Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Abnormal white-matter rich-club organization in obsessive-compulsive disorder.

Rich-club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher-order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive-compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich-club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion-weighted imaging and probabilistic tractography. Topological and weighted measures of rich-club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich-club organization, allocating a smaller fraction of all connection weights to the rich-club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three-group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich-club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network-based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.

Home alone: Social functioning as a transdiagnostic marker of mental health in youth, exploring retrospective and daily life measurements.

PURPOSE: Early detection and intervention of mental health problems in youth are topical given that mental disorders often start early in life. Young people with emerging mental disorders however, often present with non-specific, fluctuating symptoms. Recent reports indicate a decline in social functioning (SF) as an early sign of specific emerging mental disorders such as depression or anxiety, making SF a favorable transdiagnostic approach for earlier detection and intervention. Our aim was to investigate the value of SF in relation to transdiagnostic symptoms, and as a predictor of psychopathology over time, while exploring traditional retrospective versus innovative daily diary measurements of SF in youth. METHOD: Participants (N = 75) were 16-25 years of age and presented early stage psychiatric symptomatology. Psychiatric symptoms, including anxiety and depression, as well as SF -both in retrospect and in daily life- were assessed at two time points and analyzed cross-sectionally and longitudinally. RESULTS: A significant and negative association between SF and all psychiatric symptoms was found, and SF was a significant predictor of change in general psychiatric symptoms over time. Results were only significant when SF was measured traditionally retrospective. CONCLUSION: This study confirms a distinct relation between SF and transdiagnostic psychiatric symptoms in youth, even in a (sub)clinical population, and points towards SF as a predictor of transdiagnostic psychiatric symptoms. Further research is needed to learn more about the added value of daily life versus retrospective measurements.

Dedicated container for postmortem human brain ultra-high field magnetic resonance imaging.

BACKGROUND: The emerging field of ultra-high field MRI (UHF-MRI, 7 Tesla and higher) provides the opportunity to image human brains at a higher resolution and with higher signal-to-noise ratios compared to the more widely available 1.5 and 3T scanners. Scanning postmortem tissue additionally allows for greatly increased scan times and fewer movement issues leading to improvements in image quality. However, typical postmortem neuroimaging routines involve placing the tissue within plastic bags that leave room for susceptibility artifacts from tissue-air interfaces, inadequate submersion, and leakage issues. To address these challenges in postmortem imaging, a custom-built nonferromagnetic container was developed that allows whole brain hemispheres to be scanned at sub-millimeter resolution within typical head-coils. METHOD: The custom-built polymethylmethacrylaat container consists of a cylinder with a hemispheric side and a lid with valves on the adjacent side. This shape fits within common MR head-coils and allows whole hemispheres to be submerged and vacuum sealed within it reducing imaging artifacts that would otherwise arise at air-tissue boundaries. Two hemisphere samples were scanned on a Siemens 9.4T Magnetom MRI scanner. High resolution T2* weighted data was obtained with a custom 3D gradient echo (GRE) sequence and diffusion-weighted imaging (DWI) scans were obtained with a 3D kT-dSTEAM sequence along 48 directions. RESULTS: The custom-built container proved to submerge and contain tissue samples effectively and showed no interferences with MR scanning acquisition. The 3D GRE sequence provided high resolution isotropic T2* weighted data at 250 µm which showed a clear visualization of gray and white matter structures. DWI scans allowed for dense reconstruction of structural white matter connections via tractography. CONCLUSION: Using this custom-built container worked towards achieving high quality MR images of postmortem brain material. This procedure can have advantages over traditional schemes including utilization of a standardized protocol and the reduced likelihood of leakage. This methodology could be adjusted and used to improve typical postmortem imaging routines.

Childhood trauma- and cannabis-associated microstructural white matter changes in patients with psychotic disorder: a longitudinal family-based diffusion imaging study.

