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1.  Functional brain imaging studies of youth depression: A systematic review☆ 
NeuroImage : Clinical  2013;4:209-231.
Background
There is growing interest in understanding the neurobiology of major depressive disorder (MDD) in youth, particularly in the context of neuroimaging studies. This systematic review provides a timely comprehensive account of the available functional magnetic resonance imaging (fMRI) literature in youth MDD.
Methods
A literature search was conducted using PubMED, PsycINFO and Science Direct databases, to identify fMRI studies in younger and older youth with MDD, spanning 13–18 and 19–25 years of age, respectively.
Results
Twenty-eight studies focusing on 5 functional imaging domains were identified, namely emotion processing, cognitive control, affective cognition, reward processing and resting-state functional connectivity. Elevated activity in “extended medial network” regions including the anterior cingulate, ventromedial and orbitofrontal cortices, as well as the amygdala was most consistently implicated across these five domains. For the most part, findings in younger adolescents did not differ from those in older youth; however a general comparison of findings in both groups compared to adults indicated differences in the domains of cognitive control and affective cognition.
Conclusions
Youth MDD is characterized by abnormal activations in ventromedial frontal regions, the anterior cingulate and amygdala, which are broadly consistent with the implicated role of medial network regions in the pathophysiology of depression. Future longitudinal studies examining the effects of neurodevelopmental changes and pubertal maturation on brain systems implicated in youth MDD will provide a more comprehensive neurobiological model of youth depression.
Highlights
•We provide a systematic review of fMRI studies in youth MDD.•Abnormal function is found in regions of the extended medial prefrontal network.•Findings in youth MDD show some important differences compared to adult MDD.•Future studies need to focus on the effects of puberty on medial network activity.•Longitudinal studies will help inform neurobiological models of youth MDD.
doi:10.1016/j.nicl.2013.11.009
PMCID: PMC3895619  PMID: 24455472
Major depressive disorder (MDD); Youth; Functional magnetic resonance imaging (fMRI)
2.  Breakdown in the brain network subserving moral judgment in criminal psychopathy 
Neuroimaging research has demonstrated the involvement of a well-defined brain network in the mediation of moral judgment in normal population, and has suggested the inappropriate network use in criminal psychopathy. We used functional magnetic resonance imaging (fMRI) to prove that alterations in the brain network subserving moral judgment in criminal psychopaths are not limited to the inadequate network use during moral judgment, but that a primary network breakdown would exist with dysfunctional alterations outside moral dilemma situations. A total of 22 criminal psychopathic men and 22 control subjects were assessed and fMRI maps were generated to identify (i) brain response to moral dilemmas, (ii) task-induced deactivation of the network during a conventional cognitive task and (iii) the strength of functional connectivity within the network during resting-state. The obtained functional brain maps indeed confirmed that the network subserving moral judgment is underactive in psychopathic individuals during moral dilemma situations, but the data also provided evidence of a baseline network alteration outside moral contexts with a functional disconnection between emotional and cognitive elements that jointly construct moral judgment. The finding may have significant social implications if considering psychopathic behavior to be a result of a primary breakdown in basic brain systems.
doi:10.1093/scan/nsr075
PMCID: PMC3501707  PMID: 22037688
functional magnetic resonance imaging (fMRI); psychopathy; amygdala; frontal lobe; brain networks; functional connectivity
3.  Brain Structural Alterations in Obsessive-Compulsive Disorder Patients with Autogenous and Reactive Obsessions 
PLoS ONE  2013;8(9):e75273.
Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. Although structural brain alterations have been consistently reported in OCD, their interaction with particular clinical subtypes deserves further examination. Among other approaches, a two-group classification in patients with autogenous and reactive obsessions has been proposed. The purpose of the present study was to assess, by means of a voxel-based morphometry analysis, the putative brain structural correlates of this classification scheme in OCD patients. Ninety-five OCD patients and 95 healthy controls were recruited. Patients were divided into autogenous (n = 30) and reactive (n = 65) sub-groups. A structural magnetic resonance image was acquired for each participant and pre-processed with SPM8 software to obtain a volume-modulated gray matter map. Whole-brain and voxel-wise comparisons between the study groups were then performed. In comparison to the autogenous group, reactive patients showed larger gray matter volumes in the right Rolandic operculum. When compared to healthy controls, reactive patients showed larger volumes in the putamen (bilaterally), while autogenous patients showed a smaller left anterior temporal lobe. Also in comparison to healthy controls, the right middle temporal gyrus was smaller in both patient subgroups. Our results suggest that autogenous and reactive obsessions depend on partially dissimilar neural substrates. Our findings provide some neurobiological support for this classification scheme and contribute to unraveling the neurobiological basis of clinical heterogeneity in OCD.
