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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.
Background
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.
Methods
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.
Findings
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.
Interpretation
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.  Confirmatory factor analysis reveals a latent cognitive structure common to bipolar disorder, schizophrenia, and healthy adults 
Bipolar disorders  2013;15(4):422-433.
Objective
We sought to determine whether a single hypothesized latent factor structure would characterize cognitive functioning in three distinct groups.
Methods
We assessed 576 adults (340 community controls, 126 with bipolar disorder, and 110 with schizophrenia) using 15 measures derived from nine cognitive tests. Confirmatory factor analysis (CFA) was conducted to examine the fit of a hypothesized six-factor model. The hypothesized factors included attention, psychomotor speed, verbal memory, visual memory, ideational fluency, and executive functioning.
Results
The six-factor model provided an excellent fit for all three groups [community controls root mean square error of approximation (RMSEA) < 0.048 and comparative fit index (CFI) = 0.99; adults with bipolar disorder RMSEA = 0.071 and CFI = 0.99; and adults with schizophrenia RMSEA = 0.06 and CFI = 0.98]. Alternate models that combined fluency with processing speed or verbal and visual memory reduced the goodness-of-fit. Multi-group CFA results supported factor invariance across the three groups.
Conclusions
Confirmatory factor analysis supported a single six-factor structure of cognitive functioning among patients with schizophrenia or bipolar disorder and community controls. While the three groups clearly differ in level of performance, they share a common underlying architecture of information processing abilities. These cognitive factors could provide useful targets for clinical trials of treatments that aim to enhance information processing in persons with neurological and neuropsychiatric disorders.
doi:10.1111/bdi.12075
PMCID: PMC4128168  PMID: 23656284
bipolar disorder; cognition; confirmatory factor analysis; invariance; latent variable analysis; neuropsychology; schizophrenia
3.  Prefrontal Brain Network Connectivity Indicates Degree of Both Schizophrenia Risk and Cognitive Dysfunction 
Schizophrenia Bulletin  2013;40(3):653-664.
Objective:
Cognitive dysfunction is a core feature of schizophrenia, and persons at risk for schizophrenia may show subtle deficits in attention and working memory. In this study, we investigated the relationship between integrity of functional brain networks and performance in attention and working memory tasks as well as schizophrenia risk.
Methods:
A total of 235 adults representing 3 levels of risk (102 outpatients with schizophrenia, 70 unaffected first-degree relatives of persons with schizophrenia, and 63 unrelated healthy controls [HCs]) completed resting-state functional magnetic resonance imaging and a battery of attention and working memory tasks (Brief Test of Attention, Hopkins Verbal Learning Test, and Brief Visuospatial Memory Test) on the same day. Functional networks were defined based on coupling with seeds in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and primary visual cortex. Networks were then dissected into regional clusters of connectivity that were used to generate individual interaction matrices representing functional connectivity within each network.
Results:
Both patients with schizophrenia and their first-degree relatives showed cognitive dysfunction compared with HCs. First canonicals indicated an inverse relationship between cognitive performance and connectivity within the DLPFC and MPFC networks. Multivariate analysis of variance revealed multivariate main effects of higher schizophrenia risk status on increased connectivity within the DLPFC and MPFC networks.
Conclusions:
These data suggest that excessive connectivity within brain networks coupled to the DLPFC and MPFC, respectively, accompany cognitive deficits in persons at risk for schizophrenia. This might reflect compensatory reactions in neural systems required for cognitive processing of attention and working memory tasks to brain changes associated with schizophrenia.
doi:10.1093/schbul/sbt077
PMCID: PMC3984516  PMID: 23778975
resting state; fMRI; default-mode network; attention; working memory
4.  Genotype–phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder 
Brain  2013;137(5):1282-1303.
Genotype-phenotype correlations for most monogenic neurological disorders are incompletely understood. Fu et al. draw upon data on 615 HPRT mutations, including 130 new cases, and their relationship to Lesch-Nyhan disease severity. The effect of mutations on hypoxanthine-guanine phosphoribosyltransferase activity accounts for much but not all of the phenotypic variability.
Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype–phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype–phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype–phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype–phenotype correlations for other disorders.
doi:10.1093/brain/awt202
PMCID: PMC3999711  PMID: 23975452
Lesch-Nyhan disease; genotype–phenotype correlations; neurogenetics
5.  Evidence of Semantic Clustering in Letter-Cued Word Retrieval 
Letter-cued word fluency is conceptualized as a phonemically guided word retrieval process. Accordingly, word clusters typically are defined solely by their phonemic similarity. We investigated semantic clustering in two letter-cued (P and S) word fluency task performances by 315 healthy adults, each for 1 min. Singular value decomposition (SVD) and generalized topological overlap measure (GTOM) were applied to verbal outputs to conservatively extract clusters of high frequency words. The results generally confirmed phonemic clustering. However, we also found considerable semantic/associative clusters of words (e.g., pen, pencil, and paper), and some words showed both phonemic and semantic associations within a single cluster (e.g., pair, pear, peach). We conclude that letter-cued fluency is not necessarily a purely phonemic word retrieval process. Strong automatic semantic activation mechanisms play an important role in letter-cued lexical retrieval. Theoretical conceptualizations of the word retrieval process with phonemic cues may also need to be re-examined in light of these analyses.
doi:10.1080/13803395.2013.845141
PMCID: PMC4227503  PMID: 24134125
verbal fluency; cued-word retrieval; semantic system; clustering; switching
6.  Reduced anterior cingulate gray matter volume and thickness in subjects with deficit schizophrenia 
Schizophrenia research  2013;150(0):484-490.
Background
Patients with deficit schizophrenia (D-SZ) differ from patients with the non-deficit form of schizophrenia (ND-SZ) in several aspects such as risk factors, neurobiological correlates, treatment response and clinical outcome. It has been debated if brain morphology could differentiate D-SZ from ND-SZ. Anterior cingulate gyrus (ACG) region regulates cognitive and emotional processing and past studies reported structural changes in this region in patients with SZ.
Methods
1.5-T 3D MRI scans were obtained from 18 D-SZ patients, 30 ND-SZ patients and 82 healthy controls (HCs). We used FreeSurfer-initalized labeled cortical distance mapping (FSLCDM) to measure ACG gray matter volume, cortical thickness, and area of the gray/white interface. Furthermore, cortical thickness was compared among the 3 groups using the pooled labeled cortical distance mapping (LCDM) method.
Results
The ACG cortex of the D-SZ group was thinner than the ND-SZ group. Pooled LCDM demonstrated that the ACG cortex was bilaterally thinner in both the ND-SZ group and the D-SZ group compared with the control group. The right ACG gray matter volume was significantly reduced in D-SZ patients as compared with healthy controls (p = 0.005
Conclusion
Our data suggest that qualitative, categorical differences in neuroanatomy may distinguish between deficit and non-deficit subtypes of schizophrenia.
doi:10.1016/j.schres.2013.07.036
PMCID: PMC4076020  PMID: 24035178
schizophrenia; deficit schizophrenia; cortical thickness; anterior cingulate cortex
7.  Outcomes of Early Delirium Diagnosis After General Anesthesia in the Elderly 
Anesthesia and analgesia  2013;117(2):471-478.
BACKGROUND
Postoperative delirium in the elderly, measured days after surgery, is associated with significant negative clinical outcomes. In this study, we evaluated the prevalence and in-hospital outcomes of delirium diagnosed immediately after general anesthesia and surgery in elderly patients.
METHODS
Consecutive English-speaking surgical candidates, aged 70 years or older, were prospectively enrolled during July to August 2010. After surgery, each participant was evaluated for a Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of delirium in the postanesthesia care unit (PACU) and repeatedly thereafter while hospitalized. Delirium in the PACU was evaluated for an independent association with change in cognitive function from preoperative baseline testing and discharge disposition.
RESULTS
Ninety-one (58% female) patients, 78% of whom were living independently before surgery, were found to have a prevalence of delirium in the PACU of 45% (41/91); 74% (14/19) of all delirium episodes detected during subsequent hospitalization started in the PACU. Early delirium was independently associated with impaired cognition (i.e., decreased category word fluency) relative to presurgery baseline testing (adjusted difference [95% confidence interval] for change in T-score: −6.02 [−10.58 to −1.45]; P = 0.01). Patients whose delirium had resolved by postoperative day 1 showed negative outcomes that were intermediate in severity between those who were never delirious during hospitalization and those whose delirium in the PACU persisted after transfer to hospital wards (adjusted probability [95% confidence interval] of discharge to institution: 3% [0%–10%], 26% [1%–51%], 39% [0%–81%] for the 3 groups, respectively).
