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1.  Male-typical visuospatial functioning in gynephilic girls with gender dysphoria — organizational and activational effects of testosterone 
Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT).
Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well.
We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation.
Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses.
Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.
PMCID: PMC5082510  PMID: 27070350
2.  Brain Activation During Emotional Memory Processing Associated with Subsequent Course of Depression 
Neuropsychopharmacology  2015;40(10):2454-2463.
Major depressive disorder (MDD) is characterized by a heterogeneous course and identifying patients at risk for an unfavorable course is difficult. Neuroimaging studies may identify brain predictors of clinical course and may help to further unravel the neurobiological processes underlying an unfavorable course. We investigated whether brain activation during an emotional memory paradigm is associated with depressive course. To this end, we followed 74 MDD patients and 45 healthy controls (HCs) for 2 years. At baseline, participants performed an emotional word-encoding and -recognition task during functional magnetic resonance imaging. Activation patterns were compared between patients with fast remission (n=22), remission with recurrence (n=23), non-remission (n=29), and HCs. Additionally, linear relations of brain activation and time to remission during the follow-up period were investigated across patients. We observed that during encoding of negative words, non-remitters showed higher activation of the left insula than HCs. Groups also differed in activation of the right hippocampus and left amygdala during negative encoding, with a trend for higher activation in non-remitters compared with HCs. Furthermore, hippocampal activation during negative word encoding was significantly and positively correlated with time to remission, irrespective of illness severity. Our findings suggest that higher activation in the left insula could serve as a neural marker of a naturalistic non-remitting course, whereas higher hippocampal activation is associated with delayed remission. Longitudinal analyses should clarify whether abnormal activation progresses further as a function of time with depression or may serve as load-independent markers of MDD course.
PMCID: PMC4538361  PMID: 25857684
3.  Predicting the naturalistic course of major depressive disorder using clinical and multimodal neuroimaging information : a multivariate pattern recognition study 
Biological psychiatry  2014;78(4):278-286.
A chronic course of Major Depressive Disorder (MDD) is associated with profound alterations in regional brain volumes, emotional and cognitive processing. However, no neurobiological markers have been identified that prospectively predict MDD course trajectories. This study evaluated the prognostic value of different neuroimaging modalities, clinical characteristics and their combination to classify MDD course trajectories.
One-hundred-eighteen MDD patients underwent structural and functional MRI (emotional facial expressions and executive functioning) and were clinically followed-up at two years. Three MDD trajectories (chronic N=23, gradual improving N=36 and fast remission N=59) were identified based on life-chart interview measuring the presence of symptoms at each in-between month. Gaussian Process Classifiers were employed to evaluate prognostic value of neuroimaging data and clinical characteristics (including baseline severity, duration and comorbidity).
Chronic patients could be discriminated from patients with more favorable trajectories from neural responses to various emotional faces (up to 73% accuracy), but not from structural MRI and functional MRI related to executive functioning. Chronic patients could also be discriminated from remitted patients based on clinical characteristics (accuracy 69%), but not when age differences between the groups were taken into account. Combining different task contrasts or data sources increased prediction accuracies in some but not all cases.
Our findings provide evidence that the prediction of naturalistic course of depression over two years is improved by considering neuroimaging data especially derived from neural responses to emotional facial expressions. Neural responses to primary emotional salient faces more accurately predicted outcome than clinical data.
PMCID: PMC4449319  PMID: 25702259
prediction; course trajectory; major depressive disorder; probabilistic pattern recognition analysis; magnetic resonance imaging; clinical information
4.  Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology 
Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF.
PMCID: PMC5091678  PMID: 27405617
childhood maltreatment; brain-derived neurotrophic factor; BDNF; gene expression; brain structure
5.  Grey Matter Changes Associated with Heavy Cannabis Use: A Longitudinal sMRI Study 
PLoS ONE  2016;11(5):e0152482.