doi:10.1371/journal.pone.0075273
PMCID: PMC3787080  PMID: 24098688
4.  Functional Connectivity in Brain Networks Underlying Cognitive Control in Chronic Cannabis Users 
Neuropsychopharmacology  2012;37(8):1923-1933.
The long-term effect of regular cannabis use on brain function underlying cognitive control remains equivocal. Cognitive control abilities are thought to have a major role in everyday functioning, and their dysfunction has been implicated in the maintenance of maladaptive drug-taking patterns. In this study, the Multi-Source Interference Task was employed alongside functional magnetic resonance imaging and psychophysiological interaction methods to investigate functional interactions between brain regions underlying cognitive control. Current cannabis users with a history of greater than 10 years of daily or near-daily cannabis smoking (n=21) were compared with age, gender, and IQ-matched non-using controls (n=21). No differences in behavioral performance or magnitude of task-related brain activations were evident between the groups. However, greater connectivity between the prefrontal cortex and the occipitoparietal cortex was evident in cannabis users, as compared with controls, as cognitive control demands increased. The magnitude of this connectivity was positively associated with age of onset and lifetime exposure to cannabis. These findings suggest that brain regions responsible for coordinating behavioral control have an increased influence on the direction and switching of attention in cannabis users, and that these changes may have a compensatory role in mitigating cannabis-related impairments in cognitive control or perceptual processes.
doi:10.1038/npp.2012.39
PMCID: PMC3376324  PMID: 22534625
attention; brain; cannabis; cognitive control; functional connectivity; addiction & substance abuse; cannabinoids; cognition; functional connectivity; imaging; clinical or preclinical
5.  Brain Connectivity and Mental Illness 
doi:10.3389/fpsyt.2012.00072
PMCID: PMC3406306  PMID: 22866039
6.  Brain functional connectivity during induced sadness in patients with obsessive–compulsive disorder 
Background
Obsessive–compulsive disorder (OCD) is associated with a range of emotional abnormalities linked to its defining symptoms, comorbid illnesses and cognitive deficits. The aim of this preliminary study was to examine functional changes in the brain that are associated with experimentally induced sad mood in patients with OCD compared with healthy controls in a frontolimbic circuit relevant to both OCD and mood regulation.
Methods
Participants underwent a validated sad mood induction procedure during functional magnetic resonance imaging. Analyses focused on mapping changes in the functional connectivity of the subgenual anterior cingulate cortex (ACC) within and between the 2 groups in response to successfully induced sadness.
Results
We enrolled 11 patients with OCD and 10 age-, sex- and IQ-matched controls in our study. Unlike controls, patients with OCD did not demonstrate predicted increases in functional connectivity between the subgenual ACC and other frontal regions during mood induction. Instead, patients demonstrated heightened connectivity between the subgenual ACC and ventral caudate/nucleus accumbens region and the hypothalamus.
Limitations
Our study included a small, partially medicated patient cohort that precluded our ability to investigate sex or drug effects, evaluate behavioural differences between the groups and perform a whole-brain analysis.
Conclusion
The ventral striatum and ventral frontal cortex were distinctly and differentially modulated in their connectivity with the subgenual ACC during the experience of sad mood in patients with OCD. These results suggest that, in patients with OCD, induced sadness appears to have provoked a primary subcortical component of the hypothesized “OCD circuit,” which may offer insights into why OCD symptoms tend to develop and worsen during disturbed emotional states.
doi:10.1503/jpn.110074
PMCID: PMC3380094  PMID: 22452963
7.  I Undervalue You but I Need You: The Dissociation of Attitude and Memory Toward In-Group Members 
PLoS ONE  2012;7(3):e32932.
