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ObjectivesThe Clinical Evaluation Questionnaire (CEQ) is a patient-reported experience measure (PREM) that assesses the perceived benefit of therapeutic interactions of patients with advanced cancer with their healthcare providers concerning issues relevant to their illness. It was developed for a randomised controlled trial of Managing Cancer and Living Meaningfully (CALM), a brief supportive-expressive therapy for patients with advanced cancer. The present study evaluates the preliminary psychometric properties of the CEQ.MethodPatients in the CALM and usual care groups completed the CEQ 3 (n=195) and 6 (n=186) months after randomisation. The CEQ’s internal consistency, factor structure and concurrent validity were evaluated, and CEQ scores in the treatment groups were compared.ResultsThe CEQ demonstrated high internal consistency for both treatment arms (Cronbach’s α=0.94 to 0.95), and a single factor was consistently found in exploratory factor analyses. CEQ scores correlated significantly with satisfaction with the relationship with healthcare providers (r=0.23 to 0.61, p≤0.02) and life completion (r=0.24 to 0.37, p≤0.02) in both groups and with spiritual well-being in the CALM group (meaning: r=0.23 to 0.24, p=0.01 to 0.02; faith: r=0.24 to 0.34, p=0.001 to 0.02). The CALM group showed higher CEQ total scores than usual care at 6 months (CALM: 18.19±6.59; usual care: 14.36±7.67, pConclusionsThe CEQ is a reliable and valid PREM of the benefit perceived by patients with advanced cancer from their interactions with healthcare providers. Further study is needed to establish its value as a measure of perceived intervention benefit across different clinical and research settings.

BACKGROUND: Functional neuroimaging endophenotypes of obsessive-compulsive disorder (OCD) have been suggested during executive tasks. The purpose of this study was to investigate whether behavioral and neural responses during emotion processing and regulation also represent an endophenotype of OCD.METHODS: Forty-three unmedicated adult OCD patients, 19 of their unaffected siblings, and 38 healthy control participants underwent 3T functional magnetic resonance imaging during an emotion regulation task including neutral, fear-inducing, and OCD-related visual stimuli. Stimuli were processed during natural appraisal and during cognitive reappraisal, and distress ratings were collected after each picture. We performed between-group comparisons on task behavior and brain activation in regions of interest during emotion provocation and regulation.RESULTS: Siblings reported similar distress as healthy control participants during provocation, and significantly less than patients. There was no significant three-group difference in activation during fear provocation or regulation. Three-group comparisons showed that patients had higher amygdala and dorsomedial prefrontal cortex activation during OCD-related emotion provocation and regulation, respectively, while siblings were intermediate between patients and control participants but not significantly different from either. Siblings showed higher left temporooccipital activation (compared with both healthy control participants and patients) and higher frontolimbic connectivity (compared with patients) during OCD-related regulation.CONCLUSIONS: Unaffected siblings do not show the same distress and amygdala activation during emotional provocation as OCD patients. Siblings show distinct activation in a temporo-occipital region, possibly related to compensatory cognitive control. This suggests that emotion regulation is not a strong endophenotype for OCD. When replicated, this contributes to our understanding of familial risk and resilience for OCD.

Patients with small intestine neuroendocrine tumours (SINETs) face various disease-related symptoms that can affect their social functioning and quality of life. The present study aimed to explore the social consequences of disease-related symptoms in patients with a metastatic SINET and to develop a theory on how these patients experience their disease. Patients were eligible when they were diagnosed with a metastatic SINET between 2009 and 2016 and were younger than 60 years of age during diagnosis, and had a good functional performance status. Semi-structured interviews were conducted between January and June 2018. Data were transcribed and analysed independently by two researchers using grounded theory. Data saturation was reached at 10 interviews and, in total, 12 patients participated. A core component that arose from the interviews was resilience in the face of social consequences of having a metastatic SINET. Prominent physical symptoms were fatigue, diarrhoea and flushes. All of these symptoms were associated with limitations to function in work-related and social activities, as well as feelings of embarrassment and shame. Adaptive strategies, such as careful planning, or focusing on the perspective to live well with a neuroendocrine tumour, helped patients to experience the consequences as less burdensome. Other helpful factors that were identified constituted social support, engaging in meaningful activities and financial stability. Patients with a metastatic SINET experienced social consequences of disease-related symptoms in daily life, although they were able to attenuate the burden of these consequences by using adaptive problem-based, emotion-based and meaning-based coping strategies. Clinicians could explore the perceived consequences and educate patients about adaptive strategies.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

Objectives: Executive network deficits are putative neurocognitive endophenotypes for obsessive-compulsive disorder (OCD). Yet, unlike alterations in fronto-striatal and limbic connectivity, connectivity in the fronto-parietal (FPN) and cingulo-opercular (CON) networks involved in cognitive control has received little attention. Methods: The coherence of FPN, CON and fronto-limbic networks was investigated in 39 unmedicated OCD patients, 16 of their unaffected siblings and 36 healthy controls using resting-state functional-connectivity MRI and a seed-based analysis approach. Results: FPN and CON connectivity was similar for patients and controls. Siblings showed higher connectivity than patients within the CON, and between the CON and FPN compared to patients and controls (trend level). In OCD patients, but not in siblings, fronto-limbic hyperconnectivity was present compared to controls. In contrast to our expectations, no group differences in resting-state connectivity of the cognitive control networks were observed between OCD patients and controls. Conclusions: The increased within- and between-network connectivity in siblings, but not in patients, could indicate a mechanism of increased cognitive control that may act as a protective mechanism. None of the observed network alterations can be considered an endophenotype for OCD since differences were present in either patients or siblings, but not in both groups.

