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1.  Movement related slow cortical potentials in severely paralyzed chronic stroke patients 
Movement-related slow cortical potentials (SCPs) are proposed as reliable and immediate indicators of cortical reorganization in motor learning. SCP amplitude and latency have been reported as markers for the brain's computational effort, attention and movement planning. SCPs have been used as an EEG signature of motor control and as a main feature in Brain-Machine-Interfaces (BMIs). Some reports suggest SCPs are modified following stroke. In this study, we investigated movement-related SCPs in severe chronic stroke patients with no residual paretic hand movements preceding and during paretic (when they try to move) and healthy hand movements. The aim was to identify SCP signatures related to cortex integrity and complete paralysis due to stroke in the chronic stage. Twenty severely impaired (no residual finger extension) chronic stoke patients, of whom ten presented subcortical and ten cortical and subcortical lesions, underwent EEG and EMG recordings during a cue triggered hand movement (open/close) paradigm. SCP onset appeared and peaked significantly earlier during paretic hand movements than during healthy hand movements. Amplitudes were significantly larger over the midline (Cz, Fz) for paretic hand movements while contralateral (C4, F4) and midline (Cz, Fz) amplitudes were significantly larger than ipsilateral activity for healthy hand movements. Dividing the participants into subcortical only and mixed lesioned patient groups, no significant differences observed in SCP amplitude and latency between groups. This suggests lesions in the thalamocortical loop as the main factor in SCP changes after stroke. Furthermore, we demonstrated how, after long-term complete paralysis, post-stroke intention to move a paralyzed hand resulted in longer and larger SCPs originating in the frontal areas. These results suggest SCP are a valuable feature that should be incorporated in the design of new neurofeedback strategies for motor neurorehabilitation.
doi:10.3389/fnhum.2014.01033
PMCID: PMC4295525  PMID: 25642177
stroke; movement related slow cortical potentials; EEG; movement preparation; intention to move
2.  Neurofeedback of slow cortical potentials: neural mechanisms and feasibility of a placebo-controlled design in healthy adults 
To elucidate basic mechanisms underlying neurofeedback we investigated neural mechanisms of training of slow cortical potentials (SCPs) by considering EEG- and fMRI. Additionally, we analyzed the feasibility of a double-blind, placebo-controlled design in NF research based on regulation performance during treatment sessions and self-assessment of the participants. Twenty healthy adults participated in 16 sessions of SCPs training: 9 participants received regular SCP training, 11 participants received sham feedback. At three time points (pre, intermediate, post) fMRI and EEG/ERP-measurements were conducted during a continuous performance test (CPT). Performance-data during the sessions (regulation performance) in the treatment group and the placebo group were analyzed. Analysis of EEG-activity revealed in the SCP group a strong enhancement of the CNV (electrode Cz) at the intermediate assessment, followed by a decrease back to baseline at the post-treatment assessment. In contrast, in the placebo group a continuous but smaller increase of the CNV could be obtained from pre to post assessment. The increase of the CNV in the SCP group at intermediate testing was superior to the enhancement in the placebo group. The changes of the CNV were accompanied by a continuous improvement in the test performance of the CPT from pre to intermediate to post assessment comparable in both groups. The change of the CNV in the SCP group is interpreted as an indicator of neural plasticity and efficiency while an increase of the CNV in the placebo group might reflect learning and improved timing due to the frequent task repetition. In the fMRI analysis evidence was obtained for neuronal plasticity. After regular SCP neurofeedback activation in the posterior parietal cortex decreased from the pre- to the intermediate measurement and increased again in the post measurement, inversely following the U-shaped increase and decrease of the tCNV EEG amplitude in the SCP-trained group. Furthermore, we found a localized increase of activity in the anterior cingulate cortex (ACC). Analyses of the estimation of treatment assignment by the participants indicate feasibility of blinding. Participants could not assess treatment assignment confidently. Participants of the SCP-group improved regulation capability during treatment sessions (in contrast to the participants of the placebo-group), although regulation capability appeared to be instable, presumably due to diminished confidence in the training (SCP- or sham-training). Our results indicate that SCP training in healthy adults might lead to functional changes in neuronal circuits serving cognitive preparation even after a limited number of sessions.
doi:10.3389/fnhum.2014.00990
PMCID: PMC4263073  PMID: 25566020
neurofeedback; EEG-biofeedback; SCP training; fMRI; CNV; anterior cingulate cortex
3.  Neural Congruency Effects in the Multi-Source Interference Task Vanish in Healthy Youth after Controlling for Conditional Differences in Mean RT 
PLoS ONE  2013;8(4):e60710.
According to the conflict monitoring model of cognitive control, reaction time (RT) in distracter interference tasks (e.g., the Stroop task) is a more precise index of response conflict than stimulus congruency (incongruent vs. congruent). The model therefore predicts that RT should be a reliable predictor of activity in regions of the posterior medial frontal cortex (pMFC) that are posited to detect response conflict. In particular, pMFC activity should be (a) greater in slow-RT than in fast-RT trials within a given task condition (e.g., congruent) and (b) equivalent in RT-matched trials from different conditions (i.e., congruent and incongruent trials). Both of these effects have been observed in functional magnetic resonance imaging (MRI) studies of adults. However, neither effect was observed in a recent study of healthy youth, suggesting that (a) the model does not accurately describe the relationship between RT and pMFC activity in this population or (b) the recent study was characterized by high variability due to a relatively small sample size. To distinguish between these possibilities, we asked a relatively large group of healthy youth (n = 28) to perform a distracter interference task - the multi-source interference task (MSIT) - while we recorded their brain activity with functional MRI. In this relatively large sample, both of the model’s predictions were confirmed. We conclude that the model accurately describes the relationship between pMFC activity and RT in healthy youth, but that additional research is needed to determine whether processes unrelated to response conflict contribute to this relationship.
