Design of a Multi-Pinhole Collimator for I-123 DaTscan Imaging on Dual-Headed SPECT Systems in Combination with a Fan-Beam Collimator.

For the 2011 FDA approved Parkinson's Disease (PD) SPECT imaging agent I-123 labeled DaTscan, the volume of interest (VOI) is the interior portion of the brain. However imaging of the occipital lobe is also required with PD for calculation of the striatal binding ratio (SBR), a parameter of significance in early diagnosis, differentiation of PD from other disorders with similar clinical presentations, and monitoring progression. Thus we propose the usage of a combination of a multi-pinhole (MPH) collimator on one head of the SPECT system and a fan-beam on the other. The MPH would be designed to provide high resolution and sensitivity for imaging of the interior portion of the brain. The fan-beam collimator would provide lower resolution but complete sampling of the brain addressing data sufficiency and allowing a volume-of-interest to be defined over the occipital lobe for calculation of SBR's. Herein we focus on the design of the MPH component of the combined system. Combined reconstruction will be addressed in a subsequent publication. An analysis of 46 clinical DaTscan studies was performed to provide information to define the VOI, and design of a MPH collimator to image this VOI. The system spatial resolution for the MPH was set to 4.7 mm, which is comparable to that of clinical PET systems, and significantly smaller than that of fan-beam collimators employed in SPECT. With this set, we compared system sensitivities for three aperture array designs, and selected the 3 × 3 array due to it being the highest of the three. The combined sensitivity of the apertures for it was similar to that of an ultra-high resolution fan-beam (LEUHRF) collimator, but smaller than that of a high-resolution fan-beam collimator (LEHRF). On the basis of these results we propose the further exploration of this design through simulations, and the development of combined MPH and fan-beam reconstruction.

Kinetic modeling, test-retest, and dosimetry of 123I-MNI-420 in humans.

UNLABELLED: In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of (123)I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain. METHODS: Nine healthy human subjects were enrolled in this study; 7 completed (123)I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating (123)I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. RESULTS: (123)I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average test-retest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. CONCLUSION: The data indicate that (123)I-MNI-420 is a useful SPECT radiotracer for imaging A2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of (123)I-MNI-420 offers the possibility of investigating A2A activity in specific conditions and evaluating drug occupancy for A2A candidate therapeutics.

The role of the core imaging laboratory in multicenter trials.

The incorporation of imaging biomarkers and clinical trials is now common. Because of the multiple technical, clinical, and regulatory demands to ensure high-quality quantitative information, the core laboratory serves as a critical intermediary between the study sponsor and the site. It provides unique expertise not found in typical clinical research organizations. This expertise goes far beyond the passive receipt of images for conductance of central reads of data and includes the proactive and early involvement in the selection of sites for imaging, the qualification and assistance for managing the local site logistics, on-the-fly and active quality control of imaging data in close working relationship with sites, and preparation for and conductance of central image reads or quantification in a manner which bears up to regulatory scrutiny.

Optimized, automated striatal uptake analysis applied to SPECT brain scans of Parkinson's disease patients.

UNLABELLED: Reliable quantitative dopamine transporter imaging is critical for early and accurate diagnosis of Parkinson's disease (PD). Image quantitation is made difficult by the variability introduced by manual interventions during the quantitative processing steps. A fully automated objective striatal analysis (OSA) program was applied to dopamine transporter images acquired from PD subjects with early symptoms of suspected parkinsonism and compared with manual analysis by a trained image-processing technologist. METHODS: A total of 101 (123)I-beta-CIT SPECT scans were obtained of subjects recruited to participate in the Query-PD Study. Data were reconstructed and then analyzed according to a package of scripts (OSA) that reorients the SPECT brain volume to the standard geometry of an average scan, automatically locates the striata and occipital structures, locates the caudate and putamen, and calculates the background-subtracted striatal uptake ratio (V3''). The striatal uptake ratio calculated by OSA was compared with manual analysis by a trained image-processing technologist. Several parameters were varied in the automated analysis, including the number of summed transverse slices and the size and separation of the regions of interest applied to the caudate and putamen to determine the optimum OSA analysis. The parameters giving V3'' with the closest correlation to the manual analysis were accepted as optimal. RESULTS: The optimal comparison between the V3'' obtained by the human analyst and that obtained by the automated OSA analysis yielded a correlation coefficient of 0.96. CONCLUSION: Our optimized OSA delivers V3'' evaluations that closely correlate with a similar evaluation manually applied by a highly trained image-processing technologist.

Imaging onset and propagation of ECT-induced seizures.

