SPECT is a functional imaging modality that is used to determine brain blood flow based on the distribution of a radiopharmaceutical agent in the brain. A radiotracer is T A B L E 6 – 1 . Brain imaging techniques
Method
What is usually
measured Advantages
Approximate cost per study ($)
Time to complete study
(minutes) Limitations/issues SPECT Blood flow Widely available; relatively
inexpensive
800 ≤30,
depending on tracer
Requires ionizing radiation; resolution limited
PET Metabolism or blood flow
Superior to SPECT for anatomical resolution; can measure metabolism
2,000 30–40 for
FDG;
5 for 15O
Requires ionizing radiation; not widely available
fMRI Blood flow No ionizing radiation; good anatomical resolution; repeat studies can be done quickly
Not applicable for TBI
Generally 45–60
Currently research-only for TBI; cognitive activation task must be used
MRS Change in brain metabolites
No ionizing radiation;
noninvasive neurochemical measurements
Not applicable for TBI
Generally 45–60
Currently research-only for TBI
Note. FDG, fluorodeoxyglucose; fMRI, functional magnetic resonance imaging; MRS, magnetic resonance spectroscopy; PET, positron emission tomography; SPECT, single-photon emission computed tomography; TBI, traumatic brain injury.
injected into a patient’s vein. As the tracer decays, it emits a photon, which is detected and recorded by the SPECT gamma camera (Figure 6–1). The computer reconstructs these detections to produce a tomographic image of activ-ity throughout the brain, similar to the “slices” produced by CT or MRI examination. Like MRI, coronal, sagittal, and axial SPECT views as well as three-dimensional reconstructions are available. This image can be visually interpreted by a nuclear medicine specialist and/or ana-lyzed statistically using various software programs.
Older SPECT cameras, which were used for many of the studies discussed in the section below, Studies Using SPECT and Structural Imaging, had limited detectors and produced poor quality images (Figure 6–2). More credence should be given to studies performed with the newer
“tri-ple head” cameras. These provide a resolution of approxi-mately 1 cm, allowing assessment of much smaller struc-tures than those assessed with older equipment (Figures 6–3 and 6–4). Use of companion structural imaging studies (CT or MRI) in the same patient can provide greater pre-cision of anatomical location. This method is called
“coregistration” of the structural and functional images.
Tracers
The most commonly used radiotracer for clinical SPECT is technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO), which accumulates in endothelial cell membranes a few minutes after injection. Concentrations of this tracer are thus highest in regions receiving the most plentiful blood flow shortly after the injection and remain so for up to 24 hours. Because of this long half-life, multiple scans can be performed after one injection, which can be helpful if the patient moves during a scan.
However, because the tracer is taken up at a certain time, the location of tracer concentration in the brain does not change (e.g., for research purposes, one could not per-form a vision activation study and then an auditory study on one patient using the same tracer injection).
Ligand studies, in which a radioactive ligand (marker) binds with a particular receptor, transporter, or protein, are becoming an important tool in both SPECT and PET and could contribute to future understanding of neurotransmit-ter change during cognitive processes. For example, if ad-ministration of a ligand that binds specifically to one neu-rotransmitter type is followed by a scan, and then an activation task is performed, a follow-up scan could poten-tially provide information on how much ligand was dis-placed by the endogenous neurotransmitter, suggesting in-volvement of that system in the task. Receptor studies (e.g., examining benzodiazepine receptor function in alcohol de-pendency [Lingford-Hughes et al. 1998] or dopamine trans-porter function in schizophrenia [Abi Dargham et al. 2000]) have also been conducted with SPECT but are not discussed in detail in this chapter (see Table 6–2 for a review of com-monly used, U.S. Food and Drug Administration [FDA]-approved SPECT tracers). Similarly, these methods could be used in TBI to study disruption of neurotransmitter sys-tems after brain injury. However, interpretation of these re-sults is still in the preliminary stages (Laruelle 2000). We limit our discussion in this chapter to blood flow studies be-cause they are the most clinically relevant at this time.
Practical Considerations
SPECT scans can be obtained in most large medical centers and are substantially more affordable than PET. For clinical F I G U R E 6 – 1 . Procedure for obtaining a SPECT
scan.