doi:10.1371/journal.pone.0060710
PMCID: PMC3629025  PMID: 23613739
4.  An Exploratory Pilot Study of the Relationship between Neural Correlates of Cognitive Control and Reduction in Cigarette Use among Treatment-Seeking Adolescent Smokers 
Despite high rates of tobacco use during adolescence, few empirically validated smoking cessation strategies exist for adolescent smokers. Developing an understanding of the neural underpinnings of cognitive control processes in adolescent smokers, and their relationship to quit behaviors, may help advance the development of enhanced behavioral and pharmacological therapies. The current pilot study explored the relationship between brain responses during performance of the Stroop color-word interference task and reduction in tobacco use (as measured by changes in cotinine levels) in treatment-seeking adolescent smokers participating in a high-school-based smoking-cessation program. Eleven adolescent daily smokers participated in a pre-quit session during which neural activity in response to congruent and incongruent events in a Stroop task was examined using functional magnetic resonance imaging (fMRI). Changes in urine cotinine levels from pre-quit baseline to end of treatment were calculated and correlated with brain activity. Adolescents with greater activation in the inferior frontal gyrus, insula, thalamus and anterior cingulate had greater reductions in cotinine levels. The preliminary observation of a relationship between treatment outcome and neural correlates of cognitive control prior to treatment onset provides insight into individual differences in adolescent brain function that might relate importantly to treatment outcome.
doi:10.1037/a0032479
PMCID: PMC4106014  PMID: 23586458
Adolescent; Stroop; cigarette; smoking; treatment
5.  Midbrain-Driven Emotion and Reward Processing in Alcoholism 
Neuropsychopharmacology  2013;38(10):1844-1853.
Alcohol dependence is associated with impaired control over emotionally motivated actions, possibly associated with abnormalities in the frontoparietal executive control network and midbrain nodes of the reward network associated with automatic attention. To identify differences in the neural response to alcohol-related word stimuli, 26 chronic alcoholics (ALC) and 26 healthy controls (CTL) performed an alcohol-emotion Stroop Match-to-Sample task during functional MR imaging. Stroop contrasts were modeled for color-word incongruency (eg, word RED printed in green) and for alcohol (eg, BEER), positive (eg, HAPPY) and negative (eg, MAD) emotional word content relative to congruent word conditions (eg, word RED printed in red). During color-Stroop processing, ALC and CTL showed similar left dorsolateral prefrontal activation, and CTL, but not ALC, deactivated posterior cingulate cortex/cuneus. An interaction revealed a dissociation between alcohol-word and color-word Stroop processing: ALC activated midbrain and parahippocampal regions more than CTL when processing alcohol-word relative to color-word conditions. In ALC, the midbrain region was also invoked by negative emotional Stroop words thereby showing significant overlap of this midbrain activation for alcohol-related and negative emotional processing. Enhanced midbrain activation to alcohol-related words suggests neuroadaptation of dopaminergic midbrain systems. We speculate that such tuning is normally associated with behavioral conditioning to optimize responses but here contributed to automatic bias to alcohol-related stimuli.
doi:10.1038/npp.2013.102
PMCID: PMC3746685  PMID: 23615665
Alcohol & Alcoholism; attentional bias; Biological Psychiatry; Cognition; cognitive control; emotion and reward; functional connectivity; Imaging; Clinical or Preclinical; neural network; functional connectivity; functional MRI; automatic attentional bias; alcohol; emotion; Stroop task; Alcohol Use Disorder
6.  Atypical Neural Activity during Inhibitory Processing in Substance-Naïve Youth Who Later Experience Alcohol-Induced Blackouts 
Drug and alcohol dependence  2012;128(3):243-249.
BACKGROUND
Alcohol-induced blackouts are associated with the development of alcohol abuse and dependence, so it is important to consider potential neurobiological risk factors for experiencing this problem prior to the onset of substance use. This study examines whether neural activity during inhibitory processing might be atypical in substance-naïve youth who later experience alcohol-induced blackouts.
METHODS
We examined inhibitory processing during fMRI with a go/no-go task that requires withholding a prepotent response in substance-naïve youth who would later transition into heavy drinking (n=40) and youth who remain abstinent (n=20). After approximately 5 years of annual follow-up assessments, youth were classified as nondrinkers (n=20), and heavy drinking youth were classified as having experienced an alcohol-induced blackout (blackout+; n=20) or not (blackout−; n=20). Groups were matched on demographic variables, and youth who experienced blackouts were matched on follow-up substance use.
RESULTS
Prior to initiating substance use, blackout+ youth showed greater activation during inhibitory processing than nondrinkers and blackout− youth in frontal and cerebellar brain regions. Mean activation during correct inhibitory responses relative to go responses in the left and right middle frontal gyri at baseline predicted future blackout experience, after controlling for follow-up externalizing behaviors and lifetime alcohol consumption.
CONCLUSIONS
Substance-naïve adolescents who later experience alcohol-induced blackouts show increased neural effort during inhibitory processing, as compared to adolescents who go on to drink at similar levels but do not experience blackouts and healthy, nondrinking controls, suggesting a neurobiological vulnerability to alcohol-induced memory impairments.
doi:10.1016/j.drugalcdep.2012.09.003
PMCID: PMC3552086  PMID: 23021773
Adolescence; Substance use; Neuroimaging; Blackouts; Alcohol; fMRI
7.  Neural responses to incongruency in a blocked-trial Stroop fMRI task in major depressive disorder 
Journal of affective disorders  2012;143(1-3):241-247.
Background
Patients with major depressive disorder (MDD) perform poorly on the Stroop task, which is a measure of the executive control of attention, with impaired interference resolution. The neural correlates of this deficit are not well described. To examine how this deficit relates to pathophysiological abnormalities in MDD, we conducted an fMRI Stroop study comparing MDD subjects to controls.