In the present study, the in-group bias or in-group derogation among mainland Chinese was investigated through a rating task and a recognition test. In two experiments,participants from two universities with similar ranks rated novel faces or names and then had a recognition test. Half of the faces or names were labeled as participants' own university and the other half were labeled as their counterpart. Results showed that, for either faces or names, rating scores for out-group members were consistently higher than those for in-group members, whereas the recognition accuracy showed just the opposite. These results indicated that the attitude and memory for group-relevant information might be dissociated among Mainland Chinese.
doi:10.1371/journal.pone.0032932
PMCID: PMC3296752  PMID: 22412955
8.  Task-Related Deactivation and Functional Connectivity of the Subgenual Cingulate Cortex in Major Depressive Disorder 
Background: Major depressive disorder is associated with functional alterations in activity and resting-state connectivity of the extended medial frontal network. In this study we aimed to examine how task-related medial network activity and connectivity were affected in depression. Methods: 18 patients with major depressive disorder, aged 15- to 24-years-old, were matched with 19 healthy control participants. We characterized task-related activations and deactivations while participants engaged with an executive-control task (the multi-source interference task, MSIT). We used a psycho-physiological interactions approach to examine functional connectivity changes with subgenual anterior cingulate cortex. Voxel-wise statistical maps for each analysis were compared between the patient and control groups. Results: There were no differences between groups in their behavioral performances on the MSIT task, and nor in patterns of activation and deactivation. Assessment of functional connectivity with the subgenual cingulate showed that depressed patients did not demonstrate the same reduction in functional connectivity with the ventral striatum during task performance, but that they showed greater reduction in functional connectivity with adjacent ventromedial frontal cortex. The magnitude of this latter connectivity change predicted the relative activation of task-relevant executive-control regions in depressed patients. Conclusion: The study reinforces the importance of the subgenual cingulate cortex for depression, and demonstrates how dysfunctional connectivity with ventral brain regions might influence executive–attentional processes.
doi:10.3389/fpsyt.2012.00014
PMCID: PMC3289045  PMID: 22403553
major depressive disorder; cognition; anterior cingulate cortex; striatum; default mode network; connectivity; fMRI; adolescence
9.  Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder 
Neuropsychopharmacology  2010;35(11):2305-2317.
Major depressive disorder (MDD) is characterized by a constellation of affective, cognitive, and somatic symptoms associated with functional abnormalities in relevant brain systems. Painful stimuli are primarily stressful and can trigger consistent responses in brain regions highly overlapping with the regions altered in MDD patients. Duloxetine has proven to be effective in treating both core emotional symptoms and somatic complaints in depression. This study aimed to assess the effects of duloxetine treatment on brain response to painful stimulation in MDD patients. A total of 13 patients and a reference group of 20 healthy subjects were assessed on three occasions (baseline, treatment week 1, and week 8) with functional magnetic resonance imaging (fMRI) during local application of painful heat stimulation. Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.
doi:10.1038/npp.2010.108
PMCID: PMC3055320  PMID: 20668437
major depressive disorder; fMRI; pain; brain; treatment; duloxetine; depression; unipolar/bipolar; imaging; clinical or preclinical; mood/anxiety/stress disorders; biological psychiatry; fMRI; brain; antidepressant; depression
10.  Dissociation of Subjectively Reported and Behaviorally Indexed Mind Wandering by EEG Rhythmic Activity 
PLoS ONE  2011;6(9):e23124.
Inattention to current activity is ubiquitous in everyday situations. Mind wandering is an example of such a state, and its related brain areas have been examined in the literature. However, there is no clear evidence regarding neural rhythmic activities linked to mind wandering. Using a vigilance task with thought sampling and electroencephalography recording, the current study simultaneously examined neural oscillatory activities related to subjectively reported and behaviorally indexed mind wandering. By implementing time-frequency analysis, we found that subjectively reported mind wandering, relative to behaviorally indexed, showed increased gamma band activity at bilateral frontal-central areas. By means of beamformer source imaging, we found subjectively reported mind wandering within the gamma band to be characterized by increased activation in bilateral frontal cortices, supplemental motor area, paracentral cortex and right inferior temporal cortex in comparison to behaviorally indexed mind wandering. These findings dissociate subjectively reported and behaviorally indexed mind wandering and suggest that a higher degree of executive control processes are engaged in subjectively reported mind wandering.
doi:10.1371/journal.pone.0023124
PMCID: PMC3168437  PMID: 21915257
11.  Task-Induced Deactivation from Rest Extends beyond the Default Mode Brain Network 
PLoS ONE  2011;6(7):e22964.
