Image Derived Input Functions: Effects of Motion on Tracer Kinetic Analyses

Purpose: To quantify the effects of motion affected image-derived input functions (IDIF) on the outcome of tracer kinetic analyses. Procedures: Two simulation studies, one based on high and the other on low cortical uptake, were performed. Different degrees of rotational and axial translational motion were added to the final frames of simulated dynamic positron emission tomography scans. Extracted IDIFs from motion affected simulated scans were compared to original IDIFs and to outcome of tracer kinetic analysis (volume of distribution, V T). Results: Differences in IDIF values of up to 239 % were found for the last frames. Patient motion of more than 6 ° or 5 mm resulted in at least 10 % higher or lower VT values for the high cortical tracer. Conclusion: The degrees of motion studied are commonly observed in clinical studies and hamper the extraction of accurate IDIFs. Therefore, it is essential to ensure that patient motion is minimal and corrected for

Motion correction for phase-resolved dynamic optical coherence tomography imaging of rodent cerebral cortex

Cardiac and respiratory motions in animals are the primary source of image quality degradation in dynamic imaging studies, especially when using phase-resolved imaging modalities such as spectral-domain optical coherence tomography (SD-OCT), whose phase signal is very sensitive to movements of the sample. This study demonstrates a method with which to compensate for motion artifacts in dynamic SD-OCT imaging of the rodent cerebral cortex. We observed that respiratory and cardiac motions mainly caused, respectively, bulk image shifts (BISs) and global phase fluctuations (GPFs). A cross-correlation maximization-based shift correction algorithm was effective in suppressing BISs, while GPFs were significantly reduced by removing axial and lateral global phase variations. In addition, a non-origin-centered GPF correction algorithm was examined. Several combinations of these algorithms were tested to find an optimized approach that improved image stability from 0.5 to 0.8 in terms of the cross-correlation over 4 s of dynamic imaging, and reduced phase noise by two orders of magnitude in ~8% voxels.K99 NS067050 - NINDS NIH HHS; R01EB000790 - NIBIB NIH HHS; R01 EB001954 - NIBIB NIH HHS; R01 EB001954-09 - NIBIB NIH HHS; P01NS055104 - NINDS NIH HHS; R01 NS057476 - NINDS NIH HHS; K99NS067050 - NINDS NIH HHS; R01 EB000790 - NIBIB NIH HHS; R01-EB001954 - NIBIB NIH HHS; R01NS057476 - NINDS NIH HHS; P01 NS055104 - NINDS NIH HHS; P41 EB015896 - NIBIB NIH HHSPublished versio

Biological and Clinical Determinants of Treatment Resistant Schizophrenia

Up to one third of patients with schizophrenia show only limited response todopamine blocking antipsychotic medication. This could be due to distinctneurobiological abnormalities in this subgroup of patients. While there is robustevidence to suggest that the neurobiology of schizophrenia involves increasedpresynaptic striatal dopaminergic elevation, little is known as to whether thisabnormality is present in treatment resistance, and consequently therelationship between this dopamine abnormality and the lack of response totreatment remains unknown. Furthermore, it remains unclear whethertreatment resistance manifests at the outset of illness, and perhaps has aneurodevelopmental origin, or whether it evolves over time, possibly as a resultof a neurodegenerative process.The first study in this thesis investigated striatal presynaptic dopamine synthesisin twelve treatment resistant schizophrenic patients, twelve patients withschizophrenia who had responded to antipsychotics, and twelve healthyvolunteers, using [18F]-DOPA Positron Emission Tomography (PET). Thus, itwas possible to test the hypothesis that the response to treatment is determinedby differences in presynaptic dopamine function. The results demonstrated thatthere were no significant differences in striatal dopamine synthesis capacitybetween treatment resistant patients and healthy volunteers, whilst dopaminesynthesis capacity was significantly increased in responders relative totreatment resistant patients. The difference was most marked in the associativeand the limbic striatal subdivisions.A second, large follow-up study of first episode psychosis (FEP) patients,examined the course of treatment resistance over the 10 year follow up. It wasfound that over 80% of treatment resistant patients were persistently resistantfrom the initiation of antipsychotic treatment. My PET study, due to its crosssectional design, could not determine whether the normal dopamine levelspredate the antipsychotic exposure in treatment resistant patients. However, bydemonstrating that a great majority of treatment resistant patients are resistantto dopamine blocking antipsychotics at first ever initiation of treatment, mysecond study raises the possibility that these patients may have had normaldopamine levels even at the outset of their psychotic illness. In the same FEPcohort it was possible to investigate neurodevelopmental predictors of treatmentresistance. The finding that the negative symptom dimension and younger ageof onset were significant predictors of treatment resistance is compatible withthe view that TRS may be of neurodevelopmental origin.Overall, my observations in this thesis indicate that TRS may be a distinct andenduring subtype of schizophrenic illness of a possible neurodevelopmentalorigin whose pathophysiology is not marked by alterations in dopaminesynthesis capacity. Findings emerging from this thesis provide a platform forfuture studies, which may lead to the discovery of much needed new treatmentsfor this disabling and intractable condition.<br/