Methods
Forty-two unmedicated patients with current MDD and 17 control subjects underwent fMRI scanning with a color-word Stroop task. Subjects assessed font color during alternating color identification (ex. ‘XXXX’ in blue) and incongruent color/word blocks (ex. the word ‘red’ in blue). We examined neural activation that was greater in incongruent than color identification blocks (Z>2.3 and corrected p<0.05), controlling for trial-by-trial reaction time.
Results
Compared to controls, MDD subjects exhibited lower activation during incongruent blocks across multiple brain regions, including middle frontal gyrus, paracingulate and posterior cingulate, precuneus, occipital regions, and brain stem. No brain regions were identified in which MDD subjects were more active than controls during incongruent blocks.
Limitations
Not all MDD subjects were antidepressant-naïve.
Conclusions
Brain regions related to executive function, visual processing, and semantic processing are less active during processing of incongruent stimuli in MDD subjects as compared to controls. Deficits of attention in MDD may be the product of a failure to maintain activity across a distributed network in a sustained manner, as is required over the sequential trials in this block design. Further studies may clarify whether the abnormalities represent a trait or state deficit.
doi:10.1016/j.jad.2012.05.016
PMCID: PMC3501555  PMID: 22995943
Stroop task; functional magnetic resonance imaging; depression; executive function; incongruency; attention
8.  Fibromyalgia Patients Had Normal Distraction Related Pain Inhibition but Cognitive Impairment Reflected in Caudate Nucleus and Hippocampus during the Stroop Color Word Test 
PLoS ONE  2014;9(10):e108637.
The mechanisms causing cognitive problems in chronic pain patients are not well understood. We used the Stroop color word task (SCWT) to investigate distraction-induced analgesia, cognitive performance, and cerebral activation patterns in 29 fibromyalgia (FM) patients (mean age 49.8 years, range 25–64 years) and 31 healthy controls (HC) (mean age 46.3 years, range 20–63 years). In the first study, SCWT was used to investigate distraction-induced analgesia in FM patients. Two versions of the task were applied, one with only congruent color-word images and one with incongruent images. Pressure pain thresholds were assessed using a pressure algometer before, during, and following SCWT. In the second study, reaction times (RTs) were assessed and functional magnetic resonance imaging (fMRI) was used to investigate cerebral activation patterns in FM patients and HC during the SCWT. An event-related task mixing incongruent and congruent images was used. In study one, we found reduced pressure pain sensitivity during SCWT in both groups alike and no statistically significant differences were seen between the incongruent and congruent conditions. The study two revealed longer RTs during the incongruent compared to the congruent condition in both groups. FM patients had longer RTs than HC in both conditions. Furthermore, we found a significant interaction between group and congruency; that is, the group differences in RTs were more pronounced during the incongruent condition. This was reflected in a reduced activation of the caudate nucleus, lingual gyrus, temporal areas, and the hippocampus in FM patients compared to HC. In conclusion, we found normal pain inhibition during SWTC in FM patients. The cognitive difficulties seen in FM patients, reflected in longer RTs, were related to reduced activation of the caudate nucleus and hippocampus during incongruent SCWT, which most likely affected the mechanisms of cognitive learning in FM patients.
doi:10.1371/journal.pone.0108637
PMCID: PMC4183523  PMID: 25275449
9.  Reaction time in Stroop test in Nepalese Medical Students 
Background: Stroop test is one of the widely used tests in cognitive psychology. It is used both in healthy population and also in patients to assess the selective attention. The selective attention as assessed by it is also found to be altered in bilinguals. In Nepal, most of the students are bilingual since most of the courses are in English language. Thus, they learn English language along with their native languages. This study is aimed to assess the selective attention in healthy Nepalese medical students.
Objective: To study the reaction time in stroop test in medical students of Nepal.
Materials and Methods: This study was conducted on 30 healthy male students aged 23.1±2.8 yrs. They were asked to read congruent (red printed in red ink) and incongruent (red printed in blue ink) tests in classical stroop cards. The reaction times for both the tests were calculated. Median with inter-quartile range was obtained for reaction time. Wilcoxon’s Sign Rank Test was used to compare reaction time and errors between congruent and incongruent cards.
Results: The subjects took 82.10 (63.75-107.76) sec longer to read incongruent stroop test (p<0.001). The error made was 0 in congruent stroop test and 1.5 (0-3) in incongruent stroop test (p<0.001). No students made error in the congruent test but 60% (18) of students made error in incongruent test (p<.001) and interference percentage in incongruent was 157 (115.32-213.50)%.
Conclusion: The reaction time and interferences were more in incongruent stroop test than congruent test. The interference was very high than that of previous literature’s value. This indicates that Nepalese students have delayed attention while performing classical English version of stroop test.
doi:10.7860/JCDR/2014/10615.4891
PMCID: PMC4225876  PMID: 25386424
Delayed reaction time; Nepalese medical students; Stroop test
10.  Preterm birth and structural brain alterations in early adulthood 
NeuroImage : Clinical  2014;6:180-191.
