Neuroimaging Techniques And Their Relative Advantages And Disadvantages
Because neuronal pathologies cause only minor morphological changes, molecular imaging techniques are required to study brain diseases. The advancement of instrumentation and the development of molecular probes that specifically bind biochemical markers have revolutionized the possibilities for gaining insight into the human brain organization and visualizing structure-function and brain-behavior relationships. The review discusses functional brain imaging techniques’ evolution and current applications, focusing on psychiatric applications. Following a historical overview of the development of functional imaging, the principles and applications of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), two critical molecular imaging techniques that have revolutionized the ability to image molecular processes in the brain, are depicted. We conclude that combining PET and fMRI in hybrid PET/MRI scanners increases the importance of both modalities in neurology and psychiatry research and may pave the way for a new area of personalized medicine.
Diagnostic Imaging Fundamentals
Diagnostic imaging has traditionally been limited to the visualization of morphological structure aberrations. Neurological pathologies, however, rarely correlate significantly to macroscopically or microscopically visible changes in cell morphology. Because the contrast obtained for pathophysiological abnormality differentiation defines the performance of an imaging modality, susceptible methods for imaging alterations in brain functioning had to be developed. Generally, any radiation passing through the human body can be a signal source for diagnostic imaging. As a result, the variety of imaging modalities reflects the variety of capabilities of the various types of radiation used in clinical practice. The purpose of this brief review is to introduce the principles of the two most common and promising molecular imaging techniques for investigating changes in brain functioning: positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), as well as their limitations and prospects.
Computer tomography (CT), magnetic resonance imaging (MRI), PET, and ultrasound (US) can all be traced back to the German physicist Wilhelm Conrad Röntgen. Röntgen discovered that X-rays could penetrate solid matter in 1895. He also discovered that the attenuation of X-rays is affected by the properties of the object penetrated. When he later deduced the X-ray imaging technique, a great invention occurred: the visualization of structures within the body without surgery!
Since then, X-ray imaging has been shown to produce images with high anatomic resolution. CT, the corresponding tomographic modality, has further improved X-ray imaging, and billions of scans have been performed. CT imaging’s unique strength is its high anatomic resolution. The imaging is simple as long as bony or calcified tissue is investigated. The differences in X-ray attenuation in soft tissues are marginal, and contrast agents are used to providing available high-quality CT images in the major areas of the body, namely the vascular system, lungs, and kidneys. Because X-ray absorbency is almost directly proportional to the third power of an element’s atomic number, the inclusion of elements with high atomic numbers is critical for the efficacy of CT contrast agents. Unfortunately, most elements with a high atomic number are not biocompatible, and iodine-containing contrast agents predominate in clinical use. To achieve sufficient contrast, high doses of up to 42 g of contrast agent are required (Mortelé et al., 2005). As a result, the susceptible methods PET and MRI are more promising for brain imaging.
Molecular Imaging Fundamentals
The assessment of cellular functions and the visualization of metabolic processes are required tasks in brain imaging. Changes in essential cellular structures provide testimony about a cell’s health status long before macroscopically or microscopically visible changes in cell morphology occur. These delicate phenomena can only be studied using tracers/imaging agents. In the mildest cases, only a small number of receptors are available to trigger the specific accumulation of the imaging agent (Catana et al., 2012).
In general, imaging agents are classified into two types: passive agents that modulate an external signal, such as in CT and US, and probes that either produce a signal autonomously, such as radiotracers and bioluminescent dyes or transform an external signal, such as with MRI contrast agents or fluorescent probes. Because passive contrast agents only enhance the body’s signal, relatively high doses are required to distinguish their endogenous contrast. While extremely high concentrations of CT contrast agents are required, the signal of radiolabeled tracers can be measured with extraordinary sensitivity. Because the radioactive signal is emitted solely by the endogenous tracer, it can be definitively linked to the imaging agent. For molecular imaging, the short-lived positron emitters 11C and 18F are ideal. When these radioisotopes’ positrons collide with electrons, they produce gamma rays. These gamma rays enter the body and are detected by the PET scanner. The radioisotope is linked to a tracer molecule, which causes specificity by binding neuroreceptors or tracking brain hemodynamics. The assessment of neuroreceptor spatial and temporal activity virtually depicts brain functions and physiologic activities due to their pivotal role in neurotransmission and neuromodulation. As a result, PET tracers are the prototype imaging agents for functional brain imaging, and PET studies have proven to be critical for understanding and treating neurologic and psychiatric disorders.
