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ISSN: 2155-9619
Journal of Nuclear Medicine & Radiation Therapy
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Radiological Engineering in Brain Dysfunction Imaging Processes and Neuro Informatics

Ayden Jacob1*Lorenzo Nourafchan2

1Research Scientist, Medical Physics Radiotherapy. Gray Institute for Radiation Oncology and Radiobiology University of Oxford, UK

2Lorenzo Nourafchan, MBA Technion, Israel Institute of Technology Technion City, Haifa 32000, Israel

*Corresponding Author:
Ayden Jacob, M.T.M., M.SC
Research Scientist, Medical Physics Radiotherapy
Gray Institute for Radiation Oncology and Radiobiology
University of Oxford, UK
Tel: 1-310-386-3174
E-mail: aydenjacob@berkeley.edu

Received date: June 09, 2013; Accepted date: July 15, 2013; Published date: July 20, 2013

Citation: Jacob A, Nourafchan L (2013) Radiological Engineering in Brain Dysfunction Imaging Processes and Neuro Informatics. J Nucl Med Radiat Ther 4: 157. doi:10.4172/2155-9619.1000157

Copyright: © 2013 Jacob A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The recent introduction of high-resolution molecular imaging technology is considered by many experts as a major breakthrough that will potentially lead to a revolutionary paradigm shift in health care and revolutionize clinical practice. This paper explores the challenges and strengths of the current major imaging modalities, as well as the biophysics engineering their repertoire of capabilities. Advancements in the mechanical aspects of both PET and SPECT imaging will advance molecular imaging diagnostic capabilities and have a direct impact on clinical medicine and biomedical research practice. A better understanding of the strengths and limitations of functional imaging modalities in the context of their particular hardware and software mechanics will shed light onto how we can advance their diagnostic capabilities on a biological level. Herein, this paper demonstrates the fundamental biomechanical differences between PET and SPECT imaging, and how these fundamental differences translate into clinically relevant data acquisition for brain disorders.

Keywords

Schizophrenia; Functional Imaging; PET

Functional Imaging Introduction

Historically, the ability to examine the internal workings of the human body was limited to the mere study of cadavers. Medical imaging technology has transformed various arenas of medicine over the last 30 years by providing scientists and physicians with a new mechanism by which they may look into a living organism [1]. Dramatic improvements in image resolution and the biophysics engineering varying imaging mechanisms have granted the medical community the unprecedented ability to view structural and functional anatomical features of the human body in precise and exquisite detail [2]. The introduction of high-resolution molecular imaging modalities, namely PET and SPECT, has the potential to revolutionize healthcare by improving the diagnostic and treatment capabilities in virtually every specialty [3]. The strengths and limitations of PET and SPECT are uniquely governed by interplay between molecular biology and the physics of the hardware and software of these imaging devices [4]. Hence, in order to properly compare these nuclear medicine techniques, it is imperative to thoroughly explore both the physics of these devices, as well as how they perform on a physiological level.

The Basic Physics of PET and SPECT

The intricate biophysics which governs PET and SPECT imaging modalities is responsible for the vast spectrum of both the advantages and disadvantages per technique [5], as well as each modality’s specific repertoire of capabilities. Prior to elucidating the translational differences between these two nuclear imaging techniques, it is important to address their fundamental mechanisms of function.

