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1.  Functional dysconnectivity of corticostriatal circuitry and differential response to methylphenidate in youth with attention-deficit/hyperactivity disorder 
Brain frontostriatal circuits have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, effects of methylphenidate on circuit-level functional connectivity are as yet unclear. The aim of the present study was to comprehensively investigate the functional connectivity of major striatal subregions in children with ADHD, including subanalyses directed at mapping cognitive and treatment response characteristics.
Using a comprehensive seeding strategy, we examined resting-state functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen in children and adolescents with ADHD and in age- and sex-matched healthy controls.
We enrolled 83 patients with ADHD and 22 controls in our study. Patients showed significantly reduced dorsal caudate functional connectivity with the superior and middle prefrontal cortices as well as reduced dorsal putamen connectivity with the parahippocampal cortex. These connectivity measures were correlated in opposite directions in patients and controls with attentional performance, as assessed using the Continuous Performance Test. Patients showing a good response to methylphenidate had significantly reduced ventral caudate/nucleus accumbens connectivity with the inferior frontal cortices compared with poor responders.
Possible confounding effects of age-related functional connectivity change were not excluded owing to the wide age range of participants.
We observed a region-specific effect of methylphenidate on resting-state functional connectivity, suggesting the pretreatment level of ventral frontostriatal functional connectivity as a possible methylphenidate response biomarker of ADHD.
PMCID: PMC4275331  PMID: 25266402
2.  Specific functional connectivity alterations of the dorsal striatum in young people with depression 
NeuroImage : Clinical  2014;7:266-272.
Altered basal ganglia function has been implicated in the pathophysiology of youth Major Depressive Disorder (MDD). Studies have generally focused on characterizing abnormalities in ventral “affective” corticostriatal loops supporting emotional processes. Recent evidence however, has implicated alterations in functional connectivity of dorsal “cognitive” corticostriatal loops in youth MDD. The contribution of dorsal versus ventral corticostriatal alterations to the pathophysiology of youth MDD remains unclear.
Twenty-one medication-free patients with moderate-to-severe MDD between the ages of 15 and 24 years old were matched with 21 healthy control participants. Using resting-state functional connectivity magnetic resonance imaging we systematically investigated connectivity of eight dorsal and ventral subdivisions of the striatum. Voxelwise statistical maps of each subregion's connectivity with other brain areas were compared between the depressed and control groups.
Depressed youths showed alterations in functional connectivity that were confined to the dorsal corticostriatal circuit. Compared to controls, depressed patients showed increased connectivity between the dorsal caudate nucleus and ventrolateral prefrontal cortex bilaterally. Increased depression severity correlated with the magnitude of dorsal caudate connectivity with the right dorsolateral prefrontal cortex. There were no significant between-group differences in connectivity of ventral striatal regions.
The results provide evidence that alterations in corticostriatal connectivity are evident at the early stages of the illness and are not a result of antidepressant treatment. Increased connectivity between the dorsal caudate, which is usually associated with cognitive processes, and the more affectively related ventrolateral prefrontal cortex may reflect a compensatory mechanism for dysfunctional cognitive-emotional processing in youth depression.
•We systematically examine dorsal and ventral striatal connectivity in youth MDD.•Alterations in functional connectivity in youth MDD are confined to the dorsal circuit.•Youths with MDD show increased dorsal caudate connectivity with the VLPFC.•Altered dorsal caudate–VLPFC connectivity in MDD may reflect a compensatory response.
PMCID: PMC4300014  PMID: 25610789
Major Depressive Disorder; Youth; Functional magnetic resonance imaging; Striatum; Functional connectivity
3.  The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial 
Trials  2014;15(1):425.
The aim of the Youth Depression Alleviation–Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support.
YoDA-C is a double-blind, randomised controlled trial funded by the Australian government’s National Health and Medical Research Council. Participants between the ages of 15 and 25 years with moderate to severe major depressive disorder will be randomised to receive either (1) cognitive behavioural therapy (CBT) and fluoxetine or (2) CBT and placebo. The treatment duration will be 12 weeks, and follow-up will be conducted at 26 weeks. The primary outcome measure is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) after 12 weeks of treatment. The MADRS will be administered at baseline and at weeks 4, 8, 12 and 26. Secondary outcome measures will address additional clinical outcomes, functioning, quality of life and safety.
