Neural basis of positive and negative emotion regulation in remitted depression

The recurrent nature of Major Depressive Disorder (MDD) necessitates a better understanding of mechanisms facilitating relapse. MDD has often been associated with abnormal emotion regulation, underpinned by aberrant interactions between the prefrontal cortex and subcortical areas. We assessed whether neural regulation abnormalities remain after remission and relate to emotion regulation problems in daily life. At the baseline measurement of a randomized controlled trial, an emotion regulation task was performed during fMRI scanning by 46 remitted recurrent (rrMDD) patients and 24 healthy controls. We assessed both fMRI peak activity and the temporal dynamics of the neural response during passive attendance and explicit regulation of positive and negative emotions. Furthermore, we assessed regulation strategy use in daily life using questionnaires, and attentional biases using a modified attentional dot-probe task. RrMDD patients showed lower activation and different temporal dynamics in occipital, parietal, and prefrontal brain regions during passive attendance of emotional material compared to healthy controls. During explicit downregulation of negative emotions, no group differences were found. However, during explicit upregulation of positive emotions, rrMDD patients showed a different neural response over time in the insula. Behaviourally, rrMDD patients were characterized by dysfunctional regulation strategies in daily life. Within rrMDD patients, rumination was associated with activation within a limbic- prefrontal network. After remission, immediate emotional processing seems unaffected, but regulatory abnormalities remain, especially uninstructed and in daily life. Abnormal insula activation during positive upregulation suggests decreased monitoring of positive emotions. The relation between inadequate rumination and brain activity during emotion regulation suggests that regulation of both positive and negative affect is important in understanding neurocognitive underpinnings of resilience

Neurocognitive working mechanisms of the prevention of relapse in remitted recurrent depression (NEWPRIDE):protocol of a randomized controlled neuroimaging trial of preventive cognitive therapy

Background: Major Depressive Disorder (MDD) is a psychiatric disorder with a highly recurrent character, making prevention of relapse an important clinical goal. Preventive Cognitive Therapy (PCT) has been proven effective in preventing relapse, though not for every patient. A better understanding of relapse vulnerability and working mechanisms of preventive treatment may inform effective personalized intervention strategies. Neurocognitive models of MDD suggest that abnormalities in prefrontal control over limbic emotion-processing areas during emotional processing and regulation are important in understanding relapse vulnerability. Whether changes in these neurocognitive abnormalities are induced by PCT and thus play an important role in mediating the risk for recurrent depression, is currently unclear. In the Neurocognitive Working Mechanisms of the Prevention of Relapse In Depression (NEWPRIDE) study, we aim to 1) study neurocognitive factors underpinning the vulnerability for relapse, 2) understand the neurocognitive working mechanisms of PCT, 3) predict longitudinal treatment effects based on pre-treatment neurocognitive characteristics, and 4) validate the pupil dilation response as a marker for prefrontal activity, reflecting emotion regulation capacity and therapy success. Methods: In this randomized controlled trial, 75 remitted recurrent MDD (rrMDD) patients will be included. Detailed clinical and cognitive measurements, fMRI scanning and pupillometry will be performed at baseline and three-month follow-up. In the interval, 50 rrMDD patients will be randomized to eight sessions of PCT and 25 rrMDD patients to a waiting list. At baseline, 25 healthy control participants will be additionally included to objectify cross-sectional residual neurocognitive abnormalities in rrMDD. After 18 months, clinical assessments of relapse status are performed to investigate which therapy induced changes predict relapse in the 50 patients allocated to PCT. Discussion: The present trial is the first to study the neurocognitive vulnerability factors underlying relapse and mediating relapse prevention, their value for predicting PCT success and whether pupil dilation acts as a valuable marker in this regard. Ultimately, a deeper understanding of relapse prevention could contribute to the development of better targeted preventive interventions. Trial registration: Trial registration: Netherlands Trial Register, August 18, 2015, trial number NL5219

Amount and Distribution of Intracranial Calcification in Symptomatic and Asymptomatic Primary Familial Brain Calcification

BACKGROUND AND OBJECTIVES: In clinical practice, it can be difficult to differentiate between intracranial calcifications related to primary familial brain calcification (PFBC) or aging. Also, little is known about the consequences of the amount of intracranial calcifications in patients with PFBC. Therefore, we aimed to compare the amount and distribution of intracranial calcifications in persons with PFBC with controls and between asymptomatic and symptomatic PFBC cases. METHODS: This was a case-control study including patients with PFBC and controls. Controls received a CT of the brain because of a trauma and had at least some basal ganglia calcification. The Nicolas score and volume of calcification were used to quantify intracranial calcifications on the CT scans. Receiver operating characteristic curves were obtained to calculate optimal cutoff points to discriminate between cases and controls. Mann-Whitney U tests and logistic regression, adjusted for age and sex, were used to compare the amount of calcification. RESULTS: Twenty-eight cases (median age 65 years, 50.0% male) and 90 controls (median age 74 years, 46.1% male) were included. Calcification scores were higher in cases (median volume: 4.91 cm 3 against 0.03 cm 3, p < 0.001, median Nicolas score: 26.5 against 2.0, p < 0.001) than controls. Calcifications were also more diffusely distributed in cases. To differentiate between cases and controls, optimal cutoff points were ≥0.2 cm 3 for the calcification volume and ≥6.0 for the Nicolas score. Calcification was higher for symptomatic than asymptomatic cases (calcification volume: 13.62 cm 3 against 1.61 cm 3, p = 0.01, Nicolas score: 39.0 against 15.5, p = 0.02). After adjustment for age and sex, the Nicolas score remained significantly higher in symptomatic patients, and the calcification volume did not. DISCUSSION: Patients with PFBC had more severe intracranial calcifications, and these calcifications were more diffusely distributed through the brain compared with controls. Symptomatic patients with PFBC might have more intracranial calcifications than asymptomatic persons