Cannabis is the most frequently used illicit drug worldwide. Cross-sectional neuroimaging studies suggest that chronic cannabis exposure and the development of cannabis use disorders may affect brain morphology. However, cross-sectional studies cannot make a conclusive distinction between cause and consequence and longitudinal neuroimaging studies are lacking. In this prospective study we investigate whether continued cannabis use and higher levels of cannabis exposure in young adults are associated with grey matter reductions. Heavy cannabis users (N = 20, age baseline M = 20.5, SD = 2.1) and non-cannabis using healthy controls (N = 22, age baseline M = 21.6, SD = 2.45) underwent a comprehensive psychological assessment and a T1- structural MRI scan at baseline and 3 years follow-up. Grey matter volumes (orbitofrontal cortex, anterior cingulate cortex, insula, striatum, thalamus, amygdala, hippocampus and cerebellum) were estimated using the software package SPM (VBM-8 module). Continued cannabis use did not have an effect on GM volume change at follow-up. Cross-sectional analyses at baseline and follow-up revealed consistent negative correlations between cannabis related problems and cannabis use (in grams) and regional GM volume of the left hippocampus, amygdala and superior temporal gyrus. These results suggests that small GM volumes in the medial temporal lobe are a risk factor for heavy cannabis use or that the effect of cannabis on GM reductions is limited to adolescence with no further damage of continued use after early adulthood. Long-term prospective studies starting in early adolescence are needed to reach final conclusions.
PMCID: PMC4880314  PMID: 27224247
6.  Reduced task-related functional connectivity during a set-shifting task in unmedicated early-stage Parkinson’s disease patients 
BMC Neuroscience  2016;17:20.
Patients with Parkinson’s disease (PD) often suffer from cognitive impairments, including set-shifting deficits, in addition to the characteristic motor symptoms. It is hypothesized that the striatal dopamine depletion leads to a sub-optimal functional connectivity between task-related brain areas and consequently results in impaired task-performance. In this study, we aimed to examine this hypothesis by investigating the task-related functional connectivity of brain areas that are believed to be involved in set-shifting, such as the dorsolateral prefrontal cortex (DLPFC), posterior parietal cortex (PPC) and the superior frontal gyrus (SFG), during a set-shifting task. We obtained functional imaging data from 18 early-stage PD patients and 35 healthy controls, matched at the group level, using a newly developed rule-based set-shifting task that required participants to manually respond to arrow stimuli based on their location on the screen of their direction.
We found that early stage PD patients, compared with controls, showed (1) a decrease in positive coupling between the left DLPFC and the right insular cortex, and the right SFG and anterior cingulate cortex, (2) an increase in negative coupling between the right SFG and the anterior cingulate cortex, primary motor cortex, precuneus, and PPC, and (3) an increase in negative coupling between the left DLPFC and the left and right SFG. These results indicate that important task-related areas of PD patients have decreased functional connectivity with task-related regions and increased connectivity with task-unrelated areas.
The disruption of functional connectivity in early stage PD patients during set-shifting reported here is likely compensated for by the local hyperactivation we reported earlier, thereby forestalling behavioural deficits.
PMCID: PMC4872364  PMID: 27194153
Parkinson’s disease; Task-related functional connectivity; Set-shifting; Functional magnetic resonance imaging; Compensation
7.  Abnormal Hippocampal Morphology in Dissociative Identity Disorder and Posttraumatic Stress Disorder Correlates with Childhood Trauma and Dissociative Symptoms 
Human brain mapping  2014;36(5):1692-1704.
Smaller hippocampal volume has been reported in individuals with posttraumatic stress disorder (PTSD) and dissociative identity disorder (DID), but the regional specificity of hippocampal volume reductions and the association with severity of dissociative symptoms and/or childhood traumatization are still unclear. Brain structural MRI scans were analyzed for 33 outpatients (17 with DID and 16 with PTSD only) and 28 healthy controls (HC), all matched for age, sex, and education. DID patients met criteria for PTSD (PTSD-DID). Hippocampal global and subfield volumes and shape measurements were extracted. We found that global hippocampal volume was significantly smaller in all 33 patients (left: 6.75%; right: 8.33%) compared to HC. PTSD-DID (left: 10.19%; right: 11.37%) and PTSD-only with a history of childhood traumatization (left: 7.11%; right: 7.31%) had significantly smaller global hippocampal volume relative to HC. PTSD-DID had abnormal shape and significantly smaller volume in the CA2-3, CA4-DG and (pre)subiculum compared to HC. In the patient groups, smaller global and subfield hippocampal volumes significantly correlated with higher severity of childhood traumatization and dissociative symptoms. These findings support a childhood trauma-related etiology for abnormal hippocampal morphology in both PTSD and DID and can further the understanding of neurobiological mechanisms involved in these disorders.
