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1.  A Cross-Sectional Study of Regional Brain Volume Abnormalities in Lesch-Nyhan Disease and its Variants 
Lancet neurology  2013;12(12):1151-1158.
Lesch-Nyhan disease (LND) is a rare, X-linked, neurodevelopmental metabolic disorder that results from a near-complete lack of hypoxanthine phosphoribosyl-transferase enzyme activity. LND is characterized by hyperuricemia, motor neurological abnormalities, recurrent self-injury, and cognitive impairment, but its neural substrates remain poorly understood.
In this cross-sectional study, we measured gray matter abnormalities in 21 persons with LND, 17 with an attenuated variant of the phenotype (LNV), and 33 healthy controls using voxel-based morphometry. We conducted an analysis of covariance to identify group differences in regional gray matter volume (GMV), followed by six pair-wise post-hoc group comparisons.
Patients with LND showed 20% smaller intracranial volumes (17% gray and 26% white matter) than healthy adults. The largest differences were found in basal ganglia, frontotemporal, and limbic regions, with sparing of parieto-occipital regions. The gray matter volumes of LNV participants invariably fell between those of patients with classical LND and healthy controls. Compared to healthy adults, patients with LND showed additional GMV reductions in the temporal lobe and left lateralized structures, and patients with LNV showed additional reductions in lingual and precuneus regions with sparing of right frontal and temporal regions. LND participants showed reductions in the ventral striatum and prefrontal areas relative to LNV.
This study of brain morphology reveals regional abnormalities associated with known neurological and behavioral deficits in persons with LND. It also revealed that patients with LNV show milder gray matter abnormalities in many of the same brain regions and preservation of GMV in other regions which could provide important clues to the neural substrates of differences between thephenotypes.
PMCID: PMC3932536  PMID: 24383089
2.  Does the Iowa Gambling Task Measure Executive Function? 
The Iowa Gambling Task (IGT) is assumed to measure executive functioning, but this has not been empirically tested by means of both convergent and discriminant validity. We used structural equation modeling (SEM) to test whether the IGT is an executive function (EF) task (convergent validity) and whether it is not related to other neuropsychological domains (discriminant validity). Healthy community-dwelling participants (N = 214) completed a comprehensive neuropsychological battery. We analyzed the conventional IGT metric and three alternative metrics based on the overall difference of advantageous minus disadvantageous choices made during the last 60 IGT responses and advantageous minus disadvantageous choices based on two specific decks of cards (D minus A). An a priori six-factor hierarchical model of neuropsychological functioning was confirmed with SEM. Attention and processing speed were grouped as “non-associative” factors. Fluency, executive functioning, visual learning/memory, and verbal learning/memory were grouped as higher-level “associative” factors. Of the non-associative factors, attention, but not speed, predicted IGT performance. When each associative factor was entered along with attention, only EF improved the model fit and that was only for metrics based on trials 41–100. SEM indicates metrics based on trails 1–100 are influenced by attention, and metrics based on trails 41–100 are influenced by attention and EF. Its associative strength with attention is twice that of EF. Conceptually, the IGT is a multi-trait task involving novel problem-solving and attentional domains to a greater extent, and executive functioning to a lesser extent.
PMCID: PMC3254153  PMID: 22015855
Iowa Gambling Task; Decision-making; Executive function; Neuropsychological evaluation; Structural equation modeling
3.  Target Optimization in Transcranial Direct Current Stimulation 
Transcranial direct current stimulation (tDCS) is an emerging neuromodulation therapy that has been experimentally determined to affect a wide range of behaviors and diseases ranging from motor, cognitive, and memory processes to depression and pain syndromes. The effects of tDCS may be inhibitory or excitatory, depending on the relative polarities of electrodes and their proximity to different brain structures. This distinction is believed to relate to the interaction of current flow with activation thresholds of different neural complexes. tDCS currents are typically applied via a single pair of large electrodes, with one (the active electrode) sited close to brain structures associated with targeted processes. To efficiently direct current toward the areas presumed related to these effects, we devised a method of steering current toward a selected area by reference to a 19-electrode montage applied to a high-resolution finite element model of the head. We used a non-linear optimization procedure to maximize mean current densities inside the left inferior frontal gyrus (IFG), while simultaneously restricting overall current, and median current densities within the accumbens. We found that a distributed current pattern could be found that would indeed direct current toward the IFG in this way, and compared it to other candidate 2-electrode configurations. Further, we found a combination of four anterior-posterior electrodes could direct current densities to the accumbens. We conclude that a similar method using multiple electrodes may be a useful means of directing current toward or away from specific brain regions and also of reducing tDCS side effects.