CONCLUSIONS
Delirium in the PACU is common, but not universal. It is associated with subsequent delirium on the ward, and potentially with a decline in cognitive function and increased institutionalization at hospital discharge.
doi:10.1213/ANE.0b013e3182973650
PMCID: PMC4017627  PMID: 23757476
8.  A Neuropsychological Study of Personality: Trait Openness in Relation to Intelligence, Fluency, and Executive Functioning 
Openness is a personality trait that has been linked to intelligence and divergent thinking. DeYoung, Peterson, and Higgins (2005) theorized that trait Openness depends on dopamine function, especially in the prefrontal cortex. We tested their theory in 335 healthy adults by hypothesizing that individual differences in Openness would correlate more strongly with performance on tests of executive function than on tests of intelligence and fluency. However, Openness correlated more strongly with verbal/crystallized intelligence (Gc; r=0.44) than with executive functioning (r=0.16) and fluency (r=0.24). Further, the partial correlation between Openness and Gc increased from r=0.26 among young adults to r=0.53 among elderly adults. These findings suggest that Openness is more closely associated with the acquisition of broad verbal intellectual skills and knowledge than with executive abilities localized to a specific brain region or neurotransmitter system.
doi:10.1080/13803391003689770
PMCID: PMC2937090  PMID: 20408002
Openness; crystallized intelligence; fluid intelligence; personality; neuropsychology; prefrontal cortex; executive function
9.  Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an in vivo Neurochemistry Study with PET 
Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-Rs), dopamine transporter (DAT) binding potential (BP), and amphetamine (AMP)-induced dopamine release (DArel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects.
As compared with controls, DArel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D2-R increase in left ventral striatum. SERT binding potential in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS−OCD). In 3 subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DArel and 5-HT2A BP, when compared with TS−OCD subjects and normal controls.
The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DArel is a primary defect in TS (Singer et al, 2002). The finding of decreased SERT BP, and the possible elevation in 5-HT2aR in individuals with TS who had increased DArel, suggest a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.
doi:10.1038/sj.npp.1301528
PMCID: PMC3696501  PMID: 17987065
10.  Sex Differences in Cognition in Healthy Elderly Individuals 
Sex differences in patterns of cognitive test performance have been attributed to factors, such as sex hormones or sexual dimorphisms in brain structure, that change with normal aging. The current study examined sex differences in patterns of cognitive test performance in healthy elderly individuals. Cognitive test scores of 957 men and women (age 67–89), matched for overall level of cognitive test performance, age, education, and depression scale score, were compared. Men and women were indistinguishable on tests of auditory divided attention, category fluency, and executive functioning. In contrast, women performed better than men on tests of psychomotor speed and verbal learning and memory, whereas men outperformed women on tests of visuoconstruction and visual perception. Our finding that the pattern of sex differences in cognition observed in young adults is observed in old age has implications for future studies of both healthy elderly individuals and of those with cognitive disorders.
doi:10.1080/13825585.2012.690366
PMCID: PMC3518851  PMID: 22670852
Cognitive; sex differences; elderly; organizational effects; sexual dimorphism
11.  Impaired cortico-striatal functional connectivity in prodromal Huntington’s Disease 
Neuroscience Letters  2012;514(2):204-209.
Huntington’s Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD.
Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3 Tesla). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity.
Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy.
Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD.
doi:10.1016/j.neulet.2012.02.095
PMCID: PMC3331724  PMID: 22425717
12.  Effects of cognitive impairment on substance abuse treatment attendance: predictive validation of a brief cognitive screening measure 
Background and Objectives
Neuropsychological impairment among patients with substance use disorders (SUDs) contributes to poorer treatment processes and outcomes. However, neuropsychological assessment is typically not an aspect of patient evaluation in SUD treatment programs because it is prohibitively time and resource consuming. In a previous study, we examined the concurrent validity, classification accuracy, and clinical utility of a brief screening measure, the Montreal Cognitive Assessment (MoCA), in identifying cognitive impairment among SUD patients. To provide further evidence of criterion-related validity, MoCA classification should optimally predict a clinically relevant behavior or outcome among SUD patients. The purpose of this study was to examine the validity of the MoCA in predicting treatment attendance.
Methods
We compared previously-collected clinical assessment data on 60 SUD patients receiving treatment in a program of short duration and high intensity to attendance data obtained via medical chart review.
Results
Though the proportion of therapy sessions attended did not differ between groups, cognitively impaired subjects were significantly less likely than unimpaired subjects to attend all of their group therapy sessions.
Conclusion
These results complement our previous findings by providing further evidence of criterion-related validity of the MoCA in predicting a clinically relevant behavior (i.e., perfect attendance) among SUD patients.
