Faculty Bibliography

Background: Transcranial Direct Current Stimulation (TDCS)is a brain stimulation technique which some studies have suggested may improve cognition and decrease auditory hallucinations in patients with schizophrenia. We conducted a study of a study of effects of tDCS on cognition, symptoms, and brain connectivity in inpatients with relatively stable chronic schizophrenics in China who had substantial cognitive deficits but were not chosen for prominent auditory hallucinations. Method(s): Patients participated in a double blind study of 10 sessions of active or sham tDCS and followed up lasting up to 1 month. Patient were evaluated for cognitive changes by MATRICS, PASAT and COGSTATE, for symptoms on the PANSS scale, and for brain changes with fMRI for resting state and during active n-back task. Result(s): There were no significant (P<.05) changes in cognitive scores in active vs sham patients after 10 tDCS sessions compared to baseline, but MATRICS Speed of Processing scores and 1 back memory improved over testing times in the active tDCS group over several weeks (P<.05) and there were trends for improvement in other measures. The were no significant change in psychiatric symptoms. fMRI scans showed significant increases in brain activation in R and L middle frontal gurus and differences in activation on a n-back task after 10 sessions of active vs sham tDCS. Conclusion(s): Effects of tDCS in this Chinese sample did not replicate the marked cognitive improvement seen in our earlier U.S. study, but there were selective improvements in speed of processing and n-back. 10 sessions of tDCS produced significant effects on increasing brain activation in selected areas differentially in active vs sham treated subjects in resting state and during an active n-back task. 2 Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique which has shown cognitive and clinical effects in patients with schizophrenia and depression as well as controls, and there is preliminary evidence it may also effect brain networks. Its comparatively lower cost, low-side effects, and ease of administration may make it a more easily administered therapy to a wide population of patients, if efficacy can be consistently demonstrated. In an earlier study (Smith et al. 2015), in schizophrenic outpatients in the United States, we presented evidence from a double-blind study that 5 sessions of active 2 ma tDCS compared to Sham, produced statistically significant improvement in MATRICS battery scores. 3 Methods: We now report results from a larger double-blind study of active vs sham tDCS stimulation in 45 relatively stable inpatients with schizophrenia studied at the Shanghai Mental Health Center in China. Active and sham tDCS administration followed the procedures with placement of electrodes, current and other procedures described in detail in our previous published research (Smith et al. 2015). Placement of electrodes for tDCS had the anode placed over LDLPFC (F3) and the cathode over the contralateral supraorbital ridge (Fp2). The active tDCS group was stimulated with a 2 mA current for 20minutes. The sham group had stimulation with 2 mA lasting only 45 seconds, though the electrodes remained in place for 20 minutes. The main cognitive outcome measures were the composite and domain scores on the Chinese version of the MATRIC (MCCB) battery (Nuechterlein et al. 2008), which was administered at baseline, after 10 sessions of tDCS, and 2 and 4 weeks after completion of the 10^th session. Because the Chinese version of the MCCB does not contain the verbal working memory test (LNS), we used an additional task to test for verbal working memory, the Paced Auditory Serial Addition Task (PASAT)(Gronwall 1977), using the 3 second presentation module, which was evaluated at the same time points as the MATRICS battery. Additionally, we used components of the CogState battery (CS) using CS tasks - identification task, n-back (1-back/2-back). Patients were evaluated for changes in psychopathology with the PANSS scale at baseline and after completion of 10 tDCS sessions and 2 weeks and 4 weeks later. Changes in brain activation were evaluated with fMRI Brain Scans at baseline and after 10 sessions using a Siemens Trio 3.0 Tesla MRI scanner with a standard 32-channel head coil. fMRI data was evaluated for: a) Changes on resting state intensity activation, and b) Before and after 10 sessions of tDCS, participants perform 0 back and 2 back tasks while scanned in fMRI. Cortical activation during 0 back and 2 back tasks were analyzed to check the difference between low and high load tasks. For (a) resting state fMRI data were preprocessed by Configurable Pipeline for the Analysis of Connectomes. Group analysis was conducted by FMRIB's Software Library (FSL) proprietary mixed effects analysis (FLAMEO). Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>2.3 and a corrected cluster significance threshold of P=0.05. For (b) fMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.00, part of FSL. Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>2.3 and a corrected cluster significance threshold of P=0.05. 1 Results: Behavioral measures: There were no significant differences (P<=.05) in effect of Active vs. Sham tDCS on any cognitive measure tested shortly after completion of 10 sessions of stimulation. However, the active tDCS group showed trends for better improvement vs. sham group, on testing done at two and/or 4 weeks after 10 tDCS session. At the two-week time point the difference from baseline improvement scores of the MATRICS Overall Composite Score and Speed of Processing Domain score, as well as a measure of accuracy on CogState 1-back was significantly better in active than sham groups at uncorrected significance levels (P<.05). Brain Activation: In testing with the n-back during fMRI scans, in active tDCS group, we found significant improvement in accuracy of 0 back condition after 10 sessions of tDCS (p<0.01). In the active tDCS vs. sham group task activation decreased in right middle frontal gyrus after 10 sessions of tDCS for the 0 back condition. No changes were found under the 2 back condition. Comparing the 2 back and 0 back conditions, increased activation in bilateral middle frontal gyrus was evident after 10 sessions of active tDCS vs sham. In resting state brain scans, the active tDCS group vs sham showed significantly increased activation in the R middle frontal and superior gyrus and L middle frontal gyrus. [Figure presented] N=45, Active tDcs-24, sham tDCS=2. Analysis is result of mixed-model analysis including all subjects who had value for in the at baseline and after 10 sessions tDCS. Significance of difference between the active vs sham values at specific time point by t-test from mixed-model output: *P<=05 **P<=01. Benjamini-Hochberg corrected significance levels taking into account the three time-point comparisons: ^Asignificant at (a=.05) [Figure presented] 2 Discussion and Conclusion(s): The results of this study in Chinese schizophrenics did not replicate the immediate pro-cognitive effects directly after a series to tDCS sessions that we found in the U.S. sample but suggest possible pro-cognitive effects 2 or 4 weeks after treatment. The long term effects to tDCS on cognitive function reported in this and some other studies suggest that some of the positive effects of tDCS may require a consolidation period to improve some aspects of cognitive functions. The fMRI data show that the tDCS treatment had significant effects on brain activation, and the changes in n-back performance in the active tDCS group during fMRI scans suggest increased capacity for working memory performance. References: Gronwall DM (1977) Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 44: 367-73. Nuechterlein K, Green M, Kern R, Baade L, Barch D, Cohen J, Essock S, Fenton W, Frese F, Gold J, Goldberg T, Heaton R, Keefe R, Kraemer H, Seidman L, Stover E, Weinberger D, Young A, Zalcan S, Mardder S (2008) The MATRICS Consensus Cognitive Battery, Part 1: Test Selection, Reliability, and Validity. The American journal of psychiatry. Smith RC, Boules S, Mattiuz S, Youssef M, Tobe RH, Sershen H, Lajtha A, Nolan K, Amiaz R, Davis JM (2015) Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study. Schizophrenia research 168: 260-266.