PMCID: PMC4400262  PMID: 25545784
Dissociative disorders; Stress; Neuroimaging; Hippocampal volume; Childhood abuse; Gray matter
8.  Subcortical Brain Volume Abnormalities in 2,028 Individuals with Schizophrenia and 2,540 Healthy Controls via the ENIGMA Consortium 
Molecular psychiatry  2015;21(4):547-553.
The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multi-center neuroimaging data, we analyzed brain MRI scans from 2,028 schizophrenia patients and 2,540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared to healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25), and intracranial volumes (d=−0.12) and larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia that is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be employed across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.
PMCID: PMC4668237  PMID: 26033243
meta-analysis; effect size; hippocampus; pallidum; MRI
9.  Structural covariance of neostriatal and limbic regions in patients with obsessive–compulsive disorder 
Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive–compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored.
We performed a mega-analysis pooling structural MRI scans from the Obsessive–compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software.
Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex.
This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres.
Our results provide evidence for structural network–level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders.
PMCID: PMC4764480  PMID: 26505142
10.  Alterations in white matter volume and integrity in obesity and type 2 diabetes 
Metabolic Brain Disease  2016;31:621-629.
Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.
PMCID: PMC4863900  PMID: 26815786
Brain; White matter; Volume; Integrity; Type 2 diabetes; Obesity; DTI; VBM
11.  Young and Middle-Aged Schoolteachers Differ in the Neural Correlates of Memory Encoding and Cognitive Fatigue: A Functional MRI Study 
This investigation was inspired by growing evidence that middle-aged persons in a cognitively demanding profession might be characterized by subtle cognitive fatigue. We studied young and middle-aged male schoolteachers. They were compared in a study with functional magnetic resonance imaging to evaluate differences during successful memory encoding. The schoolteachers were additionally subjected to an induced fatigue condition involving the sustained performance of cognitively demanding tasks and to a control condition. Results showed age-related brain activation differences underlying behavioral performance including: (1) greater activation in middle-aged vs. young teachers in bilateral prefrontal cortex (PFC) areas; and (2) differential fatigue effects in the left anterior cingulate cortex (ACC) depending on age group. Middle-aged schoolteachers showed decreased ACC activation in the fatigue compared to the control condition, whereas no change in activation was found in young teachers. Findings demonstrate age effects in these middle-aged subjects that are typically found in older adults, specifically in PFC over-activation. Findings also indicate that already in middle age cognitive aging may be associated with greater resource depletion following sustained task performance. The findings underscore the notion that persons in a cognitively demanding profession can experience subtle age effects, which are evident on fMRI and which impact daily functioning. Possible practical implications for middle-aged schoolteachers are discussed.
PMCID: PMC4823302  PMID: 27092068
episodic memory; schoolteachers; aging; mental fatigue; fMRI; middle age
12.  Computer-Based Cognitive Training for Executive Functions after Stroke: A Systematic Review 
Background: Stroke commonly results in cognitive impairments in working memory, attention, and executive function, which may be restored with appropriate training programs. Our aim was to systematically review the evidence for computer-based cognitive training of executive dysfunctions.
Methods: Studies were included if they concerned adults who had suffered stroke or other types of acquired brain injury, if the intervention was computer training of executive functions, and if the outcome was related to executive functioning. We searched in MEDLINE, PsycINFO, Web of Science, and The Cochrane Library. Study quality was evaluated based on the CONSORT Statement. Treatment effect was evaluated based on differences compared to pre-treatment and/or to a control group.
Results: Twenty studies were included. Two were randomized controlled trials that used an active control group. The other studies included multiple baselines, a passive control group, or were uncontrolled. Improvements were observed in tasks similar to the training (near transfer) and in tasks dissimilar to the training (far transfer). However, these effects were not larger in trained than in active control groups. Two studies evaluated neural effects and found changes in both functional and structural connectivity. Most studies suffered from methodological limitations (e.g., lack of an active control group and no adjustment for multiple testing) hampering differentiation of training effects from spontaneous recovery, retest effects, and placebo effects.
Conclusions: The positive findings of most studies, including neural changes, warrant continuation of research in this field, but only if its methodological limitations are addressed.
PMCID: PMC4837156  PMID: 27148007
working memory; attention; restitution; retraining; acquired brain injury; brain training; executive functions; computer-based
13.  TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome 
Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network ( that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.