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge. Changes in [(11)C]raclopride binding potential (BP(ND)) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg(-1)) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D2/3 receptor BP(ND) and change in BP(ND) following amphetamine as a measure of dopamine release. Voxel-based analysis revealed significantly decreased baseline [(11)C]raclopride BP(ND) in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP(ND) following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP(ND) changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP(ND). This study provides evidence for decreased striatal D2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.

Objective: Endophenotype studies of obsessive-compulsive disorder (OCD) may uncover heritable traits that are related to genetic susceptibility to OCD. Deficient response inhibition is a promising endophenotype of OCD, although its functional neural correlates have not been extensively studied. The authors sought to determine the functional neural correlates of response inhibition in a large sample of medication-free OCD patients and their unaffected siblings. Method: Forty-one OCD patients, 17 of their siblings, and 37 matched healthy comparison subjects performed a stop-signal task during 3-T functional MRI. The stop-signal reaction time provided a behavioral measure of response inhibition. The neural correlates of response inhibition were assessed in a region-of-interest analysis that included the presupplementary motor area, inferior frontal gyrus, subthalamic nucleus, and inferior parietal cortex. Results: Patients with OCD had greater stop-signal reaction times relative to healthy comparison subjects. The numerical stop-signal reaction time difference between siblings and comparison subjects failed to reach significance. Both patients with OCD and their siblings showed greater activity in the left presupplementary motor area during successful inhibition relative to comparison subjects. Relative to both the comparison subjects and the siblings, patients with OCD showed decreased activity in the right inferior parietal cortex and inferior frontal gyrus. In patients and siblings, presupplementary motor area activity correlated negatively with stop-signal reaction time. Conclusions: These findings suggest that presupplementary motor area hyperactivity is a neurocognitive endophenotype of OCD that is possibly related to inefficient neural processing within the presupplementary motor area itself. Patients with OCD further showed a state-dependent deficit in recruiting right inferior parietal cortex and inferior frontal gyrus, which may contribute to their inhibition deficit.

Introduction OCD symptoms have been associated with task-dependent alterations in brain activity implying dysregulation in limbic (e.g. the amygdala) and frontal-striatal circuits. Emerging evidence shows that there are functional neural endophenotypes in executive processing suggesting compensatory hyperactivation of fronto-parietal executive control networks and fronto-limbic dysregulation in OCD patients and first-degree relatives (de Wit et al., 2012; van Velzen et al., 2015). There are however few studies on emotional processing using a family-study design. We recently showed altered frontal-parietal and limbic functioning in OCD patients during emotion processing and emotion regulation (de Wit et al., 2015), but it remains unclear if these changes are also present in first-degree relatives. Method Forty-three unmedicated adult OCD patients, 19 of their unaffected siblings and 38 healthy controls underwent functional magnetic resonance imaging (MRI) during an emotion regulation task including neutral, fear and OCD-related visual stimuli. Stimuli were processed during natural appraisal (‘attend’ instruction) and during cognitive reappraisal (‘regulate’ instruction). Self-report distress ratings were collected from each picture. The neural correlates of emotion regulation were assessed using SPM12. Results Fear and OCD symptom provocation resulted in higher self-report distress ratings in patients compared with both siblings and healthy controls. Functional MRI analyses showed that specifically during OCD-related provocation, compared with controls, BOLD activation amplitude and timing was altered in the left hippocampus, right caudate nucleus and amygdala (for both patients and siblings), and bilateral thalamus (for siblings only). During fear regulation we previously found fronto-parietal hypoactivation in OCD patients, but fronto-parietal activation was not significantly different in siblings from patients or controls. During regulation of OCD-related stimuli siblings were more similar to patients (i.e. showing hyperactivation of the dorsomedial PFC (dmPFC) compared with controls). Compared with both patients and controls, hyperactivation in siblings was more extensive (including the supplementary motor area and parietal regions), and siblings showed increased dmPFC-connectivity with the middle cingulate, superior temporal, and superior frontal cortices during OCD-related emotion regulation. The diminished dmPFC-amygdala connectivity we previously reported in OCD patients during fear-regulation was not present in the sibling group. Discussion Unaffected siblings of OCD patients were similar to controls on the behavioral response to emotional provocation, but showed dissimilar neural responses during OCD-related emotion provocation and regulation compared to healthy controls, while there were fewer differences for general fear stimuli. During OCD-related emotion provocation we observed altered activation in limbic and striatal regions in both OCD patients and siblings. During OCD-related emotion regulation siblings showed few differences compared to patients, but showed increased activation in fronto-parietal and temporal areas compared to controls. Siblings also showed extensive dmPFC hyperconnectivity compared to the patients and controls, which suggests a compensatory response. These results extend previous findings of functional endophenotypes in OCD, and show dissociation between subjective distress and brain activity during emotion processing in unaffected siblings of people with OCD.