Alterations in cortical development and impaired neurodevelopmental outcomes have been described following very preterm (VPT) birth in childhood and adolescence, but only a few studies to date have investigated grey matter (GM) and white matter (WM) maturation in VPT samples in early adult life. Using voxel-based morphometry (VBM) we studied regional GM and WM volumes in 68 VPT-born individuals (mean gestational age 30 weeks) and 43 term-born controls aged 19–20 years, and their association with cognitive outcomes (Hayling Sentence Completion Test, Controlled Oral Word Association Test, Visual Reproduction test of the Wechsler Memory Scale-Revised) and gestational age. Structural MRI data were obtained with a 1.5 Tesla system and analysed using the VBM8 toolbox in SPM8 with a customized study-specific template. Similarly to results obtained at adolescent assessment, VPT young adults compared to controls demonstrated reduced GM volume in temporal, frontal, insular and occipital areas, thalamus, caudate nucleus and putamen. Increases in GM volume were noted in medial/anterior frontal gyrus. Smaller subcortical WM volume in the VPT group was observed in temporal, parietal and frontal regions, and in a cluster centred on posterior corpus callosum/thalamus/fornix. Larger subcortical WM volume was found predominantly in posterior brain regions, in areas beneath the parahippocampal and occipital gyri and in cerebellum. Gestational age was associated with GM and WM volumes in areas where VPT individuals demonstrated GM and WM volumetric alterations, especially in temporal, parietal and occipital regions. VPT participants scored lower than controls on measures of IQ, executive function and non-verbal memory. When investigating GM and WM alterations and cognitive outcome scores, subcortical WM volume in an area beneath the left inferior frontal gyrus accounted for 14% of the variance of full-scale IQ (F = 12.9, p < 0.0001). WM volume in posterior corpus callosum/thalamus/fornix and GM volume in temporal gyri bilaterally, accounted for 21% of the variance of executive function (F = 9.9, p < 0.0001) and WM in the posterior corpus callosum/thalamus/fornix alone accounted for 17% of the variance of total non-verbal memory scores (F = 9.9, p < 0.0001). These results reveal that VPT birth continues to be associated with altered structural brain anatomy in early adult life, although it remains to be ascertained whether these changes reflect neurodevelopmental delays or long lasting structural alterations due to prematurity. GM and WM alterations correlate with length of gestation and mediate cognitive outcome.
Highlights
•Preterm birth is associated with brain alterations in early adulthood•Preterm birth affects maturation of both white and grey matter•Volume alterations are observed in temporal, frontal, parietal and occipital areas•Regional alterations mediate the effects of preterm birth on cognitive functioning
doi:10.1016/j.nicl.2014.08.005
PMCID: PMC4215396  PMID: 25379430
Very preterm; White matter; Grey matter; Brain volume; Cognitive outcome
11.  Neural Activation during Inhibition Predicts Initiation of Substance Use in Adolescence 
Drug and alcohol dependence  2011;119(3):216-223.
Background
Problems inhibiting non-adaptive behaviors have been linked to an increased risk for substance use and other risk taking behaviors in adolescence. This study examines the hypothesis that abnormalities in neural activation during inhibition in early adolescence may predict subsequent substance involvement.
Methods
Thirty eight adolescents from local area middle schools, ages 12–14, with very limited histories of substance use, underwent functional magnetic resonance imaging (fMRI) as they performed a go/no-go task of response inhibition and response selection. Adolescents and their parents were then followed annually with interviews covering substance use and other behaviors. Based on follow-up data, youth were classified as transitioning to heavy use of alcohol (TU; n=21), or as healthy controls (CON; n=17).
Results
At baseline, prior to the onset of use, youth who later transitioned into heavy use of alcohol showed significantly less activation than those who went on to remain non to minimal users throughout adolescence. Activation reductions in TU at baseline were seen on no-go trials in 12 brain regions, including right inferior frontal gyrus, left dorsal and medial frontal areas, bilateral motor cortex, cingulate gyrus, left putamen, bilateral middle temporal gyri, and bilateral inferior parietal lobules (corrected p < .01, each cluster ≥ 32 contiguous voxels).
Conclusions
These results support the hypothesis that less neural activity during response inhibition demands predicts future involvement with problem behaviors such as alcohol and other substance use.
doi:10.1016/j.drugalcdep.2011.06.019
PMCID: PMC3208054  PMID: 21782354
alcohol; adolescence; fMRI; inhibition; go/no-go
12.  Interindividual Differences in Mid-Adolescents in Error Monitoring and Post-Error Adjustment 
PLoS ONE  2014;9(2):e88957.
A number of studies have concluded that cognitive control is not fully established until late adolescence. The precise differences in brain function between adults and adolescents with respect to cognitive control, however, remain unclear. To address this issue, we conducted a study in which 185 adolescents (mean age (SD) 14.6 (0.3) years) and 28 adults (mean age (SD) 25.2 (6.3) years) performed a single task that included both a stimulus-response (S-R) interference component and a task-switching component. Behavioural responses (i.e. reaction time, RT; error rate, ER) and brain activity during correct, error and post-error trials, detected by functional magnetic resonance imaging (fMRI), were measured. Behaviourally, RT and ER were significantly higher in incongruent than in congruent trials and in switch than in repeat trials. The two groups did not differ in RT during correct trials, but adolescents had a significantly higher ER than adults. In line with similar RTs, brain responses during correct trials did not differ between groups, indicating that adolescents and adults engage the same cognitive control network to successfully overcome S-R interference or task switches. Interestingly, adolescents with stronger brain activation in the bilateral insulae during error trials and in fronto-parietal regions of the cognitive control network during post-error trials did have lower ERs. This indicates that those mid-adolescents who commit fewer errors are better at monitoring their performance, and after detecting errors are more capable of flexibly allocating further cognitive control resources. Although we did not detect a convincing neural correlate of the observed behavioural differences between adolescents and adults, the revealed interindividual differences in adolescents might at least in part be due to brain development.
doi:10.1371/journal.pone.0088957
PMCID: PMC3928333  PMID: 24558455
13.  Neural Correlates of Stress and Favorite-Food Cue Exposure in Adolescents: A Functional Magnetic Resonance Imaging Study 
Human brain mapping  2012;34(10):2561-2573.
