David R. Roalf

Comparative accuracies of two common screening instruments for classification of Alzheimer's disease, mild cognitive impairment, and healthy aging

The aim of this study was to compare the utility and diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination (MMSE) in the diagnosis of Alzheimers disease (AD) and mild cognitive impairment (MCI) in a clinical cohort.

Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity.

&NA; Since initial reports regarding the impact of motion artifact on measures of functional connectivity, there has been a proliferation of participant‐level confound regression methods to limit its impact. However, many of the most commonly used techniques have not been systematically evaluated using a broad range of outcome measures. Here, we provide a systematic evaluation of 14 participant‐level confound regression methods in 393 youths. Specifically, we compare methods according to four benchmarks, including the residual relationship between motion and connectivity, distance‐dependent effects of motion on connectivity, network identifiability, and additional degrees of freedom lost in confound regression. Our results delineate two clear trade‐offs among methods. First, methods that include global signal regression minimize the relationship between connectivity and motion, but result in distance‐dependent artifact. In contrast, censoring methods mitigate both motion artifact and distance‐dependence, but use additional degrees of freedom. Importantly, less effective de‐noising methods are also unable to identify modular network structure in the connectome. Taken together, these results emphasize the heterogeneous efficacy of existing methods, and suggest that different confound regression strategies may be appropriate in the context of specific scientific goals. HighlightsWe evaluate 14 participant‐level de‐noising pipelines for functional connectivity.Pipeline performance is markedly heterogeneous.GSR minimizes the impact of motion but introduces distance dependence.Censoring reduces motion and improves network identifiability.

Olfactory Functioning in Schizophrenia: Relationship to Clinical, Neuropsychological, and Volumetric MRI Measures

Deficits in odor identification and detection threshold sensitivity have been observed in schizophrenia but their relationship to clinical, cognitive, and biologic measures have not been clearly established. Our objectives were to examine the relationship between measures of odor identification and detection threshold sensitivity and clinical, neuropsychological, and anatomic brain measures. Twenty-one patients with schizophrenia and 20 healthy controls were administered psychophysical tests of odor identification and detection threshold sensitivity to phenyl ethyl alcohol. In addition, clinical symptom ratings, neuropsychological measures of frontal and temporal lobe function and whole brain MRIs were concurrently obtained. Patients exhibited significant deficits in odor identification but normal detection threshold sensitivity. Poorer odor identification scores were associated with longer duration of illness, increased negative and disorganized symptoms, and the deficit syndrome, as well as impairments in verbal and nonverbal memory. Better odor detection thresholds were specifically associated with first-rank or productive symptoms. Larger left temporal lobe volumes with MRI were associated with better odor identification in controls but not in patients. Given the relevance of the neural substrate, and the evidence of performance deficits, psychophysical probes of the integrity of the olfactory system hold special promise for illuminating aspects of the neurobiology underlying schizophrenia.

Functional Maturation of the Executive System during Adolescence

Adolescence is characterized by rapid development of executive function. Working memory (WM) is a key element of executive function, but it is not known what brain changes during adolescence allow improved WM performance. Using a fractal n-back fMRI paradigm, we investigated brain responses to WM load in 951 human youths aged 8–22 years. Compared with more limited associations with age, WM performance was robustly associated with both executive network activation and deactivation of the default mode network. Multivariate patterns of brain activation predicted task performance with a high degree of accuracy, and also mediated the observed age-related improvements in WM performance. These results delineate a process of functional maturation of the executive system, and suggest that this process allows for the improvement of cognitive capability seen during adolescence.

Behavioral and physiological findings of gender differences in global-local visual processing

Hemispheric asymmetries in global-local visual processing are well-established, as are gender differences in cognition. Although hemispheric asymmetry presumably underlies gender differences in cognition, the literature on gender differences in global-local processing is sparse. We employed event related brain potential (ERP) recordings during performance of a global-local reaction time task to compare hemispheric asymmetries and processing biases in adult men (n=15) and women (n=15). Women responded more quickly to local targets while men did not differentially respond to hierarchical stimuli. ERP data indicated that women had P100 responses that were selectively lateralized to the left hemisphere in response to local targets and N150 responses that were smaller for global targets. They also had P300 responses that were greater following local stimuli. The physiological data demonstrate that male-female performance differences arise from biologically based differences in hemispheric asymmetry. Findings are discussed in the context of existing literature regarding gender differences, hemispheric specialization, and the role of stimulus characteristics.

Impact of puberty on the evolution of cerebral perfusion during adolescence

Significance Blood perfusion is a fundamental property of brain physiology and is known to be higher in adult females than in males. However, it is unknown when such a sex difference emerges during the lifespan, or what biological processes may cause it. In the largest study of brain perfusion yet reported, we establish for the first time to our knowledge that patterns of development of cerebral perfusion during adolescence are markedly different in males and females, and such differences are attributable in part to the effects of puberty. These results may have important implications for neuropsychiatric disorders with adolescent onset and strong gender disparities, such as mood disorders, anxiety disorders, and schizophrenia. Puberty is the defining biological process of adolescent development, yet its effects on fundamental properties of brain physiology such as cerebral blood flow (CBF) have never been investigated. Capitalizing on a sample of 922 youths ages 8–22 y imaged using arterial spin labeled MRI as part of the Philadelphia Neurodevelopmental Cohort, we studied normative developmental differences in cerebral perfusion in males and females, as well as specific associations between puberty and CBF. Males and females had conspicuously divergent nonlinear trajectories in CBF evolution with development as modeled by penalized splines. Seventeen brain regions, including hubs of the executive and default mode networks, showed a robust nonlinear age-by-sex interaction that surpassed Bonferroni correction. Notably, within these regions the decline in CBF was similar between males and females in early puberty and only diverged in midpuberty, with CBF actually increasing in females. Taken together, these results delineate sex-specific growth curves for CBF during youth and for the first time to our knowledge link such differential patterns of development to the effects of puberty.

