Presuming patient autonomy in the face of therapeutic misconception

Therapeutic misconception involves the failure of subjects either to understand or to incorporate into their own expectations the distinctions in nature and purpose of personally responsive therapeutic care, and the generic relationship between subject and investigator which is constrained by research protocols. Researchers cannot disregard this phenomenon if they are to ensure that subjects engage in research on the basis of genuine informed consent. However, our presumption of patient autonomy must be sustained unless we have compelling evidence of serious misunderstanding. This article argues that the mere expression of aspects of therapeutic misconception should not necessarily displace the presumption of subject autonomy or undermine ethical inclusion in research for at least three reasons. First, some interpretations of the empirical data do not suggest misunderstanding. Second, assessment of misestimation and optimism are delicate and value‐laden, and turn quickly from questions of autonomy to questions of judgment. Third, incomplete understanding may yet be sufficient to allow a subject to engage in a substantially autonomous decision‐making process. Our point is not to dismiss the possibility of genuine therapeutic misconception, but to question its frequency and fatality to the consent process.     

Therapeutic Subthalamic Nucleus Deep Brain Stimulation Reverses Cortico-Thalamic Coupling during Voluntary Movements in Parkinson's Disease

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted treatment for patients experiencing the motor complications of Parkinson''s disease (PD). While its successes are becoming increasingly apparent, the mechanisms underlying its action remain unclear. Multiple studies using radiotracer-based imaging have investigated DBS-induced regional changes in neural activity. However, little is known about the effect of DBS on connectivity within neural networks; in other words, whether DBS impacts upon functional integration of specialized regions of cortex. In this work, we report the first findings of fMRI in 10 subjects with PD and fully implanted DBS hardware receiving efficacious stimulation. Despite the technical demands associated with the safe acquisition of fMRI data from patients with implanted hardware, robust activation changes were identified in the insula cortex and thalamus in response to therapeutic STN DBS. We then quantified the neuromodulatory effects of DBS and compared sixteen dynamic causal models of effective connectivity between the two identified nodes. Using Bayesian model comparison, we found unequivocal evidence for the modulation of extrinsic (between region), i.e. cortico-thalamic and thalamo-cortical connections. Using Bayesian model parameter averaging we found that during voluntary movements, DBS reversed the effective connectivity between regions of the cortex and thalamus. This casts the therapeutic effects of DBS in a fundamentally new light, emphasising a role in changing distributed cortico-subcortical interactions. We conclude that STN DBS does impact upon the effective connectivity between the cortex and thalamus by changing their sensitivities to extrinsic afferents. Furthermore, we confirm that fMRI is both feasible and is tolerated well by these patients provided strict safety measures are adhered to.     

Lay people's attitudes to treatment of depression: results of opinion poll for Defeat Depression Campaign just before its launch.

OBJECTIVE: To investigate the attitudes of the general public towards depression before the Defeat Depression Campaign of the Royal Colleges of Psychiatrists and General Practitioners; these results form the baseline to assess the change in attitudes brought about by the campaign. DESIGN: Group discussions generated data for initial qualitative research. The quantitative survey comprised a doorstep survey of 2003 people in 143 places around the United Kingdom. RESULTS: The lay public in general seemed to be sympathetic to those with depression but reluctant to consult. Most (1704 (85%)) believed counselling to be effective but were against antidepressants. Many subjects (1563 (78%)) regarded antidepressants as addictive. CONCLUSIONS: Although people are sympathetic towards those with depression, they may project their prejudices about depression on to the medical profession. Doctors have an important role in educating the public about depression and the rationale for antidepressant treatment. In particular, patients should know that dependence is not a problem with antidepressants.     

Acute and Chronic Mood and Apathy Outcomes from a Randomized Study of Unilateral STN and GPi DBS

Objective

To study mood and behavioral effects of unilateral and staged bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) for Parkinson''s disease (PD).

Background

There are numerous reports of mood changes following DBS, however, most have focused on bilateral simultaneous STN implants with rapid and aggressive post-operative medication reduction.