The same scanner is used for imaging many body systems, includ-ing brain, heart, bone, and lung. Details of the procedure differ.
Before brain imaging, the patient receives an intravenous injection of the radioactive tracer while lying in a darkened room. After a short period in the darkened room that allows the tracer to distrib-ute through the brain, the patient is ready to be scanned. The tracer distribution is stable for several hours, thus allowing a considerable time window for scanning to occur. After the patient is positioned on the scanner table, the gamma camera head(s) are moved in as close to the patient’s head as possible, as illustrated (IREX, Philips Medical Systems, Andover, MA). The three cameras of this mul-tidetector system are indicated by arrows. The camera(s) rotate around the patient’s head during the imaging examination. Data are collected from multiple positions as the camera(s) rotate around the patient’s head. The data are transmitted to a computer that pro-duces tomographic images in the desired plane(s) of section.
Source. Picture courtesy of Philips Medical Systems.
use, a resting SPECT scan of the whole brain is generally ordered. Intravenous radioactive tracer is injected into the patient a few minutes before scanning, preferably in a quiet, controlled environment to minimize blood flow changes due to anxiety and presence of loud noise. The patient should be able to lie still in a supine position in the scanner for the duration of the scan––up to half an hour. If the patient is too agitated to remain still, sedation may be given after tracer injection to minimize effects on the uptake and distribution of tracer. With the most commonly used SPECT tracer (i.e., 99mTc-HMPAO), the concentrations of tracer remain stable in the brain for up to a day, so the patient can be imaged several hours after the injection is given.
Because the patient is exposed to ionizing radiation with this technique, consideration must be given to the number and recency of prior scans using radioactive tracers.
Indications
At this time, no clear guidelines exist for use of SPECT in evaluation and treatment of TBI. Clinicians generally order SPECT scans when brain injury is suspected but not seen on structural studies, or when structural studies do not indicate damage extensive enough to explain a patient’s deficits.
Limitations
SPECT studies typically provide information only about relative CBF, not absolute CBF as can be evaluated with
PET. The xenon gas–inhalation technique produces quantitative CBF values, but the images are of relatively poor quality and low resolution compared with those obtained by PET, as discussed later in the section Positron Emission Tomography. There are no SPECT tracers for the study of cerebral metabolism. Interpreta-tion is often performed by visual rating of scans for abnor-malities rather than by use of statistical methods, which introduces problems inherent in the use of subjective, nonstandardized ratings. This circumstance introduces methodological difficulties, because interrater reliability cannot be standardized. Comparison of results from dif-ferent studies becomes increasingly problematic because some groups may report only the presence of overall abnormality whereas others report the number of individ-ual lesions seen in each scan (see Herscovitch 1996 for a detailed review of these issues).
Overview of Abnormal Findings in Other Psychiatric Disorders
There are some research applications of SPECT in psy-chiatry. It is sometimes useful in helping differentiate causes of dementia. It has also been used in small studies of headaches, pain, and sleep disorders. SPECT’s use for psychiatric evaluation or prognosis in other conditions is still a matter of debate. Frontal lobe hypoperfusion is seen in most studies of depression, often in the lateral prefron-tal cortex. Work with anxiety disorder patients has led to the discovery of abnormally increased flow in the anterior F I G U R E 6 – 2 . SPECT imaging then and now.
Axial single-photon emission computed tomography images acquired in 1982, early 1990s, and early 2000s of brain. Note the signif-icant improvement in resolution since the 1980s.
Source. SPECT images (1982) reprinted by permission of the Society of Nuclear Medicine from Hill TC, et al: “Initial Experience With SPECT (Single Photon Computerized Tomography) of the Brain Using N-isopropyl I-123 p-iodoamphetamine: Concise Com-munication.” Journal of Nuclear Medicine 23:193, 1982. SPECT images (early 1900s and 2000s) courtesy of Philips Medical Systems.
cingulate and orbitofrontal cortices in some patients with obsessive-compulsive disorder. Schizophrenic patients have been reported to have frontal cortex flow loss, along with basal ganglia and temporal lobe deficits. SPECT study abnormalities have also been seen in patients with substance abuse, sleep disorders, pain syndromes, and headaches. SPECT is more frequently used in neurolog-ical practice for assessment of patients with stroke, epi-lepsy, and ischemic attacks.