Activity decreases, or deactivations, of midline and parietal cortical brain regions are routinely observed in human functional neuroimaging studies that compare periods of task-based cognitive performance with passive states, such as rest. It is now widely held that such task-induced deactivations index a highly organized ‘default-mode network’ (DMN): a large-scale brain system whose discovery has had broad implications in the study of human brain function and behavior. In this work, we show that common task-induced deactivations from rest also occur outside of the DMN as a function of increased task demand. Fifty healthy adult subjects performed two distinct functional magnetic resonance imaging tasks that were designed to reliably map deactivations from a resting baseline. As primary findings, increases in task demand consistently modulated the regional anatomy of DMN deactivation. At high levels of task demand, robust deactivation was observed in non-DMN regions, most notably, the posterior insular cortex. Deactivation of this region was directly implicated in a performance-based analysis of experienced task difficulty. Together, these findings suggest that task-induced deactivations from rest are not limited to the DMN and extend to brain regions typically associated with integrative sensory and interoceptive processes.
doi:10.1371/journal.pone.0022964
PMCID: PMC3146521  PMID: 21829564
12.  White matter microstructure in patients with obsessive–compulsive disorder 
Background
Previous diffusion tensor imaging (DTI) studies in patients with obsessive–compulsive disorder (OCD) have reported inconsistent findings, and it is not known whether observed findings are related to abnormalities in axonal structure or myelination.
Methods
In this DTI study, we investigated fractional anisotropy, as well as axial and radial diffusivity, in 21 patients with OCD and 29 healthy controls.
Results
We found decreased fractional anisotropy in the body of the corpus callosum in the OCD group, which was underpinned by increased radial diffusivity.
Limitations
The cross-sectional design was the main limitation.
Conclusion
Our findings of increased radial diffusivity provide preliminary evidence for abnormal myelination in patients with OCD.
doi:10.1503/jpn.100082
PMCID: PMC3004974  PMID: 21118658
13.  Alien Hand Syndrome: Neural Correlates of Movements without Conscious Will 
PLoS ONE  2010;5(12):e15010.
Background
The alien hand syndrome is a striking phenomenon characterized by purposeful and autonomous movements that are not voluntarily initiated. This study aimed to examine neural correlates of this rare neurological disorder in a patient with corticobasal degeneration and alien hand syndrome of the left hand.
Methodology/Principal Findings
We employed functional magnetic resonance imaging to investigate brain responses associated with unwanted movements in a case study. Results revealed that alien hand movements involved a network of brain activations including the primary motor cortex, premotor cortex, precuneus, and right inferior frontal gyrus. Conscious and voluntary movements of the alien hand elicited a similar network of brain responses but lacked an activation of the inferior frontal gyrus. The results demonstrate that alien and unwanted movements may engage similar brain networks than voluntary movements, but also imply different functional contributions of prefrontal areas. Since the inferior frontal gyrus was uniquely activated during alien movements, the results provide further support for a specific role of this brain region in inhibitory control over involuntary motor responses.
Conclusions/Significance
We discuss the outcome of this study as providing evidence for a distributed neural network associated with unwanted movements in alien hand syndrome, including brain regions known to be related to movement execution and planning as well as areas that have been linked to inhibition control (inferior frontal gyrus) and experience of agency (precuneus).
doi:10.1371/journal.pone.0015010
PMCID: PMC3001471  PMID: 21179436
14.  Mapping Brain Response to Pain in Fibromyalgia Patients Using Temporal Analysis of fMRI 
PLoS ONE  2009;4(4):e5224.
Background
Nociceptive stimuli may evoke brain responses longer than the stimulus duration often partially detected by conventional neuroimaging. Fibromyalgia patients typically complain of severe pain from gentle stimuli. We aimed to characterize brain response to painful pressure in fibromyalgia patients by generating activation maps adjusted for the duration of brain responses.
Methodology/Principal Findings
Twenty-seven women (mean age: 47.8 years) were assessed with fMRI. The sample included nine fibromyalgia patients and nine healthy subjects who received 4 kg/cm2 of pressure on the thumb. Nine additional control subjects received 6.8 kg/cm2 to match the patients for the severity of perceived pain. Independent Component Analysis characterized the temporal dynamics of the actual brain response to pressure. Statistical parametric maps were estimated using the obtained time courses. Brain response to pressure (18 seconds) consistently exceeded the stimulus application (9 seconds) in somatosensory regions in all groups. fMRI maps following such temporal dynamics showed a complete pain network response (sensory-motor cortices, operculo-insula, cingulate cortex, and basal ganglia) to 4 kg/cm2 of pressure in fibromyalgia patients. In healthy subjects, response to this low intensity pressure involved mainly somatosensory cortices. When matched for perceived pain (6.8 kg/cm2), control subjects showed also comprehensive activation of pain-related regions, but fibromyalgia patients showed significantly larger activation in the anterior insula-basal ganglia complex and the cingulate cortex.