PMCID: PMC4994475  PMID: 27601976
Initial Training Network; Gilles de la Tourette Syndrome; tourette disorder; etiology; genetics; neuroimaging; animal models
15.  Hypoactive medial prefrontal cortex functioning in adults reporting childhood emotional maltreatment 
Childhood emotional maltreatment (CEM) has adverse effects on medial prefrontal cortex (mPFC) morphology, a structure that is crucial for cognitive functioning and (emotional) memory and which modulates the limbic system. In addition, CEM has been linked to amygdala hyperactivity during emotional face processing. However, no study has yet investigated the functional neural correlates of neutral and emotional memory in adults reporting CEM. Using functional magnetic resonance imaging, we investigated CEM-related differential activations in mPFC during the encoding and recognition of positive, negative and neutral words. The sample (N = 194) consisted of patients with depression and/or anxiety disorders and healthy controls (HC) reporting CEM (n = 96) and patients and HC reporting no abuse (n = 98). We found a consistent pattern of mPFC hypoactivation during encoding and recognition of positive, negative and neutral words in individuals reporting CEM. These results were not explained by psychopathology or severity of depression or anxiety symptoms, or by gender, level of neuroticism, parental psychopathology, negative life events, antidepressant use or decreased mPFC volume in the CEM group. These findings indicate mPFC hypoactivity in individuals reporting CEM during emotional and neutral memory encoding and recognition. Our findings suggest that CEM may increase individuals’ risk to the development of psychopathology on differential levels of processing in the brain; blunted mPFC activation during higher order processing and enhanced amygdala activation during automatic/lower order emotion processing. These findings are vital in understanding the long-term consequences of CEM.
PMCID: PMC4249477  PMID: 24493840
Anxiety; childhood abuse; depression; emotional maltreatment; magnetic resonance imaging (MRI); medial prefrontal cortex (PFC)
16.  Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes 
Diabetologia  2015;58(12):2688-2698.
The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that endogenous GLP-1 has effects on CNS reward and satiety circuits.
This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible if they were 40–65 years. Inclusion criteria for the healthy lean individuals included a BMI <25 kg/m2 and normoglycaemia. Inclusion criteria for the patients with type 2 diabetes included BMI >26 kg/m2, HbA1c levels between 42 and 69 mmol/mol (6.0–8.5%) and treatment for diabetes with only oral glucose-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures.
All patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS areas involved in the regulation of feeding (insula, amygdala and orbitofrontal cortex) in response to food pictures compared with lean individuals (p ≤ 0.04). Meal intake reduced activation in the insula in response to food pictures in both groups (p ≤ 0.05), but this was more pronounced in patients with type 2 diabetes. Blocking actions of endogenous GLP-1 significantly prevented meal-induced reductions in bilateral insula activation in response to food pictures in patients with type 2 diabetes (p ≤ 0.03).
Our findings support the hypothesis that endogenous GLP-1 is involved in postprandial satiating effects in the CNS of obese patients with type 2 diabetes.
Trial registration: NCT 01363609
Funding The study was funded in part by a grant from Novo Nordisk.
PMCID: PMC4630252  PMID: 26385462
fMRI; Food intake; GLP-1; Neuroimaging; Obesity; Type 2 diabetes
17.  The effect of computer-based cognitive flexibility training on recovery of executive function after stroke: rationale, design and methods of the TAPASS study 
BMC Neurology  2015;15:144.
Stroke survivors frequently suffer from executive impairments even in the chronic phase after stroke, and there is a need for improved rehabilitation of these functions. One way of improving current rehabilitation treatment may be by online cognitive training. Based on a review of the effectiveness of computer-based cognitive training in healthy elderly, we concluded that cognitive flexibility may be a key element for an effective training, which results in improvements not merely on trained tasks but also in untrained tasks (i.e., far transfer). The aim of the current study was to track the behavioral and neural effects of computer-based cognitive flexibility training after stroke. We expected that executive functioning would improve after the cognitive flexibility training, and that neural activity and connectivity would normalize towards what is seen in healthy elderly.
