Uncoupling of Ca2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia.

The deficit in cerebral blood flow (CBF) seen in patients with hypertension-induced vascular dementia is increasingly viewed as a therapeutic target for disease-modifying therapy. Progress is limited, however, due to uncertainty surrounding the mechanisms through which elevated blood pressure reduces CBF. To investigate this, we used the BPH/2 mouse, a polygenic model of hypertension. At 8 mo of age, hypertensive mice exhibited reduced CBF and cognitive impairment, mimicking the human presentation of vascular dementia. Small cerebral resistance arteries that run across the surface of the brain (pial arteries) showed enhanced pressure-induced constriction due to diminished activity of large-conductance Ca2+-activated K+ (BK) channels-key vasodilatory ion channels of cerebral vascular smooth muscle cells. Activation of BK channels by transient intracellular Ca2+ signals from the sarcoplasmic reticulum (SR), termed Ca2+ sparks, leads to hyperpolarization and vasodilation. Combining patch-clamp electrophysiology, high-speed confocal imaging, and proximity ligation assays, we demonstrated that this vasodilatory mechanism is uncoupled in hypertensive mice, an effect attributable to physical separation of the plasma membrane from the SR rather than altered properties of BK channels or Ca2+ sparks, which remained intact. This pathogenic mechanism is responsible for the observed increase in constriction and can now be targeted as a possible avenue for restoring healthy CBF in vascular dementia.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Experiences of nurses and other health workers participating in a reflective course on compassion-based care.

BACKGROUND: the risk of compassion fatigue in healthcare staff is real, especially when considering the current financial pressures. A course in compassion-based care (CBC) was delivered to mental health staff at a hospital in north-west England, with the intention of rehabilitating ward culture and, subsequently, improving patient experience. AIMS: to explore staff experiences of participating in the CBC course. METHODS: a qualitative study using semi-structured interviews with participants (n=12) was conducted. All staff attending the course were eligible and were invited to participate. Interview transcripts were thematically analysed. FINDINGS: five themes characterising participant experience emerged from the data: meeting a need; creating the space; reorientation; prioritising self-care; and influencing team dynamics. Data overwhelmingly indicated the success of the CBC course. CONCLUSION: the CBC course appeared to have a profound effect on participants; it should be considered for further rollout and evaluation.

Telehealth-delivered cognitive rehabilitation for people with cognitive impairment as part of the post-COVID syndrome: protocol for a randomised controlled trial as part of the CICERO (Cognitive Impairment in Long COVID: Phenotyping and Rehabilitation) study.

BACKGROUND: Between 25 and 75% of people with persistent post-acute sequelae of SARS-CoV-2 infection (PASC) experience cognitive difficulties, compromising functional ability, quality of life, and activities of daily living, including work. Despite this significant morbidity, there is a paucity of interventions for this disorder that have undergone evaluation within a formal trial setting. Therefore, we have developed a cognitive rehabilitation programme, specifically designed to address the cognitive symptoms of PASC, notably impaired attention and processing speed, while also accounting for other PASC symptoms (fatigue, post-exertional malaise) that may aggravate the cognitive impairment. This study protocol outlines a randomised controlled trial (RCT) designed to evaluate the effectiveness of this programme compared to standard clinical care. METHODS: This is a multi-centre, parallel-group, individually randomised controlled trial, comparing standard clinical care with and without cognitive rehabilitation. We will recruit 120 non-hospitalised adults (aged 30-60 years) from three NHS sites in England with a history of COVID-19 infection and cognitive impairment persisting more than 3 months after the acute infection. Participants will be randomised (1:1) to the intervention or control groups, with the latter represented as a provision of standard clinical care without cognitive rehabilitation. The cognitive rehabilitation programme consists of ten 1-hour sessions, delivered weekly. Outcomes will be collected at baseline, 3, and 6 months, with participant-defined goal-attainment scores, relating to functional goals, at 3 months as the primary outcome measure. Secondary outcomes will be cognitive function, measures of quality of life, social functioning, mental health, fatigue, sleep, post-exertional malaise, and social and health care service use. We will also evaluate the health-economic benefits of cognitive rehabilitation in this population. DISCUSSION: Cognitive impairment in PASC is a major cause of functional disability with no effective treatment. Accordingly, we will undertake an RCT of cognitive rehabilitation, the protocol of which is published here. If this trial is successful in delivering improvements in trial outcomes, it will address a major unmet need relating to this emergent disorder, with a significant impact on affected individuals and the wider health economy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05731570. Registered on February 16, 2023.