Adolescence is a critical period of neurodevelopment for stress and appetitive processing, as well as a time of increased vulnerability to stress and engagement in risky behaviors. The current study was conducted to examine brain activation patterns during stress and favorite-food-cue experiences relative to a neutral-relaxing condition in adolescents. Functional magnetic resonance imaging was employed using individualized script-driven guided imagery to compare brain responses to such experiences in 43 adolescents. Main effects of condition and gender were found, without a significant gender-by-condition interaction. Stress imagery, relative to neutral, was associated with activation in the caudate, thalamus, left hippocampus/parahippocampal gyrus, midbrain, left superior/middle temporal gyrus, and right posterior cerebellum. Appetitive imagery of favorite food was associated with caudate, thalamus, and midbrain activation compared to the neutral-relaxing condition. To understand neural correlates of anxiety and craving, subjective (self-reported) measures of stress-induced anxiety and favorite-food-cue-induced craving were correlated with brain activity during stress and appetitive food-cue conditions, respectively. High self-reported stress-induced anxiety was associated with hypoactivity in the striatum, thalamus, hippocampus and midbrain. Self-reported favorite-food-cue-induced craving was associated with blunted activity in cortical-striatal regions, including the right dorsal and ventral striatum, medial prefrontal cortex, motor cortex, and left anterior cingulate cortex. The current findings in adolescents indicate the activation of predominantly subcortical-striatal regions in the processing of stressful and appetitive experiences and link hypoactive striatal circuits to self-reported stress-induced anxiety and cue-induced favorite-food craving.
doi:10.1002/hbm.22089
PMCID: PMC3479342  PMID: 22504779
Stress; Psychological; Adolescence; Motivation; Appetite; fMRI
14.  Cognitive and Electrophysiological Correlates of the Bilingual Stroop Effect 
The color word Stroop effect in bilinguals is commonly half the magnitude when the written and naming languages are different (between) than when they are the same (within). This between-within language Stroop difference (BWLS) is likened to a response set effect, with greater response conflict for response relevant than irrelevant words. The nature of the BWLS was examined using a bilingual Stroop task. In a given block (Experiment 1), color congruent and incongruent words appeared in the naming language or not (single), or randomly in both languages (mixed). The BWLS effect was present for both balanced and unbalanced bilinguals, but only partially supported a response set explanation. As expected, color incongruent trials during single language blocks, lead to slower response times within than between languages. However, color congruent trials during mixed language blocks led to slower times between than within languages, indicating that response-irrelevant stimuli interfered with processing. In Experiment 2, to investigate the neural timing of the BWLS effect, event related potentials were recorded while balanced bilinguals named silently within and between languages. Replicating monolingual findings, an N450 effect was observed with larger negative amplitude for color incongruent than congruent trials (350–550 ms post-stimulus onset). This effect was equivalent within and between languages, indicating that color words from both languages created response conflict, contrary to a strict response set effect. A sustained negativity (SN) followed with larger amplitude for color incongruent than congruent trials, resolving earlier for between than within language Stroop. This effect shared timing (550–700 ms), but not morphology or scalp distribution with the commonly reported sustained potential. Finally, larger negative amplitude (200–350 ms) was observed between than within languages independent of color congruence. This negativity, likened to a no-go N2, may reflect processes of inhibitory control that facilitate the resolution of conflict at the SN, while the N450 reflects parallel processing of distracter words, independent of response set (or language). In sum, the BWLS reflects brain activity over time with contributions from language and color conflict at different points.
doi:10.3389/fpsyg.2012.00081
PMCID: PMC3317261  PMID: 22485099
bilingual; Stroop; response conflict; between language interference; N450; N2; event related potential; language dominance
15.  Adolescents at Risk for Alcohol Abuse Demonstrate Altered Frontal Lobe Activation during Stroop Performance 
Background
Children and adolescents, family history positive (FH+) for alcoholism, exhibit differences in brain structure and functional activation when compared to family history negative (FH-) counterparts. Given that frontal brain regions, and associated reciprocal connections with limbic structures, undergo the most dramatic maturational changes during adolescence, the objective of this study was to compare functional brain activation during a frontally-mediated test of response inhibition in 32 adolescents separated into low-risk (FH-) and high-risk (FH+) groups.
Methods
Functional magnetic resonance (fMRI) blood oxygen level dependent (BOLD) data were acquired at 1.5 Tesla during performance of Stroop Color Naming, Word Reading and Interference. Preprocessing and statistical analyses, covaried for age, were conducted in SPM99 using a search territory that included superior, middle, and inferior frontal gyri (trigone region), anterior cingulate gyrus, and left and right amygdala.
Results
Significantly greater activation in the fronto-limbic search territory was observed in FH+ relative to FH- subjects during Stroop Interference. In addition, a significant regression between brain activation and family history density was observed, with a greater density being associated with increased activation in regions including middle frontal gyrus (BA9) and cingulate gyrus (BA24).
Conclusions
These data demonstrate a significant influence of FH status on brain activation during the performance of a response inhibition task, perhaps reflecting a neurobiological vulnerability associated with FH status that may include reduced neuronal efficiency and/or recruitment of additional neuronal resources. These findings are important given that the adolescent developmental period is already associated with reduced inhibitory capacity, even prior to the onset of alcohol use.
doi:10.1111/j.1530-0277.2010.01337.x
PMCID: PMC3058318  PMID: 21073483
frontal lobe; fMRI; FH; alcohol abuse; adolescence
16.  Regional brain gray and white matter changes in perinatally HIV-infected adolescents☆ 
NeuroImage : Clinical  2013;4:29-34.
