Educational Objectives:
1) Understand the basic techniques of Single Photon Emission Computerized Tomography (SPECT) and Positron Emission Tomography (PET)
2) Identify prominent functional imaging research findings in major neuropsychiatric disorders.

Introduction:
 The new tools of functional imaging offer psychiatrists a broad range of investigative techniques for exploring the brain’s structure and function.  Positron emission tomography (PET) and single emission computed tomography (SPECT) are constantly evolving imaging techniques that allow for in vivo assessment of brain physiology and biochemistry including cerebral blood flow (CBF), cerebral glucose metabolism (LCMRGIc), cerebral oxygen metabolism (CMRO2), cerebral oxygen extraction, and blood-brain barrier permeability ¹. The basic principle behind both PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) is that blood supply and glucose metabolism within a brain region are largely coupled ². As neuronal activity increases, there is an associated increase in blood flow, which supports the oxygen and glucose consumption required. Nevertheless, in certain situations such as intense sensory stimulation or a stroke, blood flow and glucose metabolism can be uncoupled from activity ³. In addition to imaging non-specific markers of brain activity such as blood flow or metabolism, by tagging specific ligands, SPECT and PET allow imaging of neurochemical systems such as dopamine, opiates and acetylcholine receptors ⁴. PET radiotracers have also been made by attaching a radio-labelled carbon atom to various neuroactive compounds such as deprenyl and fluoxetine. Both PET and SPECT have  provided crucial information about the pathophysiology of mental illnesses, and basic cognitive neuroscience. They are also assuming an increasing importance in clinical settings, although this is still limited.

Techniques:
  SPECT and  PET are used in neuropsychiatry to determine the three-dimensional distribution of a radiotracer within the human brain. They both involve the peripheral injection of a radiotracer into a vein, which then travels to the brain and deposits into neurons and glia ⁵. Different radiotracers bind to brain structures and have different half-lives which determine when the image can be acquired. The radiotracer can be a radioactive element (e.g., 99Tcm-HexaMethyl Propylene Amine Oxide (HMPAO) , Xe-133) or as complicated as a labeled neurotransmitter antagonist (e.g., I-123-3 QNB).

The radiopharmaceuticals for SPECT are distinguished from those used in PET in that SPECT tracers emit a single gamma ray, while PET radiopharmaceuticals emit positrons. Positrons are highly unstable particles which travel a short distance and then collide with an electron. This reaction releases two gamma rays simultaneously in exactly opposite directions. This distinction in gamma ray emission leads to the distinction in instrumentation between SPECT and PET. Single-photon tomographs are designed to detect single photons (gamma rays) and to determine their point of origin based solely on their trajectory. Thus the resolution of SPECT is about 8 - 10 mm, which is adequate for most structural distinctions. PET makes valuable use of the dual photon emissions to determine the exact point of origin based on the trajectories of both gamma rays and the timing with which the two photons arrive at the surface of the tomograph’s detector (called coincidence detection) ⁶.  This gives PET higher image resolution, which in some recent scanners is around 4 mm (See figure 1). This also makes PET much more expensive than SPECT, because it requires a cyclotron for on sight production of positron-emitting tracers and a technical crew’s support.

    Single Photon Emission Computed Tomography  has two major strengths for clinical use in neuropsychiatry. The first is its availability and affordability. The second is its capacity to provide three-dimensional measurements of regional cerebral blood flow long after the injection of the radiotracer. With a long-half life and a relatively short time to deposit within active brain regions (2-5 min), subjects can be injected away from the nuclear medicine suite and outside the actual camera. If necessary, tranquilizing medications can then be given to sedate the patient for scanning which will not affect the actual image acquired, as the perfusion pattern has already been deposited.  This is particularly helpful for studying diseases such as epilepsy or mania, or research done while injecting a tracer in a naturalistic setting. For example using this technique, Starkstein et al. documented a relative right temporal hypoactivity in manic subjects who were injected away from the scanner and then sedated for image acquisition ^7,8. In another example, at MUSC our lab has used a differential time in injecting the radiotracer and imaging the brain, investigating the effect of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy individuals and in depressed subjects ^9,10.

    Positron Emission Tomography, like SPECT,  has also two major groups of applications- the assessment of metabolic activity by measuring blood flow (O-15 PET) or by tagging glucose with a radiotracer (typically 18-fluoro deoxy glucose -FDG) and calculating how much of this tracer deposits in the brain.  PET O15 imaging takes approximately 1-5 minutes, with FDG requiring on the order of 20-30 minutes. In early studies of major mental illnesses, investigators focused on the measurement on cerebral metabolism at rest and used deoxyglucose. PET can also be used in measuring neurotransmitter function by using specific pharmacological ligands.

Clinical Applications:
  Dementia: The strongest clinical application of SPECT to date has been in the study of Alzheimer’s disease (AD). Both SPECT and FDG-PET studies in AD have shown decreased hippocampal and temporoparietal cerebral metabolism ¹¹. This temporo-parietal hypoactivity is sometimes seen early after the appearance of significant cognitive, visual-spatial, or language symptoms ¹². Numerous studies have correlated FDG-PET metabolic abnormalities with cognitive and behavioral changes. Other studies have explored  FDG-PET changes as a diagnostic tool in predicting familial AD ^13-15. However those sensitive findings in AD are unfortunately not specific. Unfortunately, there is overlap with other dementing processes. Vascular dementia, Parkinson’s disease , and Creutzfeldt-Jakob disease can have similar and / or overlapping abnormalities ¹⁶.

****Insert Figure 2 Here, PET in AD****

 Hence, SPECT and  PET techniques could potentially find particular clinical usefulness in differentiating dementia syndromes and in characterizing metabolic disturbances in early stages of Alzheimer’s disease, or even before symptoms become manifest ¹⁵. There are many putative anti-Alzheimer’s agents on the market or in pre-clinical trials. If they are shown to be effective in slowing the progression of AD in those at risk, a non-invasive functional image may be the only method of assessing the effectiveness of the drug. Also, if differences in flow patterns are clearly present in depression and Alzheimer’s disease, the observation of blood flow could be very useful for the differential diagnosis of dementia versus depression in the elderly, one of the most difficult of the differential diagnoses that psychiatrists must make ¹⁷.

    Mood disorders: SPECT and PET studies in patients with mood disorders have rather consistently found reduced global cerebral blood flow or metabolism, particularly in unipolar patients, and possibly reduced basal ganglia flow/metabolism in both bipolar and unipolar populations ¹⁸. Additionally, most recent works, but not all, have reported decreased activity in the prefrontal cortex in depression, usually worse on the left (for further reading see 19,20). Several studies have also found that the more depressed a subject is, the less their prefrontal activity. There has been some progress in studying whether an initial functional scan might be able to predict who will respond to treatment, or even tease out who is likely to respond to a certain type of treatment. For example, several studies have found that increased activity in the cingulate gyrus at rest, predicts who will respond to sleep deprivation ^21-23 or treatment with fluoxetine ²⁴. Additionally, treatment studies have also showed correlation with symptomatic improvement, with a reversal of baseline cingulate hypermetabolism or prefrontal hypometabolism with response ²⁴. However, there is a large clinical heterogeneity within the umbrella diagnoses of depression and to date the findings of decreased prefrontal activity or blunted limbic response do not appear to be specific or sensitive enough to use in a clinical setting. There is a great deal of research in this area however and in the near future researchers may discover a functional scan within the area of mood dysregulation that will either improve diagnosis, guide treatment, or both.
 