Stigma toward mental and physical illness: attitudes of healthcare professionals, healthcare students and the general public in Pakistan.

BACKGROUND: The evidence base for stigma in mental health largely originates from high-income countries. AIMS: This study from Pakistan aimed to address the gap in literature on stigma from low- and middle-income countries. METHOD: This cross-sectional study surveyed 1470 adults from Karachi, Pakistan. Participants from three groups (healthcare professionals, healthcare students and the general public) completed the adapted Bogardus Social Distance Scale (SDS) as a measure of stigma. RESULTS: All three groups reported higher scores of stigma toward mental disorders compared with physical disorders. SDS scores for mental illness in the general public were significantly higher than in healthcare students (mean difference (MD) 6.93, 95% CI 5.45-8.45, P < 0.001) and healthcare professionals (MD 6.93, 95% CI 5.48-8.38, P < 0.001). However, SDS scores between healthcare students and healthcare professionals were not significantly different (MD 0.003, 95% CI -1.14-1.14, P > 0.99). Being female was associated with lower stigma scores and being over the age of 30 years was associated with higher stigma scores. CONCLUSIONS: Stigma campaigns in Pakistan need to target the general population. However, evidence of negative attitudes toward mental illness in healthcare students and healthcare professionals supports the need for stronger emphasis on psychiatric education within undergraduate and postgraduate training in Pakistan.

A roadmap to develop dementia research capacity and capability in Pakistan: A model for low- and middle-income countries.

OBJECTIVE: To produce a strategic roadmap for supporting the development of dementia research in Pakistan. BACKGROUND: While global research strategies for dementia research already exist, none is tailored to the specific needs and challenges of low- and middle-income countries (LMIC) like Pakistan. METHODS: We undertook an iterative consensus process with lay and professional experts to develop a Theory of Change-based strategy for dementia research in Pakistan. This included Expert Reference Groups (ERGs), strategic planning techniques, a "research question" priority survey, and consultations with Key Opinion Leaders. RESULTS: We agreed on ten principles to guide dementia research in Pakistan, emphasizing pragmatic, resource sparing, real-world approaches to support people with dementia, both locally and internationally. Goals included capacity/capability building. Priority research topics included raising awareness and understanding of dementia, and improving quality of life. CONCLUSION: This roadmap may be a model for other LMIC health ecosystems with emerging dementia research cultures.

BDNF plasma levels and genotype in depression and the response to electroconvulsive therapy.

BACKGROUND: Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and the antidepressant response. Electroconvulsive therapy (ECT) is reported to increase BDNF levels in blood, though only a small number of studies have been conducted to date. OBJECTIVE: Our objectives were to: 1) compare plasma BDNF levels in medicated patients with depression and controls; 2) assess the effect of ECT on plasma BDNF levels in medicated patients with depression; 3) explore the relationship between plasma BDNF levels and the Val66Met (rs6265) BDNF polymorphism; and 4) examine the relationship between plasma BDNF levels and clinical symptoms and outcomes with ECT. METHODS: Plasma BDNF levels were analyzed in samples from 61 medicated patients with a major depressive episode and 50 healthy controls, and in patient samples following a course of ECT. Fifty-two samples from the depressed patient group were genotyped for the Val66Met BDNF polymorphism. RESULTS: There was no difference in plasma BDNF levels between the control and depressed groups, and there was no difference in plasma BDNF levels in patients following treatment with ECT. In line with previous reports, we show that, in medicated patients with depression, Met-carriers had higher plasma BDNF levels than Val-carriers, though genotype was not related to clinical response. We found no association between plasma BDNF levels and depression severity or the clinical response to ECT. CONCLUSIONS: Our results suggest that plasma BDNF does not represent a suitable candidate biomarker for determining the therapeutic response to ECT.