Despite the success of antiretroviral therapy (ART), perinatally infected HIV remains a major health problem worldwide. Although advance neuroimaging studies have investigated structural brain changes in HIV-infected adults, regional gray matter (GM) and white matter (WM) volume changes have not been reported in perinatally HIV-infected adolescents and young adults. In this cross-sectional study, we investigated regional GM and WM changes in 16 HIV-infected youths receiving ART (age 17.0 ± 2.9 years) compared with age-matched 14 healthy controls (age 16.3 ± 2.3 years) using magnetic resonance imaging (MRI)-based high-resolution T1-weighted images with voxel based morphometry (VBM) analyses. White matter atrophy appeared in perinatally HIV-infected youths in brain areas including the bilateral posterior corpus callosum (CC), bilateral external capsule, bilateral ventral temporal WM, mid cerebral peduncles, and basal pons over controls. Gray matter volume increase was observed in HIV-infected youths for several regions including the left superior frontal gyrus, inferior occipital gyrus, gyrus rectus, right mid cingulum, parahippocampal gyrus, bilateral inferior temporal gyrus, and middle temporal gyrus compared with controls. Global WM and GM volumes did not differ significantly between groups. These results indicate WM injury in perinatally HIV-infected youths, but the interpretation of the GM results, which appeared as increased regional volumes, is not clear. Further longitudinal studies are needed to clarify if our results represent active ongoing brain infection or toxicity from HIV treatment resulting in neuronal cell swelling and regional increased GM volume. Our findings suggest that assessment of regional GM and WM volume changes, based on VBM procedures, may be an additional measure to assess brain integrity in HIV-infected youths and to evaluate success of current ART therapy for efficacy in the brain.
Highlights
•First time investigation of gray/white matter changes in HIV-infected youths•Brain white matter atrophy observed in the HIV-infected youths•Significantly increased gray matter volume emerged in several regions.•Pilot findings indicate white matter injury in perinatally HIV-infected youths.
doi:10.1016/j.nicl.2013.10.012
PMCID: PMC3874468  PMID: 24380059
ART, antiretroviral therapy; MRI, magnetic resonance imaging; VBM, voxel based morphometry; GM, gray matter; WM, white matter; SPM, statistical parametric mapping; CSF, cerebrospinal fluid; WMV, white matter volume; GMV, gray matter volume; HIV; Antiretroviral therapy; Voxel based morphometry; Statistical parametric mapping; Gray matter; White matter
17.  Dynamic assembly, localization and proteolysis of the Bacillus subtilis SMC complex 
BMC Cell Biology  2005;6:28.
Background
SMC proteins are key components of several protein complexes that perform vital tasks in different chromosome dynamics. Bacterial SMC forms a complex with ScpA and ScpB that is essential for chromosome arrangement and segregation. The complex localizes to discrete centres on the nucleoids that during most of the time of the cell cycle localize in a bipolar manner. The complex binds to DNA and condenses DNA in an as yet unknown manner.
Results
We show that in vitro, ScpA and ScpB form different complexes with each other, among which the level of the putative 2 ScpA/4 ScpB complex showed a pronounced decrease in level upon addition of SMC protein. Different mutations of the ATPase-binding pocket of SMC reduced, but did not abolish interaction of mutant SMC with ScpA and ScpB. The loss of SMC ATPase activity led to a loss of function in vivo, and abolished proper localization of the SMC complex. The formation of bipolar SMC centres was also lost after repression of gyrase activity, and was abnormal during inhibition of replication, resulting in single central clusters. Resumption of replication quickly re-established bipolar SMC centres, showing that proper localization depends on ongoing replication. We also found that the SMC protein is subject to induced proteolysis, most strikingly as cells enter stationary phase, which is partly achieved by ClpX and LonA proteases. Atomic force microscopy revealed the existence of high order rosette-like SMC structures in vitro, which might explain the formation of the SMC centres in vivo.
Conclusion
Our data suggest that a ScpA/ScpB sub-complex is directly recruited into the SMC complex. This process does not require SMC ATPase activity, which, however, appears to facilitate loading of ScpA and ScpB. Thus, the activity of SMC could be regulated through binding and release of ScpA and ScpB, which has been shown to affect SMC ATPase activity. The proper bipolar localization of the SMC complex depends on a variety of physiological aspects: ongoing replication, ATPase activity and chromosome supercoiling. Because the cellular concentration of SMC protein is also regulated at the posttranscriptional level, the activity of SMC is apparently regulated at multiple levels.
doi:10.1186/1471-2121-6-28
PMCID: PMC1188057  PMID: 15987505
18.  Synaptonemal Complex Protein 3 Is a Prognostic Marker in Cervical Cancer 
PLoS ONE  2014;9(6):e98712.
Synaptonemal complex protein 3 (SCP3), a member of Cor1 family, is up-regulated in various cancer cells; however, its oncogenic potential and clinical significance has not yet been characterized. In the present study, we investigated the oncogenic role of SCP3 and its relationship with phosphorylated AKT (pAKT) in cervical neoplasias. The functional role of SCP3 expression was investigated by overexpression or knockdown of SCP3 in murine cell line NIH3T3 and human cervical cancer cell lines CUMC6, SiHa, CaSki, and HeLa both in vitro and in vivo. Furthermore, we examined SCP3 expression in tumor specimens from 181 cervical cancer and 400 cervical intraepithelial neoplasia (CIN) patients by immunohistochemistry and analyzed the correlation between SCP3 expression and clinicopathologic factors or survival. Overexpression of SCP3 promoted AKT-mediated tumorigenesis both in vitro and in vivo. Functional studies using NIH3T3 cells demonstrated that the C-terminal region of human SCP3 is important for AKT activation and its oncogenic potential. High expression of SCP3 was significantly associated with tumor stage (P = 0.002) and tumor grade (P<0.001), while SCP3 expression was positively associated with pAKT protein level in cervical neoplasias. Survival times for patients with cervical cancer overexpressing both SCP3 and pAKT (median, 134.0 months, n = 68) were significantly shorter than for patients with low expression of either SCP3 or pAKT (161.5 months, n = 108) as determined by multivariate analysis (P = 0.020). Our findings suggest that SCP3 plays an important role in the progression of cervical cancer through the AKT signaling pathway, supporting the possibility that SCP3 may be a promising novel cancer target for cervical cancer therapy.
doi:10.1371/journal.pone.0098712
PMCID: PMC4048308  PMID: 24905095
19.  Risky Decisions and Their Consequences: Neural Processing by Boys with Antisocial Substance Disorder 
PLoS ONE  2010;5(9):e12835.