Economic Evaluation of an Internet-Based Preventive Cognitive Therapy With Minimal Therapist Support for Recurrent Depression

__Background__ Major depressive disorder (MDD) is highly recurrent and has a significant disease burden. Although the effectiveness of internet-based interventions has been established for the treatment of acute MDD, little is known about their cost effectiveness, especially in recurrent MDD. __Objectives__ Our aim was to evaluate the cost effectiveness and cost utility of an internet-based relapse prevention program (mobile cognitive therapy, M-CT). __Methods__ The economic evaluation was performed alongside a single-blind parallel group randomized controlled trial. Participants were recruited via media, general practitioners, and mental health care institutions. In total, 288 remitted individuals with a history of recurrent depression were eligible, of whom 264 were randomly allocated to M-CT with minimal therapist support added to treatment as usual (TAU) or TAU alone. M-CT comprised 8 online lessons, and participants were advised to complete 1 lesson per week. The economic evaluation was performed from a societal perspective with a 24-month time horizon. The health outcomes were number of depression-free days according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) criteria assessed with the Structured Clinical Interview for DSM-IV axis I disorders by blinded interviewers after 3, 12, and 24 months. Quality-adjusted life years (QALYs) were self-assessed with the three level version of the EuroQol Five Dimensional Questionnaire (EQ-5D-3L). Costs were assessed with the Trimbos and Institute for Medical Technology Assessment Questionnaire on Costs Associated with Psychiatric Illness (TiC-P). Incremental cost-effectiveness ratios were calculated and cost-effectiveness planes and cost-effectiveness acceptability curves were displayed to assess the probability that M-CT is cost effective compared to TAU. __Results__ Mean total costs over 24 months were €8298 (US $9415) for M-CT and €7296 (US$8278) for TAU. No statistically significant differences were found between M-CT and TAU regarding depression-free days and QALYs (P=.37 and P=.92, respectively). The incremental costs were €179 (US $203) per depression-free day and €230,816 (US$261,875) per QALY. The cost-effectiveness acceptability curves suggested that for depression-fr

The Association between Intracranial Calcifications and Symptoms in Patients with Primary Familial Brain Calcification

(1) Background: Primary Familial Brain Calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcifications of the basal ganglia and other intracranial areas. Many patients experience symptoms of motor dysfunction and cognitive disorders. The aim of this study was to investigate the association between the amount and location of intracranial calcifications with these symptoms. (2) Methods: Patients with suspected PFBC referred to our outpatient clinic underwent a clinical work-up. Intracranial calcifications were visualized on Computed Tomography (CT), and a Total Calcification Score (TCS) was constructed. Logistic and linear regression models were performed. (3) Results: Fifty patients with PFBC were included in this study (median age 64.0 years, 50% women). Of the forty-one symptomatic patients (82.0%), 78.8% showed motor dysfunction, and 70.7% showed cognitive disorders. In multivariate analysis, the TCS was associated with bradykinesia/hypokinesia (OR 1.07, 95%-CI 1.02-1.12, p < 0.01), gait ataxia (OR 1.06, 95%-CI 1.00-1.12, p = 0.04), increased fall risk (OR 1.04, 95%-CI 1.00-1.08, p = 0.03), and attention/processing speed disorders (OR 1.06, 95%-CI 1.01-1.12, p = 0.02). Calcifications of the lentiform nucleus and subcortical white matter were associated with motor and cognitive disorders. (4) Conclusions: cognitive and motor symptoms are common among patients with PFBC, and there is an association between intracranial calcifications and these symptoms

The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial

BACKGROUND: Fahr's disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr's disease or syndrome. METHODS: The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr's disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. RESULTS: Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. CONCLUSIONS: Fahr's disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr's disease or syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402

Disrupting the rhythm of depression using Mobile Cognitive Therapy for recurrent depression: randomized controlled trial design and protocol