Conclusions/Significance
The results suggest that data-driven fMRI assessments may complement conventional neuroimaging for characterizing pain responses and that enhancement of brain activation in fibromyalgia patients may be particularly relevant in emotion-related regions.
doi:10.1371/journal.pone.0005224
PMCID: PMC2667672  PMID: 19381292
15.  Modulation of Brain Resting-State Networks by Sad Mood Induction 
PLoS ONE  2008;3(3):e1794.
Background
There is growing interest in the nature of slow variations of the blood oxygen level-dependent (BOLD) signal observed in functional MRI resting-state studies. In humans, these slow BOLD variations are thought to reflect an underlying or intrinsic form of brain functional connectivity in discrete neuroanatomical systems. While these ‘resting-state networks’ may be relatively enduring phenomena, other evidence suggest that dynamic changes in their functional connectivity may also emerge depending on the brain state of subjects during scanning.
Methodology/Principal Findings
In this study, we examined healthy subjects (n = 24) with a mood induction paradigm during two continuous fMRI recordings to assess the effects of a change in self-generated mood state (neutral to sad) on the functional connectivity of these resting-state networks (n = 24). Using independent component analysis, we identified five networks that were common to both experimental states, each showing dominant signal fluctuations in the very low frequency domain (∼0.04 Hz). Between the two states, we observed apparent increases and decreases in the overall functional connectivity of these networks. Primary findings included increased connectivity strength of a paralimbic network involving the dorsal anterior cingulate and anterior insula cortices with subjects' increasing sadness and decreased functional connectivity of the ‘default mode network’.
Conclusions/Significance
These findings support recent studies that suggest the functional connectivity of certain resting-state networks may, in part, reflect a dynamic image of the current brain state. In our study, this was linked to changes in subjective mood.
doi:10.1371/journal.pone.0001794
PMCID: PMC2263138  PMID: 18350136
16.  The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members▿  
Molecular and Cellular Biology  2007;27(9):3542-3555.
Genetic and biochemical studies have shown that Ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed DNA-dependent p53 acetylation and B-cell tumor suppression. However, the protein kinases that mediate this modification are not well defined. A cell-free Ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including CHK2, CHK1, DAPK-1, DAPK-3, DRAK-1, and AMPK, as Ser20 kinases. Phosphorylation of a p53 transactivation domain fragment at Ser20 by these enzymes in vitro can be mediated in trans by a docking site peptide derived from the BOX-V domain of p53, which also harbors the ubiquitin signal for MDM2. Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser20 kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser20 phosphorylation of p53. Using CHK1 as a prototypical in vivo Ser20 kinase, we demonstrate that (i) CHK1 protein depletion using small interfering RNA can attenuate p53 phosphorylation at Ser20, (ii) an enhanced green fluorescent protein (EGFP)-BOX-V fusion peptide can attenuate Ser20 phosphorylation of p53 in vivo, (iii) the EGFP-BOX-V fusion peptide can selectively bind to CHK1 in vivo, and (iv) the Δp53 spliced variant lacking the BOX-V motif is refractory to Ser20 phosphorylation by CHK1. These data indicate that the BOX-V motif of p53 has evolved the capacity to bind to enzymes that mediate either p53 phosphorylation or ubiquitination, thus controlling the specific activity of p53 as a transcription factor.
doi:10.1128/MCB.01595-06
PMCID: PMC1899961  PMID: 17339337
17.  The Queen and I: Neural Correlates of Altered Self-Related Cognitions in Major Depressive Episode 
PLoS ONE  2013;8(10):e78844.
Background
Pervasive negative thoughts about the self are central to the experience of depression. Brain imaging studies in the general population have localised self-related cognitive processing to areas of the medial pre-frontal cortex.
Aims
To use fMRI to compare the neural correlates of self-referential processing in depressed and non-depressed participants.
