Mei-See Man

Systematic review of stepped wedge cluster randomized trials shows that design is particularly used to evaluate interventions during routine implementation

OBJECTIVE To describe the application of the stepped wedge cluster randomized controlled trial (CRCT) design. STUDY DESIGN AND SETTING Systematic review. We searched Medline, Embase, PsycINFO, HMIC, CINAHL, Cochrane Library, Web of Knowledge, and Current Controlled Trials Register for articles published up to January 2010. Stepped wedge CRCTs from all fields of research were included. Two authors independently reviewed and extracted data from the studies. RESULTS Twenty-five studies were included in the review. Motivations for using the design included ethical, logistical, financial, social, and political acceptability and methodological reasons. Most studies were evaluating an intervention during routine implementation. For most of the included studies, there was also a belief or empirical evidence suggesting that the intervention would do more good than harm. There was variation in data analysis methods and insufficient quality of reporting. CONCLUSIONS The stepped wedge CRCT design has been mainly used for evaluating interventions during routine implementation, particularly for interventions that have been shown to be effective in more controlled research settings, or where there is lack of evidence of effectiveness but there is a strong belief that they will do more good than harm. There is need for consistent data analysis and reporting.

Face pictures reduce behavioural, autonomic, endocrine and neural indices of stress and fear in sheep.

Faces are highly emotive stimuli and we find smiling or familiar faces both attractive and comforting, even as young babies. Do other species with sophisticated face recognition skills, such as sheep, also respond to the emotional significance of familiar faces? We report that when sheep experience social isolation, the sight of familiar sheep face pictures compared with those of goats or inverted triangles significantly reduces behavioural (activity and protest vocalizations), autonomic (heart rate) and endocrine (cortisol and adrenaline) indices of stress. They also increase mRNA expression of activity–dependent genes (c–fos and zif/268) in brain regions specialized for processing faces (temporal and medial frontal cortices and basolateral amygdala) and for emotional control (orbitofrontal and cingulate cortex), and reduce their expression in regions associated with stress responses (hypothalamic paraventricular nucleus) and fear (central and lateral amygdala). Effects on face recognition, emotional control and fear centres are restricted to the right brain hemisphere. Results provide evidence that face pictures may be useful for relieving stress caused by unavoidable social isolation in sheep, and possibly other animal species, including humans. The finding that sheep, like humans, appear to have a right brain hemisphere involvement in the control of negative emotional experiences also suggests that functional lateralization of brain emotion systems may be a general feature in mammals.

Autonomic arousal in an appetitive context in primates: a behavioural and neural analysis

Central to many emotional responses is the accompanying peripheral somatic and autonomic arousal, feedback from which has been hypothesized to enhance emotional memory and to contribute to appraisal processes and decision making, and dysfunction of which may contribute to antisocial behaviour. Whilst peripheral arousal may accompany both positive and negative emotional contexts, its relationship with the former is poorly understood, as are the neural mechanisms underlying such a relationship. The purpose of the present study was to determine the autonomic correlates of anticipation, as well as consumption, of high incentive food, in the freely moving common marmoset and to investigate the contribution of the amygdala to such effects. Blood pressure (BP) and heart rate (HR) were measured remotely by a telemetric device implanted into the descending aorta and behavioural responses were monitored whilst marmosets viewed preferred or non‐preferred foods and were then allowed access to eat those foods. A marked rise in blood pressure in unrestrained marmosets was observed in response both to the sight of highly preferred foods (anticipatory period) as well as during the actual consumption of those foods (consummatory period). Excitotoxic lesions of the amygdala abolished the autonomic arousal in the anticipatory period, but spared both the behavioural arousal in the anticipatory period and the autonomic arousal in the consummatory period. Together these data serve as an important step towards understanding the role of autonomic arousal in emotion and its neural underpinnings.

Lesions of Ventrolateral Prefrontal or Anterior Orbitofrontal Cortex in Primates Heighten Negative Emotion

BACKGROUND Heightened fear and anxiety are core symptoms of a variety of neuropsychiatric disorders. They are associated with structural and activity changes throughout neural circuitry that includes the ventral and medial prefrontal cortices (PFC), the amygdala, and hippocampus. Although the contributions of the medial PFC, amygdala, and hippocampus to fear and anxiety have been studied extensively with animal models, the selective roles of the ventral PFC-including the ventrolateral prefrontal cortex (vlPFC) and orbitofrontal cortex-are poorly understood. METHODS We investigated the effects of selective excitotoxic lesions of either the vlPFC or anterior orbitofrontal cortex (antOFC) on anxious behavior and Pavlovian conditioned autonomic and behavioral fear responses in the New World primate, the common marmoset. RESULTS Both vlPFC and antOFC lesions resulted in stronger, less adaptable conditioned fear responses. They also heightened the anxiety responses of a marmoset to a human intruder. In contrast, only a lesion of the vlPFC affected the coping style that a marmoset displayed in the presence of the human intruder, increasing the likelihood of proactive mobbing. CONCLUSIONS These results suggest that both the antOFC and vlPFC can downregulate fear and anxiety and, together, provide necessary but independent contributions to the top-down control of negative emotion.