The design was a multicenter, double blind, randomized controlled trial (RCT) with three groups: an experimental intervention group, an active control group who did a mock training, and a waiting list control group. Stroke patients (3 months to 5 years post-stroke) with cognitive complaints were included. Training consisted of 58 half-hour sessions spread over 12 weeks. The primary study outcome was objective executive function. Secondary measures were improvement on training tasks, cognitive flexibility, objective cognitive functioning in other domains than the executive domain, subjective cognitive and everyday life functioning, and neural correlates assessed by both structural and resting-state functional Magnetic Resonance Imaging. The three groups were compared at baseline, after six and twelve weeks of training, and four weeks after the end of the training. Furthermore, they were compared to healthy elderly who received the same training.
The cognitive flexibility training consisted of several factors deemed important for effects that go beyond improvement on merely the training task themselves. Due to the presence of two control groups, the effects of the training could be compared with spontaneous recovery and with the effects of a mock training. This study provides insight into the potential of online cognitive flexibility training after stroke. We also compared its results with the effectiveness of the same training in healthy elderly.
Trial registration
The Netherlands National Trial Register NTR5174. Registered 22 May 2015.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0397-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4545547  PMID: 26286548
Stroke; Cognitive flexibility training; Computer-based training; Online testing; Rehabilitation outcome; Executive functions; Cognitive control; Randomized controlled trial; Cognition; Structural and functional Magnetic Resonance Imaging (MRI and fMRI)
18.  Predicting the Naturalistic Course of Major Depressive Disorder Using Clinical and Multimodal Neuroimaging Information: A Multivariate Pattern Recognition Study 
Biological Psychiatry  2015;78(4):278-286.
A chronic course of major depressive disorder (MDD) is associated with profound alterations in brain volumes and emotional and cognitive processing. However, no neurobiological markers have been identified that prospectively predict MDD course trajectories. This study evaluated the prognostic value of different neuroimaging modalities, clinical characteristics, and their combination to classify MDD course trajectories.
One hundred eighteen MDD patients underwent structural and functional magnetic resonance imaging (MRI) (emotional facial expressions and executive functioning) and were clinically followed-up at 2 years. Three MDD trajectories (chronic n = 23, gradual improving n = 36, and fast remission n = 59) were identified based on Life Chart Interview measuring the presence of symptoms each month. Gaussian process classifiers were employed to evaluate prognostic value of neuroimaging data and clinical characteristics (including baseline severity, duration, and comorbidity).
Chronic patients could be discriminated from patients with more favorable trajectories from neural responses to various emotional faces (up to 73% accuracy) but not from structural MRI and functional MRI related to executive functioning. Chronic patients could also be discriminated from remitted patients based on clinical characteristics (accuracy 69%) but not when age differences between the groups were taken into account. Combining different task contrasts or data sources increased prediction accuracies in some but not all cases.
Our findings provide evidence that the prediction of naturalistic course of depression over 2 years is improved by considering neuroimaging data especially derived from neural responses to emotional facial expressions. Neural responses to emotional salient faces more accurately predicted outcome than clinical data.
PMCID: PMC4449319  PMID: 25702259
Clinical information; Course trajectory; Magnetic resonance imaging; Major depressive disorder; Prediction; Probabilistic pattern recognition analysis
19.  Using fMRI to Investigate Memory in Young Children Born Small for Gestational Age 
PLoS ONE  2015;10(7):e0129721.
Intrauterine growth restriction (IUGR) can lead to infants being born small for gestational age (SGA). SGA is associated with differences in brain anatomy and impaired cognition. We investigated learning and memory in children born SGA using neuropsychological testing and functional Magnetic Resonance Imaging (fMRI).
Study Design
18 children born appropriate for gestational age (AGA) and 34 SGA born children (18 with and 16 without postnatal catch-up growth) participated in this study. All children were between 4 and 7 years old. Cognitive functioning was assessed by IQ and memory testing (Digit/Word Span and Location Learning). A newly developed fMRI picture encoding task was completed by all children in order to assess brain regions involved in memory processes.
Neuropsychological testing demonstrated that SGA children had IQ’s within the normal range but lower than in AGA and poorer performances across measures of memory. Using fMRI, we observed memory related activity in posterior parahippocampal gyrus as well as the hippocampus proper. Additionally, activation was seen bilaterally in the prefrontal gyrus. Children born SGA showed less activation in the left parahippocampal region compared to AGA.
This is the first fMRI study demonstrating different brain activation patterns in 4-7 year old children born SGA, suggesting that intrauterine growth restriction continues to affect neural functioning in children later-on.