Method
Cross-sectional comparison of regional activation using Blood Oxygen Level Dependent (BOLD) fMRI in 13 non-medicated participants with major depressive episode and 14 comparison participants, whilst carrying out a self-referential cognitive task.
Results
Both groups showed significant activation of the dorsomedial pre-frontal cortex and posterior cingulate cortex in the ‘self-referent’ condition. The depressed group showed significantly greater activation in the medial superior frontal cortex during the self-referent task. No difference was observed between groups in the ‘other-referent’ condition.
Conclusions
Major depressive episode is associated with specific neurofunctional changes related to self-referential processing.
doi:10.1371/journal.pone.0078844
PMCID: PMC3813625  PMID: 24205330
18.  Altered Olfactory Processing of Stress-Related Body Odors and Artificial Odors in Patients with Panic Disorder 
PLoS ONE  2013;8(9):e74655.
Background
Patients with Panic Disorder (PD) direct their attention towards potential threat, followed by panic attacks, and increased sweat production. Onés own anxiety sweat odor influences the attentional focus, and discrimination of threat or non-threat. Since olfactory projection areas overlap with neuronal areas of a panic-specific fear network, the present study investigated the neuronal processing of odors in general and of stress-related sweat odors in particular in patients with PD.
Methods
A sample of 13 patients with PD with/ without agoraphobia and 13 age- and gender-matched healthy controls underwent an fMRI investigation during olfactory stimulation with their stress-related sweat odors (TSST, ergometry) as well as artificial odors (peach, artificial sweat) as non-fearful non-body odors.
Principal Findings
The two groups did not differ with respect to their olfactory identification ability. Independent of the kind of odor, the patients with PD showed activations in fronto-cortical areas in contrast to the healthy controls who showed activations in olfaction-related areas such as the amygdalae and the hippocampus. For artificial odors, the patients with PD showed a decreased neuronal activation of the thalamus, the posterior cingulate cortex and the anterior cingulate cortex. Under the presentation of sweat odor caused by ergometric exercise, the patients with PD showed an increased activation in the superior temporal gyrus, the supramarginal gyrus, and the cingulate cortex which was positively correlated with the severity of the psychopathology. For the sweat odor from the anxiety condition, the patients with PD showed an increased activation in the gyrus frontalis inferior, which was positively correlated with the severity of the psychopathology.
Conclusions
The results suggest altered neuronal processing of olfactory stimuli in PD. Both artificial odors and stress-related body odors activate specific parts of a fear-network which is associated with an increased severity of the psychopathology.
doi:10.1371/journal.pone.0074655
PMCID: PMC3782473  PMID: 24086358
19.  Anxiety, Affect, Self-Esteem, and Stress: Mediation and Moderation Effects on Depression 
PLoS ONE  2013;8(9):e73265.
Background
Mediation analysis investigates whether a variable (i.e., mediator) changes in regard to an independent variable, in turn, affecting a dependent variable. Moderation analysis, on the other hand, investigates whether the statistical interaction between independent variables predict a dependent variable. Although this difference between these two types of analysis is explicit in current literature, there is still confusion with regard to the mediating and moderating effects of different variables on depression. The purpose of this study was to assess the mediating and moderating effects of anxiety, stress, positive affect, and negative affect on depression.
Methods
Two hundred and two university students (males  = 93, females  = 113) completed questionnaires assessing anxiety, stress, self-esteem, positive and negative affect, and depression. Mediation and moderation analyses were conducted using techniques based on standard multiple regression and hierarchical regression analyses.
Main Findings
The results indicated that (i) anxiety partially mediated the effects of both stress and self-esteem upon depression, (ii) that stress partially mediated the effects of anxiety and positive affect upon depression, (iii) that stress completely mediated the effects of self-esteem on depression, and (iv) that there was a significant interaction between stress and negative affect, and between positive affect and negative affect upon depression.
Conclusion
The study highlights different research questions that can be investigated depending on whether researchers decide to use the same variables as mediators and/or moderators.
doi:10.1371/journal.pone.0073265
PMCID: PMC3767811  PMID: 24039896
20.  Acute Effects of Modafinil on Brain Resting State Networks in Young Healthy Subjects 
PLoS ONE  2013;8(7):e69224.
Background
There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects.
Methodology
A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven’s Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; NCT01684306; http://clinicaltrials.gov/ct2/show/NCT01684306.