Background
Adolescents with conduct and substance problems (“Antisocial Substance Disorder” (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys.
Methodology/Principal Findings
We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere.
Conclusions/Significance
Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders.
doi:10.1371/journal.pone.0012835
PMCID: PMC2943904  PMID: 20877644
20.  Deficits in Analogical Reasoning in Adolescents with Traumatic Brain Injury 
Individuals with traumatic brain injury (TBI) exhibit deficits in executive control, which may impact their reasoning abilities. Analogical reasoning requires working memory and inhibitory abilities. In this study, we tested adolescents with moderate to severe TBI and typically developing (TD) controls on a set of picture analogy problems. Three factors were varied: complexity (number of relations in the problems), distraction (distractor item present or absent), and animacy (living or non-living items in the problems). We found that TD adolescents performed significantly better overall than TBI adolescents. There was also an age effect present in the TBI group where older participants performed better than younger ones. This age effect was not observed in the TD group. Performance was affected by complexity and distraction. Further, TBI participants exhibited lower performance with distractors present than TD participants. The reasoning deficits exhibited by the TBI participants were correlated with measures of executive function that required working memory updating, attention, and attentional screening. Using MRI-derived measures of cortical thickness, correlations were carried out between task accuracy and cortical thickness. The TD adolescents showed negative correlations between thickness and task accuracy in frontal and temporal regions consistent with cortical maturation in these regions. This study demonstrates that adolescent TBI results in impairments in analogical reasoning ability. Further, TBI youth have difficulty effectively screening out distraction, which may lead to failures in comprehension of the relations among items in visual scenes. Lastly, TBI youth fail to show robust cortical–behavior correlations as observed in TD individuals.
doi:10.3389/fnhum.2010.00062
PMCID: PMC2938978  PMID: 20844604
analogy; reasoning; traumatic brain injury; gray matter; adolescent; distraction
21.  Nicotine withdrawal modulates frontal brain function during an affective Stroop task 
Psychopharmacology  2011;220(4):707-718.
Background
Among nicotine-dependent smokers, smoking abstinence disrupts multiple cognitive and affective processes including conflict resolution and emotional information processing (EIP). However, the neurobiological basis of abstinence effects on resolving emotional interference on cognition remains largely uncharacterized. In this study, functional magnetic resonance imaging (fMRI) was used to investigate smoking abstinence effects on emotion–cognition interactions.
Methods
Smokers (n=17) underwent fMRI while performing an affective Stroop task (aST) over two sessions: once following 24-h abstinence and once following smoking as usual. The aST includes trials that serially present incongruent or congruent numerical grids bracketed by neutral or negative emotional distractors and view-only emotional image trials. Statistical analyses were conducted using a statistical threshold of p<0.05 cluster corrected.
Results
Smoking abstinence increased Stroop blood-oxygenation-level-dependent response in the right middle frontal and rostral anterior cingulate gyri. Moreover, withdrawal-induced negative affect was associated with less activation in frontoparietal regions during negative emotional information processing; whereas, during Stroop trials, negative affect predicted greater activation in frontal regions during negative, but not neutral emotional distractor trials.
Conclusion
Hyperactivation in the frontal executive control network during smoking abstinence may represent a need to recruit additional executive resources to meet task demands. Moreover, abstinence-induced negative affect may disrupt cognitive control neural circuitry during EIP and place additional demands on frontal executive neural resources during cognitive demands when presented with emotionally distracting stimuli.
doi:10.1007/s00213-011-2522-y
PMCID: PMC3619410  PMID: 21989805
Smoking; Withdrawal; Emotion; Affect; Cognition; fMRI; Nicotine; Stroop; Cingulate; PFC
22.  Fertility properties and regulation of antimicrobial substance production by plasmid SCP2 of Streptomyces coelicolor. 
Journal of Bacteriology  1979;140(2):359-368.
Streptomyces coelicolor A3(2) possesses two plasmids (SCP1 and SCP2) that act as sex factors. The plasmid deoxyribonucleic acid isolated from S. coelicolor A3(2) SCP1- strains A617 and A585 had the same molecular weight and endonuclease cleavage pattern as the SCP2 plasmid. The plasmidless strain S18 SCP2- was isolated from the A617 X A585 cross. SCP2 plasmid-containing strains acted as donors of chromosomal markers, whereas the plasmidless strain acted as recipient. The transfer of SCP2+ donor strain markers into the SCP2- recipient occurred at high frequencies (approximately 75%), was unidirectional, was initiated from a fixed region of the chromosome, and had the SCP2 fertility factor transferred first. The introduction of the SCP2 plasmid into a recipient strain greatly reduced the recombination frequency. These fertility properties differed from those previously reported, thereby suggesting that the SCP2 plasmid examined in this investigation may be an additional variant to those described in the literature. The SCP2 plasmid also regulated production of three antibacterial substances and conveyed resistance for S. coelicolor A3(2) strains against growth inhibition by one of them.
Images
PMCID: PMC216657  PMID: 500559
23.  Visualization of White Matter Tracts Using a Non-Diffusion Weighted Magnetic Resonance Imaging Method: Does Intravenous Gadolinium Injection Four Hours Prior to the Examination Affect the Visualization of White Matter Tracts? 
PLoS ONE  2014;9(3):e91860.