Background: Major depressive disorder (MDD) is projected to rank second on a list of 15 major diseases in terms of burden in 2030. The major contribution of MDD to disability and health care costs is largely due to its highly recurrent nature. Accordingly, efforts to reduce the disabling effects of this chronic condition should shift to preventing recurrence, especially in patients at high risk of recurrence. Given its high prevalence and the fact that interventions are necessary during the remitted phase, new approaches are needed to prevent relapse in depression. Methods/design: The best established effective and available psychological intervention is cognitive therapy. However, it is costly and not available for most patients. Therefore, we will compare the effectiveness and cost-effectiveness of self-management supported by online CT accompanied by SMS based tele-monitoring of depressive symptomatology, i.e. Mobile Cognitive Therapy (M-CT) versus treatment as us usual (TAU). Remitted patients (n = 268) with at least two previous depressive episodes will be recruited and randomized over (1) M-CT in addition to TAU versus (2) TAU alone, with follow-ups at 3, 12, and 24 months. Randomization will be stratified for number of previous episodes and type of treatment as usual. Primary outcome is time until relapse/recurrence over 24 months using DSM-IV-TR criteria as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). For the economic evaluation the balance between costs and health outcomes will be compared across strategies using a societal perspective. Discussion: Internet-based interventions might be helpful in empowering patients to become their own disease managers in this lifelong recurrent disorder. This is, as far as we are aware of, the first study that examines the (cost) effectiveness of an E-mental health program using SMS monitoring of symptoms with therapist support to prevent relapse in remitted recurrently depressed patient

Pitfalls in clinical assessment of neurotoxic diseases: negative effects of repeated diagnostic evaluation, illustrated by a clinical case

Exposure to different toxic substances can have acute and chronic neurological and neuropsychiatric health effects on humans. Patients often report impaired concentration and memory, irritability, fatigue, instability of affect and difficulties in impulse control. The diagnostic process for neurotoxic diseases is complex and relies heavily on the exclusion of differential diagnosis and substantiating the cognitive complaints by neuropsychological assessment. Diagnostic evaluations have the purpose to help the patient by finding an explanation for the symptoms to guide treatment strategy or prevent further deterioration. But what if the diagnostic process in itself leads to problems that can be quite persistent and difficult to manage? The iatrogenic, or sick-making, side effects of the diagnostic process are the main focus of this case stud

A screening programme on chronic solvent-induced encephalopathy among Dutch painters

Background: Long-term exposure to organic solvents may lead to chronic solvent induced encephalopathy (CSE) in painters. In combination with reduction of exposure, a workers' health surveillance programme was developed, resulting in a three-stage CSE screening procedure for early neurobehavioural changes possibly predicting chronic health effects. The screening consists of a questionnaire (Neurosymptom Screening Checklist 60, NSC-60), computerised neurobehavioural functioning testing (Neurobehavioural Evaluation System; NES2) and multidisciplinary differential diagnostic evaluation by experts (called 'Solvent Team'). Results from the screening were compared with the results of the 'care as usual' (CAU), in which symptomatic patients were referred directly to the Solvent Team by occupational physicians, general practitioners or medical specialists. Parallel to the screening programme, a legal ban on indoor use of solvent-based paints resulted in lower exposure to solvents. Objective: To investigate the usefulness of the NSC-60 questionnaire as a screening tool for CSE among painters and to investigate the course of the number of CSE cases over the years as a potential consequence of improved prevention and control. Results: From 1998 to 2004, more than 40,000 painters were invited to participate in a health surveillance programme including a periodical occupational health examination (PHE) and 50% did participate. Four percent (N = 794) of these had a positive score on the NSC-60. The Solvent Team assessed 101 of these for CSE, which resulted in 27 CSE cases diagnosed. CAU during the same period of the surveillance (1998-2004) yielded 619 painters and 75 of these had the diagnosis CSE. After 2002 the number of CSE diagnosed cases dropped considerably and in 2004 only one case of CSE could be diagnosed. The substantially lower prevalence of CSE diagnosed cases in painters after 2002 might partly be explained as a result of a successful participation in the screening procedure of most prevalent CSE cases during the years 1998-2002. A second reason for the reduction of new diagnosed cases of CSE can be the effectiveness of the ban on indoor use of solvent-based paints resulting in lower exposure levels at work. Conclusion: The screening procedure is useful to screen for CSE among people taking part in the PHE programme. Control of CSE can be achieved by an integrated preventive approach with reduction of exposure and screening on early health effects. (C) 2012 Elsevier Inc. All rights reserve

Awareness in dementia: a review of clinical correlates

This article provides a review of the literature on clinical correlates of awareness in dementia. Most inconsistencies were found with regard to an association between depression and higher levels of awareness. Dysthymia, but not major depression, is probably related to higher levels of awareness. Anxiety also appears to be related to higher levels of awareness. Apathy and psychosis are frequently present in patients with less awareness, and may share common neuropathological substrates with awareness. Furthermore, unawareness seems to be related to difficulties in daily life functioning, increased caregiver burden, and deterioration in global dementia severity. Factors that may be of influence on the inconclusive data are discussed, as are future directions of researc