Scientific Significance
The capacity of the MoCA to predict a clinically relevant behavior provides support for its validity as a brief cognitive screening measure.
doi:10.3109/00952990.2012.670866
PMCID: PMC3593077  PMID: 22443860
substance use disorder; addiction; cognitive screening measure; Montreal Cognitive Assessment
13.  Neuropsychological Functioning in Bipolar Disorder and Schizophrenia 
Biological psychiatry  2006;62(2):179-186.
Background
Some patients with bipolar disorder (BD) demonstrate neuropsychological deficits even when stable. However, it remains unclear whether these differ qualitatively from those seen in schizophrenia (SZ).
Method
We compared the nature and severity of cognitive deficits shown by 106 patients with SZ and 66 patients with BD to 316 healthy adults (NC). All participants completed a cognitive battery with 19 individual measures. After adjusting their test performance for age, sex, race, education, and estimated premorbid IQ, we derived regression-based T-scores for each measure and the six cognitive domains.
Results
Both patient groups performed significantly worse than NCs on most (BD) or all (SZ) cognitive tests and domains. The resulting effect sizes ranged from 0.37 to 1.32 (mean = 0.97) across tests for SZ patients and from 0.23 to 0.87 (mean = 0.59) for BD patients. The Pearson correlation of these effect sizes was 0.71 (p < 0.001).
Conclusions
Patients with bipolar disorder suffer from cognitive deficits that are milder but qualitatively similar to those of patients with schizophrenia. These findings support the notion that schizophrenia and bipolar disorder show greater phenotypic similarity in terms of the nature than severity of their neuropsychological deficits.
doi:10.1016/j.biopsych.2006.09.025
PMCID: PMC2041824  PMID: 17161829
bipolar disorder; schizophrenia; cognitive testing; neuropsychology; biomarker
14.  Levodopa is Not a Useful Treatment for Lesch-Nyhan Disease 
Lesch-Nyhan disease (LND) is characterized by dystonia, cognitive abnormalities, and self-injurious behavior. No effective therapies are available. LND is associated with a presynaptic dopaminergic deficit, but the reported effects of dopamine replacement therapy are conflicting. The current prospective open-label study assesses the effects of levodopa on both neurological and behavioral features of LND. All 6 study participants discontinued levodopa early, due to lack of effect and sometimes worsening of motor function. The results provide important clues for pathophysiological mechanisms and suggestions for future treatment options.
doi:10.1002/mds.23478
PMCID: PMC3523804  PMID: 21506156
Lesch-Nyhan disease; treatment; levodopa; dystonia; dyskinesias; self-injurious behavior
15.  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.
doi:10.1093/arclin/acr082
PMCID: PMC3254153  PMID: 22015855
Iowa Gambling Task; Decision-making; Executive function; Neuropsychological evaluation; Structural equation modeling
16.  Delineation of the motor disorder of Lesch–Nyhan disease 
Brain : a journal of neurology  2006;129(Pt 5):1201-1217.
Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.
doi:10.1093/brain/awl056
PMCID: PMC3508431  PMID: 16549399
cerebral palsy; choreoathetosis; dystonia; neurogenetics
17.  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.
doi:10.3389/fpsyt.2012.00090
PMCID: PMC3474130  PMID: 23087654
tDCS; neuroplasticity; finite element model; optimization
18.  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.
doi:10.3389/fpsyt.2012.00073
PMCID: PMC3412390  PMID: 22888321
verbal fluency; clustering; switching; transcranial direct current stimulation
19.  Mechanisms for phenotypic variation in Lesch–Nyhan disease and its variants 
Human genetics  2010;129(1):71-78.
Lesch–Nyhan disease is a neurogenetic disorder caused by mutation of the HPRT1 gene on the X chromosome. There is significant variation in the clinical phenotype, with more than 300 different known mutations. There are few studies that have addressed whether similar mutations result in similar phenotypes across different patients because hypoxanthine–guanine phosphoribosyltransferase (HGprt) deficiency is rare, and most mutations are unique or limited to individual families. However, recent studies have revealed multiple unrelated patients with similar mutations, providing an opportunity to examine genotype–phenotype correlations. We found significant variation among the clinical features of 10 patients from 8 unrelated families all carrying a mutation replacing guanine with adenine at base position 143 (c.143G>A) in the HPRT1 gene. This mutation results in replacement of arginine by histidine at amino acid position 48 (p.arg48his) in the HGprt enzyme. Biochemically, the enzyme exhibits reduced thermal integrity, a mechanism that may explain clinical variation. The literature reveals similar clinical variation among other patients with similar mutations, although the variation is relatively minor across the whole population of patients. Identifiable sources of clinical variation include known limitations of clinical ascertainment and mechanisms that affect residual enzyme activity and stability. These results are helpful for understanding genotype–phenotype correlations and discordance and likely are applicable to other neurogenetic disorders where similar variation occurs.