Data sharing is increasingly recommended as a means of accelerating science by facilitating collaboration, transparency, and reproducibility. While few oppose data sharing philosophically, a range of barriers deter most researchers from implementing it in practice. To justify the significant effort required for sharing data, funding agencies, institutions, and investigators need clear evidence of benefit. Here, using the International Neuroimaging Data-sharing Initiative, we present a case study that provides direct evidence of the impact of open sharing on brain imaging data use and resulting peer-reviewed publications. We demonstrate that openly shared data can increase the scale of scientific studies conducted by data contributors, and can recruit scientists from a broader range of disciplines. These findings dispel the myth that scientific findings using shared data cannot be published in high-impact journals, suggest the transformative power of data sharing for accelerating science, and underscore the need for implementing data sharing universally.

Background: Transcranial direct current stimulation (tDCS) has been reported to improve cognition and symptoms in schizophrenia. The brain mechanisms underlying these effects have not been systematically explored. We report a doubleblind study which measured effects of tDCS on cognition, symptoms, and brain activation in schizophrenia. Methods: 41 Chinese schizophrenics were randomized to receive 10 sessions of Active or Sham tDCS. Cognition was evaluated with the MATRICS(MCCB), Paced Auditory Serial Addition Task and CogState. Psychiatric symptoms were evaluated with PANSS. Brain function were evaluated with fMRI at baseline and after 10 tDCS sessions for resting state changes in brain activation. Results: There were no strong effects (P<.05) of Active vs Sham tDCS on cognition, but there were significant (P<.01) effects on differences in brain activation assessed by fMRI. On MCCB, there were trends (P=.06) for Active tDCS vs. Sham tDCS to improve Speed of Processing. There were no effects of active vs sham tDCS on psychiatric symptoms. There were significant differences between active vs sham tDCS on resting state activation in several brain areas including middle frontal gyrus, superior frontal gyrus and superior and inferior parietal gyrus; active tDCS increased and sham tDCS decreased activation. There were significant relationships between changes in several MCCB scores and changes in brain activation in specific areas. Conclusions: tDCS had significant effects on resting state brain activation which were significantly related to changes in MCCB. However, in this sample 10 sessions of active vs sham tDCS did not show marked effects on overall cognitive function

Complementing long-standing traditions centered on histology, fMRI approaches are rapidly maturing in delineating brain areal organization at the macroscale. The non-human primate (NHP) provides the opportunity to overcome critical barriers in translational research. Here, we establish the data requirements for achieving reproducible and internally valid parcellations in individuals. We demonstrate that functional boundaries serve as a functional fingerprint of the individual animals and can be achieved under anesthesia or awake conditions (rest, naturalistic viewing), though differences between awake and anesthetized states precluded the detection of individual differences across states. Comparison of awake and anesthetized states suggested a more nuanced picture of changes in connectivity for higher-order association areas, as well as visual and motor cortex. These results establish feasibility and data requirements for the generation of reproducible individual-specific parcellations in NHPs, provide insights into the impact of scan state, and motivate efforts toward harmonizing protocols.

We discuss the factors that encouraged us to examine the question of whether exercise training has a positive influence on cognitive health of older adults in 2003. At that time there was a substantial literature on exercise and cognition. However, cognitive assessment instruments, exercise protocols (including type of exercise, length, and intensity of exercise programs), and subject-selection criteria differed widely. Our meta-analysis enabled us to examine both the main question under study-exercise effects on cognition-and potential moderators of this effect. Several interesting findings, which are briefly detailed in the present article, were revealed by our analyses. The current article also examines where the literature has gone since our 2003 article.

We extend the notion of an influence or hat matrix to regression with functional responses and scalar predictors. For responses depending linearly on a set of predictors, our definition is shown to reduce to the conventional influence matrix for linear models. The pointwise degrees of freedom, the trace of the pointwise influence matrix, are shown to have an adaptivity property that motivates a two-step bivariate smoother for modeling nonlinear dependence on a single predictor. This procedure adapts to varying complexity of the nonlinear model at different locations along the function, and thereby achieves better performance than competing tensor product smoothers in an analysis of the development of white matter microstructure in the brain.