volume effects (Krishnan KR,1999).
Radiopharmaceuticals
The versatility and sensitivity of SPECT arise largely from the ability of radiochemists to synthesize a radiopharmaceutical of high chemical purity, high radioactive yield, and small mass dose. high purity and high specific activity (expressed in units of radioactivity per chemical quantity: Ci/mmol) are paramount. However, the physical nature of radioactive decay and the short half-lives of most suitable radionuclidic species constantly challenge the radiochemist's efforts. Chemical yield generally improves with increasing reaction times; however, radioactivity and specific activity diminishes with increasing decay times. Thus, an optimal synthetic scheme is a balanced one in which chemical yield is maximized, radioactive byproducts are minimized, and the final product is capable of prompt purification. Given the high affinity of many radiopharmaceuticals (e.g., neurotransmitter receptor ligands) for their physiological targets, specific activities of greater than 2000 Ci/mmol are generally required. SPECT isotopes like 99mTc (Half life = 6 hours) may be obtained from inexpensive molybdenum generators located in many hospital radiopharmacies. Alternatively, 123I has a sufficiently long half-life (13 hours) to permit centralized production at distant commercial reactors (Laruelle M, etal, 1999).
The choice of a candidate molecule for radiopharmaceutical development depends primarily upon the physiological process under investigation. In the case of regional cerebral blood flow, relatively nonspecific and often nonorganic, diffusible tracers may beemployed (e.g., the gaseous tracer 133Xe). In contrast, the measurement of aspects of brain neurochemistry require much greater biochemical selectivity. Thus, SPECT radiopharmaceuticals are most often naturally occurring substances, structural analogues, or ligands that selectively label a particular brain target. In this regard. The metallic nature and multiple valence states of 99mTc necessitate bulky complexing groups for its molecular stabilization. These barriers have largely limited the initial uses of 99mTc to nonselective processes (e.g., the blood flow agent [99mTc]-hexamethyl propyleneamine oxime; [99mTc]HMPAO). However, in 1997, 99mTc-labeled probes of the dopamine transporter were developed, and SPECT imaging has demonstrated appropriate labeling in human brain. Extension of these efforts is certain to result in the development of many other 99mTc-labeled probes in the future (Meltzer CC, 1999). Table 3 states the most common radionuclides used in brain imaging (Kirk A. F., 2000).
Table 3 : Radionuclides used in brain imaging
(Kirk A. F., 2000)
Nuclide Half-Life Type of Emission Representative   Tracers Measured Process
15 O 120 min positron [15 O]H2 O Blood flow
[15 O]CO Blood volume
[15 O]O2 Oxygen metabolism
11 C 20 min positron [11 C]Raclopride D2 dopamine receptors
[11 C]Flumazenil Benzodiazepine receptors
[11 C]Carfentanyl Mu opiate receptors
[11 C]Diprenorphine Opiate receptors (nonselective)
[11C]N-methylpiperidyl benzilate Muscarinic cholinergic receptors
[11 C]Methylphenidate Dopamine transporter (cocaine site)
[11 C]Dihydrotetrabanazine Monoamine vesicles
[11 C]Deprenyl Monoamine oxidase-B
[11 C]PMP Acetylcholinesterase
[11 C]Methionine Protein Synthesis
13 N 10 min positron [13 N]NH3 Blood flow
18 F 110 min positron [18 F]Fluorodeoxyglucose Glucose metabolism
[18 F]FluoroDOPA Dopamine synthesis
99m Tc 6 hr gamma [99m Tc]HMPAO Blood flow
[99m Tc]ECD Blood flow
13 hr gamma [123 I]Iodoamphetamine Blood flow
123 I 
[123 I]Iomazenil Benzodiazepine receptors
[123 I]IBZM D2 dopamine receptors
[123 I] beta-CIT Dopamine transporter (cocaine site)
[123 I] Iodobenzovesamicol Cholinergic vesicles
Technetium-99m ligands
Since the main radio pharmaceutical applied during this study is Technetium-99m, a closer look on the nature of this neuclotide would be worthy of interst. Technetium-99m has a photopeak of 140 KeV and a half-life of 6 hours. It is eluted from a Molybdenum-99 generator, and preparation of radiopharmaceuticals can be performed on-site from unlabeled kits, currently the two available prepartions are:
1.Technetium-99m-hexamethyl propylamine oxime (Tc-99m-HMPAO, Ceretec, Amersham Ltd., U.K.), now known as Tc-99m-exametazime, is a lipid soluble macrocyclic amine. Brain uptake of the radiotracer is rapid and reaches its maximum within 10 minutes post-injection time. Its first-pass extraction into the brain is less than that of I-123-IMP, and it underestimates rCBF. However, this underestimation can be corrected by accounting for the freely exchangeable component of HMPAO. The distribution of the radiotracer remains constant for many hours post-injection. Once it crosses the blood brain barrier, 99m-Tc-HMPAO is converted into a hydrophilic compound in the presence of intracellular glutathione and is trapped, with slow blood clearance.
Limitations:
-Perfusion defects are not seen as sharply as with I-123-IMP.
-Tc-99m-HMPAO may also mask ischemic lesions in subacute stroke because of hyperemia resulting in normal or increased tracer uptake.
- The radiopharmaceutical is chemically unstable in vitro by 30 minutes after preparation.
-Technetium-99m-bicisate (bicisate ethyl cysteinate dimer, Tc-99m-ECD, Neurolite, Dupont-Merck pharmaceutical Co.) another 99m-Tc-labeled ligand, has high initial cerebral extraction and very slow clearance from the brain. Brain uptake is rapid, and peak brain activity compares favorably with that of other brain perfusion agents, reaching 6% of the injected dose by 5 minutes after intravenous injection. Blood clearance is also rapid, resulting in high brain-to-soft-tissue activity ratios early after injection that improve with time (Handak C, 1995).
Radiolabeling with Tc-99m onsite followed by mandated quality control measures, such as chromatography, must be performed in an experienced nuclear medicine laboratory. These procedures are standard in all nuclear medicine services and are commonly performed for other organ systems. During the presented study.
Safety of Techniques of SPECT
With regard to studies in humans, SPECT methods give rise to similar safety concerns for radiation exposure and pharmacological toxicity of the injected radio pharmaceutical. The radiation exposures from typical SPECT scans are thought to bereasonably safe within the context of the present knowledge of radiation biology. limits of radiation exposure to various organs of the body and to the body as a whole has been established by several organizations, these limits are applied to research studies and are often lower than exposures in routine clinical nuclear medicine procedures. Although these limits are presently thought to provide adequate safety, the long-term biological effects of ionizing radiation are an area of active investigation and even controversy. The estimation of the dose received by the body depends on multiple factors including the amount of activity, the type of emission, and the residence time in the body (Hendren RL etal, 2000).
Fortunately, the pharmacological toxicity of radiopharmaceuticals is usually not a significant issue. The sensitivity of functional imaging is so high that minuscule mass doses of compound may be injected, although that small mass is associated with significant levels of radioactivity. For example, some radiopharmaceuticals are injected at mg/kg doses that are a millionfold lower than the minimal dose required to have any pharmacological effect. In such situations no pharmacological toxicity would be expected and only an unusual immunological adverse effect could be anticipated. Nevertheless, the potential pharmacological effects and toxicity of radiopharmaceuticals needs to be evaluated relative to previously established criteria for nonradioactive pharmaceuticals. The final formulation of any radiotracer must meet established guidelines for purity, sterility, and lack of pyrogenicity (Bremner JD, 1999).
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