BACKGROUND: Decreased white matter (WM) integrity in patients with psychotic disorder has been a consistent finding in diffusion tensor imaging (DTI) studies. However, the contribution of environmental risk factors to these WM alterations is rarely investigated. The current study examines whether individuals with (increased risk for) psychotic disorder will show increased WM integrity change over time with increasing levels of childhood trauma and cannabis exposure. METHODS: DTI scans were obtained from 85 patients with a psychotic disorder, 93 non-psychotic siblings and 80 healthy controls, of which 60% were rescanned 3 years later. In a whole-brain voxel-based analysis, associations between change in fractional anisotropy (ΔFA) and environmental exposures as well as interactions between group and environmental exposure in the model of FA and ΔFA were investigated. Analyses were adjusted for a priori hypothesized confounding variables: age, sex, and level of education. RESULTS: At baseline, no significant associations were found between FA and both environmental risk factors. At follow-up as well as over a 3-year interval, significant interactions between group and, respectively, cannabis exposure and childhood trauma exposure in the model of FA and ΔFA were found. Patients showed more FA decrease over time compared with both controls and siblings when exposed to higher levels of cannabis or childhood trauma. CONCLUSIONS: Higher levels of cannabis or childhood trauma may compromise connectivity over the course of the illness in patients, but not in individuals at low or higher than average genetic risk for psychotic disorder, suggesting interactions between the environment and illness-related factors.

From laboratory to life: associating brain reward processing with real-life motivated behaviour and symptoms of depression in non-help-seeking young adults.

BACKGROUND: Depression has been associated with abnormalities in neural underpinnings of Reward Learning (RL). However, inconsistencies have emerged, possibly owing to medication effects. Additionally, it remains unclear how neural RL signals relate to real-life behaviour. The current study, therefore, examined neural RL signals in young, mildly to moderately depressed - but non-help-seeking and unmedicated - individuals and how these signals are associated with depressive symptoms and real-life motivated behaviour. METHODS: Individuals with symptoms along the depression continuum (n = 87) were recruited from the community. They performed an RL task during functional Magnetic Resonance Imaging and were assessed with the Experience Sampling Method (ESM), completing short questionnaires on emotions and behaviours up to 10 times/day for 15 days. Q-learning model-derived Reward Prediction Errors (RPEs) were examined in striatal areas, and subsequently associated with depressive symptoms and an ESM measure capturing (non-linearly) how anticipation of reward experience corresponds to actual reward experience later on. RESULTS: Significant RPE signals were found in the striatum, insula, amygdala, hippocampus, frontal and occipital cortices. Region-of-interest analyses revealed a significant association between RPE signals and (a) self-reported depressive symptoms in the right nucleus accumbens (b = -0.017, p = 0.006) and putamen (b = -0.013, p = .012); and (b) the quadratic ESM variable in the left (b = 0.010, p = .010) and right (b = 0.026, p = 0.011) nucleus accumbens and right putamen (b = 0.047, p < 0.001). CONCLUSIONS: Striatal RPE signals are disrupted along the depression continuum. Moreover, they are associated with reward-related behaviour in real-life, suggesting that real-life coupling of reward anticipation and engagement in rewarding activities might be a relevant target of psychological therapies for depression.

Neurobehavioural mechanisms of threat generalization moderate the link between childhood maltreatment and psychopathology in emerging adulthood

Background: Childhood maltreatment is a transdiagnostic risk factor for later psychopathology and has been associated with altered brain circuitry involved in the processing of threat and safety. Examining threat generalization mechanisms in young adults with childhood maltreatment and psychiatric symptoms may elucidate a pathway linking early-life adversities to the presence of subclinical psychopathology. Methods: We recruited youth aged 16­25 years with subclinical psychiatric symptomatology and healthy controls. They were dichotomized into 2 groups: 1 with a high level of childhood maltreatment (n = 58) and 1 with no or a low level of childhood maltreatment (n = 55). Participants underwent a functional MRI threat generalization paradigm, measuring self-reported fear, expectancy of an unconditioned stimulus (US) and neural responses. Results: We observed interactions between childhood maltreatment and threat generalization indices on subclinical symptom load. In individuals reporting high levels of childhood maltreatment, enhanced generalization in self-reported fear and US expectancy was related to higher levels of psychopathology. Imaging results revealed that in the group with high levels of childhood maltreatment, lower activation in the left hippocampus during threat generalization was associated with a higher symptom load. Associations between threat generalization and psychopathology were nonsignificant overall in the group with no or low levels of childhood maltreatment. Limitations: The data were acquired in a cross-sectional manner, precluding definitive insight into the causality of childhood maltreatment, threat generalization and psychopathology. Conclusion: Our results suggest that threat generalization mechanisms may moderate the link between childhood maltreatment and subclinical psychopathology during emerging adulthood. Threat generalization could represent a vulnerability factor for developing later psychopathology in individuals being exposed to childhood maltreatment.