In evaluation of dementia, a pattern of bilateral pos-terior temporal and/or parietal decreases in blood flow (i.e., hypoperfusion) is suggestive of Alzheimer’s disease (AD). However, a similar pattern of perfusion loss may be seen in Parkinson’s disease patients who have demen-tia (Pizzolato et al. 1988). Reports of sensitivity and specificity of SPECT for detection of blood flow
changes related to AD vary. Bonte et al. (1997) corre-lated autopsy diagnosis, the gold standard for determin-ing cause of dementia, with SPECT finddetermin-ings. They found that SPECT showed 86% sensitivity and 73%
specificity for detection of AD. Jobst et al. (1998) found similar results with histological confirmation of diagno-sis. Masterman et al. (1997) found SPECT to be less useful for differentiating probable AD from other de-mentias. In their study, sensitivity was 75% and specific-ity was 52% when comparing probable AD versus un-likely AD groups. Ishii et al. (1996) found a high sensitivity but low specificity for AD prediction with SPECT (95.2% and 56.9%, respectively). In some cases, SPECT may also be useful in distinguishing AD from vascular, frontotemporal, or Lewy body dementia (see Van Heertum et al. 2001 for a review).
F I G U R E 6 – 3 . Serial axial SPECT images of a normal adult brain.
Reference numbers for brain slice order are shown next to each slice.
Imaging work with migraine patients has shown vari-able results (see Cutrer et al. 2000 for a review). Inter-hemispheric asymmetry in superior frontal and occipital cortices of migraine patients has been reported (Mirza et
al. 1998; see Aurora and Welch 2000 for a review of im-aging in migraine). Cluster headache patients also show abnormalities on SPECT during experimental applica-tion of painful stimuli; the authors suggest that such ab-F I G U R E 6 – 4 . Current SPECT imaging capabilities.
Three-dimensional reconstruction of SPECT results obtained 2 months post–traumatic brain injury (A). Areas of normal blood flow are red. Note the absence of flow in the right anterior temporal and frontal lobes (foreground), resulting in visualization of the left temporal and frontal lobes from the medial side. Seeing blood flow deficits in three dimensions improves appreciation of the extent of lesions. Merging blood flow data with anatomical imaging also improves identification of areas of abnormality. Sectional SPECT images overlaid on T1-weighted magnetic resonance images (B–D).
Source. B–D, pictures courtesy of Philips Medical Systems.
T A B L E 6 – 2 . U.S. Food and Drug Administration–approved, commonly used tracers for SPECT
Tracer
Parameter
measured Comments
99mTc-HMPAO Blood flow Most commonly used clinical tracer for SPECT. Slow washout, so scan can be done long after injection of tracer.
123I-IMP Blood flow Distributes quickly in brain, so scan must be done within 1 hour of injection.
201Tl Blood flow Used for cardiac studies and assessment of malignancies throughout the body.
Note. 99mTc-HMPAO=technetium-99m-hexamethylpropyleneamine oxime; 123I-IMP=iodine-123 N-isopropyl-p-iodoamphetamine; 201Tl=
thallium-201.
normalities may reflect a modification of pain-detection systems (Di Piero et al. 1997). Studies of chronic pain and fibromyalgia have reported decreased thalamic flow (Mountz et al. 1995; Nakabeppu et al. 2001), which some groups suggest could be linked to low threshold for pain perception (Mountz et al. 1995). SPECT abnormalities have been reported in limited studies of primary insomnia (Smith et al. 2002), narcolepsy (Asenbaum et al. 1995), and rapid eye movement–sleep behavioral disorder (Shirakawa et al. 2002).
