Faculty Bibliography

Imaging studies of visuomotor learning have reported practice-related activation in brain regions mediating sensorimotor functions. However, development and testing of functional motor learning models, based on the relationship between imaging and behavioral measures, is complicated by the multidimensional nature of motoric control. In the present study, multivariate techniques were used to analyze [15O]water PET and kinematic correlates of learning in a visuomotor tracing task. Fourteen subjects traced a geometric form over a series of eight tracing trials, preceded and followed by baseline trials in which they passively viewed the geometric form. Simultaneous evaluation of multiple behavioral measures indicated that performance improvement was most strongly associated with a global performance measure and least strongly associated with measures of fine motor control. Results of three independent analytic techniques (i.e., intertrial correlation matrices, power function modeling, iterative canonical variate analysis) indicated that imaging and behavioral measures were most closely related on early learning trials. Performance improvement was associated with covarying increases in normalized activity among superior parietal, postcentral gyrus, and premotor regions and covarying decreases in normalized activity among cerebellar, inferior parietal, pallidal, and medial occipital regions. These findings suggest that performance improvement may be associated with increased activation in neural systems previously implicated in visually guided reaching and decreased activation in neural systems previously implicated in attentive visuospatial processing

OBJECTIVE: In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTIs), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection. DESIGN: Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy. SETTING: Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites. PATIENTS: Adult HIV-infected patients (n = 1313) with CD4 counts < 50 x 10(6) cells/l. INTERVENTIONS: Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddl), or in combination with zalcitabine (ddC), ddl or ddl and nevirapine. MAIN OUTCOME MEASURES: Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects. RESULTS: Triple therapy and ZDV/ddl combination preserved or improved neurological performance over time compared with the alternating ZDV/ddl and ZDV/ddC regimens (P < 0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P < 0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations. CONCLUSIONS: Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection

Although Positron Emission Tomography (PET) and functional magnetic resonance imaging (fMRI) studies commonly subtract data obtained during two or more experimental conditions to decompose a complex task, there have been few opportunities to evaluate this approach directly. In the present study, PET was used to study three motor speech tasks selected such that two were constituent components of the third, making possible a direct examination of decomposition by subtraction. In Experiment 1, a group of 13 right-handed normal volunteers participated in three activation studies: syllable repetition; phonation; and repetitive lip closure. A scanning session was devoted to a single task, repeated four times. In Experiment 2, six of the original subjects performed the same three activation studies during a single scanning session. Whether tasks were studied in separate scanning sessions or combined within a single session, the results of decomposition by compound subtraction differed significantly from the results obtained when individual tasks were compared to a simple baseline condition. These data failed to demonstrate task additivity, a necessary property if decomposition by subtraction is to provide an accurate characterization of the brain activity accompanying complex behavior

Generalization can be defined quantitatively and can be used to assess the performance of principal component analysis (PCA). The generalizability of PCA depends on the number of principal components retained in the analysis. We provide analytic and test set estimates of generalization. We show how the generalization error can be used to select the number of principal components in two analyses of functional magnetic resonance imaging activation sets.

AIDS Dementia Complex (ADC) is a frequent and devastating complication of HIV infection. There is evidence that zidovudine (ZDV) has an effect in alleviating the symptoms of ADC, and may have a role in its prevention. It is therefore important that new antiretroviral therapies be evaluated not only for the risk of neurologic side effects, but also for their relative efficacy to ZDV in the prevention of ADC. The present study reports the effects of 2'3'-dideoxyinosine (DDI, didanosine, Videx) therapy on neuropsychological performance in the context of several large clinical trials targeting advanced systemic HIV-1 infection. Subjects treated with DDI had stable neurologic performance in quantitative tests over a 1 year period and were similar to zidovudine treated subjects

This study was undertaken in order to extend our previous finding of relative basal ganglia hypermetabolism in AIDS dementia complex (ADC) and to develop clinically useful metabolic indices of CNS involvement in HIV-seropositive (HIV+) subjects. METHODS: Twenty-one HIV+ subjects (11 with AIDS) underwent FDG-PET scanning; 12 had a follow-up scan at 6 mo and 4 had a third scan at 12 mo. Forty-three age-matched heterosexual volunteers served as controls. FDG-PET scanning was performed with arterial blood sampling, and scan data were analyzed using the Scaled Subprofile Model (SSM) with principal component analysis. RESULTS: SSM/principal component analysis of the combined (HIV+ and controls) FDG-PET dataset extracted two major disease-related metabolic components: (a) a nonspecific indicator of cerebral dysfunction, which was significantly correlated with age, cerebral atrophy and ADC stage and (b) the striatum, which was heavily weighted (relatively hypermetabolic) and appeared to provide a disease-specific measure of early CNS involvement. CONCLUSION: FDG-PET scans provide quantitative measures of abnormal functional connectivity in HIV-seropositives-with or without AIDS or ADC. These measures, which are robust across centers with respect to instrumentation, scanning technique and disease severity, appear to track the progression of CNS involvement in patients with subclinical neurologic or neuropsychologic dysfunction

In a pilot open-labeled study 10 subjects with AIDS dementia complex (ADC) were treated with didanosine. Only half of the subjects were able to complete the trial as a result of side effects. Five subjects exhibited improved performance on neuropsychological testing, but the mean change in performance in this small group was not statistically significant. The study suggests that this drug may have some value in ADC patients unable to tolerate other therapies, but that further study is needed to establish this firmly

Using [15O]water PET and a previously well studied motor activation task, repetitive finger-to-thumb opposition, we compared the spatial activation patterns produced by (1) global normalization and intersubject averaging of paired-image subtractions, (2) the mean differences of ANCOVA-adjusted voxels in Statistical Parametric Mapping, (3) ANCOVA-adjusted voxels followed by principal component analysis (PCA), (4) ANCOVA-adjustment of mean image volumes (mean over subjects at each time point) followed by F-masking and PCA, and (5) PCA with Scaled Subprofile Model pre- and postprocessing. All data analysis techniques identified large positive focal activations in the contralateral sensorimotor cortex and ipsilateral cerebellar cortex, with varying levels of activation in other parts of the motor system, e.g., supplementary motor area, thalamus, putamen; techniques 1-4 also produced extensive negative areas. The activation signal of interest constitutes a very small fraction of the total nonrandom signal in the original dataset, and the exact choice of data preprocessing steps together with a particular analysis procedure have a significant impact on the identification and relative levels of activated regions. The challenge for the future is to identify those preprocessing algorithms and data analysis models that reproducibly optimize the identification and quantification of higher-order sensorimotor and cognitive responses