Methods

A standardized evaluation was applied to a subset of patients undergoing STN and GPi DBS and who were also enrolled in the NIH COMPARE study. The Unified Parkinson Disease Rating Scale (UPDRS III), the Hamilton depression (HAM-D) and anxiety rating scales (HAM-A), the Yale-Brown obsessive-compulsive rating scale (YBOCS), the Apathy Scale (AS), and the Young mania rating scale (YMRS) were used. The scales were repeated at acute and chronic intervals. A post-operative strategy of non-aggressive medication reduction was employed.

Results

Thirty patients were randomized and underwent unilateral DBS (16 STN, 14 GPi). There were no baseline differences. The GPi group had a higher mean dopaminergic dosage at 1-year, however the between group difference in changes from baseline to 1-year was not significant. There were no differences between groups in mood and motor outcomes. When combining STN and GPi groups, the HAM-A scores worsened at 2-months, 4-months, 6-months and 1-year when compared with baseline; the HAM-D and YMRS scores worsened at 4-months, 6-months and 1-year; and the UPDRS Motor scores improved at 4-months and 1-year. Psychiatric diagnoses (DSM-IV) did not change. No between group differences were observed in the cohort of bilateral cases.

Conclusions

There were few changes in mood and behavior with STN or GPi DBS. The approach of staging STN or GPi DBS without aggressive medication reduction could be a viable option for managing PD surgical candidates. A study of bilateral DBS and of medication reduction will be required to better understand risks and benefits of a bilateral approach.     

Deep brain stimulation for movement and other neurologic disorders

Deep brain stimulation (DBS) was introduced as a treatment for patients with parkinsonism and other movement disorders in the early 1990s. The technique rapidly became the treatment of choice for these conditions, and is now also being explored for other diseases, including Tourette syndrome, gait disorders, epilepsy, obsessive-compulsive disorder, and depression. Although the mechanism of action of DBS remains unclear, it is recognized that DBS works through focal modulation of functionally specific circuits. The fact that the same DBS parameters and targets can be used in multiple diseases suggests that DBS does not counteract the pathophysiology of any specific disorder, but acts to replace pathologic activities in disease-affected brain circuits with activity that is more easily tolerated. Despite the progress made in the use of DBS, much remains to be done to fully realize the potential of this therapy. We describe some of the most active areas of research in this field, both in terms of exploration of new targets and stimulation parameters, and in terms of new electrode or stimulator designs.     

Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration

Background

Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.

Methods and Findings

We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.

Conclusions

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.     

Habenula--a new target for treatment of intractable depression

Despite substantial advancement in psychopharmacological and electro-magnetic treatments over the last decades on the depression patients, there are non-responders remain with a chronic disease and high suicidal risk yet. Deep brain stimulation (DBS) is now being experimentally to treat the intractable depression and yielded an impressive therapeutic benefit, and especially few adverse effect occurred. The beneficial action of DBS is closely related to the stimulation sit. And the efficacy of high frequency stimulation of lateral habenula is one of the best choice. In depression, the concentration of 5-HT released by the raphe nuclei is decreased. It's due to mainly the overactivation of the lateral habenula. High frequency stimulation of lateral habenula impairs the activation of lateral habenula, and the inhibitory effect of lateral habenula on raphe nuclei is decreased. Then, the 5-HT concentration released by the raphe nuclei is increased, the pathological changes of depression is eliminated. The lateral habenula could be a promising novel target for BDS in the cases of intractable depression.     

Computational modeling of epileptiform activities in medial temporal lobe epilepsy combined with <Emphasis Type="Italic">in vitro</Emphasis> experiments