    Schizophrenia: Patterns of relative hypofrontality were observed in patients with schizophrenia and those with bipolar disorder, although, as in rCBF, this finding has not been consistently replicated and there appears to be a large heterogeneity within this diagnosis ²⁵.There was a great deal of interest in initial PET activation studies which demonstrated that patients with schizophrenia did not show prefrontal blood flow changes during the Wisconsin Card Sorting Task ²⁶. Although this deficit is disease specific and not seen in other disorders like depression ²⁷, the blunted activation is not limited to the prefrontal cortex, or even tasks which require attentional components. For example, all activation studies in schizophrenia have shown a disordered blood flow response, even using thumb movement or staring at a flickering light ^28,29. Thus, coupling imaging with activation studies in schizophrenia has not proven to be useful in a clinical setting for diagnosis, although the research is likely to enlighten underlying disease mechanisms. For example, in large group studies, using both deoxyglucose and 15O-labeled water, investigators have found a relative increase in metabolic activity in subcortical regions in schizophrenia , particularly in basal ganglia ³⁰. This pattern of hypofrontality coupled with increase in subcortical regions in schizophrenia may be consistent with the model for the simultaneous generation of positive and negative symptoms. Thus, functional imaging in schizophrenia, because of the poor sensitivity and specificity of the findings, have filed to translate into clinically relevant techniques.

    Anxiety disorders:  PET has also been used to study anxiety disorders, again, more in research than a clinical setting. A specific area of hyperactivity has been identified in the right parahippocampal gyrus, reflecting susceptibility to lactate -induced panic attacks ^31-33. Because this is an important region for encoding memory , this finding is particularly interesting, in that the experience of panic either may be triggered by old anxiety - producing memories or may involve the encoding of new memories that may later trigger subsequent attacks. This locus is thus consistent with the behavioral phenomenon recognized as stimulus generalization. In General Anxiety Disorder (GAD), an increase in glucose metabolism in the thalamus was found and a relative decrease in the visual cortex (left >right) after treatment with benzodiazepine ³⁴.
  In obsessive-compulsive disorder, patterns of increased metabolic activity have been observed in the frontal lobes (mainly right orbito-frontal) and basal ganglia ^35-37.  Studies looking at treatment response indicate that increased caudate and orbitofrontal activity is state related and resolves with symptom resolution irrespective of the treatment method ³⁶. Again, the localization of increased activity is consistent with current knowledge concerning the function of the frontal lobes, particularly orbitofrontal cortex. Patients with obsessive-compulsive disorder have a tendency to be over-abstract and over-intellectualize, to worry and plan excessively for the future, and to have compulsions. These findings complement findings in SPECT studies and support a cortico-striatal-thalamic-cortical loop theory in the pathology of OCD ³⁸. Again, these exciting research findings do not as yet have a clinical application. Functional imaging in an OCD patient is not to the point where it can help confirm the diagnosis or predict treatment response, although many researchers are working in this area attempting to build on these findings ³⁹.

    Eating and Personality disorders: The cerebral metabolic rate for glucose (CMRGlu) on FDG-PET images in bulimic patients showed a loss of  right greater then left cortical asymmetry compared to normals ⁴⁰. The limited studies and lack of replication limit at this point any firm extrapolations concerning this disorder. Similar to eating disorders, there is an emerging preliminary literature on functional imaging in personality disorders.  In schizotypal personality disorder abnormalities have been found in frontal lobes, cingulate, striatum and temporal lobes. Another finding emerging from functional imaging of personality is the association of decreased frontal activity with increased aggression ⁴¹. Borderline personality disorder and antisocial personality disorder are also being investigated. The difficulty in clinical diagnoses and correlation with specific behaviors and symptoms is a crucial step in establishing some commonality between the different results. Finally recent preliminary PET studies suggest that there may be links between stable personality traits (harm avoidance, novelty seeking, and obsessionality) in the normal population and regional brain function ⁴².