Objectives
Visualization of white matter (WM)-tracts such as the corticospinal tract (CST), medial lemniscus (ML), and superior cerebellar peduncle (SCP) using delayed enhanced (DE)-heavily T2-weighted three-dimensional fluid-attenuated inversion-recovery (hT2w-3D-FLAIR) imaging has recently been reported. In that report, all patients were clinically suspected of having Ménière’s disease, because DE-hT2w-3D-FLAIR imaging of the inner ear has been reported to separately visualize perilymph and endolymph fluid and can identify the presence of endolymphatic hydrops. Therefore, the previous report could not rule out the possible effect of delayed enhancement. From this perspective, the purpose of this study was to elucidate if the use of gadolinium affects the visualization of WM-tracts on hT2w-3D-FLAIR.
Materials and Methods
The records of nine patients with suspected Ménière’s disease who underwent plain (P) and DE-hT2w-3D-FLAIR by 3-Tesla were retrospectively analyzed. The regions of interest were set on the CST, ML, and SCP, and on contiguous brain parenchyma: The thalamus (Th), pontine parenchyma (PP), and cerebellar parenchyma (CP), respectively. The signal intensity ratio between each WM-tract and the relevant contiguous brain parenchyma was calculated for both P- and DE-hT2w-3D-FLAIR images, and statistically compared using paired t-tests.
Results
The CST/Th signal intensity ratio was 3.75±0.67 on P-hT2w-3D-FLAIR and 3.62±0.50 on DE-hT2w-3D-FLAIR (p = 0.24). The ML/PP signal intensity ratio was 2.19±0.59 on P-hT2w-3D-FLAIR and 2.08±0.53 on DE-hT2w-3D-FLAIR (p = 0.25). The SCP/CP signal intensity ratio was 4.08±0.91 on P-hT2w-3D-FLAIR and 4.04±0.96 on DE-hT2w-3D-FLAIR (p = 0.43). There were no significant differences in the signal intensity ratios between P- and DE-hT2w-3D-FLAIR images.
Conclusions
The use of gadolinium is not necessary for visualization of WM-tracts using hT2w-3D-FLAIR, and P-hT2w-3D-FLAIR without gadolinium may have future clinical applications as an imaging procedure.
doi:10.1371/journal.pone.0091860
PMCID: PMC3951503  PMID: 24622649
24.  LOOKING UNDER THE HOOD OF THE DOT-PROBE TASK: AN fMRI STUDY IN ANXIOUS YOUTH 
Depression and anxiety  2014;31(3):178-187.
Background
Anxious youth have shown altered behavioral performance on the dot-probe task, but neural activation patterns provoked by the task remain poorly understood. In particular, neural mechanisms of threat disengagement, a clinically relevant construct, have been inadequately explored.
Method
During fMRI acquisition, 121 youth (ages 9–13; 90 with Generalized Anxiety Disorder, Separation Anxiety Disorder, and/or Social Phobia; 31 nonanxious controls) completed a dot-probe task, which required participants to identify the location of a dot replacing either a neutral or fearful face in a pair containing both faces. We assessed neural substrates of threat disengagement by comparing congruent trials (in which the dot replaces the fearful face) to incongruent trials (in which the dot replaces the neutral face).
Results
Across subjects, decreased rostrodorsal anterior cingulate cortex (rdACC) activity was observed specifically during incongruent trials. Nonanxious youth showed a convergent pattern in bilateral parahippocampal and hippocampal regions, whereas anxious youth showed an opposing pattern in these limbic areas, suggesting less integration of response across cortical and limbic areas relevant to threat appraisal. Reduced functional connectivity between rdACC and left parahippocampus/hippocampus was associated with greater anxiety.
Conclusions
In the largest dot-probe fMRI sample to date, both anxious and nonanxious youth showed a neural pattern consistent with successful disengagement of threat reactivity in the rdACC. However, anxious youth showed evidence of abnormal disengagement in bilateral parahippocampal/hippocampal clusters when attention was directed away from threat. Early interventions targeting neural mechanisms of threat disengagement may be beneficial, for example, by increasing integration across rdACC and limbic regions.
doi:10.1002/da.22255
PMCID: PMC3992818  PMID: 24578016
fMRI; anxiety; pediatric; attentional bias; dot-probe task
25.  Amplitude of Low Frequency Fluctuation Abnormalities in Adolescents with Online Gaming Addiction 
PLoS ONE  2013;8(11):e78708.
The majority of previous neuroimaging studies have demonstrated both structural and task-related functional abnormalities in adolescents with online gaming addiction (OGA). However, few functional magnetic resonance imaging (fMRI) studies focused on the regional intensity of spontaneous fluctuations in blood oxygen level-dependent (BOLD) during the resting state and fewer studies investigated the relationship between the abnormal resting-state properties and the impaired cognitive control ability. In the present study, we employed the amplitude of low frequency fluctuation (ALFF) method to explore the local features of spontaneous brain activity in adolescents with OGA and healthy controls during resting-state. Eighteen adolescents with OGA and 18 age-, education- and gender-matched healthy volunteers participated in this study. Compared with healthy controls, adolescents with OGA showed a significant increase in ALFF values in the left medial orbitofrontal cortex (OFC), the left precuneus, the left supplementary motor area (SMA), the right parahippocampal gyrus (PHG) and the bilateral middle cingulate cortex (MCC). The abnormalities of these regions were also detected in previous addiction studies. More importantly, we found that ALFF values of the left medial OFC and left precuneus were positively correlated with the duration of OGA in adolescents with OGA. The ALFF values of the left medial OFC were also correlated with the color-word Stroop test performance. Our results suggested that the abnormal spontaneous neuronal activity of these regions may be implicated in the underlying pathophysiology of OGA.
doi:10.1371/journal.pone.0078708
PMCID: PMC3817073  PMID: 24223843

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