Positron emission tomography

Positron emission tomography (PET) is an analytical imaging technology [6] developed to use compounds labeled with positron emission radioisotopes as molecular probes to image and measure biochemical processes in vivo [7]. Positron emitters contain protonrich nuclei and attempt to stabilize themselves by gaining neutrons and ridding themselves of excess protons. This can be accomplished in one of two isobaric decay processes: positron emission or electron capture; the mass number in both the parent and daughter nuclei remains the same in either process [8]. The positron is an antimatter electron, having the same mass but a positive charge. A transmutation of elements occurs with the daughter nucleus having the same mass number but an atomic number reduced by one. Simultaneously, a neutrino is emitted, which escapes without interacting with its surrounding material. The positron, due to its small mass and positive charge, is highly active and travels a short distance, when it is then slowed down by the scattering processes in the electron clouds of the patient’s tissue. As the positron travels through the surrounding material, there is a continuous loss in its energy until it combines with an electron to- annihilate completely and emit a pair of 511 keV photons Figure 1). The emitted pair of 511 keV photons, the annihilation photons, have an energy equivalent to the combined rest mass of an electron and a positron [9], and they are emitted in opposite directions at approximately 180° from each other. The opposing PET detectors register the arrival of the annihilation photons as an event if they are detected within a narrow time frame [10], the timing window of the coincidence circuit, which is typically 3-15 nanoseconds in length. This requirement of detecting both the photons within a time window is the fundamental basis of coincidence detection and is termed electronic collimation [6]. The interaction is assumed to have taken place somewhere on the straight line drawn between the two detectors, the line being referred to as the line of response or the coincidence line [1]. Millions of recorded coincidence events, forming a large number of intersecting coincidence lines, provide information about the quantity and location of the positrons in the body. A PET scanner detects annihilation photons in coincidence, which results in a PET image. This image is a map of the distribution of annihilation points within the object (brain tissue) being scanned. The resulting map shows the tissues in which the molecular tracer has become concentrated, and can be interpreted by a nuclear medicine physician or radiologist in the context of the patient’s diagnosis and treatment plan [10]. For the analysis of PET images, the region of interest method has been widely used [11]. However, this method can be difficult to reproduce [12]. Therefore, interpretation of PET images using stereotactic brain coordinate systems, such as 3D stereotactic surface projections (3D-SSP) and statistical parametric mapping (SPM) would allow greater consistency in the reported results and make it easy to determine the spatial extent of the abnormal site on the brain map [11].

nuclear-medicine-basic-biophysics

Figure 1: An illustration of the basic biophysics which generates an image utilizing PET technology.

Single photon emission computed tomography

The biological components of SPECT imaging includes the injection of a gamma-emitting radioisotope into the bloodstream of the patient. A marker radioisotope attaches to a specific radioligand, which we contains a chemical affinity for the specific tissue of interest. This marriage allows the combination of ligand and radioisotope to be carried and attached to the specific area of interest in the target organ [13]. Subsequently, due to the gamma-emission of the isotope [8], the ligand concentration is visualized by a gamma-camera. SPECT scans have conventionally been viewed as slices in the transverse, sagittal, or coronal dimensions [4]. With the utilization of current medical technologies, SPECT images can give a three dimensional representation of the organ. SPECT acquisition is performed by rotating the gamma camera around the patient while acquiring data into the digital matrix of a computer at all angles which the target organ is imaged (Figure 2) [4]. The gamma camera contains a collimator, a crystal, and an array of photomultiplier tubes. The collimator design ensures that the camera records only the photons that come directly from the patient. The crystal is a material that emits flashes of visible light known as scintillations when high energy X-ray or γ-ray photons strike it. The light emitted by the scintillator hits the surface of the nearest photomultiplier tube. The photomultiplier tube converts a flash of light into an electrical signal that allows measurement of the energy of the incoming γ photon. A series of images are produced as the cameras move around the patient and record data from multiple angles. The more angles obtained by the camera, the better the resolution of the image. The total scan time is typically around 20 minutes. Patient motion and the amount and specific activity of the radiopharmaceutical affect image quality.

nuclear-medicine-next-viewing-angle

Figure 2: SPECT data is acquired in the following manner. For each view projected by the target, the computer sends a message to the gamma camera to step to the next viewing angle. Subsequently, the camera sends a message back to the computer that it is ready to acquire and the computer will acquire the projection image at that angle for that specific time.

The selection of the matrix size in the computer is a uniquely vital element in SPECT imaging. The computer divides the field of view of the gamma camera into pixels - square areas; the conventional sizes of the matrix for SPECT are 64×64 and 128×128 (rows and columns). The size of a pixel in a SPECT image can be calculated in millimeters by the following equation [4]:

D 5 FOV/(Z 3 n) ----> Where

FOV = the widest dimension of the computer image matrix

Z= zoom factor during image acquistion

n - number of pixels, either 64 or 128

D = size of the pixel

Thus, for example, if we are using a gamma camera which has an FOV of width of 400 millimeters, then the pixel size for a 128×128 matrix would be 3.125 mm; in comparison, a 64×64 matrix under these conditions would have a 6.25 mm pixel size. The matrix number is also important when taking into consideration the spatial resolution which the SPECT image can offer. Ideally, in order to reconstruct a precise image of the target tissue, the number of angular views over 360 degrees should minimally equal the projection image matrix size; meaning, for a 64×64 matrix there should be 64 views, and 128 views for a 128×128 matrix. As the number of views becomes less than the minimum (matrix number) artifacts may begin to appear in the images, thereby distorting the resolution.