Bitemporal Versus High-Dose Unilateral Twice-Weekly Electroconvulsive Therapy for Depression (EFFECT-Dep): A Pragmatic, Randomized, Non-Inferiority Trial.

OBJECTIVE: ECT is the most effective treatment for severe depression. Previous efficacy studies, using thrice-weekly brief-pulse ECT, reported that high-dose (6× seizure threshold) right unilateral ECT is similar to bitemporal ECT but may have fewer cognitive side effects. The authors aimed to assess the effectiveness and cognitive side effects of twice-weekly moderate-dose (1.5× seizure threshold) bitemporal ECT with high-dose unilateral ECT in real-world practice. METHOD: This was a pragmatic, patient- and rater-blinded, noninferiority trial of patients with major depression (N=138; 63% female; age=56.7 years [SD=14.8]) in a national ECT service with a 6-month follow-up. Participants were independently randomly assigned to bitemporal or high-dose unilateral ECT. The primary outcome was change in the 24-item Hamilton Depression Rating Scale (HAM-D) score after the ECT course; the prespecified noninferiority margin was 4.0 points. Secondary outcomes included response and remission rates, relapse status after 6 months, and cognition. RESULTS: Of the eligible patients, 69 were assigned to bitemporal ECT and 69 to unilateral ECT. High-dose unilateral ECT was noninferior to bitemporal ECT regarding the 24-item HAM-D scores after the ECT course (mean difference=1.08 points in favor of unilateral ECT [95% CI=-1.67 to 3.84]). There were no significant differences for response and remission or 6-month relapse status. Recovery of orientation was quicker following unilateral ECT (median=19.1 minutes versus 26.4 minutes). Bitemporal ECT was associated with a lower percent recall of autobiographical information (odds ratio=0.66) that persisted for 6 months. CONCLUSIONS: Twice-weekly high-dose unilateral ECT is not inferior to bitemporal ECT for depression and may be preferable because of its better cognitive side-effect profile.

Construction and updating of a public events questionnaire for repeated measures longitudinal studies.

Impairments of retrospective memory and cases of retrograde amnesia are often seen in clinical settings. A measure of the proportion of memories retained over a specified time can be useful in clinical situations and public events questionnaires may be valuable in this respect. However, consistency of retention of public events memory has rarely been studied in the same participants. In addition, when used in a research context, public events questionnaires require updating to ensure questions are of equivalent age with respect to when the test is taken. This paper describes an approach to constructing and updating a Public Events Questionnaire (PEQ) for use with a sample that is recruited and followed-up over a long time-period. Internal consistency, parallel-form reliability, test-retest reliability, and secondary validity analyses were examined for three versions of the PEQ that were updated every 6 months. Versions 2 and 3 of the questionnaire were reliable across and within versions and for recall and recognition. Change over time was comparable across each version of the PEQ. These results show that PEQs can be regularly updated in a standardized fashion to allow use throughout studies with long recruitment periods.

Systematic review and meta-analysis of bifrontal electroconvulsive therapy versus bilateral and unilateral electroconvulsive therapy in depression.