The impact of quality assurance assessment on diffusion tensor imaging outcomes in a large-scale population-based cohort.

BACKGROUND Diffusion tensor imaging (DTI) is applied in investigation of brain biomarkers for neurodevelopmental and neurodegenerative disorders. However, the quality of DTI measurements, like other neuroimaging techniques, is susceptible to several confounding factors (e.g., motion, eddy currents), which have only recently come under scrutiny. These confounds are especially relevant in adolescent samples where data quality may be compromised in ways that confound interpretation of maturation parameters. The current study aims to leverage DTI data from the Philadelphia Neurodevelopmental Cohort (PNC), a sample of 1601 youths with ages of 8-21 who underwent neuroimaging, to: 1) establish quality assurance (QA) metrics for the automatic identification of poor DTI image quality; 2) examine the performance of these QA measures in an external validation sample; 3) document the influence of data quality on developmental patterns of typical DTI metrics. METHODS All diffusion-weighted images were acquired on the same scanner. Visual QA was performed on all subjects completing DTI; images were manually categorized as Poor, Good, or Excellent. Four image quality metrics were automatically computed and used to predict manual QA status: Mean voxel intensity outlier count (MEANVOX), Maximum voxel intensity outlier count (MAXVOX), mean relative motion (MOTION) and temporal signal-to-noise ratio (TSNR). Classification accuracy for each metric was calculated as the area under the receiver-operating characteristic curve (AUC). A threshold was generated for each measure that best differentiated visual QA status and applied in a validation sample. The effects of data quality on sensitivity to expected age effects in this developmental sample were then investigated using the traditional MRI diffusion metrics: fractional anisotropy (FA) and mean diffusivity (MD). Finally, our method of QA is compared with DTIPrep. RESULTS TSNR (AUC=0.94) best differentiated Poor data from Good and Excellent data. MAXVOX (AUC=0.88) best differentiated Good from Excellent DTI data. At the optimal threshold, 88% of Poor data and 91% Good/Excellent data were correctly identified. Use of these thresholds on a validation dataset (n=374) indicated high accuracy. In the validation sample 83% of Poor data and 94% of Excellent data was identified using thresholds derived from the training sample. Both FA and MD were affected by the inclusion of poor data in an analysis of an age, sex and race matched comparison sample. In addition, we show that the inclusion of poor data results in significant attenuation of the correlation between diffusion metrics (FA and MD) and age during a critical neurodevelopmental period. We find higher correspondence between our QA method and DTIPrep for Poor data, but we find our method to be more robust for apparently high-quality images. CONCLUSION Automated QA of DTI can facilitate large-scale, high-throughput quality assurance by reliably identifying both scanner and subject induced imaging artifacts. The results present a practical example of the confounding effects of artifacts on DTI analysis in a large population-based sample, and suggest that estimates of data quality should not only be reported but also accounted for in data analysis, especially in studies of development.

The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth.

The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale study of child development that combines neuroimaging, diverse clinical and cognitive phenotypes, and genomics. Data from this rich resource is now publicly available through the Database of Genotypes and Phenotypes (dbGaP). Here we focus on the data from the PNC that is available through dbGaP and describe how users can access this data, which is evolving to be a significant resource for the broader neuroscience community for studies of normal and abnormal neurodevelopment.

Sex Differences in the Effect of Puberty on Hippocampal Morphology

OBJECTIVE Puberty is the defining process of adolescence, and is accompanied by divergent trajectories of behavior and cognition for males and females. Here we examine whether sex differences exist in the effect of puberty on the morphology of the hippocampus and amygdala. METHOD T1-weighted structural neuroimaging was performed in a sample of 524 pre- or postpubertal individuals ages 10 to 22 years. Hippocampal and amygdala volume and shape were quantified using the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) FIRST procedure and scaled by intracranial volume. The effects on regional volume of age, sex, puberty, and their interactions were examined using linear regression. Postpubertal sex differences were examined using a vertex analysis. RESULTS Prepubertal males and females had similar hippocampal volumes, whereas postpubertal females had significantly larger bilateral hippocampi, resulting in a significant puberty-by-sex interaction even when controlling for age and age-by-sex. This effect was regionally specific and was not apparent in the amygdala. Vertex analysis revealed that postpubertal differences were most prominent in the lateral aspect of the hippocampus bilaterally, corresponding to the CA1 subfield. CONCLUSIONS These results establish that there are regionally specific sex differences in the effect of puberty on the hippocampus. These findings are relevant for the understanding of psychiatric disorders that have both hippocampal dysfunction and prominent gender disparities during adolescence.

Within-individual variability in neurocognitive performance: Age- and sex-related differences in children and youths from ages 8 to 21

OBJECTIVE The transition from childhood to adulthood is characterized by improved motor and cognitive performance in many domains. Developmental studies focus on average performance in single domains but ignore consistency of performance across domains. Within-individual variability (WIV) provides an index of that evenness and is a potential marker of development. METHOD We gave a computerized battery of 14 neurocognitive tests to 9138 youths ages 8-21 from the Philadelphia Neurodevelopmental Cohort. RESULTS As expected, performance improved with age, with both accuracy and speed peaking in adulthood. WIV, however, showed a U-shaped course: highest in childhood, declining yearly into mid-adolescence, and increasing again into adulthood. Young females outperformed and were less variable than males, but by early adulthood male performance matched that of females despite being more variable. CONCLUSION We conclude that WIV declines from childhood to adolescence as developmental lags are overcome, and then increases into adulthood reflecting the emergence of cognitive specializations related to skill-honing and brain maturation.