PURPOSE: Regions of seizure onset and propagation in human generalized tonic-clonic seizures are not well understood. Cerebral blood flow (CBF) measurements with single photon emission computed tomography (SPECT) during electroconvulsive therapy (ECT)-induced seizures provide a unique opportunity to investigate seizure onset and propagation under controlled conditions. METHODS: ECT stimulation induces a typical generalized tonic-clonic seizure, resembling spontaneous generalized seizures in both clinical and electroencephalogram (EEG) manifestations. Patients were divided into two groups based on timing of ictal (during seizure) SPECT tracer injections: 0 s after ECT stimulation (early group), and 30 s after ECT (late group). Statistical parametric mapping (SPM) was used to determine regions of significant CBF changes between ictal and interictal scans on a voxel-by-voxel basis. RESULTS: In the early injection group, we saw increases near the regions of the bitemporal stimulating electrodes as well as some thalamic and basal ganglia activation. With late injections, we observed increases mainly in the parietal and occipital lobes, regions that were quiescent 30 s prior. Significant decreases occurred only at the later injection time, and these were localized to the bilateral cingulate gyrus and left dorsolateral frontal cortex. CONCLUSIONS: Activations in distinct regions at the two time points, as well as sparing of intermediary brain structures, suggest that ECT-induced seizures propagate from the site of initiation to other specific brain regions. Further work will be needed to determine if this propagation occurs through cortical-cortical or cortico-thalamo-cortical networks. A better understanding of seizure propagation mechanisms may lead to improved treatments aimed at preventing seizure generalization.

Localizing value of ictal-interictal SPECT analyzed by SPM (ISAS).

PURPOSE: The goal of neuroimaging in epilepsy is to localize the region of seizure onset. Single-photon emission computed tomography with tracer injection during seizures (ictal SPECT) is a promising tool for localizing seizures. However, much uncertainty exists about how to interpret late injections, or injections done after seizure end (postictal SPECT). A widely available and objective method is needed to interpret ambiguous ictal and postictal scans, with changes in multiple brain regions. METHODS: Ictal or postictal SPECT scans were performed by using [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO), and images were analyzed by comparison with interictal scans for each patient. Forty-seven cases of localized epilepsy were studied. We used methods that can be implemented anywhere, based on freely downloadable software and normal SPECT databases (http://spect.yale.edu). Statistical parametric mapping (SPM) was used to localize a single region of seizure onset based on ictal (or postictal) versus interictal difference images for each patient. We refer to this method as ictal-interictal SPECT analyzed by SPM (ISAS). RESULTS: With this approach, ictal SPECT identified a single unambiguous region of seizure onset in 71% of mesial temporal and 83% of neocortical epilepsy cases, even with late injections, and the localization was correct in all (100%) cases. Postictal SPECT, conversely, with injections performed soon after seizures, was very poor at localizing a single region based on either perfusion increases or decreases, often because changes were similar in multiple brain regions. However, measuring which hemisphere overall had more decreased perfusion with postictal SPECT, lateralized seizure onset to the correct side in approximately 80% of cases. CONCLUSIONS: ISAS provides a validated and readily available method for epilepsy SPECT analysis and interpretation. The results also emphasize the need to obtain SPECT injections during seizures to achieve unambiguous localization.

Positive and negative network correlations in temporal lobe epilepsy.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

Selective frontal, parietal, and temporal networks in generalized seizures.

Are "generalized" seizures truly generalized? Generalized tonic-clonic seizures are classified as either secondarily generalized with local onset or primarily generalized, without known focal onset. In both types of generalized seizures widespread regions of the nervous system engage in abnormally synchronous and high-frequency neuronal firing. However, emerging evidence suggests that all neurons are not homogeneously involved; specific nodes within the network may be crucial for the propagation and behavioral manifestations of generalized tonic-clonic seizures. Study of human tonic-clonic seizures has been limited by problems with patient movement and variable seizure types. To circumvent these problems, we imaged generalized tonic-clonic seizures during electroconvulsive therapy, in which seizure type and timing are well controlled. (99m)Tc-hexamethylpropylene amine oxime injections during seizures provide a "snapshot" of cerebral blood flow that can be imaged by single photon emission computed tomography (SPECT) after seizure termination. Here we show that focal regions of frontal and parietal association cortex show the greatest relative signal increases. Involvement of the higher-order association cortex may explain the profound impairment of consciousness seen in generalized seizures. In addition, focal involvement of the dominant temporal lobe was associated with impaired retrograde verbal memory. Similar focal increases were also seen in imaging of spontaneous secondarily generalized tonic-clonic seizures. Relative sparing of many brain regions during both spontaneous and induced seizures suggests that specific networks may be more important than others in so-called generalized seizures.

Display of fused images: methods, interpretation, and diagnostic improvements.