Trial registration
Australian and New Zealand Clinical Trials Registry ID: ACTRN12612001281886 (registered on 11 December 2012)
PMCID: PMC4230740  PMID: 25370185
Adolescence; Antidepressants; Cognitive behavioural therapy; Depression; Fluoxetine; Selective serotonin reuptake inhibitors; Youth
4.  Disruption of brain white matter microstructure in women with anorexia nervosa 
The etiology of anorexia nervosa is still unknown. Multiple and distributed brain regions have been implicated in its pathophysiology, implying a dysfunction of connected neural circuits. Despite these findings, the role of white matter in anorexia nervosa has been rarely assessed. In this study, we used diffusion tensor imaging (DTI) to characterize alterations of white matter microstructure in a clinically homogeneous sample of patients with anorexia nervosa.
Women with anorexia nervosa (restricting subtype) and healthy controls underwent brain DTI. We used tract-based spatial statistics to compare fractional anisotropy (FA) and mean diffusivity (MD) maps between the groups. Furthermore, axial (AD) and radial diffusivity (RD) measures were extracted from regions showing group differences in either FA or MD.
We enrolled 19 women with anorexia nervosa and 19 healthy controls in our study. Patients with anorexia nervosa showed significant FA decreases in the parietal part of the left superior longitudinal fasciculus (SLF; pFWE < 0.05), with increased MD and RD but no differences in AD. Patients with anorexia nervosa also showed significantly increased MD in the fornix (pFWE < 0.05), accompanied by decreased FA and increased RD and AD.
Limitations include our modest sample size and cross-sectional design.
Our findings support the presence of white matter pathology in patients with anorexia nervosa. Alterations in the SLF and fornix might be relevant to key symptoms of anorexia nervosa, such as body image distortion or impairments in body–energy–balance and reward processes. The differences found in both areas replicate those found in previous DTI studies and support a role for white matter pathology of specific neural circuits in individuals with anorexia nervosa.
PMCID: PMC4214871  PMID: 24913136
5.  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.
PMCID: PMC3787080  PMID: 24098688
6.  Brain Connectivity and Mental Illness 
PMCID: PMC3406306  PMID: 22866039
7.  Functional brain imaging studies of youth depression: A systematic review☆ 
NeuroImage : Clinical  2013;4:209-231.
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.
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.
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.
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.
•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.
PMCID: PMC3895619  PMID: 24455472
Major depressive disorder (MDD); Youth; Functional magnetic resonance imaging (fMRI)
8.  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.
PMCID: PMC3501707  PMID: 22037688
functional magnetic resonance imaging (fMRI); psychopathy; amygdala; frontal lobe; brain networks; functional connectivity
9.  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.
PMCID: PMC3376324  PMID: 22534625
attention; brain; cannabis; cognitive control; functional connectivity; addiction & substance abuse; cannabinoids; cognition; functional connectivity; imaging; clinical or preclinical
10.  Brain functional connectivity during induced sadness in patients with obsessive–compulsive disorder 
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.
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.
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.
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.
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.
PMCID: PMC3380094  PMID: 22452963
11.  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.
PMCID: PMC3289045  PMID: 22403553
major depressive disorder; cognition; anterior cingulate cortex; striatum; default mode network; connectivity; fMRI; adolescence
12.  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.
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
13.  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.
PMCID: PMC3146521  PMID: 21829564
14.  White matter microstructure in patients with obsessive–compulsive disorder 
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.
In this DTI study, we investigated fractional anisotropy, as well as axial and radial diffusivity, in 21 patients with OCD and 29 healthy controls.
We found decreased fractional anisotropy in the body of the corpus callosum in the OCD group, which was underpinned by increased radial diffusivity.
The cross-sectional design was the main limitation.
Our findings of increased radial diffusivity provide preliminary evidence for abnormal myelination in patients with OCD.
PMCID: PMC3004974  PMID: 21118658
15.  Mapping Brain Response to Pain in Fibromyalgia Patients Using Temporal Analysis of fMRI 
PLoS ONE  2009;4(4):e5224.
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.
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.
PMCID: PMC2667672  PMID: 19381292
16.  Modulation of Brain Resting-State Networks by Sad Mood Induction 
PLoS ONE  2008;3(3):e1794.
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’.
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.
PMCID: PMC2263138  PMID: 18350136
17.  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.
PMCID: PMC1899961  PMID: 17339337

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