Objective Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with moderate genetic influences and white matter (WM) abnormalities in frontal-striatal and limbic regions. Inconsistencies in reported WM results from diffusion tensor imaging (DTI) studies can be explained, at least partly, by medication use and between-group differences in disease profile and stage. We used a family design aiming to establish whether WM abnormalities, if present in un-medicated OCD patients, also exist in their unaffected siblings. Method Forty-four un-medicated OCD patients, 15 of their unaffected siblings and 37 healthy controls (HC) underwent DTI using a 3-Tesla MRI-scanner. Data analysis was done using tract-based spatial statistics (TBSS). Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values were compared within seven skeletonised regions of interest (ROIs), i.e., corpus callosum (CC), bilateral cingulum bundle (CB), bilateral inferior longitudinal fasciculus/frontal-occipital fasciculus (ILF/FOF) and bilateral superior longitudinal fasciculus (SLF). Results Un-medicated OCD patients, compared with HC, had significantly lower FA in the left CB. FA was trend-significantly lower in all other ROIs, except for the CC. Significant three-group differences in FA (and in RD at trend-significant level) were observed in the left CB, with the unaffected siblings representing an intermediate group between OCD patients and HC. Conclusions OCD patients showed lower FA in the left CB, partly driven by trend-significantly higher values in RD. Since the unaffected siblings were found to be an intermediate group between OCD patients and HC, this WM alteration may be considered an endophenotype for OCD.

BACKGROUND: Recent studies have shown that response inhibition is impaired in patients with obsessive–compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive–compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive–compulsive disorder and their unaffected siblings. METHODS: Forty‐one unmedicated patients with obsessive–compulsive disorder, 17 of their unaffected siblings and 37 healthy controls performed a stop signal task during functional magnetic resonance imaging. Psycho‐physiological interaction analysis was used to examine functional connectivity between the following regions of interest: the bilateral inferior frontal gyri, presupplementary motor area, subthalamic nuclei, inferior parietal lobes, anterior cingulate cortex, and amygdala. We then used dynamic causal modeling to investigate the directionality of the networks involved. RESULTS: Patients, and to a lesser extent also their unaffected siblings, show altered connectivity between the inferior frontal gyrus and the amygdala during response inhibition. The follow‐up dynamic causal modeling suggests a bottom‐up influence of the amygdala on the inferior frontal gyrus in healthy controls, whereas processing occurs top‐down in patients with obsessive–compulsive, and in both directions in siblings. CONCLUSIONS: Our findings suggest that amygdala activation in obsessive–compulsive disorder interferes differently with the task‐related recruitment of the inhibition network, underscoring the role of limbic disturbances in cognitive dysfunctions in obsessive–compulsive disorder. Hum Brain Mapp 36:4064–4075, 2015. © 2015 Wiley Periodicals, Inc.

ObjectiveThe need for symmetry and ordering objects related to a “just right”-feeling is a common symptom in Tourette's syndrome (TS) and resembles symmetry behavior in obsessive-compulsive disorder, but its pathophysiology is unknown. We used a symptom provocation paradigm to investigate the neural correlates of symmetry behavior in TS and hypothesized the involvement of frontal-striatal and limbic brain areas.MethodsPictures of asymmetrically and symmetrically arranged objects were presented in randomized blocks (4 blocks of each condition) to 14 patients with TS and 10 matched healthy controls (HC). A H215O positron emission tomography scan was acquired during each stimulus block, resulting in 8 scans per subject. After each scan, state anxiety and symmetry behavior (the urge to rearrange objects) were measured using a visual analogue scale.ResultsDuring the asymmetry condition, TS patients showed increased regional cerebral blood flow (rCBF) in the anterior cingulate cortex, supplementary motor area, and inferior frontal cortex, whereas HC showed increased rCBF in the visual cortex, primary motor cortex, and dorsal prefrontal cortex. Symmetry ratings during provocation correlated positively with orbitofrontal activation in the TS group and sensorimotor activation in the HC group, and negatively with dorsal prefrontal activity in HC.ConclusionsResults suggest that both motor and limbic circuits are involved in symmetry behavior in TS. Motor activity may relate to an urge to move or perform tics, and limbic activation may indicate that asymmetry stimuli are salient for TS patients. In contrast, symmetry provocation in HC resulted in activation of brain regions implicated in sensorimotor function and cognitive control.

Fragile X mental retardation is caused by absence of the RNA-binding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1 -knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo . This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome.