John J. Sidtis

The Quantitative Evaluation of Functional Neuroimaging Experiments: The NPAIRS Data Analysis Framework

We introduce a data-analysis framework and performance metrics for evaluating and optimizing the interaction between activation tasks, experimental designs, and the methodological choices and tools for data acquisition, preprocessing, data analysis, and extraction of statistical parametric maps (SPMs). Our NPAIRS (nonparametric prediction, activation, influence, and reproducibility resampling) framework provides an alternative to simulations and ROC curves by using real PET and fMRI data sets to examine the relationship between prediction accuracy and the signal-to-noise ratios (SNRs) associated with reproducible SPMs. Using cross-validation resampling we plot training-test set predictions of the experimental design variables (e.g., brain-state labels) versus reproducibility SNR metrics for the associated SPMs. We demonstrate the utility of this framework across the wide range of performance metrics obtained from [(15)O]water PET studies of 12 age- and sex-matched data sets performing different motor tasks (8 subjects/set). For the 12 data sets we apply NPAIRS with both univariate and multivariate data-analysis approaches to: (1) demonstrate that this framework may be used to obtain reproducible SPMs from any data-analysis approach on a common Z-score scale (rSPM[Z]); (2) demonstrate that the histogram of a rSPM[Z] image may be modeled as the sum of a data-analysis-dependent noise distribution and a task-dependent, Gaussian signal distribution that scales monotonically with our reproducibility performance metric; (3) explore the relation between prediction and reproducibility performance metrics with an emphasis on bias-variance tradeoffs for flexible, multivariate models; and (4) measure the broad range of reproducibility SNRs and the significant influence of individual subjects. A companion paper describes learning curves for four of these 12 data sets, which describe an alternative mutual-information prediction metric and NPAIRS reproducibility as a function of training-set sizes from 2 to 18 subjects. We propose the NPAIRS framework as a validation tool for testing and optimizing methodological choices and tools in functional neuroimaging.

The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry

The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6–85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

Neuropsychological characterization of the AIDS dementia complex: a preliminary report.

The AIDS dementia complex (ADC) is a frequent complication of advanced HIV infection. In order to better define the neuropsychological character and progression of the ADC, four groups of subjects were studied with a battery of neuropsychological tests: an HIV-seronegative comparison group (n = 20), asymptomatic HIV-seropositive patients (n = 16), newly diagnosed AIDS patients (n = 44) and AIDS patients who were referred for neurological consultation (n = 40). Results showed significant reductions in performance in the two AIDS groups, with impairment being most prominent in tests that assessed motor speed and fine control, concentration, problem solving and visuospatial performance. This pattern of neuropsychological dysfunction is consistent with the characterization of the ADC as a subcortical dementia.

Generalizable patterns in neuroimaging: how many principal components?

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.

Selective Reductions in Plasma Aβ 1-42 in Healthy Elderly Subjects During Longitudinal Follow-Up: A Preliminary Report

OBJECTIVE Longitudinal changes in plasma beta amyloid protein 1-42 and 1-40 (Abeta42 and Abeta40) levels and possible relationships with cognitive decline and apolipoprotein (APOE) genotype were studied in healthy elderly individuals. METHODS Authors determined cognitive level and plasma Abeta40 and Abeta42 levels twice, approximately 4 years apart, in 34 elderly subjects. RESULTS Analyses revealed a selective reduction in Abeta42 levels at follow-up, which were not modulated by the epsilon4 allele. Greater reductions and higher baseline plasma Abeta42 levels were associated with reductions in cognitive scores. CONCLUSIONS Alterations in plasma Abeta42 levels may be associated with subtle cognitive decline in elderly subjects without dementia.

Early HIV-1 infection and the AIDS dementia complex.

While infection by human immunodeficiency virus type 1 (HIV-1) may be complicated by a host of neurologic disorders, among the most common and most intriguing from both clinical and pathogenetic perspectives is the AIDS dementia complex (ADC), a syndrome of «subcortical dementia» affecting cognitive, motor and, at timpes, behavioral function

Dysprosodic speech following basal ganglia insult: Toward a conceptual framework for the study of the cerebral representation of prosody.