SPECT has been used for evaluation of other psychi-atric conditions with varying results. Studies of depressed patients with SPECT have been inconclusive. There is some consensus that frontal lobe flow deficits are seen in patients with depression, usually affecting the lateral pre-frontal cortex. SPECT studies have shown hypoperfusion of the prefrontal, temporal, and cingulate cortices and left caudate nucleus in depression (Devous 1992; Van Heer-tum and O’Connell 1991). The heterogeneous spectrum of patients seen with depression is probably a factor in the lack of consistency in these studies.
SPECT studies with obsessive-compulsive disorder pa-tients have generally shown abnormally high blood flow (i.e., hyperperfusion) in the anterior cingulate and orbito-frontal cortices, with basal ganglia hyperperfusion also re-ported (Hoehn-Saric et al. 1991b; Machlin et al. 1991). A pre- and posttreatment SPECT study showed that perfu-sion normalized after successful treatment (Hoehn-Saric et al. 1991a). Hypoperfusion of the frontal lobes, caudate, and thalamus has also been found (Lucey et al. 1995).
In schizophrenia patients, SPECT most frequently shows frontal cortex hypoperfusion, especially during ac-tivation studies; basal ganglia and temporal lobe flow loss has also been reported (Woods 1992). However, medica-tion status (whether the patient is taking or not taking medication) and presence of positive or negative symp-toms may affect SPECT findings (Sabri et al. 1997).
Global, diffuse hypoperfusion has been shown in pa-tients who abuse alcohol and those who abuse cocaine (Devous 1992; Holman et al. 1991). Blood flow abnor-malities due to cocaine abuse may resolve after cessation of drug abuse (Holman et al. 1993). Abuse of other sub-stances may produce similar blood flow deficits. Psy-chogenic disorders have been the subject of limited study with SPECT to date (Garcia-Campayo et al. 2001; Tii-honen et al. 1995; Yazici and Kostakoglu 1998), with het-erogeneous results such as hyper- or hypoperfusion in sensorimotor, parietal, frontal, temporal, or cerebellar re-gions. In other work, Vuilleumier et al. (2001) found de-creased flow to the basal ganglia and thalamus contralat-eral to the side of sensorimotor deficits in a study of seven patients with psychogenic symptoms that resolved after
recovery of function, suggesting failure to modulate vol-untary motor function in psychogenic illness. The vari-ability and range of psychiatric conditions that may cause blood flow changes provide a cautionary note in interpre-tation of SPECT and other imaging studies of TBI pa-tients, who often have one or more comorbid psychiatric conditions.
Overview of Abnormal SPECT Findings in TBI
Despite the promise of SPECT as an accessible, low-cost method for the study of brain activity after TBI and dur-ing recovery from injury, there are relatively few method-ologically sound studies in the literature. There are even fewer studies incorporating other methods of assessment, such as neuropsychological testing and standardized rat-ings for recovery, in conjunction with SPECT for evalu-ation of TBI.
Studies Using SPECT and Structural Imaging SPECT has been used in combination with structural imaging in numerous studies (Abdel-Dayem et al. 1987;
Audenaert et al. 2003; Gray et al. 1992; Ichise et al. 1994;
Jacobs et al. 1994; Kesler et al. 2000; Newton et al. 1992;
Oder et al. 1992; Prayer et al. 1993; Roper et al. 1991;
Umile et al. 2002). It should be noted that in these stud-ies, the SPECT scan was not coregistered with a struc-tural image. Instead, the scans were interpreted sepa-rately, and functional results were compared with those from structural modalities.
In general, more abnormalities are seen on SPECT scans than on structural imaging scans such as CT and MRI in studies of patients with TBI over a wide range of recency and severity (Figures 6–5, 6–6, 6–7) (Abdel-Dayem et al. 1987; Audenaert et al. 2003; Gray et al.
1992; Ichise et al. 1994; Jacobs et al. 1994; Newton et al.
1992; Roper et al. 1991). MRI is generally superior to CT for visualization of anatomical regions, and thus more lesions are usually seen with MRI than CT. Fac-tors such as bony artifact limit CT studies in areas of particular interest in TBI, such as the temporal lobes.