PMCID: PMC3474130  PMID: 23087654
tDCS; neuroplasticity; finite element model; optimization
4.  Altering Automatic Verbal Processes with Transcranial Direct Current Stimulation 
Background: Word retrieval during verbal fluency tasks invokes both automatic and controlled cognitive processes. A distinction has been made between the generation of words clusters and switches between such clusters on verbal fluency tasks. Clusters, defined by the reporting of contiguous words that constitute semantic or phonemic subcategories, are thought to reflect relatively automatic processing. In contrast, switching from one subcategory to another is thought to require a more controlled, effortful form of cognitive processing. Objective: In this single-blind, sham-controlled experiment, we investigated whether anodal and cathodal transcranial direct current stimulation (tDCS) can differentially modify controlled or automatic processes that support lexical retrieval, as assessed by clustering and switching on verbal fluency tasks, in 24 healthy right-handed adults. Methods: Participants were randomly assigned to receive 1 mA of either anodal (excitatory) or cathodal (inhibitory) active tDCS over the left dorsolateral prefrontal cortex in addition to sham stimulation over the same region in counterbalanced order. Participants engaged in various cognitive activities during the first 23 min of stimulation. Then, during the final segment of each 30-min session, they completed letter- and category-cued word fluency tasks. Results: Participants reported more words on category-cued word fluency tasks during anodal than sham stimulation (25.9 vs. 23.0 words; p = 0.055). They also showed a net increase in the number of clustered words during anodal stimulation compared to a net decrease during cathodal stimulation (1.3 vs. −1.5 words; p = 0.038). Conclusion: tDCS can selectively alter automatic aspects of speeded lexical retrieval in a polarity-dependent fashion during a category-guided fluency task.
PMCID: PMC3412390  PMID: 22888321
verbal fluency; clustering; switching; transcranial direct current stimulation
5.  Cranial Volume, Mild Cognitive Deficits, and Functional Limitations Associated with Diabetes in a Community Sample 
Diabetes is associated with dementia in older adults, but it remains unclear whether nondemented adults with type 2 diabetes show subtle abnormalities across cognition, neuroanatomy, and everyday functioning. Using the Aging, Brain Imaging, and Cognition study sample of 301 community-dwelling, middle-aged and older adults, we conducted a secondary analysis on 28 participants with and 150 participants without diabetes. We analyzed brain magnetic resonance imaging data, cognitive test performance, and informant ratings of personal and instrumental activities of daily living (PADL/IADL). Relative to controls, participants with diabetes had lower brain-to-intracranial volume ratios (69.3 ± 4.5% vs. 71.7 ± 4.6%; p < .02), and performed more poorly on measures of working memory, processing speed, fluency, and crystallized intelligence (all p <.05). Decrements in working memory and processing speed were associated with IADL limitations (p < .01). Nondemented adults with diabetes exhibit neuroanatomic and cognitive abnormalities. Their cognitive deficits correlate with everyday functional limitations.
PMCID: PMC2809552  PMID: 19942595
Diabetes; Endocrine disorders; Cognition; Neuropsychological testing; MRI; Function; Behavior
6.  White Matter Abnormalities and Cognition in a Community Sample 
White matter hyperintensities (WMH) can compromise cognition in older adults, but differences in sampling, WMH measurements, and cognitive assessments contribute to discrepant findings across studies. We examined linear and nonlinear effects of WMH volumes on cognition in 253 reasonably healthy adults. After adjusting for demographic characteristics and total brain volumes, WMH burden was not associated with cognition in those aged 20–59. In participants aged 60 and older, models accounted for ≥58% of the variance in performance on tests of working memory, processing speed, fluency, and fluid intelligence, and WMH volumes accounted for variance beyond that explained by age and other demographic characteristics. Larger increases in WMH burden over 5 years also were associated with steeper cognitive declines over the same interval. Results point to both age-related and age-independent effects of WMH on cognition in later life and suggest that the accumulation of WMH might partially explain normal age-related declines in cognition.
PMCID: PMC2765350  PMID: 19617597
White matter hyperintensities; Aging; Cognition; Cardiovascular disease

Results 1-6 (6)