Progress in understanding brain/behavior relationships in adult-acquired dysprosody has led to models of cortical hemispheric representation of prosodic processing based on functional (linguistic vs affective) or physical (timing vs pitch) parameters. These explanatory perspectives have not been reconciled, and also a number of neurobehavior syndromes that include dysprosody among their neurological signs have not yet been integrated. In addition to expanding the functional perspective on prosody, some of these syndromes have implicated a significant role of subcortical nuclei in prosodic competence. In this article, two patients with acquired dysprosodic speech following damage to basal ganglia nuclei were evaluated using behavioral, acoustic, cognitive, and radiographic approaches. Selective quantitative measures were performed on each individuals performance to provide detailed verification and clarification of clinical observations, and to test hypotheses regarding prosodic function. These studies, combined with a review of related clinical research findings, exemplify the value of a broader perspective on the neurobehavioral dysfunction underlying acquired adult dysprosodic speech, and lead to a new, proposed conceptual framework for the cerebral representation of prosody.

Elevation in Plasma Abeta42 in Geriatric Depression: A Pilot Study

Elevated plasma amyloid beta 1–42 (Aβ42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Aβ levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer’s disease, have not been studied. We compared plasma Aβ in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Aβ42 levels and the Aβ42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Aβ42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Aβ levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Aβ42 and Aβ42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.

Timed Gait Test: Normative Data for the Assessment of the AIDS Dementia Complex

The Timed Gait test is a standardized procedure assessing motor dysfunction of lower extremities and gait abnormalities associated with AIDS dementia complex. Heretofore, interpretations of Timed Gait results have been hampered by the lack of normative data. We provide results on this test derived from 1,549 subjects (HIV−seronegatives (HIV−) and seropositives (HIV+) classified according to ADC stage). Timed Gait was found to be a useful screening and assessment tool for evaluating ADC and correlated with clinical ADC staging as well as more extensive structured neurological and neuropsychological evaluations. Analysis of covariance results (with age and education as covariates) revealed symptomatic HIV+(SX) and AIDS groups having significantly slower Timed Gait scores than those in the HIV− and asymptomatic HIV+(ASX) groups. The SX group obtained significantly slower timed gait scores than those in the AIDS group. There was a significant increase in Timed Gait scores with each increase in dementia staging with the HIV− subjects having the fastest mean Timed Gait scores and the HIV+ dementia stage 2+ having the slowest. These normative data should prove useful in both recognition of ADC and treatment response. Given its minimal training requirements, the Timed Gait would have utility in resource limited settings.

Mapping cerebral blood flow during speech production in hereditary ataxia

Dysarthria is a significant feature of the dominantly inherited spinocerebellar ataxias (SCA), but little is known about the patterns of brain activity associated with this disorder of motor speech control. Positron emission tomography (PET) was used to study regional cerebral blood flow during speech and rest in a group of 24 subjects with hereditary ataxia with mild-to-moderate dysarthria. These data were compared to the results obtained from a group of 13 age-matched, normal speakers. In the ataxic subjects, speech rates during scanning were significantly slowed compared to normal speakers. Significant reductions in mean regional blood flow were found in the cerebellum but not in supratentorial regions in the ataxic subjects. Multiple linear regression was used to model speech rate from regional blood flow. Four regions were identified as having significant relationships with speech rate in the model: the left inferior frontal and transverse temporal regions, and the right inferior cerebellar region and caudate nucleus. The relationship between flow and rate was positive in the inferior frontal and cerebellar regions and negative in the caudate and the transverse temporal region. The ataxic model represents an elaboration of the relationship previously reported for normal speakers, likely reflecting both the effects of, and compensation for, cerebellar degeneration in motor speech control. Although the mean regional blood flow values presented a pattern of functional organization for motor speech control at odds with lesion data, the performance-based model was in agreement with clinical experience. Incorporating performance data in functional image analysis may be more revealing of system characteristics than simply examining mean blood flow values.