PET Tracer Applications
Selective radioligands are frequently derived from psychoactive drugs, and their specificity is gained by mimicking neurotransmitters. Visualizing their specific binding to a target, such as a receptor, a transporter, or an enzyme, allows for the detection of various pathologic conditions. PET tracers that target receptors, proteins or neurotransmitters, or glucose consumption will be discussed further below.
Typical PET radiotracers include ligands for quantitative imaging of specific neuroreceptor subtypes, such as [11C]raclopride and [18F]fallypride for dopamine D2/D3 receptors in the differential diagnosis of movement disorders and for assessing receptor occupancy by neuroleptic drugs in schizophrenia (Siessmeier et al., 2005). Tracers that bind arterial nicotinic acetylcholine receptors and acetylcholinesterase, such as [18F]-2-fluoro-A85380, have been developed as biomarkers for cognitive and memory impairment, Parkinson’s disease, and multiple system atrophy (Bucerius et al., 2012). Serotonin (5-hydroxytryptamine, 5-HT) receptors and the 5-HT transporter have been shown to bind [11C]DASB, [11C]McN 5652, and [18F]FMe-McN5652. These transporters are dysregulated in affective disorders and will be helpful to structures for assessing antidepressant activity. Tracers such as [11C]McN5652 can assess lower 5-HT transporter binding in the midbrain and amygdala of patients with major depressive disorder (Parsey et al., 2006). Furthermore, this class of tracers can detect abnormalities in serotonin transporter and dopamine transporter binding due to neurotransmitter system abnormalities in autistic people’s brains (Hesse et al., 2012). Because opioid systems play an essential role in neuropathic pain (Maarrawi et al., 2013), PET imaging of opioid receptors aids in the understanding of the molecular and cellular mechanisms of pain generation and aids in the use and advancement of pain medication, spinal cord stimulation, and spinal infusion pumps. The opioid receptor binding tracer [11C]diprenorphine reveals decreased opioid receptor densities in patients with neuropathic pain. [11C]flumazenil, another tracer that binds to GABA receptors, has been used to study increased cortical excitability in focal epilepsy (Szelies et al., 2002).
The general search for Alzheimer’s disease drug treatments has prompted tracers to provide an intimate link to the diagnostics of this potential blockbuster market. Radiotracers that bind the plaque-forming proteins beta-amyloid and tau-protein are a simple treatment for this disease. As a result, several different tracers of the Pittsburgh compound, such as florbetaben and flutemetamol, have recently been approved for detecting Alzheimer’s disease-related protein plaques and the associated potential for disease staging (Nordberg et al., 2010). Interestingly, a radiolabeled derivative of the dye thioflavin T has been shown to bind amyloid protein deposits in the brains of Alzheimer’s disease patients (Kreisl et al., 2013). Other PET tracers for neuroimaging include 6-[18F]fluoro-L-DOPA, which allows imaging of presynaptic dopamine and can be used to determine dopamine turnover in Parkinson’s patients (Sossi et al., 2002).
The study of tracers that map regional differences in blood flow represents a novel approach to visualizing pathological changes and gaining information about brain function. The gold standard for this purpose is 15O-H2O (Grüner et al., 2012). This is supplemented by 2-[18F]fluoro-2-deoxy-D-glucose (FDG), the modern molecular imaging workhorse (de Leon et al., 2001). Furthermore, by providing perfusion data, FDG enables conclusions about neuronal activity based on energy metabolism. As a result of phosphorylation by the enzyme hexokinase, FDG is taken up by glucose transporters and trapped inside the cell as 6-phosphate. Because the progression of Alzheimer’s disease is accompanied by decreased brain metabolism, FDG-PET can be used to diagnose it in its early stages and distinguish it from other dementia processes (Mosconi et al., 2008). Because of the short half-lives of 11C (20 min) and 18F (108 min), tiny amounts of the tracer are required to achieve the desired signal intensity, and the total radiation exposure is comparable to that obtained by whole-body CT scans. The radiotracers’ short half-lives necessitate on-demand synthesis, ideally with a cyclotron close to the PET imaging facility. The effective doses are constantly reduced by tracers with short physical and biological half-lives, minimizing the amount of activity injected and continuously improving the sensitivity of PET scanners.