Electrical stimulation of sub-cortical brain regions (the basal ganglia), known as deep brain stimulation (DBS), is an effective treatment for Parkinson’s disease (PD). Chronic high frequency (HF) DBS in the subthalamic nucleus (STN) or globus pallidus interna (GPi) reduces motor symptoms including bradykinesia and tremor in patients with PD, but the therapeutic mechanisms of DBS are not fully understood. We developed a biophysical network model comprising of the closed loop cortical-basal ganglia-thalamus circuit representing the healthy and parkinsonian rat brain. The network properties of the model were validated by comparing responses evoked in basal ganglia (BG) nuclei by cortical (CTX) stimulation to published experimental results. A key emergent property of the model was generation of low-frequency network oscillations. Consistent with their putative pathological role, low-frequency oscillations in model BG neurons were exaggerated in the parkinsonian state compared to the healthy condition. We used the model to quantify the effectiveness of STN DBS at different frequencies in suppressing low-frequency oscillatory activity in GPi. Frequencies less than 40 Hz were ineffective, low-frequency oscillatory power decreased gradually for frequencies between 50 Hz and 130 Hz, and saturated at frequencies higher than 150 Hz. HF STN DBS suppressed pathological oscillations in GPe/GPi both by exciting and inhibiting the firing in GPe/GPi neurons, and the number of GPe/GPi neurons influenced was greater for HF stimulation than low-frequency stimulation. Similar to the frequency dependent suppression of pathological oscillations, STN DBS also normalized the abnormal GPi spiking activity evoked by CTX stimulation in a frequency dependent fashion with HF being the most effective. Therefore, therapeutic HF STN DBS effectively suppresses pathological activity by influencing the activity of a greater proportion of neurons in the output nucleus of the BG.     

Iterative design of a simulation-based module for teaching evolution by natural selection

Background

This research builds on a previous study that looked at the effectiveness of a simulation-based module for teaching students about the process of evolution by natural selection. While the previous study showed that the module was successful in teaching how natural selection works, the research uncovered some weaknesses in the design. In this paper, we used design-based research to investigate how design changes to the module affected not only students' understanding of the concepts but also their usage of misconceptions in the assessments. We present results from two studies. In study 1, we looked at gains in understanding on a pre and post-assessment for students who used the revised version of the module. We also examined misconception uses in their answer selections. In study 2, we compared the performance on a summative assessment between students who used the revised version and students who used the original version of the module. We also looked at misconception uses in their answer selections.

Results

In study 1, we saw a significant improvement in the pre-post assessment for students who used the revised version. In study 2, we did not find a significant difference on the overall performance outcome between students who used the revised and those that used the original version of the module. In both studies, however, we saw a  lower use of misconceptions after students used the revised module. In particular, we saw less use of the adaptive mutation misconception, the belief that mutations are adaptive responses to the environment and are biased towards advantageous mutations. This is promising because in the previous study there was no evidence of decreased use of this misconception.

Conclusions

Students showed learning gains on all targeted key concepts, and reduced expression of all targeted misconceptions, which was not found previously for students using the older workbook version of the module. In particular, the revised version appears to help students overcome the adaptive mutation misconception. This article demonstrates how design-based research can contribute to the ongoing improvement of evidence-based instruction in undergraduate biology classrooms.

     

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson’s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 MΩ was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.     

Translational principles of deep brain stimulation

Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.     

Guidelines for cross‐cultural Participatory Action Research partnerships: A case study of a customary seabird harvest in New Zealand

Abstract

Adaptive co‐management and Participatory Action Research (PAR) promotes social ecological resilience by simultaneously protecting wildlife and its habitat and promoting capacity and motivation for sustainable harvest management by communities. We report here on a case study of learning through a partnership (1994–2009) between science and Traditional Ecological Knowledge (TEK) to determine the sustainability of titi (sooty shearwater, Puffinus griseus) harvests by Rakiura Maori in southern New Zealand. Testimony of Maori elders and titi harvesters (birders), members of the Rakiura Titi Islands Administering Body, researchers and participants in workshops and meetings were recorded throughout the 14‐year research project to identify critical determinants of success of the partnership. A large majority of participants supported the research, mainly because it expanded their knowledge by investigating the reasons for declining bird numbers and the means of ensuring the continuation of their muttonbirding heritage. Initial concerns about the research included fear that prohibition or quota would be imposed through political pressure from external groups; the intrusion of strangers on the islands; the misconception that the research was being promulgated by government regulatory agencies; and scepticism about research findings. Research also precipitated conflict and division within the Rakiura community, and some birders feared that science might displace matauranga Maori (TEK) of the Rakiura people for guiding harvest management. Core conditions for community engagement included trust between parties, effective communication of the science, equitable decision‐making responsibility, and building scientific capability and monetary support to enable meaningful participation. The most fundamental requirement is mutual respect for each party's knowledge. Attention to this inclusive, equitable, slow and prolonged process makes it more likely that the community will uptake results to improve sustainability of harvesting. The research has heightened awareness within the harvesting community of conservation issues facing the titi and of potential options to mitigate them. Eradication or control of weka (Gallirallus australis), and reducing titi harvest levels from around a quarter of the manu (family birding territories), are the main practical ways of increasing sustainability, but the magnitude and direction of climate change impacts on the shearwater population remains uncertain.     