OBJECTIVES: Our aim was to perform a meta-analysis of randomized controlled trials comparing efficacy and side effects of bifrontal (BF) ECT to bitemporal (BT) or unilateral (RUL) ECT in depression. METHODS: We performed a systematic review of randomized controlled trials comparing BF ECT with RUL or BT ECT in depression. Eight trials (n=617) reported some cognitive outcome. Efficacy was measured by reduction in Hamilton Depression Rating Scale score. Cognitive outcomes were limited to Mini-Mental State Examination (MMSE) in seven studies, with two studies measuring each of: Complex-figure delayed recall, Trail-making tests and verbal learning. RESULTS: Efficacy was equal between BF and BT ECT (Hedges's g=0.102, P=0.345, confidence interval (CI): -0.110, 0.313) and BF and RUL ECT (standardized mean difference=-0.12, P=0.365, CI: -0.378, 0.139). Post-treatment MMSE score decline was less for BF than BT ECT (g=0.89, CI: 0.054, 1.724) but not RUL ECT. RUL ECT impaired Complex figure recall more than BF ECT (g=0.76, CI :0.487, 1.035), but BF ECT impaired word recall more than RUL ECT (g=-1.45, CI: -2.75, -0.15). CONCLUSIONS: Bifrontal ECT is not more effective than BT or RUL ECT but may have modest short-term benefits for specific memory domains. BF ECT has potential advantages, but given longer experience with BT and RUL, bifrontal ECT requires better characterization.

Antidepressant augmentation and combination in unipolar depression: strong guidance, weak foundations.

Depression will be the second leading contributor to the global burden of disease by 2020. In Ireland, in 2009, 6061 people were hospitalised with depressive disorders. This represents a significant economic and social burden. There is growing awareness of the difficulty in treating depression with medications alone. The likelihood that a patient will achieve remission with the first antidepressant tried is around 30%, and the rates are similar for the second antidepressant tried. This falls to around 15% after three trials. Many patients are exposed to pharmacotherapy for extended periods of time with little beneficial effect, but often with side-effects. Patients are therefore in great need of clear information with regard to their chance of success. Clinicians are in need of clear guidance on prescribing strategies which have proven efficacy. However, this guidance often discusses treatment strategies based on varying levels of evidence. Guiding bodies may approach the problem from varying perspectives. The UK National Institute for Health and Clinical Excellence (NICE) has a clear government mandate with regard to provision of not only effective but cost-effective treatments. The British Association of Psychopharmacology (BAP) is an independent body of interested researchers and therefore may discuss prescribing options from the point of view of tertiary care institutions, and university centres. The South London and Maudsley NHS Foundation Trust publish the popular Maudsley guidelines. These are perhaps more pragmatic in nature, but include very low levels of evidence, including case series. The American Psychiatric Association (APA) is an independent member association which also publishes guidelines. These are published in the American Journal of Psychiatry and the latest guidelines were published in October 2010. All these bodies attempt to weigh their advice according to the level of evidence available and aim to provide clinical guidance in difficult situations. The burden on guiding organisations is to provide some direction and clarity in areas that are often unclear or controversial. Clinical guidelines are one method of providing support and guidance to busy clinicians. However, this clinician-centered approach has limitations. The onus is on the authors of the guidance to provide ever-more treatment options. This may mean that conclusions about the efficacy of medications is overstated or the limitations of the literature not fully explored in explanatory notes.

Electroconvulsive therapy, capacity and the law in Ireland.

The Mental Health Act (MHA) 2001 has major implications for treating patients with electroconvulsive therapy (ECT), especially as those referred for treatment are among the most severely ill and often lose capacity. Under the MHA 2001, a person may only be treated without consent if they are an involuntary patient. However, there is no provision in the Act for treating voluntary inpatients whose mental state has deteriorated but who do not seek to leave hospital. Such people may lack capacity to make treatment decisions but be passively compliant. The Wards of Court system is currently the only legal recourse but has been criticised by the Law Reform Commission and is unwieldy. Further legislation governing treatment of people lacking capacity to consent to ECT or withhold consent is required to protect and advance treatment of all concerned.