Uncoupling of behavioral and autonomic responses after lesions of the primate orbitofrontal cortex

Successful adaptation to changes in an animals emotional and motivational environment depends on behavioral flexibility accompanied by changes in bodily responses, e.g., autonomic and endocrine, which support the change in behavior. Here, we identify the orbitofrontal cortex (OFC) as pivotal in the flexible regulation and coordination of behavioral and autonomic responses during adaptation. Using an appetitive Pavlovian task, we demonstrate that OFC lesions in the marmoset (i) impair an animals ability to rapidly suppress its appetitive cardiovascular arousal upon termination of a conditioned stimulus and (ii) cause an uncoupling of the behavioral and autonomic components of the adaptive response after reversal of the reward contingencies. These findings highlight the role of the OFC in emotional regulation and are highly relevant to our understanding of disorders such as schizophrenia and autism in which uncoupling of emotional responses may contribute to the experiential distress and disadvantageous behavior associated with these disorders.

Bespoke smoking cessation for people with severe mental ill health (SCIMITAR): a pilot randomised controlled trial

BACKGROUND People with severe mental ill health are three times more likely to smoke but typically do not access conventional smoking cessation services, contributing to widening health inequalities and reduced life expectancy. We aimed to pilot an intervention targeted at smokers with severe mental ill health and to test methods of recruitment, randomisation, and follow up before implementing a full trial. METHODS The Smoking Cessation Intervention for Severe Mental Ill Health Trial (SCIMITAR) is a pilot randomised controlled trial of a smoking cessation strategy designed specifically for people with severe mental ill health, to be delivered by mental health nurses and consisting of behavioural support and drugs, compared with a conventional smoking cessation service (ie, usual care). Adults (aged 18 years or older) with bipolar disorder or schizophrenia, who were current smokers, were recruited from NHS primary care and mental health settings in the UK (York, Scarborough, Hull, and Manchester). Eligible participants were randomly allocated to either usual care (control group) or usual care plus the bespoke smoking cessation strategy (intervention group). Randomisation was done via a central telephone system, with computer-generated random numbers. We could not mask participants, family doctors, and researchers to the treatment allocation. Our primary outcome was smoking status at 12 months, verified by carbon monoxide measurements or self-report. Only participants who provided an exhaled CO measurement or self-reported their smoking status at 12 months were included in the primary analysis. The trial is registered at ISRCTN.com, number ISRCTN79497236. FINDINGS Of 97 people recruited to the pilot study, 51 were randomly allocated to the control group and 46 were assigned to the intervention group. Participants engaged well with the bespoke smoking cessation strategy, but no individuals assigned to usual care accessed NHS smoking cessation services. At 12 months, 35 (69%) controls and 33 (72%) people assigned to the intervention group provided a CO measurement or self-reported their smoking status. Smoking cessation was highest among individuals who received the bespoke intervention (12/33 [36%] vs 8/35 [23%]; adjusted odds ratio 2·9, 95% CI 0·8-10·5). INTERPRETATION We have shown the feasibility of recruiting and randomising people with severe mental ill health in a trial of this nature. The level of engagement with a bespoke smoking cessation strategy was higher than with a conventional approach. The effectiveness and safety of a smoking cessation programme designed particularly for people with severe mental ill health should be tested in a fully powered randomised controlled trial. FUNDING National Institute of Health Research Health Technology Assessment Programme.

Corticosterone modulation of somatodendritic 5-HT1A receptor function in mice

Corticosteroid modulation of serotonergic function may play a central role in mood disorders. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) produces a hypothermia in mice that serves as an in-vivo model of somatodendritic 5-HT1A autoreceptor function. Daily injections (s.c.) of 50 mg/kg of corticosterone (CORT) for 3 days attenuates 8-OH-DPAT hypothermia tested 24 h later. This study sought to further clarify the nature of the CORT-mediated attenuation of somatodendritic 5-HT1A receptor function. Mice underwent various CORT manipulations prior to an 8-OH-DPAT challenge. Neither 14-day bilateral adrenalectomy (ADX), nor CORT 50 mg/kg/day, administered continuously by osmotic minipump over 72 h had any effect on the 8-OH-DPAT hypothermic response. In contrast, daily injections of CORT over three consecutive days caused a significant attenuation in 8-OH-DPAT hypothermia when tested 24 h later. However, administration of an additional dose of CORT 2 h prior to the 8-OH-DPAT challenge occluded this CORT-mediated attenuation in a dose-dependent fashion. The findings demonstrate that CORT modulates somatodendritic 5-HT1A receptor function in a complex manner. Attenuation is seen only after intermittent administration of CORT. In addition, the degree of attenuation depends on CORT concentrations at the time of testing. These findings may have implications regarding mechanisms of adaptation to stress.