Habenula volume change in Parkinson's disease: A 7T MRI study.

OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and early non-motor symptoms. The habenula is implicated in the pathophysiology of depression. This study investigates habenular volume in PD patients without clinical depression to show the changes in PD unrelated to depression. METHODS: The study used high-resolution 7 Tesla MRI data from the TRACK-PD study involving 104 PD patients and 44 healthy controls (HCs). The habenula was manually segmented, and volumes were measured, considering demographic data and depression scores via the Beck Depression Inventory (BDI). RESULTS: No significant correlation was found between habenular volume and BDI scores in PD patients or HCs. However, the PD group exhibited a significantly larger mean and right habenular volume than HCs. Although PD patients showed higher BDI scores, indicating more subthreshold depression, these did not correlate with the habenular volume. CONCLUSION: The results suggest that while the habenula may be involved in the symptoms of PD, its role in depression within this cohort is unclear. The changes might be related to the role of the habenula in motor symptoms. This study provides a new perspective on the role of the habenula in PD, but future research could lead to a greater understanding of the neuroanatomical features of the habenula in PD.

The habenula in Parkinson's disease: Anatomy, function, and implications for mood disorders - A narrative review.

Parkinson's disease (PD), a widespread neurodegenerative disorder, often coexists with mood disorders. Degeneration of serotonergic neurons in brainstem raphe nuclei have been linked to depression and anxiety. Additionally, the locus coeruleus and its noradrenergic neurons are among the first areas to degenerate in PD and contribute to stress, emotional memory, motor, sensory, and autonomic symptoms. Another brain region of interest is habenula, which is especially related to anti-reward processing, and its function has recently been linked to PD and to mood-related symptoms. There are several neuroimaging studies that investigated role of the habenula in mood disorders. Differences in habenular size and hemispheric symmetry were found in healthy controls compared to individuals with mood disorders. The lateral habenula, as a link between the dopaminergic and serotonergic systems, is thought to contribute to depressive symptoms in PD. However, there is only one imaging study about role of habenula in mood disorders in PD, although the relationship between PD and mood disorders is known. There is little known about habenula pathology in PD but given these observations, the question arises whether habenular dysfunction could play a role in PD and the development of PD-related mood disorders. In this review, we evaluate neuroimaging techniques and studies that investigated the habenula in the context of PD and mood disorders. Future studies are important to understand habenula's role in PD patients with mood disorders. Thus, new potential diagnostic and treatment opportunities would be found for mood disorders in PD.

Neuromelanin related ultra-high field signal intensity of the locus coeruleus differs between Parkinson's disease and controls.

INTRODUCTION: Neuromelanin related signal changes in catecholaminergic nuclei are considered as a promising MRI biomarker in Parkinson's disease (PD). Until now, most studies have investigated the substantia nigra (SN), while signal changes might be more prominent in the locus coeruleus (LC). Ultra-high field MRI improves the visualisation of these small brainstem regions and might support the development of imaging biomarkers in PD. OBJECTIVES: To compare signal intensity of the SN and LC on Magnetization Transfer MRI between PD patients and healthy controls (HC) and to explore its association with cognitive performance in PD. METHODS: This study was conducted using data from the TRACK-PD study, a longitudinal 7T MRI study. A total of 78 early-stage PD patients and 36 HC were included. A mask for the SN and LC was automatically segmented and manually corrected. Neuromelanin related signal intensity of the SN and LC was compared between PD and HC. RESULTS: PD participants showed a lower contrast-to-noise ratio (CNR) in the right SN (p = 0.029) and left LC (p = 0.027). After adding age as a confounder, the CNR of the right SN did not significantly differ anymore between PD and HC (p = 0.055). Additionally, a significant positive correlation was found between the SN CNR and memory function. DISCUSSION: This study confirms that neuromelanin related signal intensity of the LC differs between early-stage PD patients and HC. No significant difference was found in the SN. This supports the theory of bottom-up disease progression in PD. Furthermore, loss of SN integrity might influence working memory or learning capabilities in PD patients.