The thorough understanding of the basic biological and physical mechanisms of these 2 nuclear medicine imaging technologies will allow us to further probe their strengths and limitations relative to one another, both from a biological and engineering perspective. Herein we will explore the advantages and disadvantages of both imaging modalities from both perspectives: that of cell biology and physics.

A Physics and Hardware Perspective: Comparing the Pros and Cons of PET and SPECT

Imaging sensitivity

The ability of PET to detect and record a higher percentage of the emitted events relative to SPECT is probably its most vital asset. This higher sensitivity of PET ranges about two to three orders of magnitude higher than SPECT, thus providing a much greater sensitivity. The limited sensitivity of SPECT is because in single photon imaging, physical collimators are needed in order to reject photons that aren’t within a small angular range; thus, collimators exhibit a very low percentage of detected to emitted photon [1]. However, since single photon emitters have a longer half-life, SPECT has the unique advantage of offering the possibility of a wider observational time window; this is significant because it would allow biomedical scientists to observe in vivo biological processes many hours following the administration of the labeled compound. PET contains an exclusive advantage over SPECT because it affords a much larger angle of acceptance at each detector position. The larger angle of acceptance is due to the nature of positron annihilation: 2 opposite annihilation photons are emitted by one event [1]. Consequently, the physical collimators become obsolete in PET since the collimation can be performed completely electronically instead. The implications of this biophysics advantage in terms of sensitivity for PET are fourfold:

✓ Improvements in sensitivity improve signal to noise ratios in the data acquired, and thereby correspond to an improved image.

✓ The increase in sensitivity affords PET the possibility to perform shorter scans.

✓ The capability to perform shorter scans allows for the feasibility of performing multiple scans of a patient at different fields of view in a pragmatic duration of time.

✓ An increased sensitivity yields an increased ability to obtain shorter frames and a higher number of frames, resulting in an improved ability to study dynamic biological events with increased temporal resolution.

Another important factor which assists in increasing sensitivity in PET is the short half-life of the radionuclides used in this method. Compared to SPECT imaging, the radiotracers with a short half-life can be injected in higher activities to the patient, while excluding any additional radiation risks. Overall, this means that PET has the advantage which generates an increased detectable radiation over a shorter amount of time [5].

Spatial and temporal resolution between PET and SPECT

The spatial resolution of these modalities is governed by different forces. For SPECT, the spatial resolution is only limited by technology, for example by the design of the collimator, whereas for PET the limitations are bound by 2 elements: A) positron range B) photon noncollinearity. A novel technological advancement which is afforded only to SPECT is the Pinhole technique. This has introduced the possibility of considerably enhancing image resolution, specifically in the context of animal imaging, to the submillimeter scale. The tradeoff for this resolution, though, is the sensitivity advantage which PET offers. It should also be noted that a disadvantage to the high-resolution capabilities of the pinhole approach is the task of calibrating the SPECT devices (Figure 3).

nuclear-medicine-design-U-SPECT-I

Figure 3: The design of U-SPECT-I contains a total of 75 gold pinhole apertures: 15 pinholes in each ring (left) with a total of nine rings (right).