Both MRI and SPECT results were found to be abnor-mal in a study of severe TBI patients with norabnor-mal CT scans (Prayer et al. 1993). However, lesions seen with SPECT do not always correlate with abnormalities seen on MRI (Newton et al. 1992; Prayer et al. 1993). A large, recent study of patients with mild, moderate, or severe TBI (average of 3 years postinjury) found 67% agree-ment between SPECT and MRI on location of brain in-jury (Kesler et al. 2000). The very limited research in this area to date suggests that SPECT may be useful in cases of mild TBI in which there is no evidence of
ab-normality on a structural scan. However, because struc-tural scans and SPECT are both generally interpreted by subjective visual analyses, direct comparison of these differing modalities is difficult. It should be noted that few of the SPECT studies reviewed in this discussion used noninjured control comparison groups. One of the studies did have a control comparison group; Ichise et al.
(1994) found neuroimaging abnormalities in a small number of noninjured control subjects, which the re-searchers attributed to possible underlying, unrecog-nized neurological abnormalities. This circumstance raises the issue of the importance of careful control se-lection in studies with any imaging modality.
The limited work that has been done at this time suggests that a normal SPECT scan after TBI is predic-tive of a good outcome (Abdel-Dayem et al. 1987; Jacobs et al. 1994; Oder et al. 1992). In one study, a negative initial SPECT, determined by expert visual rating, was 97% predictive of good clinical outcome for mild and
moderate TBI within 4 weeks of injury (Jacobs et al.
1994). Good clinical outcome in this study was judged according to neurological examination findings, ques-tioning on postconcussive symptoms, and unspecified memory and concentration tests. Clinical evaluation for outcome was performed on all subjects, but only those with an initial abnormal scan received a follow-up SPECT scan. An initial SPECT rated as abnormal was a predictor of poor outcome only 59% of the time. At follow-up, 95% of patients with clinical evidence of TBI seque-lae continued to show abnormal perfusion on SPECT.
Abdel-Dayem et al. (1987) used SPECT to study coma-tose acute TBI patients and noninjured controls. They found that a bad outcome in patients (i.e., death) was re-lated to size, multiplicity, and location of lesions, as rated by two experienced raters. In a study by Oder et al.
(1992) of 12 patients in persistent vegetative states after TBI, SPECT global hypoperfusion had a 100% positive predictive value for poor outcome. However, evidence F I G U R E 6 – 5 . Early subacute presentation of traumatic brain injury on SPECT.
A 61-year-old man had a single-motor-vehicle collision with a tree. This resulted in severe trauma with loss of consciousness requiring neurosurgical interventions. After several weeks of hospitalization, the patient was released. Within a few days, the patient’s family brought him to a psychiatric emergency service with agitation, incoherence, cognitive impairment, and psychosis. Two different sectional levels in the brain are illustrated with companion axial CT, T2-weighted MR, FLAIR MR, and SPECT. Note that the injury is more apparent on the FLAIR images than on the T2-weighted MR and CT images. The true extent of the injury, however, can be appreciated only on the SPECT images. FLAIR=fluid attenuated inversion recovery.
of focal flow deficits alone did not reliably predict good long-term outcome. All patients with poor outcome had MRI evidence of diffuse axonal injury, whereas none of those with good outcome showed such injury. Mazzini and others (2003) also found that degree of temporal lobe hypoperfusion on SPECT was one predictor of posttraumatic epilepsy in a series of 143 patients, ap-proximately 19% of whom developed seizures.
Especially in cases of mild TBI, SPECT may show le-sions where no abnormalities are seen on structural imag-ing, which may be helpful in explaining the cause of per-sistent behavioral changes. However, in some cases, lesions on structural scans are not detected with SPECT.
An initial negative SPECT after TBI may be predictive of good clinical outcome; the use of an abnormal scan for prognosis is less clear. It should be noted that little work has been done to elucidate the true relationship between an abnormal scan and objective outcome measures, espe-cially for cases of subtle hypoperfusion.
Studies Using Behavioral Measures
Only a few studies have tried to correlate abnormal cere-bral perfusion patterns with behavioral changes after TBI. Behavioral problems are an important clinical con-found, and accurate assessments of them are often miss-ing. Use of SPECT for prediction of which patients may
be at risk to develop behavioral problems after TBI has not been explored to date.