Magnetic Resonance Imaging Principles
While PET imaging can assess neurotransmitter concentrations in the brain, it cannot reveal micro- and macroscopic structural abnormalities in the white and gray matter. Furthermore, PET cannot detect rapid changes in brain activation. Furthermore, despite the enormous accomplishments of PET imaging, there is always concern about the radiation risks associated with this modality. Magnetic resonance spectroscopy (MRS) is an alternative because it detects endogenous compounds involved in brain biochemistry. The chemical structure of protons determines their resonance frequency, and MRS measures the concentration of marker molecules such as methionine or lipids (van der Graaf, 2010). Again, the imaging modality’s performance is limited by contrast-enhancing molecules: the concentrations of significant compounds in the brain, such as neurotransmitters, are far below the detection limit.
In contrast, the majority of the signal in magnetic resonance imaging comes from free water, which is abundant. The significant differences ranging from 99 percent in the CSF to about 80 percent in gray matter to 70 percent in white matter are the foundation for the excellent soft tissue contrast seen in brain MRI images (Neeb et al., 2006). MRI has become the clinically preferred method of imaging soft tissues, such as the brain, due to its high spatial resolution and ability to detect changes in brain morphology without tracers.
While MRI can be performed without using contrast agents on the patient, contrast agents must be used for diagnostic purposes, such as early detection of strokes. At first glance, the sensitivity of MRI appears to be similar to that of CT, and high contrast agent concentrations should be required. However, the contrast agents used in CT and MRI are fundamentally different. The current MRI contrast agents (primarily gadolinium complexes that cause T1-shortening) work indirectly by influencing the relaxation of water molecules in their coordination sphere. Many water molecules are relaxed within one scan due to the high exchange rate of water in the sphere of gadolinium complexes (typically 2–3 s). As a result, the effect appears to be amplified several thousand times. As a result, a wide range of MRI contrast agents has been developed (van der Graaf, 2010).
Following the description of evidence for a link between nephrogenic systemic fibrosis (NFS) and gadolinium contrast agents (Cowper et al., 2000), the risk of NSF has become an essential issue in radiology. There is widespread agreement that the residual risk posed by gadolinium contrast agents exists only in patients with impaired kidney function. Even though NFS was associated with a negligible number of patients diagnosed with gadolinium contrast agents, their link to the risk of NSF has had a significant impact on the development of MRI contrast agents, and the FDA’s approval of novel MRI contrast agents has since collapsed. This is an untenable situation: MRI contrast agents provide invaluable benefits to today’s health care due to their essential role in patient care. A discussion of the obligation to strike a balance between the benefits of novel contrast agents and the risk of their widespread application (please keep in mind that previously approved contrast agents are still used out of necessity!) is beyond the scope of this article.
Magnetic Resonance Imaging (fMRI)
Given the difficulties described in developing specific MRI contrast agents, fMRI was eventually developed. As previously stated, the success of MRI is due in large part to the fact that an endogenous contrast agent is detected with high sensitivity. fMRI provides additional characteristics that contribute to this outstanding performance. The iron in deoxyhemoglobin acts as a paramagnetic contrast agent in the preferred application of the fMRI technique, similar to gadolinium in common MRI contrast agents. Adult blood contains approximately 750 g of hemoglobin, which is difficult to achieve with endogenous contrast agents. Because it contains four unpaired electrons, iron in deoxygenated hemoglobin is paramagnetic. Hemoglobin loses its contrast-enhancing properties when oxidized. As a result, the signal intensity is defined by the deoxyhemoglobin/oxyhemoglobin ratio. The so-called blood oxygen level-dependent (BOLD) effect can be traced back to neural activity (rather than neuron spiking), most likely due to increased glutamate uptake in astrocytes (Logothetis et al., 2001; Raichle, 2001).
Several fundamental characteristics contribute to fMRI’s unrivaled performance for neurological applications:
- Its clinical convenience—fMRI is performed with standard MRI scanners and does not require the injection of contrast agents. It is achieved by measuring an endogenous contrast agent at high concentrations in the brain.
- The fact that contrast agent is functional and responsive to stimuli.
- The fact that fMRI is not invasive.
Neuroimaging Techniques And Their Relative Advantages And Disadvantages
Describe various neuroimaging techniques and their relative advantages and disadvantages.
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