Principal Findings
Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed.
Conclusions and Significance
Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects.
Trial Registration
ClinicalTrials.gov NCT01684306 http://clinicaltrials.gov/ct2/show/NCT01684306.
doi:10.1371/journal.pone.0069224
PMCID: PMC3723829  PMID: 23935959
21.  Communicative versus Strategic Rationality: Habermas Theory of Communicative Action and the Social Brain 
PLoS ONE  2013;8(5):e65111.
In the philosophical theory of communicative action, rationality refers to interpersonal communication rather than to a knowing subject. Thus, a social view of rationality is suggested. The theory differentiates between two kinds of rationality, the emancipative communicative and the strategic or instrumental reasoning. Using experimental designs in an fMRI setting, recent studies explored similar questions of reasoning in the social world and linked them with a neural network including prefrontal and parietal brain regions. Here, we employed an fMRI approach to highlight brain areas associated with strategic and communicative reasoning according to the theory of communicative action. Participants were asked to assess different social scenarios with respect to communicative or strategic rationality. We found a network of brain areas including temporal pole, precuneus, and STS more activated when participants performed communicative reasoning compared with strategic thinking and a control condition. These brain regions have been previously linked to moral sensitivity. In contrast, strategic rationality compared with communicative reasoning and control was associated with less activation in areas known to be related to moral sensitivity, emotional processing, and language control. The results suggest that strategic reasoning is associated with reduced social and emotional cognitions and may use different language related networks. Thus, the results demonstrate experimental support for the assumptions of the theory of communicative action.
doi:10.1371/journal.pone.0065111
PMCID: PMC3666968  PMID: 23734238
22.  What Does Brain Response to Neutral Faces Tell Us about Major Depression? Evidence from Machine Learning and fMRI 
PLoS ONE  2013;8(4):e60121.
Introduction
A considerable number of previous studies have shown abnormalities in the processing of emotional faces in major depression. Fewer studies, however, have focused specifically on abnormal processing of neutral faces despite evidence that depressed patients are slow and less accurate at recognizing neutral expressions in comparison with healthy controls. The current study aimed to investigate whether this misclassification described behaviourally for neutral faces also occurred when classifying patterns of brain activation to neutral faces for these patients.
Methods
Two independent depressed samples: (1) Nineteen medication-free patients with depression and 19 healthy volunteers and (2) Eighteen depressed individuals and 18 age and gender-ratio-matched healthy volunteers viewed emotional faces (sad/neutral; happy/neutral) during an fMRI experiment. We used a new pattern recognition framework: first, we trained the classifier to discriminate between two brain states (e.g. viewing happy faces vs. viewing neutral faces) using data only from healthy controls (HC). Second, we tested the classifier using patterns of brain activation of a patient and a healthy control for the same stimuli. Finally, we tested if the classifier’s predictions (predictive probabilities) for emotional and neutral face classification were different for healthy controls and depressed patients.
Results
Predictive probabilities to patterns of brain activation to neutral faces in both groups of patients were significantly lower in comparison to the healthy controls. This difference was specific to neutral faces. There were no significant differences in predictive probabilities to patterns of brain activation to sad faces (sample 1) and happy faces (samples 2) between depressed patients and healthy controls.
Conclusions
Our results suggest that the pattern of brain activation to neutral faces in depressed patients is not consistent with the pattern observed in healthy controls subject to the same stimuli. This difference in brain activation might underlie the behavioural misinterpretation of the neutral faces content by the depressed patients.
doi:10.1371/journal.pone.0060121
PMCID: PMC3613341  PMID: 23560073
23.  Activation of Midbrain and Ventral Striatal Regions Implicates Salience Processing during a Modified Beads Task 
PLoS ONE  2013;8(3):e58536.
Introduction
Metacognition, i.e. critically reflecting on and monitoring one’s own reasoning, has been linked behaviorally to the emergence of delusions and is a focus of cognitive therapy in patients with schizophrenia. However, little is known about the neural processing underlying metacognitive function. To address this issue, we studied brain activity during a modified beads task which has been used to measure a “Jumping to Conclusions” (JTC) bias in schizophrenia patients.
Methods
We used functional magnetic resonance imaging to identify neural systems active in twenty-five healthy subjects when solving a modified version of the “beads task”, which requires a probabilistic decision after a variable amount of data has been requested by the participants. We assessed brain activation over the duration of a trial and at the time point of decision making.