PMCID: PMC4488594  PMID: 26132815
20.  Interaction of neuropeptide Y genotype and childhood emotional maltreatment on brain activity during emotional processing 
Neuropeptide Y (NPY) has been associated with stress reactivity in affective disorders and is most densely expressed in the amygdala. An important stressor associated with affective disorders is the experience of childhood emotional maltreatment (CEM). We investigated whether the interaction of NPY risk genotype and CEM would affect brain activation. From the Netherlands Study of Depression and Anxiety, 33 healthy controls and 85 patients with affective disorders were scanned with functional magnetic resonance imaging while making gender decisions of emotional facial expressions. Results showed interactions between genotype and CEM, within carriers of the risk genotype, CEM was associated with higher amygdala activation, whereas CEM did not influence activation in non-risk carriers. In the posterior cingulate cortex (PCC), less activation was seen in those with CEM and the risk genotype, whereas genotype did not influence PCC activation in those without CEM. In addition, those carrying the risk genotype and with experience of CEM made a faster gender decision than those without CEM. Thus, the combined effect of carrying NPY risk genotype and a history of CEM affected amygdala and PCC reactivity, areas related to emotion, self-relevance processing and autobiographical memory. These results are consistent with the notion that the combination of risk genotype and CEM may cause hypervigilance.
PMCID: PMC4014098  PMID: 23482625
NPY; amygdala; fMRI; depression; childhood abuse
21.  Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders 
Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia.
We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori–defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored.
We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found.
We were unable to correct for possible confounding effects of smoking or antipsychotic medication.
Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume.
PMCID: PMC4409437  PMID: 25510948
22.  Common genetic variants influence human subcortical brain structures 
Hibar, Derrek P. | Stein, Jason L. | Renteria, Miguel E. | Arias-Vasquez, Alejandro | Desrivières, Sylvane | Jahanshad, Neda | Toro, Roberto | Wittfeld, Katharina | Abramovic, Lucija | Andersson, Micael | Aribisala, Benjamin S. | Armstrong, Nicola J. | Bernard, Manon | Bohlken, Marc M. | Boks, Marco P. | Bralten, Janita | Brown, Andrew A. | Chakravarty, M. Mallar | Chen, Qiang | Ching, Christopher R. K. | Cuellar-Partida, Gabriel | den Braber, Anouk | Giddaluru, Sudheer | Goldman, Aaron L. | Grimm, Oliver | Guadalupe, Tulio | Hass, Johanna | Woldehawariat, Girma | Holmes, Avram J. | Hoogman, Martine | Janowitz, Deborah | Jia, Tianye | Kim, Sungeun | Klein, Marieke | Kraemer, Bernd | Lee, Phil H. | Olde Loohuis, Loes M. | Luciano, Michelle | Macare, Christine | Mather, Karen A. | Mattheisen, Manuel | Milaneschi, Yuri | Nho, Kwangsik | Papmeyer, Martina | Ramasamy, Adaikalavan | Risacher, Shannon L. | Roiz-Santiañez, Roberto | Rose, Emma J. | Salami, Alireza | Sämann, Philipp G. | Schmaal, Lianne | Schork, Andrew J. | Shin, Jean | Strike, Lachlan T. | Teumer, Alexander | van Donkelaar, Marjolein M. J. | van Eijk, Kristel R. | Walters, Raymond K. | Westlye, Lars T. | Whelan, Christopher D. | Winkler, Anderson M. | Zwiers, Marcel P. | Alhusaini, Saud | Athanasiu, Lavinia | Ehrlich, Stefan | Hakobjan, Marina M. H. | Hartberg, Cecilie B. | Haukvik, Unn K. | Heister, Angelien J. G. A. M. | Hoehn, David | Kasperaviciute, Dalia | Liewald, David C. M. | Lopez, Lorna M. | Makkinje, Remco R. R. | Matarin, Mar | Naber, Marlies A. M. | McKay, D. Reese | Needham, Margaret | Nugent, Allison C. | Pütz, Benno | Royle, Natalie A. | Shen, Li | Sprooten, Emma | Trabzuni, Daniah | van der