The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure

Cycle and treadmill exercise tests are unsuitable for elderly, frail and severely limited patients with heart failure and may not reflect capacity to undertake day-to-day activities. Walking tests have proved useful as measures of outcome for patients with chronic lung disease. To investigate the potential value of the 6-minute walk as an objective measure of exercise capacity in patients with chronic heart failure, the test was administered six times over 12 weeks to 18 patients with chronic heart failure and 25 with chronic lung disease. The subjects also underwent cycle ergometer testing, and their functional status was evaluated by means of conventional measures. The walking test proved highly acceptable to the patients, and stable, reproducible results were achieved after the first two walks. The results correlated with the conventional measures of functional status and exercise capacity. The authors conclude that the 6-minute walk is a useful measure of functional exercise capacity and a suitable measure of outcome for clinical trials in patients with chronic heart failure.     

Deep brain stimulation: eye movements reveal anomalous effects of electrode placement and stimulation

One of the major difficulties in evaluating the efficacy of deep brain stimulation (DBS), or understanding its mechanism, is the need to distinguish the effects of stimulation itself from those of the lesion inevitably created during surgery. Recent work has shown that DBS of the subthalamic nucleus in Parkinson's disease greatly reduces the time it takes the eyes to make a saccade in response to a visual stimulus. Since this saccadic latency can be rapidly and objectively measured, we used it to compare the effects of surgery and of stimulation. We used a saccadometer to measure the saccadic latencies of 9 DBS patients (1) preoperatively, (2) the day after insertion of subthalamic nucleus electrodes, (3) three weeks later, prior to turning on the stimulator, and (4) after commencement of stimulation. Patients were on their anti-Parkinsonian medication throughout the study. It revealed an entirely unexpected and puzzling finding. As in previous studies an amelioration of symptoms is seen immediately after surgery, and then a further improvement when finally the stimulator is turned on, but in the case of saccadic latency the pattern is different: surgery produces a transient increase in latency, returning to baseline within three weeks, while subsequent stimulation reduced latency. Thus the differential effects of electrode placement and stimulation are completely different for saccades and for more general motor symptoms. This important finding rules out some over-simple interpretations of the mechanism of DBS, and needs to be taken into account in future attempts at modelling the neurophysiology of DBS.     

Structural Brain Changes as Biomarkers and Outcome Predictors in Patients with Late-Life Depression: A Cross-Sectional and Prospective Study

The relationship between structural changes in grey matter and treatment response in patients with late-life depression remains an intriguing area of research. This magnetic resonance imaging (MRI) study compares the baseline grey matter volume of elderly people with and without major depression (according to the DSM-IV-TR criteria) and assesses its association with antidepressant treatment response. Brain MRI scans were processed using statistical parametric mapping and voxel-based morphometry. The sample consisted of 30 patients with depression and 22 healthy controls. We found a significant volumetric reduction in the orbitofrontal cortex bilaterally in patients in comparison with controls. According to their remission status after antidepressant treatment, patients were classified as remitted or not remitted. Compared with controls, remitted patients showed a volumetric reduction in the orbitofrontal cortex bilaterally and in another cluster in the right middle temporal pole. Non-remitted patients showed an even greater volumetric reduction in the orbitofrontal cortex bilaterally compared with controls. To investigate predictive factors of remission after antidepressant treatment, we used a logistic regression. Both baseline Mini Mental State Examination score and baseline left superior lateral orbitofrontal cortex volume (standardized to the total grey matter volume) were associated with remission status. Our findings support the use of regional brain atrophy as a potential biomarker for depression. In addition, baseline cognitive impairment and regional grey matter abnormalities predict antidepressant response in patients with late-life depression.     