Furthermore, in SPECT imaging, the image is generated from a point source which becomes degraded by a number of factors related to collimators and detectors within the gamma cameras; this is thus referred to as the collimator- detector response (CDR). Thus, CDR is a good measure for finite image resolution, and the incorporation of CDR modelling in reconstruction algorithms has been shown to result in improvements in spatial resolution, improved myocardial defect detection, and enhanced tumor detection. In comparison to the resolution in SPECT, 3 factors contribute to the degradation of resolution in PET [1]:

1. Detector related effects

2. Photon non-collinearity

3. Positron range

The positron range is particularly important. Emitted positions will travel a certain distance in the medium before they reach thermal energies and become annihilated; this distance is the positron range, which differs for various isotopes. How frequently an imaging instrument is capable of capturing a good quality image in the field of view is highly important. Due to the fact that the distribution of a radiopharmaceutical within the body via a bio-distribution process is what usually gives valuable information in detection and diagnoses, the ability to take a high quantity amount of acceptable images is imperative. It is important to note that PET has an intrinsic advantage over SPECT for temporal resolution because in SPECT it is necessary to perform complete angle tomography via camera rotations for each frame, which limits the speed at which each frame may be acquired.

Biological Comparisons: Brain PET and SPECT

Aside from the technological differences between these two imaging techniques, their abilities to be used in a clinical setting vary depending on the nature of the medical case. A particular organ which can be illustrating these differences in a clear manner, from a physiological perspective, is the brain. The introduction of brain imaging techniques to enhance our treatment of brain disorders has entered a new stage of efficacy unseen hitherto. Amen et al. discuss in a prospective case series how often SPECT adds relevant information for diagnosis or treatment beyond current standard assessment tools in complex psychiatric cases [14]. Charts of 109 evaluated outpatients from four psychiatrics clinics that routinely utilize SPECT imaging for complex cases were analyzed in two stages [15]. In stage one, psychiatrists reviewed detailed clinical histories, mental status exams, and the structured clinical interview for DSM-IV, but not the results of SPECT studies, assigned a diagnosis based on DSM-IV criteria, and then developed a thorough treatment plan. In stage two, evaluators were given access to the SPECT studies for each patient. The addition of SPECT modified the diagnosis or treatment plan in 78.9% (n=86; rated level 2 or 3 change) of cases. The most clinically significant changes were undetected brain trauma (22.9%), toxicity patterns (22.9%) and the need for a structural imaging study (9.2%). Specific functional abnormalities were seen as follows that potentially could impact treatment: temporal lobe dysfunction (66.1%) and prefrontal hypoperfusion (47.7%) [14]. This study illustrated the significant implications of SPECT in the clinical setting, and how it has the potential to add clinically meaningful information to enhance patient care beyond current assessment tools in complex or treatment resistant cases. In order to fully compare and contrast the abilities of PET and SPECT from a biological perspective (which is clearly a manifestation of the engineering differences between both techniques) we will explore how they are used in 2 different neurological disorders: schizophrenia and Alzheimer’s disease.

Schizophrenic data acquisition by PET and SPECT

Schizophrenia is a major mental disorder characterized by functional impairment and the presentation, persistence, and severity of symptoms. Characterized as a brain disorder, the etiology of schizophrenia remains elusive. Nevertheless, neuroimaging modalities have advanced the understanding of the neuroscientific community in regard to the structural and functional abnormalities inherent in the brains of schizophrenics. A number of PET studies have been performed to determine whether left hemispheric dysfunction is also a finding associated with schizophrenia [15]. Several studies have found that, at rest, patients with schizophrenia have increased perfusion and metabolism in the left hemispheric cerebral cortex relative to the right [16]. These studies also suggest that the severity of the symptoms found in schizophrenics is correlated with the degree of hyperactivation of the left hemisphere, and specifically not with the degree of hypofrontality. Sheppard et al. reports a finding which agrees with this, in that increased blood flow to the left hemisphere was found using 15O H2O PET [17]. In further studies, Early et al. found increased cerebral blood flow in the left globus pallidus in patients with schizophrenics [18]. In supporting the concept of disrupted brain lateralization in schizophrenics, Laasko et al. conducted a study with PET imaging which illustrated that patients do lack asymmetry in caudate dopamine transporter binding compared to controls [19]. The utilization of PET studies in schizophrenics is not exclusive to metabolic and blood flow studies. PET imaging of the dopmaninergic system in patients has been vital since the dopaminergic system which has been demonstrated to be involved in the pathophysiology of this disorder is also the site of action for neuroleptic drugs. These drugs are an important therapeautic modality in these patients. Kessler report that when using 18F Fallypride in schizophrenic patients the subjects demonstrated an increase in dopamine D2 receptor levels in the substantia nigra and a significant correlation between symptoms of disorganized thinking and non paranoid delusions with binding in the right temporal cortex. In comparison, Brain SPECT most frequently shows hypofrontality, especially during a specific task; perfusional changes in the basal ganglia, possibly related to the use of neuroleptic drugs [20]; and temporal lobe hypoperfusion, usually on the left side and frequently associated with ipsilateral frontal lobe hypoperfusion. Injection of perfusion agents at the time of visual or auditory hallucinations shows hyperperfusion of the primary visual or auditory cortex, respectively (Figures 4 and 5).