Oder et al. (1992), in a study of severe TBI, found a significant correlation between frontal hypoperfusion and disinhibition, left hemisphere hyperperfusion and social isolation, and right hemisphere hypoperfusion and ag-gression. Varney et al. (1995) examined whether blood flow changes in mild TBI patients––relative to nonin-jured control subjects––were related to functional diffi-culties postinjury. Specifically, they studied employment difficulties in those patients who had been consistently employed before TBI and had normal postinjury struc-tural scans. Both patient and control SPECT scans were rated by visual inspection, with the rater blind to whether the scan was from a patient or a control. All control SPECT scans were rated as normal. Two of the mild TBI scans were also rated as normal. The remaining 12 patient SPECT scans demonstrated flow changes, mainly in the anterior mesial temporal lobes and also, in some patients, in orbitofrontal regions. Quantitative analysis was also performed on the SPECT scans, showing hypoperfusion, mainly in the anterior mesial temporal regions, along with some indications of orbitofrontal flow loss in pa-tients with employment difficulties. This study suggests that even mild TBI can have an impact on a patient’s func-tional abilities. These preliminary studies indicate that F I G U R E 6 – 6 . Late subacute presentation of traumatic brain injury.
A 24-year-old man had a motor vehicle accident with no loss of consciousness 10 years after a mild head injury. Shortly thereafter, the patient presented with severe cognitive deficits, depression, agitation, aggression, and psychosis. Symptoms were sufficiently severe to require prolonged psychiatric hospitalization. MR examination during this time was normal. Numerous perfusion abnor-malities were evident on SPECT scans acquired 2 years later (three coronal and a single sagittal section are illustrated). The most pronounced abnormality was moderately reduced perfusion in the left parietal lobe near the posterior Sylvian fissure and in both temporal lobes. Mildly reduced perfusion was noted in the occipital lobes (left greater than right) and basal ganglia (particularly near the caudate heads). Some of these abnormalities are visible on both the sagittal and coronal images, as indicated by arrows.
SPECT may prove helpful in assessment of behavioral se-quelae of TBI.
Studies Using Neuropsychological Assessments There have been limited comparisons of blood flow changes and performance deficits on neuropsychological testing in TBI patients. SPECT results have not been consistently correlated with neuropsychological test results in most studies. In one study, a relationship was found between perfusion deficits and neuropsychological test performance in only 14 of 120 comparisons (Wied-mann et al. 1989). In a recent small study, Audenaert et al.
(2003) found a relationship between location of focal frontal and temporal abnormalities on 57Co SPECT and deficits in neuropsychological testing in six of eight mild TBI patients. Comparison of 28 mild TBI patients who had long-standing clinical complaints with 20 matched noninjured control subjects by another group found that
hypoperfusion of frontal, left posterior, and some subcor-tical regions on SPECT was predictive of performance deficits on neuropsychological evaluation. However, other brain regions did not show the same concordance with test results (Bonne et al. 2003). Umile and others (2002) also found that neuropsychological test perfor-mance deficits could not be consistently predicted by regional perfusion abnormalities using SPECT and PET in mild TBI patients with persistent postinjury symp-toms. In another study, although neuropsychological tests predicted SPECT finding, the converse was not true (Umile et al. 1998). Thus, results have been less than encouraging. At the present time, SPECT cannot be used to predict neuropsychological/cognitive testing deficits.
Only preliminary work has been done to examine whether SPECT and neuropsychological test results can be used in conjunction to improve assessment of progress in rehabilitation. Laatsch et al. (1997, 1999) found flow F I G U R E 6 – 7 . Chronic presentation of traumatic brain injury.
A 52-year-old man had a high-impact closed head injury 30 years before scanning. He presented with a 30-year history of emotional incontinence and depression. Additionally, the patient reported a loss of singing ability after the accident. Two different sectional levels in the brain are illustrated with companion axial T2-weighted MR and SPECT. There are minimal white matter changes in the parietal region apparent on the MR. Mildly decreased perfusion is evident in the medial frontal lobes (left greater than right, arrowhead). Moderately decreased perfusion is evident in the right anterior temporal lobe adjacent to the Sylvian fissure (arrow).