Comparison of Olfactory Tract Diffusion Measures Between Early Stage Parkinson's Disease Patients and Healthy Controls Using Ultra-High Field MRI.

BACKGROUND: MRI is a valuable method to assist in the diagnostic work-up of Parkinson's disease (PD). The olfactory tract (OT) has been proposed as a potential MRI biomarker for distinguishing PD patients from healthy controls. OBJECTIVE: This study aims to further investigate whether diffusion measures of the OT differ between early stage PD patients and healthy controls. METHODS: Twenty hyposmic/anosmic PD patients, 65 normosmic PD patients, and 36 normosmic healthy controls were evaluated and a 7T diffusion weighted image scan was acquired. Manual seed regions of interest were drawn in the OT region. Tractography of the OT was performed using a deterministic streamlines algorithm. Diffusion measures (fractional anisotropy and mean- radial- and axial diffusivity) of the generated streamlines were compared between groups. RESULTS: Diffusion measures did not differ between PD patients compared to healthy controls and between hyposmic/anosmic PD patients, normosmic PD patients, and normosmic healthy controls. A positive correlation was found between age and mean- and axial diffusivity within the hyposmic/anosmic PD subgroup, but not in the normosmic groups. A positive correlation was found between MDS-UPDRSIII scores and fractional anisotropy. CONCLUSION: This study showed that fiber tracking of the OT was feasible in both early stage PD and healthy controls using 7T diffusion weighted imaging data. However, 7T MRI diffusion measures of the OT are not useful as an early clinical biomarker for PD. Future work is needed to clarify the role of other OT measurements as a biomarker for PD and its different subgroups.

Brain network characteristics and cognitive performance in motor subtypes of Parkinson's disease: A resting state fMRI study.

INTRODUCTION: Parkinson's disease (PD) is a heterogeneous disorder with great variability in motor and non-motor manifestations. It is hypothesized that different motor subtypes are characterized by different neuropsychiatric and cognitive symptoms, but the underlying correlates in cerebral connectivity remain unknown. Our aim is to compare brain network connectivity between the postural instability and gait disorder (PIGD) and tremor-dominant (TD) subtypes, using both a within- and between-network analysis. METHODS: This cross-sectional resting-state fMRI study includes 81 PD patients, 54 belonging to the PIGD and 27 to the TD subgroup. Group-level spatial maps were created using independent component analysis. Differences in functional connectivity were investigated using dual regression analysis and inter-network connectivity analysis. An additional voxel-based morphometry analysis was performed to examine if results were influenced by grey matter atrophy. RESULTS: The PIGD subgroup scored worse than the TD subgroup on all cognitive domains. Resting-state fMRI network analyses suggested that the connection between the visual and sensorimotor network is a potential differentiator between PIGD and TD subgroups. However, after correcting for dopaminergic medication use these results were not significant anymore. There was no between-group difference in grey matter volume. CONCLUSION: Despite clear motor and cognitive differences between the PIGD and TD subtypes, no significant differences were found in network connectivity. Methodological challenges, substantial symptom heterogeneity and many involved variables make analyses and hypothesis building around PD subtypes highly complex. More sensitive visualisation methods combined with machine learning approaches may be required in the search for characteristic underpinnings of PD subtypes.

Neuroimaging Detectable Differences between Parkinson's Disease Motor Subtypes: A Systematic Review.