doi:10.1007/s00439-010-0901-9
PMCID: PMC3034646  PMID: 20981450
21.  Rapid Cognitive Screening of Patients with Substance Use Disorders 
To date, there has not been a time-efficient and resource-conscious way to identify cognitive impairment in patients with substance use disorders (SUD). The present study assesses the validity, accuracy, and clinical utility of a brief (10 min) screening instrument, the Montreal Cognitive Assessment (MoCA), in identifying cognitive impairment among SUD patients. The Neuropsychological Assessment Battery-Screening Module (NAB-SM), a 45-minute battery with known sensitivity to the mild-to-moderate deficits observed in SUD patients, was used as the reference criterion for determining agreement, rates of correct and incorrect decision classifications, and criterion-related validity for the MoCA. Classification accuracy of the MoCA, based on receiver-operating characteristic (ROC) analysis, was strong, with an area under the ROC curve = 0.86 [95% CI: 0.75-0.97]. The MoCA also showed acceptable sensitivity (83.3%) and specificity (72.9%) for the identification of cognitive impairment. Using a cut-off of 25 on the MoCA, the overall agreement was 75.0%; chance-corrected agreement (kappa) was 41.9%. These findings indicate that the MoCA provides a time-efficient and resource-conscious way to identify SUD patients with neuropsychological impairment, thus addressing a critical need in the addiction treatment research community.
doi:10.1037/a0017260
PMCID: PMC3144764  PMID: 19803633
22.  Gray matter in amnestic mild cognitive impairment: voxel-based morphometry 
Neuroreport  2010;21(4):259-263.
Multiple regression voxel-based morphometry analyses were used to examine the relationship between regional gray matter volumes and neurocognitive performance in 10 patients with amnestic mild cognitive impairment and 20 healthy age-matched controls. Cognitive functioning was assessed with seven standardized neuropsychological tests. Patients with amnestic mild cognitive impairment exhibited impaired cognitive performance (on the Mini Mental State Examination, tests of verbal fluency, verbal and spatial learning and memory, and visual-motor abilities) and reduced gray matter volume in the right temporal pole. Across all participants, better performance on several neuropsychological tests was associated with higher regional gray matter volumes. Voxel-based morphometry provides an operator-unbiased means to investigate volumetric differences, which may be related to impaired neuropsychological functioning.
doi:10.1097/WNR.0b013e328335642a
PMCID: PMC3041512  PMID: 20042900
aging; gray matter volume; mild cognitive impairment; neuropsychological assessment; temporal lobe; voxel-based morphometry
23.  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.
doi:10.1093/arclin/acp091
PMCID: PMC2809552  PMID: 19942595
Diabetes; Endocrine disorders; Cognition; Neuropsychological testing; MRI; Function; Behavior
24.  Aggression after Traumatic Brain Injury: Prevalence & Correlates 
Aggression after traumatic brain injury (TBI) is common but not well defined. Sixty-seven participants with first-time TBI were seen within three months of injury and evaluated for aggression. The prevalence of aggression was found to be 28.4% and to be predominantly verbal aggression. Post-TBI aggression was associated with new-onset major depression (p=0.02), poorer social functioning (p=0.04), and increased dependency on activities of daily living (p=0.03), but not with a history of substance abuse or adult/childhood behavioral problems. Implications of the study include early screening for aggression, evaluation for depression, and consideration of psychosocial support in aggressive patients.
doi:10.1176/appi.neuropsych.21.4.420
PMCID: PMC2918269  PMID: 19996251
25.  Predictors of New-Onset Depression after Mild Traumatic Brain Injury 
Mild traumatic brain injury (mTBI) is the most common form of TBI. Most people recover after mTBI but a small percentage continues to have persistent problems, predominantly depression. There is however minimal literature on the risk factors associated with mTBI depression. In a sample of 43 mTBI patients, followed longitudinally for one year the prevalence of new-onset depression was found to be 18%. Older age and presence of frontal subdural hemorrhage were the only two significant findings noted in the depressed group compared to the non-depressed group. Identifying risk factors for mTBI depression can aid in early diagnosis and treatment.
doi:10.1176/appi.neuropsych.22.1.100
PMCID: PMC2918274  PMID: 20160216

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