Effectiveness and cost-effectiveness of a telehealth intervention to support the management of long-term conditions: study protocol for two linked randomized controlled trials

BackgroundAs the population ages, more people are suffering from long-term health conditions (LTCs). Health services around the world are exploring new ways of supporting people with LTCs and there is great interest in the use of telehealth: technologies such as the Internet, telephone and home self-monitoring.Methods/DesignThis study aims to evaluate the effectiveness and cost-effectiveness of a telehealth intervention delivered by NHS Direct to support patients with LTCs. Two randomized controlled trials will be conducted in parallel, recruiting patients with two exemplar LTCs: depression or raised cardiovascular disease (CVD) risk. A total of 1,200 patients will be recruited from approximately 42 general practices near Bristol, Sheffield and Southampton, UK. Participants will be randomly allocated to either usual care (control group) or usual care plus the NHS Direct Healthlines Service (intervention group). The intervention is based on a conceptual model incorporating promotion of self-management, optimisation of treatment, coordination of care and engagement of patients and general practitioners. Participants will be provided with tailored help, combining telephone advice from health information advisors with support to use a range of online resources. Participants will access the service for 12 months. Outcomes will be collected at baseline, four, eight and 12 months for the depression trial and baseline, six and 12 months for the CVD risk trial. The primary outcome will be the proportion of patients responding to treatment, defined in the depression trial as a PHQ-9 score <10 and an absolute reduction in PHQ-9 ≥5 after 4 months, and in the CVD risk trial as maintenance or reduction of 10-year CVD risk after 12 months. The study will also assess whether the intervention is cost-effective from the perspective of the NHS and personal social services. An embedded qualitative interview study will explore healthcare professionals’ and patients’ views of the intervention.DiscussionThis study evaluates a complex telehealth intervention which combines evidence-based components and is delivered by an established healthcare organisation. The study will also analyse health economic information. In doing so, the study hopes to address some of the limitations of previous research by demonstrating the effectiveness and cost-effectiveness of a real world telehealth intervention.Trial registrationCurrent Controlled Trials: Depression trial ISRCTN14172341 and cardiovascular disease risk trial ISRCTN27508731.

Acupuncture for irritable bowel syndrome: primary care based pragmatic randomised controlled trial.

BackgroundAcupuncture is used by patients as a treatment for irritable bowel syndrome (IBS) but the evidence on effectiveness is limited. The purpose of the study was to evaluate the effectiveness of acupuncture for irritable bowel syndrome in primary care when provided as an adjunct to usual care.MethodsDesign: A two-arm pragmatic randomised controlled trial.Setting: Primary care in the United Kingdom.Patients: 233 patients had irritable bowel syndrome with average duration of 13 years and score of at least 100 on the IBS Symptom Severity Score (SSS).Interventions: 116 patients were offered 10 weekly individualised acupuncture sessions plus usual care, 117 patients continued with usual care alone.Measurements: Primary outcome was the IBS SSS at three months, with outcome data collected every three months to 12 months.ResultsThere was a statistically significant difference between groups at three months favouring acupuncture with a reduction in IBS Symptom Severity Score of −27.43 (95% CI: –48.66 to −6.21, p = 0.012). The number needed to treat for successful treatment (≥50 point reduction in the IBS SSS) was six (95% CI: 3 to 17), based on 49% success in the acupuncture group vs. 31% in the control group, a difference between groups of 18% (95% CI: 6% to 31%). This benefit largely persisted at 6, 9 and 12 months.ConclusionsAcupuncture for irritable bowel syndrome provided an additional benefit over usual care alone. The magnitude of the effect was sustained over the longer term. Acupuncture should be considered as a treatment option to be offered in primary care alongside other evidenced based treatments.Trial RegistrationCurrent Controlled Trials ISRCTN08827905

The Role of the Orbitofrontal Cortex and Medial Striatum in the Regulation of Prepotent Responses to Food Rewards

An impairment in learning to inhibit prepotent responses to positive stimuli is associated with damage to the orbitofrontal cortex (OFC) in rats, monkeys, and humans performing discrimination reversal, extinction, and detour reaching tasks. In contrast, a recent study showed that OFC-lesioned rhesus monkeys could learn to select the smaller of 2 quantities of food reward in order to receive the larger reward, at an equivalent rate to controls, despite the requirement to inhibit a prepotent response. Given this result, the aim of the present study was to further specify the contexts under which the OFC regulates responding and to identify additional components of limbic circuitry that contribute to such regulation. Marmosets with lesions of the OFC and medial striatum (MS), but not the amygdala, made more prepotent responses to a clear Perspex box containing high incentive food before learning to choose the box containing low incentive food, to obtain reward. However, having learned the incongruent incentive discrimination OFC- and MS-lesioned monkeys were impaired upon reversal of the reward contingencies, repeatedly selecting the previously rewarded low incentive object. These findings identify the critical contribution of the OFC and MS in the regulation of responding by affective cues.