Moving toward a generalizable application of central thalamic deep brain stimulation for support of forebrain arousal regulation in the severely injured brain

This review considers the challenges ahead for developing a generalizable strategy for the use of central thalamic deep brain stimulation (CT/DBS) to support arousal regulation mechanisms in the severely injured brain. Historical efforts to apply CT/DBS to patients with severe brain injuries and a proof-of-concept result from a single-subject study are discussed. Circuit and cellular mechanisms underlying the recovery of consciousness are considered for their relevance to the application of CT/DBS, to improve consciousness and cognition in nonprogressive brain injuries. Finally, directions for development, and testing of generalizable criteria for CT/DBS are suggested, which aim to identify neuronal substrates and behavioral profiles that may optimally benefit from support of arousal regulation mechanisms.     

Clinical Associations of 11-Hydroxycorticosteroid Suppression and Non-suppression in Severe Depressive Illnesses

Fifty patients with severe depression were separated into two groups by the responses of their plasma 11-hydroxycorticosteriod levels to a midnight dose of 2 mg. of dexamethasone. Clinical and questionary comparisons were made between the two groups of patients, who were similar as regards age, sex, and length of symptoms before admission to hospital. No differences were found between the groups of severely ill patients as regards the severity of their depression and anxiety assessed by questionary. Nevertheless, agitation was significantly greater in the patients whose corticosteroid levels were not suppressed by dexamethasone and adverse childhood experiences in those whose levels were suppressed.     

Bacterial Utilization of Dodecyl Sulfate and Dodecyl Benzene Sulfonate

Two unknown bacterial isolants (C12 and C12B) were obtained from enriched soils and cultured on media containing detergent compounds as sole sources of carbon. Either isolant destroyed the foaming capacity of cultures containing dodecyl sulfate; but C12B, which could grow on dodecyl benzene sulfonate (DBS) whereas C12 could not, did not destroy the foaming capacity of this surfactant. The source of DBS available in quantity was a mixture of isomers derived from kerosene, and the bacteria utilized only one-fifth to one-fourth of this material during growth. Both isolants grew on short- or long-chained organic acids, and resting cells of both rapidly oxidized several long-chain acids and alcohols. Three of five phenyl-placement isomers of DBS (with the phenyl group at carbon 2, 3, or 6 on the alkyl chains) were excellent substrates for growth of C12B, but isomers with phenyl placement at carbon 4 or 5 were toxic and killed the bacteria.     

Validation of an Optimized ELISA for Quantitative Assessment of Epstein-Barr Virus Antibodies from Dried Blood Spots

Our objective was to validate a commercially available ELISA to measure antibody titers against Epstein-Barr virus (EBV) in dried blood spots (DBS) to replace a previously validated assay for DBS that is no longer available. We evaluated the precision, reliability, and stability of the assay for the measurement of EBV antibodies in matched plasma, fingerprick DBS, and venous blood DBS samples from 208 individuals. Effects of hematocrit and DBS sample matrix on EBV antibody determination were also investigated, and the cutoff for seropositivity in DBS was determined. A conversion equation was derived to enable comparison of results generated using this method with the former DBS method. There was a high correlation between plasma and DBS EBV antibody titers (R² = 0.93) with very little bias (?0.07 based on Bland-Altman analysis). The assay showed good linearity and did not appear to be affected by the DBS matrix, and physiological hematocrit levels had no effect on assay performance. There was reasonable agreement between DBS EBV titer estimates obtained using this assay and the previously validated assay (R² = 0.72). The commercially available ELISA assay for EBV antibody titers that we validated for use with DBS will facilitate continued investigation of EBV antibody titers in DBS.