    Epilepsy:  One of the common features of epilepsy is a change in glucose metabolism at the site of seizure activity during (ictal) and between (interictal) seizures.  PET and SPECT can both used to image abnormalities in the epileptic brain ⁴³. SPECT is easier to systematically administer during seizures, with the radiotracer sitting on the epilepsy floor while subjects are being monitored, and injected as soon as a seizure starts. Both PET and SPECT can be used to image interictal abnormalities. Literature review suggests that of interictal techniques, PET has the highest diagnostic sensitivity in temporal lobe epilepsy (TLE) while SPECT has the highest sensitivity in extratemporal epilepsy (ETE). This is achieved by ictal imaging with SPECT . One reason for the wide discrepancy of results in TLE and ETE might be the differing pathologic substrates. Imaging findings associated with mesial temporal sclerosis (MTS), developmental lesion or tumor as the underlying abnormality associated with epilepsy supports this explanation. PET is more sensitive to MTS than SPECT . On the other hand, in developmental lesions the two techniques are equally sensitive, while  PET is superior in tumors. Interestingly, using PET in tumor patients to measure both blood flow and metabolism, has revealed physiological uncoupling. Preliminary evidence also indicates that the distribution of hyperperfusion on ictal SPECT can differentiate subtypes of TLE. Combining the results of refined imaging techniques holds great promise in epilepsy localization and diagnosis. If one suspects that a psychiatric patient has an underlying diagnosis of epilepsy, then an ictal SPECT scan may be of some use, especially if the tracer can be injected during the period of abnormal behavior.

****Insert Figure 4 Here, PET in Epilepsy****

Substance Abuse
 Functional imaging studies in patients who have abused alcohol or cocaine have revealed a host of information about the brain effects of substances of abuse. PET studies of the acute and long-term effects of alcohol use consistently reveal that alcohol is a global brain depressant ⁴⁴, and that the long-term effects of alcohol use can take several weeks of abstinence before resolving ⁴⁵. In contrast, acute cocaine administration causes marked increases in regional blood flow ⁴⁶, and chronic cocaine use is associated with a particular PET and SPECT finding of patchy hypoperfusion, which resolves with abstinence ^47,48. Other exciting research using imaging and substance abuse involves activation studies examining the neural substrate of craving^46,49, and investigating whether different use patterns or detoxification medications differentially affect brain activity ⁵⁰.  As in many other areas of psychiatry, these exciting research findings have not yet translated into clinically useful applications in individual patients.

Activation Studies:
 The principle behind activation studies is to control for a variable stimulus across two sets of images - have someone perform a task while imaging and then in the next images have them perform exactly everything the same, except for the behavior that you are studying. The change in conditions from baseline will generate regional changes in neuronal activity, and therefore in cerebral blood flow or glucose metabolism.  Initial activation studies used visual, motor and cognitive tasks ^51,52. Now that some groups have achieved virtual reality setups in the imaging suite, there is really no limit to what you can begin to image with this method.  With this technique one can literally begin to map the mind. Of particular interest to psychiatrists are studies in healthy adults who are experiencing different emotional states ^33,53,54 or are viewing faces with different emotional content ^55-57 (see figure 5).

Conclusion:
 The complex interaction of structural and functional systems in the central nervous system makes it unlikely that single sites are responsible for such disorders, or even that single systems are abnormal in isolation. The brain processes and regions that together may be associated with a particular cognitive process or behavior may be seen as a functional unit or neural circuit. The same function may be performed by different combinations of neural circuits at different times and under different conditions. At present, brain imaging provides a modest amount of information that is useful in differential diagnosis, as in distinctions between depression and dementia. PET is being used clinically in the evaluation of patients with dementia, brain tumors , medically refractory partial complex seizures , cerebrovascular disease, and various psychiatric disorders. As PET and SPECT applications becomes more widespread , it may be possible to use the results to physiologically characterize, classify, and diagnose various neurological and psychiatric disorders, and possibly predict therapeutic effects and outcome.

References:
 

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