nuclear-medicine-non-schizophrenic-twin

Figure 4: The image above shows PET scan images from a set of monozygotic twin.The ones on the right is from the brain of a schizophrenic twin, the ones on the left from non-schizophrenic twin.

nuclear-medicine-Further-images-illustrating

Figure 5: Further images illustrating the differences shown via PET imaging in schizophrenic brains.

In comparison, brain SPECT in schizophrenics shows hypofrontality, especially during a specific task; perfusion changes in the basal ganglia, possibly related to the use of neuroleptic drugs; and temporal lobe hypoperfusion, usually on the left side and frequently associated with ipsilateral frontal lobe hypoperfusion. Injection of perfusion agents at the time of visual or auditory hallucinations shows hyperperfusion of the primary visual or auditory cortex, respectively (Figure 6).

nuclear-medicine-dysfunctional-areas-schizophrenic

Figure 6: Images illustrate the dysfunctional areas of schizophrenic patients’ brains.

PET and SPECT in alzheimer’s disease

Brain SPECT of AD patients typically shows bilateral hypoperfusion of the parietal and posterior temporal lobes. The perfusion defects are frequently symmetric but not necessarily of the same magnitude and severity. Some authors consider hypoperfusion of the posterior association cortices as specific evidence for AD diagnosis. According to Dewan, The sensitivity and specificity of brain SPECT for the diagnosis of AD are 86% and 96%, respectively, with a diagnostic confidence of 98%. Labeling of the amyloid and plaques for a more specific diagnosis of AD has been attempted. With monoclonal antibody for Aβ protein 1-28 labeled with 99mTc, uptake of the tracer in AD patients could not be shown with brain SPECT. More recently, rhenium complexes, analogs of the potential imaging agent 99mTc, were shown to bind to Aβ amyloid fibrils in vitro and to stain amyloid plaques and vascular amyloid in postmortem brain sections of AD patients [20].

Severe AD patients present with these regions being significantly augmented in their hypometabolic state. An additional role which PET imaging may play in AD is its ability to measure changes in neurotransmitter systems that might be affected by the disease. Shinotoh et al. showed significant decreases in acetylcholinesterase activity in the neocortex, hippocampus, and amygdala of all patients with AD, suggesting a loss of cholinergic innervations in the basal forebrain. The temporal and parietal cortices were the most affected, although reductions were relatively uniform in the cerebral neocortex. PET can also play an important role in the evaluation of varying therapeutic interventions for the disease. The development of different neuropharmacological interventions for AD provides an important area for PET imaging as it is capable of tracing these interventional methods with high accuracy.

Conclusion

Radiological instrumentation has been widely used in the study of various central nervous system (CNS) disorders, oncology, psychiatric disease, and infectious disease. Functional imaging has advanced our abilities to both treat and diagnose with accuracy various disorders. PET and SPECT imaging technologies will continue to play a critical role in both clinical and research applications with regard to improving illness diagnostics and treatments. The potential to improve the capabilities of both PET and SPECT is exponential, and we are already seeing the field of radiology using the hybridization of PET and SPECT / CT imaging to accomplish newer heights. What is of utmost interest is the interrelationship between the mechanisms of these nuclear imaging technologies from a physics perspective with the corresponding biological capabilities. There is an intrinsic correlation, as illustrated in this paper, which exists between the technological aspects of these imaging modalities and their biological repertoire. As the technologies which engineer these imaging modalities continue to grow alongside the exponential growth in our understanding of cell biology, oncology and disease, side by side these two dynamics will revolutionize the way in which we can detect and treat illness across the medical field.

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