Marel, Saskia S. L. | van Hulzen, Kimm J. E. | Walton, Esther | Wolf, Christiane | Almasy, Laura | Ames, David | Arepalli, Sampath | Assareh, Amelia A. | Bastin, Mark E. | Brodaty, Henry | Bulayeva, Kazima B. | Carless, Melanie A. | Cichon, Sven | Corvin, Aiden | Curran, Joanne E. | Czisch, Michael | de Zubicaray, Greig I. | Dillman, Allissa | Duggirala, Ravi | Dyer, Thomas D. | Erk, Susanne | Fedko, Iryna O. | Ferrucci, Luigi | Foroud, Tatiana M. | Fox, Peter T. | Fukunaga, Masaki | Gibbs, J. Raphael | Göring, Harald H. H. | Green, Robert C. | Guelfi, Sebastian | Hansell, Narelle K. | Hartman, Catharina A. | Hegenscheid, Katrin | Heinz, Andreas | Hernandez, Dena G. | Heslenfeld, Dirk J. | Hoekstra, Pieter J. | Holsboer, Florian | Homuth, Georg | Hottenga, Jouke-Jan | Ikeda, Masashi | Jack, Clifford R. | Jenkinson, Mark | Johnson, Robert | Kanai, Ryota | Keil, Maria | Kent, Jack W. | Kochunov, Peter | Kwok, John B. | Lawrie, Stephen M. | Liu, Xinmin | Longo, Dan L. | McMahon, Katie L. | Meisenzahl, Eva | Melle, Ingrid | Mohnke, Sebastian | Montgomery, Grant W. | Mostert, Jeanette C. | Mühleisen, Thomas W. | Nalls, Michael A. | Nichols, Thomas E. | Nilsson, Lars G. | Nöthen, Markus M. | Ohi, Kazutaka | Olvera, Rene L. | Perez-Iglesias, Rocio | Pike, G. Bruce | Potkin, Steven G. | Reinvang, Ivar | Reppermund, Simone | Rietschel, Marcella | Romanczuk-Seiferth, Nina | Rosen, Glenn D. | Rujescu, Dan | Schnell, Knut | Schofield, Peter R. | Smith, Colin | Steen, Vidar M. | Sussmann, Jessika E. | Thalamuthu, Anbupalam | Toga, Arthur W. | Traynor, Bryan J. | Troncoso, Juan | Turner, Jessica A. | Valdés Hernández, Maria C. | van ’t Ent, Dennis | van der Brug, Marcel | van der Wee, Nic J. A. | van Tol, Marie-Jose | Veltman, Dick J. | Wassink, Thomas H. | Westman, Eric | Zielke, Ronald H. | Zonderman, Alan B. | Ashbrook, David G. | Hager, Reinmar | Lu, Lu | McMahon, Francis J. | Morris, Derek W. | Williams, Robert W. | Brunner, Han G. | Buckner, Randy L. | Buitelaar, Jan K. | Cahn, Wiepke | Calhoun, Vince D. | Cavalleri, Gianpiero L. | Crespo-Facorro, Benedicto | Dale, Anders M. | Davies, Gareth E. | Delanty, Norman | Depondt, Chantal | Djurovic, Srdjan | Drevets, Wayne C. | Espeseth, Thomas | Gollub, Randy L. | Ho, Beng-Choon | Hoffmann, Wolfgang | Hosten, Norbert | Kahn, René S. | Le Hellard, Stephanie | Meyer-Lindenberg, Andreas | Müller-Myhsok, Bertram | Nauck, Matthias | Nyberg, Lars | Pandolfo, Massimo | Penninx, Brenda W. J. H. | Roffman, Joshua L. | Sisodiya, Sanjay M. | Smoller, Jordan W. | van Bokhoven, Hans | van Haren, Neeltje E. M. | Völzke, Henry | Walter, Henrik | Weiner, Michael W. | Wen, Wei | White, Tonya | Agartz, Ingrid | Andreassen, Ole A. | Blangero, John | Boomsma, Dorret I. | Brouwer, Rachel M. | Cannon, Dara M. | Cookson, Mark R. | de Geus, Eco J. C. | Deary, Ian J. | Donohoe, Gary | Fernández, Guillén | Fisher, Simon E. | Francks, Clyde | Glahn, David C. | Grabe, Hans J. | Gruber, Oliver | Hardy, John | Hashimoto, Ryota | Hulshoff Pol, Hilleke E. | Jönsson, Erik G. | Kloszewska, Iwona | Lovestone, Simon | Mattay, Venkata S. | Mecocci, Patrizia | McDonald, Colm | McIntosh, Andrew M. | Ophoff, Roel A. | Paus, Tomas | Pausova, Zdenka | Ryten, Mina | Sachdev, Perminder S. | Saykin, Andrew J. | Simmons, Andy | Singleton, Andrew | Soininen, Hilkka | Wardlaw, Joanna M. | Weale, Michael E. | Weinberger, Daniel R. | Adams, Hieab H. H. | Launer, Lenore J. | Seiler, Stephan | Schmidt, Reinhold | Chauhan, Ganesh | Satizabal, Claudia L. | Becker, James T. | Yanek, Lisa | van der Lee, Sven J. | Ebling, Maritza | Fischl, Bruce | Longstreth, W. T. | Greve, Douglas | Schmidt, Helena | Nyquist, Paul | Vinke, Louis N. | van Duijn, Cornelia M. | Xue, Luting | Mazoyer, Bernard | Bis, Joshua C. | Gudnason, Vilmundur | Seshadri, Sudha | Ikram, M. Arfan | Martin, Nicholas G. | Wright, Margaret J. | Schumann, Gunter | Franke, Barbara | Thompson, Paul M. | Medland, Sarah E.
Nature  2015;520(7546):224-229.
The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
PMCID: PMC4393366  PMID: 25607358
24.  The associations of depression and hypertension with brain volumes: Independent or interactive? 
NeuroImage : Clinical  2015;8:79-86.
Independent studies on major depressive disorder (MDD) and hypertension, suggest overlapping abnormalities in brain regions associated with emotional and autonomic processing. However, the unique and interactive effects of MDD and hypertension have never been studied in a single sample. Brain volume in these areas may be an explanatory link in the comorbidity between MDD and hypertension. Voxel-based morphometry was used to test for main effects of MDD (N = 152) and hypertension (N = 82) and their interactions on gray and white matter volumes. Voxel-wise results are reported at p < .05 FWE corrected for the spatial extent of the whole brain and a-priori regions of interest (ROIs: hippocampus, anterior cingulate cortex (ACC) and inferior frontal gyrus (IFG)). In addition, analyses on the extracted total volumes of our ROIs were performed. Interactive effects in the mid-cingulate cortex (MCC) (pFWE = .01), cerebellum (pFWE = .01) and in the ACC total ROI volume (p = .02) were found. MDD in the presence, but not in the absence of hypertension was associated with lower volumes in the ACC and MCC, and with a trend towards larger gray matter volume in the cerebellum. No associations with white matter volumes were observed. Results suggest that the combination of MDD and hypertension has a unique effect on brain volumes in areas implicated in the regulation of emotional and autonomic functions. Brain volume in these regulatory areas may be an explanatory link in the comorbidity between hypertension and MDD.
•We tested for main and interaction effects of MDD and hypertension on brain volumes.•Voxel based morphometry was used to test effects on gray and white matter volumes.•Both whole brain and region of interest analyses were performed.•The combination of MDD and hypertension has unique effects on regional brain volumes.•Brain volume may be a link in the comorbidity between hypertension and MDD.
PMCID: PMC4473298  PMID: 26106530
Depression; Blood pressure; Hypertension; Comorbidity; MRI; Gray matter
25.  Decreased Resting-State Connectivity between Neurocognitive Networks in Treatment Resistant Depression 
Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission after various treatment options and develop treatment resistant depression (TRD). So far, little is known about the pathophysiology of TRD. Studies in MDD patients showed aberrant functional connectivity (FC) of three “core” neurocognitive networks: the salience network (SN), cognitive control network (CCN), and default mode network (DMN). We used a cross-sectional design and performed resting-state FC MRI to assess connectivity of the SN, CCN, and both anterior and posterior DMN in 17 severe TRD, 18 non-TRD, and 18 healthy control (HC) subjects. Relative to both non-TRD and HC subjects, TRD patients showed decreased FC between the dorsolateral prefrontal cortex and angular gyrus, which suggests reduced FC between the CCN and DMN, and reduced FC between the medial prefrontal cortex and precuneus/cuneus, which suggests reduced FC between the anterior and posterior DMN. No significant differences in SN FC were observed. Our results suggest that TRD is characterized by a disturbance in neurocognitive networks relative to non-TRD and HC.
PMCID: PMC4345766  PMID: 25784881
major depressive disorder; treatment resistant depression; functional connectivity; salience network; cognitive control network; default mode network

Results 1-25 (67)