The use of integrated visualization for medical images aims at assisting clinicians in the difficult task of mentally translating and integrating medical image data from multiple sources into a three-dimensional (3D) representation of the patient. This interpretation of the enormous amount and complexity of contemporary, multiparameter, and multimodal image data demands efficient methods for integrated presentation. This article reviews methods for fused display with the main focus on integration of functional with anatomical images. First, an overview of integrated two-dimensional (2D) and 3D medical image display techniques is presented, and topics related to the interpretation of the integrated images are discussed. Then we address the key issue for clinical acceptance, ie, whether these novel visualization techniques lead to diagnostic improvements. Methods for fused display appear to be powerful tools to assist the clinician in the retrieval of relevant information from multivariate medical image data. Evaluation of the different methods for fused display indicates that the diagnostic process improves, notably as concerns the anatomical localization (typically of functional processes), the registration procedure, enhancement of signal, and efficiency of information presentation (which increases speed of interpretation and comprehension). Consequently, fused display improves communication with referring specialists, increases confidence in the observations, and facilitates the intra- and intersubject comparison of a large part of the data from the different sources, thereby simplifying the extraction of additional, valuable information. In most diagnostic tasks the clinician is served best by providing several (interactive and flexible) 2D and 3D methods for fused display for a thorough assessment of the wealth of image information from multiple sources.

Targeted prefrontal cortical activation with bifrontal ECT.

The anatomical brain regions involved in the therapeutic and adverse actions of electroconvulsive therapy (ECT) are unknown. Previous studies suggest that bifrontal vs. bitemporal ECT differ in therapeutic efficacy and cognitive side effects. We therefore performed cerebral blood flow (CBF) imaging during bitemporal vs. bifrontal ECT-induced seizures to identify regions crucial for the differences between these treatments. Patients with major depression, undergoing bitemporal or bifrontal ECT, were studied. Ictal-interictal SPECT images were analyzed with statistical parametric mapping for bitemporal (n=11 image pairs in 8 patients) and bifrontal (n=4 image pairs in 2 patients) ECT-induced seizures to identify regions of ictal CBF changes. Bifrontal ECT was found to cause increases in CBF in prefrontal and anterior cingulate regions. Bitemporal ECT, however, caused CBF increases in the lateral frontal cortex and in the anterior temporal lobes. In bifrontal ECT, a greater increase in prefrontal activation, while sparing the temporal lobes, may result in a better therapeutic response and fewer adverse effects on memory than bitemporal ECT.

Developments in instrumentation for emission computed tomography.

Instrumentation for emission computed tomography continues to evolve, taking advantage of developments in detector technology, data processing and correction methods, and reconstruction algorithms. This article reviews the basic principles and latest developments in emission computed tomography instrumentation, for both positron emission tomography and single-photon emission computed tomography applications.

Comparison of statistical parametric mapping and SPECT difference imaging in patients with temporal lobe epilepsy.

PURPOSE: Statistical parametric mapping (SPM) is an image-analysis tool that assesses the statistical significance of cerebral blood flow (CBF) changes on a voxel-by-voxel basis, thereby removing the subjectivity inherent in conventional region-of-interest (ROI) analysis. Our platform of single-photon emission computed tomography (SPECT) ictal-interictal difference imaging in clinical epilepsy has been validated for localizing seizure onset. We extend the tools of SPM by further applying statistical measures for the significance of perfusion changes in individual patients to localize epileptogenic foci in patients with defined temporal lobe epilepsy by using paired scans in this preliminary study. METHODS: Twelve patients with pairs of periictal and interictal SPECT scans were analyzed in this comparison study between SPECT difference imaging and SPM difference analysis by using a reference database of paired normal healthy images. These 12 patients possessed seizure foci localized to the mesial temporal lobe as confirmed by surgical outcome and by hippocampal sclerosis on pathology. SPM was used to identify clusters of increased or decreased CBF in each patient in contrast to our control group. RESULTS: The regions having the most significant increased or decreased CBF by SPM analysis were in agreement with regions identified by conventional difference imaging and visual analysis by viewers blinded to the results of the SPM analysis. Differentiated further by time of radiopharmaceutical injection, six of seven patients injected within 100 s of seizure onset displayed hyperperfusion changes localized to the corresponding epileptogenic temporal lobe by both techniques. Among patients receiving injections after 100 s, both techniques showed primarily regions of hypoperfusion, which again were similar between these two methods. CONCLUSIONS: The results provide strong evidence supporting SPM difference analysis in assessing regions of significant CBF change from baseline in concordance with our current clinically used technique of SPECT ictal--interictal difference imaging in epilepsy patients. Difference analysis using SPM could serve as a useful diagnostic tool in the evaluation of seizure focus in temporal lobe epilepsy.