Results
Analysis of activation during the whole process of probabilistic reasoning showed an extended network including the prefronto-parietal executive functioning network as well as medial parieto-occipital regions. During the decision process alone, activity in midbrain and ventral striatum was detected, as well as in thalamus, medial occipital cortex and anterior insula.
Conclusions
Our data show that probabilistic reasoning shares neural substrates with executive functions. In addition, our finding that brain regions commonly associated with salience processing are active during probabilistic reasoning identifies a candidate mechanism that could underlie the behavioral link between dopamine-dependent aberrant salience and JTC in schizophrenia. Further studies with delusional schizophrenia patients will have to be performed to substantiate this link.
doi:10.1371/journal.pone.0058536
PMCID: PMC3590224  PMID: 23484034
24.  Corticolimbic Functional Connectivity in Adolescents with Bipolar Disorder 
PLoS ONE  2012;7(11):e50177.
Convergent evidence supports regional dysfunction within a corticolimbic neural system that subserves emotional processing and regulation in adolescents and adults with bipolar disorder (BD), with abnormalities prominent within the amygdala and its major anterior paralimbic cortical connection sites including ventral anterior cingulate, orbitofrontal, insular and temporopolar cortices. Recent studies of adults with BD demonstrate abnormalities in the functional connectivity between the amygdala and anterior paralimbic regions suggesting an important role for the connections between these regions in the development of the disorder. This study tests the hypothesis that these functional connectivity abnormalities are present in adolescents with BD. Fifty-seven adolescents, twenty-one with BD and thirty-six healthy comparison (HC) adolescents, participated in functional magnetic resonance imaging while processing emotional face stimuli. The BD and HC groups were compared in the strength of functional connectivity from amygdala to the anterior paralimbic cortical regions, and explored in remaining brain regions. Functional connectivity was decreased in the BD group, compared to the HC group, during processing of emotional faces in ventral anterior cingulate (VACC), orbitofrontal, insular and temporopolar cortices (p<0.005). Orbitofrontal and VACC findings for the happy condition, and additionally right insula for the neutral condition, survived multiple comparison correction. Exploratory analyses did not reveal additional regions of group differences. This study provides evidence for decreased functional connectivity between the amygdala and anterior paralimbic cortices in adolescents with BD. This suggests that amygdala-anterior paralimbic connectivity abnormalities are early features of BD that emerge at least by adolescence in the disorder.
doi:10.1371/journal.pone.0050177
PMCID: PMC3503984  PMID: 23185566
25.  The Extended Functional Neuroanatomy of Emotional Processing Biases for Masked Faces in Major Depressive Disorder 
PLoS ONE  2012;7(10):e46439.
Background
Major depressive disorder (MDD) is associated with a mood-congruent processing bias in the amygdala toward face stimuli portraying sad expressions that is evident even when such stimuli are presented below the level of conscious awareness. The extended functional anatomical network that maintains this response bias has not been established, however.
Aims
To identify neural network differences in the hemodynamic response to implicitly presented facial expressions between depressed and healthy control participants.
Method
Unmedicated-depressed participants with MDD (n = 22) and healthy controls (HC; n = 25) underwent functional MRI as they viewed face stimuli showing sad, happy or neutral face expressions, presented using a backward masking design. The blood-oxygen-level dependent (BOLD) signal was measured to identify regions where the hemodynamic response to the emotionally valenced stimuli differed between groups.
Results
The MDD subjects showed greater BOLD responses than the controls to masked-sad versus masked-happy faces in the hippocampus, amygdala and anterior inferotemporal cortex. While viewing both masked-sad and masked-happy faces relative to masked-neutral faces, the depressed subjects showed greater hemodynamic responses than the controls in a network that included the medial and orbital prefrontal cortices and anterior temporal cortex.
Conclusions
Depressed and healthy participants showed distinct hemodynamic responses to masked-sad and masked-happy faces in neural circuits known to support the processing of emotionally valenced stimuli and to integrate the sensory and visceromotor aspects of emotional behavior. Altered function within these networks in MDD may establish and maintain illness-associated differences in the salience of sensory/social stimuli, such that attention is biased toward negative and away from positive stimuli.
doi:10.1371/journal.pone.0046439
PMCID: PMC3466291  PMID: 23056309

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