Clinical evaluation questionnaire in advanced cancer: a psychometric study of a novel measure of healthcare provider interactions.

OBJECTIVES: The 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. METHOD: Patients 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. RESULTS: The 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, p<0.001). CONCLUSIONS: The 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.

Coping with social consequences of disease-related symptoms in patients with a metastatic small intestinal neuroendocrine tumour: A qualitative study.

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.

Emotion Regulation in Obsessive-Compulsive Disorder, Unaffected Siblings, and Unrelated Healthy Control Participants.

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 temporo-occipital 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.

Cognitive control networks in OCD: A resting-state connectivity study in unmedicated patients with obsessive-compulsive disorder and their unaffected relatives.

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.

Tic-Related Versus Tic-Free Obsessive-Compulsive Disorder: Clinical Picture and 2-Year Natural Course.

OBJECTIVE: The tic-related subtype of obsessive-compulsive disorder (OCD) has a distinct clinical profile. The course of tic-related OCD has previously been investigated in treatment studies, with inconclusive results. This study aimed to compare clinical profiles between tic-related and tic-free OCD patients and to establish the influence of tics on the 2-year natural course in adult OCD patients. METHODS: Within the Netherlands OCD Association cohort, 377 patients with a current DSM-IV diagnosis of OCD were divided into a tic-related group (28%) and a tic-free group and compared on clinical variables with t tests or χ² tests. Linear mixed-model analyses were used to compare the 2-year course between the groups, with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as primary outcome measure. Data were collected from 2005 to 2007 and from 2007 to 2009. RESULTS: Compared to patients with tic-free OCD, those with tic-related OCD reported earlier disease onset (P = .009) and more symmetry/ordering symptoms (P = .002). Overall symptom severity was similar in both groups. Patients with tic-related OCD reported increased traits of attention-deficit hyperactivity (P < .001) and autism (P = .005) compared to the tic-free OCD group. Clinical improvement at 2-year follow-up (mean = 5.3-point decrease on the Y-BOCS, P < .001, 95% CI = 4.3 to 6.3) was not significantly moderated by tic status (P = .24). This remained unchanged after correcting for baseline differences. CONCLUSIONS: Tics do not critically affect the 2-year course of adult OCD, but tic-related OCD shows differences from tic-free OCD, such as early onset and increased autism and ADHD traits, that may indicate a neurodevelopmental subtype.

Altered inhibition-related frontolimbic connectivity in obsessive-compulsive disorder.

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.

Mild White Matter Changes in Un-medicated Obsessive-Compulsive Disorder Patients and Their Unaffected Siblings.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with moderate genetic influences and white matter abnormalities in frontal-striatal and limbic regions. Inconsistencies in reported white matter 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 white matter abnormalities, if present in un-medicated OCD patients, also exist in their unaffected siblings. METHOD: Forty-four OCD patients, un-medicated for at least the past 4 weeks, 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, bilateral cingulum bundle, 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 cingulum bundle. FA was trend-significantly lower in all other ROIs, except for the corpus callosum. Significant three-group differences in FA (and in RD at trend-significant level) were observed in the left cingulum bundle, with the unaffected siblings representing an intermediate group between OCD patients and HC. CONCLUSIONS: OCD patients showed lower FA in the left cingulum bundle, 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 white matter alteration may be considered an endophenotype for OCD.

Compensatory frontoparietal activity during working memory: an endophenotype of obsessive-compulsive disorder.

BACKGROUND: Subtle deficits in executive functioning are present in patients with obsessive-compulsive disorder (OCD) and their first-degree relatives, suggesting involvement of the frontoparietal circuits. The neural correlates of working memory may be a neurocognitive endophenotype of OCD. METHODS: Forty-three unmedicated OCD patients, 17 unaffected siblings, and 37 matched comparison subjects performed a visuospatial n-back task, with a baseline condition (N0) and three working memory load levels (N1, N2, N3) during functional magnetic resonance imaging. Task-related brain activity was compared between groups in frontoparietal regions of interest. Generalized psychophysiological interaction analyses were used to study task-related changes in functional connectivity. RESULTS: Obsessive-compulsive disorder patients, compared with comparison subjects and siblings, showed increased error rates at N3. Compared with comparison subjects, OCD patients showed task-related hyperactivation in left dorsal frontal areas and left precuneus associated with better task performance. Siblings exhibited hyperactivation in a bilateral frontoparietal network. Increased task load was associated with increased task-related brain activity, but in OCD patients and siblings this increase was smaller from load N2 to N3 than in comparison subjects. Obsessive-compulsive disorder patients, compared with siblings and comparison subjects, showed increased task-related functional connectivity between frontal regions and bilateral amygdala. CONCLUSIONS: These findings indicate that compensatory frontoparietal brain activity in OCD patients and their unaffected relatives preserves task performance at low task loads but is insufficient to maintain performance at high task loads. Frontoparietal dysfunction may constitute a neurocognitive endophenotype for OCD, possibly reflecting limbic interference with and neural inefficiency within the frontoparietal network.

Limbic and motor circuits involved in symmetry behavior in Tourette's syndrome.

OBJECTIVE: The 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. METHODS: Pictures 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 H2 15O 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. RESULTS: During 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. CONCLUSIONS: Results 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.

Presupplementary motor area hyperactivity during response inhibition: a candidate endophenotype of obsessive-compulsive disorder.

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.

Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses.

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.