BACKGROUND: The neuroanatomical substrates of Parkinson's disease (PD) with tremor-dominance (TD) and those with non-tremor dominance (nTD), postural instability and gait difficulty (PIGD), and akinetic-rigid (AR) are not fully differentiated. A better understanding of symptom specific pathoanatomical markers of PD subtypes may result in earlier diagnosis and more tailored treatment. Here, we aim to give an overview of the neuroimaging literature that compared PD motor subtypes. METHODS: A systematic literature review on neuroimaging studies of PD subtypes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Search terms submitted to the PubMed database included: "Parkinson's disease", "MRI" and "motor subtypes" (TD, nTD, PIGD, AR). The results are first discussed from macro to micro level of organization (i.e., (1) structural; (2) functional; and (3) molecular) and then by applied imaging methodology. FINDINGS: Several neuroimaging methods including diffusion imaging and positron emission tomography (PET) distinguish specific PD motor subtypes well, although findings are mixed. Furthermore, our review demonstrates that nTD-PD patients have more severe neuroalterations compared to TD-PD patients. More specifically, nTD-PD patients have deficits within striato-thalamo-cortical (STC) circuitry and other thalamocortical projections related to cognitive and sensorimotor function, while TD-PD patients tend to have greater cerebello-thalamo-cortical (CTC) circuitry dysfunction. CONCLUSIONS: Based on the literature, STC and CTC circuitry deficits seem to be the key features of PD and the subtypes. Future research should make greater use of multimodal neuroimaging and techniques that have higher sensitivity in delineating subcortical structures involved in motor diseases.

Selective effects of aging on brain white matter microstructure: a diffusion tensor imaging tractography study.

We examined age-related changes in the cerebral white matter. Structural magnetic resonance images (MRIs) and diffusion tensor images (DTIs) were acquired from 69 healthy subjects aged 22-84 years. Quantitative DTI tractography was performed for nine different white matter tracts to determine tract volume, fractional anisotropy (FA), mean diffusivity (MD), axial, and radial diffusivities. We used automated and manual segmentation to determine volumes of gray matter (GM), white mater (WM), cerebrospinal fluid (CSF), and intracranial space. The results showed significant effects of aging on WM, GM, CSF volumes, and selective effects of aging on structural integrity of different white matter tracts. WM of the prefrontal region was the most vulnerable to aging, while temporal lobe connections, cingulum, and parieto-occipital commissural connections showed relative preservation with age. This study was cross-sectional, and therefore, additional longitudinal studies are needed to confirm our findings.

Neural responses during extinction learning predict exposure therapy outcome in phobia: results from a randomized-controlled trial.

Extinction learning is assumed to represent a core mechanism underlying exposure therapy. Empirical evaluations of this assumption, however, are largely lacking. The current study investigated whether neural activations and self-report outcomes during extinction learning and extinction recall could specifically predict exposure therapy response in specific phobia. In this double-blind randomized controlled trial, individuals with spider phobia (N = 45; female/male = 41/4) were on group basis randomly allocated to exposure therapy (n = 25; female/male = 24/1) or progressive muscle relaxation (PMR; n = 20; female/male = 17/3). Intervention effects were measured with the Fears of Spiders questionnaire. Participants also underwent a three-day fear conditioning, extinction learning, and extinction recall paradigm during functional magnetic resonance imaging at baseline. Extinction outcomes were self-reported fear and threat expectancy, and neural responses during conditioned stimulus processing and during extinction-related prediction errors (US omissions) in regions of interest (ventromedial prefrontal cortex (vmPFC) and nucleus accumbens). Results showed that exposure therapy resulted in stronger symptom reductions than PMR (Cohen's d = 0.90). Exposure therapy response was specifically predicted by prediction-error related vmPFC activation during early extinction. There were also indications vmPFC activations during conditioned safety stimulus processing at early extinction predicted therapy outcome. Neural activations during extinction recall and self-report data did however not predict therapy outcome. These findings indicate that exposure therapy may rely on neural extinction learning processes. Prediction errors are thought to drive the extinction learning process, and prediction error-related vmPFC activation specifically predicted therapy outcome. The extent to which vmPFC processes safety signals may additionally be predictive of exposure therapy response, but the specificity is less clear.

White matter microstructure and network-connectivity in emerging adults with subclinical psychotic experiences.

Group comparisons of individuals with psychotic disorder and controls have shown alterations in white matter microstructure. Whether white matter microstructure and network connectivity is altered in adolescents with subclinical psychotic experiences (PE) at the lowest end of the psychosis severity spectrum is less clear. DWI scan were acquired in 48 individuals with PE and 43 healthy controls (HC). Traditional tensor-derived indices: Fractional Anisotropy, Axial Diffusivity, Mean Diffusivity and Radial Diffusivity, as well as network connectivity measures (global/local efficiency and clustering coefficient) were compared between the groups. Subclinical psychopathology was assessed with the Community Assessment of Psychic Experiences (CAPE) and Montgomery-Åsberg Depression Rating Scale (MADRS) questionnaires and, in order to capture momentary subclinical expression of psychosis, the Experience Sampling Method (ESM) questionnaires. Within the PE-group, interactions between subclinical (momentary) symptoms and brain regions in the model of tensor-derived indices and network connectivity measures were investigated in a hypothesis-generating fashion. Whole brain analyses showed no group differences in tensor-derived indices and network connectivity measures. In the PE-group, a higher positive symptom distress score was associated with both higher local efficiency and clustering coefficient in the right middle temporal pole. The findings indicate absence of microstructural white matter differences between emerging adults with subclinical PE and controls. In the PE-group, attenuated symptoms were positively associated with network efficiency/cohesion, which requires replication and may indicate network alterations in emerging mild psychopathology.

Blended care in the treatment of subthreshold symptoms of depression and psychosis in emerging adults: A randomised controlled trial of Acceptance and Commitment Therapy in Daily-Life (ACT-DL).

In this study, the feasibility and efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL), ACT augmented with a daily life application, was investigated in 55 emerging adults (age 16 to 25) with subthreshold depressive and/or psychotic complaints. Participants were randomized to ACT-DL (n = 27) or to active control (n = 28), with assessments completed at pre- and post-measurement and 6- and 12-months follow-up. It took up to five (ACT-DL) and 11 (control) months to start group-based interventions. Participants attended on average 4.32 out of 5 ACT-DL sessions. On the app, they filled in on average 69 (48%) of signal-contingent beep-questionnaires, agreed to 15 (41%) of offered beep-exercises, initiated 19 on-demand exercises, and rated ACT-DL metaphors moderately useful. Relative to active control, interviewer-rated depression scores decreased significantly in ACT-DL participants (p = .027). Decreases in self-reported depression, psychotic-related distress, anxiety, and general psychopathology did not differ between conditions. ACT-DL participants reported increased mean NA (p = .011), relative to active controls. Mean PA did not change in either group, nor did psychological flexibility. ACT-DL is a feasible intervention, although adaptations in future research may improve delivery of and compliance with the intervention. There were mixed findings for its efficacy in reducing subthreshold psychopathology in emerging adults. Dutch Trial Register no.: NTR3808.

Microstructural white matter network-connectivity in individuals with psychotic disorder, unaffected siblings and controls.

BACKGROUND: Altered structural network-connectivity has been reported in psychotic disorder but whether these alterations are associated with genetic vulnerability, and/or with phenotypic variation, has been less well examined. This study examined i) whether differences in network-connectivity exist between patients with psychotic disorder, siblings of patients with psychotic disorder and controls, and ii) whether network-connectivity alterations vary with (subclinical) symptomatology. METHODS: Network-connectivity measures (global efficiency (GE), density, local efficiency (LE), clustering coefficient (CC)) were derived from diffusion weighted imaging (DWI) and were compared between 85 patients with psychotic disorder, 93 siblings without psychotic disorder and 80 healthy comparison subjects using multilevel regression models. In patients, associations between Positive and Negative Syndrome Scale (PANSS) symptoms and topological measures were examined. In addition, interactions between subclinical psychopathology and sibling/healthy comparison subject status were examined in models of topological measures. RESULTS: While there was no main effect of group with respect to GE, density, LE and CC, siblings had a significantly higher CC compared to patients (B = 0.0039, p = .002). In patients, none of the PANSS symptom domains were significantly associated with any of the four network-connectivity measures. The two-way interaction between group and SIR-r positive score in the model of LE was significant (χ2 = 6.24, p = .01, df = 1). In the model of CC, the interactions between group and respectively SIS-r positive (χ2 = 5.59, p = .02, df = 1) and negative symptom scores (χ2 = 4.71, p = .03, df = 1) were significant. Stratified analysis showed that, in siblings, decreased LE and CC was significantly associated with increased SIS-r positive scores (LE: B = -0.0049, p = .003, CC: B = -0.0066, p = .01) and that decreased CC was significantly associated with increased SIS-r negative scores (B = -0.012, p = .003). There were no significant interactions between group and SIS-r scores in the models of GE and density. CONCLUSION: The findings indicate absence of structural network-connectivity alterations in individuals with psychotic disorder and in individuals at higher than average genetic risk for psychotic disorder, in comparison with healthy subjects. The differential subclinical symptom-network connectivity associations in siblings with respect to controls may be a sign of psychosis vulnerability in the siblings.

Functional neuroimaging of associative learning and generalization in specific phobia.

BACKGROUND: Theoretical models have implicated classical fear conditioning, fear generalization, and extinction learning in the development of anxiety disorders. To date, it is largely unknown to what extent these mechanisms and the underlying neurobiology may be altered in specific phobia, a disorder characterized by focal fears. The current study systematically examined fear conditioning, fear generalization, extinction learning, and extinction recall in a sample of individuals with a specific phobia. METHODS: Participants with a specific phobia (SP) of spiders (n = 46) and healthy controls (HC) (n = 48) underwent a 3-day fMRI cue-conditioning protocol, including a fear acquisition and a fear generalization phase (day 1), an extinction learning phase (day 2), and an extinction recall phase (day 3). Stimuli were phobia-irrelevant, as geometrical shapes served as conditioned threat (CS+) and safety stimuli (CS-), and an electrical shock as the unconditioned stimulus (US). Self-reported fear, US expectancy, and blood-oxygen-level dependent responses were measured. RESULTS: Behavioral results only revealed enhanced CS+/CS-differentiation in fear scores during acquisition retention in SP. Some neural differences were observed during other task phases. During early fear acquisition, SP showed enhanced differential activation in the angular gyrus and lateral occipital cortex, and during extinction recall, more precuneus deactivation was found in SP compared to HC. There were no clear indications of altered neural fear generalization or extinction learning mechanisms in the SP group. CONCLUSIONS: Results indicate that spider phobia may be characterized by enhanced differential fear retention and altered brain activation patterns during fear acquisition and extinction recall. The findings provide insight into the nature of fear learning alterations in specific phobia, and how these may differ from those found in disorders characterized by broad anxious distress.

Reward anticipation in individuals with subclinical psychotic experiences: A functional MRI approach.

Previous research in patients with psychotic disorder has shown widespread abnormalities in brain activation during reward anticipation. Research at the level of subclinical psychotic experiences in individuals unexposed to antipsychotic medication is limited with inconclusive results. Therefore, brain activation during reward anticipation was examined in a larger sample of individuals with subclinical psychotic experiences (PE). Participants in the PE-group were included based on CAPE scores. A sample of emerging adults aged 16-26 years (n = 47) with PE and healthy controls (HC) (n = 40) underwent fMRI scanning. The Monetary Incentive Delay task was conducted with cues related to win, loss or neutral conditions. fMRI nonparametric tests were used to examine the reward versus neutral cue contrast. A significant main effect of the large win (€3.00) > neutral contrast was found in both groups showing activation in many brain areas, including classic reward regions. Whole brain analysis on the group comparison regarding the large win > neutral contrast showed significantly decreased activation in the right insula, putamen and supramarginal gyrus in the PE-group compared to controls. There was no group difference in the hypothesized reward-related region. Decreased activation in the right insula, putamen and supramarginal gyrus during reward anticipation in individuals with PE may be consistent with altered processing of sensory information, related to decreased emotional valuing and motivational tendencies and/or altered motor-cognitive processes. The absence of group differences in striatal activation suggests that activation here is intact in the earliest stages of psychosis and may exhibit progressive deterioration in as the disease develops.