Mental Capacity and Decisional Autonomy: An Interdisciplinary Challenge

With the waves of reform occurring in mental health legislation in England and other jurisdictions, mental capacity is set to become a key medico-legal concept. The concept is central to the law of informed consent and is closely aligned to the philosophical concept of autonomy. It is also closely related to mental disorder. This paper explores the interdisciplinary terrain where mental capacity is located. Our aim is to identify core dilemmas and to suggest pathways for future interdisciplinary research. The terrain can be separated into three types of discussion: philosophical, legal and psychiatric. Each discussion approaches mental capacity and judgmental autonomy from a different perspective yet each discussion struggles over two key dilemmas: whether mental capacity and autonomy is/should be a moral or a psychological notion and whether rationality is the key constitutive factor. We suggest that further theoretical work will have to be interdisciplinary and that this work offers an opportunity for the law to enrich its interpretation of mental capacity, for psychiatry to clarify the normative elements latent in its concepts and for philosophy to advance understanding of autonomy through the study of decisional dysfunction. The new pressures on medical and legal practice to be more explicit about mental capacity make this work a priority

Manic Temporality

Time-consciousness has long been a focus of research in phenomenology and phenomenological psychology. We advance and extend this tradition of research by focusing on the character of temporal experience under conditions of mania. Symptom scales and diagnostic criteria for mania are peppered with temporally inflected language: increased rate of speech, racing thoughts, flight of ideas, hyperactivity. But what is the underlying structure of temporal experience in manic episodes? We tackle this question using a strategically hybrid approach. We recover and reconstruct three hypotheses regarding manic temporality that were advanced and modelled by two pioneers of clinical phenomenology: Eugène Minkowski (1885-1972) and Ludwig Binswanger (1881-1966). We then test, critique, and refine these hypotheses using heterophenomenological methods in an interview-based study of persons with a history of bipolar and a current diagnosis of acute mania. Our conclusions support a central hypothesis due to Minkowski and Binswanger, viz., that disturbance in the formal structure of temporal experience is a core feature of mania. We argue that a suitably refined variant of Binswanger’s model of disturbance in manic protention helps to explain a striking pattern of impaired insight and impaired reasoning in manic episodes

Temporal inabilities and decision-making capacity in depression

We report on an interview-based study of decision-making capacity in two classes of patients suffering from depression. Developing a method of second-person hermeneutic phenomenology, we articulate the distinctive combination of temporal agility and temporal inability characteristic of the experience of severely depressed patients. We argue that a cluster of decision-specific temporal abilities is a critical element of decision-making capacity, and we show that loss of these abilities is a risk factor distinguishing severely depressed patients from mildly/moderately depressed patients. We explore the legal and clinical consequences of this result

Decision-making capacity for treatment in psychiatric and medical in-patients: Cross-sectional, comparative study

BackgroundIs the nature of decision-making capacity (DMC) for treatment significantly different in medical and psychiatric patients?AimsTo compare the abilities relevant to DMC for treatment in medical and psychiatric patients who are able to communicate a treatment choice.MethodA secondary analysis of two cross-sectional studies of consecutive admissions: 125 to a psychiatric hospital and 164 to a medical hospital. The MacArthur Competence Assessment Tool – Treatment and a clinical interview were used to assess decision-making abilities (understanding, appreciating and reasoning) and judgements of DMC. We limited analysis to patients able to express a choice about treatment and stratified the analysis by low and high understanding ability.ResultsMost people scoring low on understanding were judged to lack DMC and there was no difference by hospital (P=0.14). In both hospitals there were patients who were able to understand yet lacked DMC (39% psychiatric v. 13% medical in-patients, P&lt;0.001). Appreciation was a better ‘test’ of DMC in the psychiatric hospital (where psychotic and severe affective disorders predominated) (P&lt;0.001), whereas reasoning was a better test of DMC in the medical hospital (where cognitive impairment was common) (P=0.02).ConclusionsAmong those with good understanding, the appreciation ability had more salience to DMC for treatment in a psychiatric setting and the reasoning ability had more salience in a medical setting.</jats:sec

Misevaluating the Future: Affective Disorder and Decision-Making Capacity for Treatment-A Temporal Understanding

Background: Within psychiatric practice and policy there is considerable controversy surrounding the nature and assessment of impairments of decision-making capacity (DMC) for treatment in persons diagnosed with affective disorders. We identify the problems of "cognitive bias" and "outcome bias" in assessment of DMC for treatment in affective disorder and aim to help resolve these problems with an analysis of how time is experienced in depression and mania. Sampling and Methods: We conducted purposeful sampling and a qualitative phenomenological analysis of interview data on patients with depression and mania, exploring temporal experience and decision-making regarding treatment. Results: In both severe depression and mania there is a distinctive experience of the future. Two consequences can follow: a loss of evaluative differentiation concerning future outcomes and, relatedly, inductive failure. This temporal inability can compromise an individual's ability to appreciate or "use or weigh" treatment information. Conclusions: The decision-making abilities required for self-determination involve an ability to evaluate alternative future outcomes. Our results show that, within severe depression or mania, anticipation of future outcomes is inflexibly fixed at one end of the value spectrum. We therefore propose a temporal model of decision-making abilities, which could be used to improve assessment of DMC in affective disorder

Clinical assessment of decision-making capacity in acquired brain injury with personality change

Assessment of decision-making capacity (DMC) can be difficult in acquired brain injury (ABI) particularly with the syndrome of organic personality disorder (OPD) (the “frontal lobe syndrome”). Clinical neuroscience may help but there are challenges translating its constructs to the decision-making abilities considered relevant by law and ethics. An in-depth interview study of DMC in OPD was undertaken. Six patients were purposefully sampled and rich interview data were acquired for scrutiny using interpretative phenomenological analysis. Interview data revealed that awareness of deficit and thinking about psychological states can be present. However, the awareness of deficit may not be “online” and effectively integrated into decision-making. Without this online awareness of deficit the ability to appreciate or use and weigh information in the process of deciding some matters appeared absent. We argue that the decision-making abilities discussed are: (1) necessary for DMC, (2) threatened by ABI , and (3) assessable at interview. Some advice for practically incorporating these abilities within assessments of DMC in patients with OPD is outlined

Real-time fMRI neurofeedback to down-regulate superior temporal gyrus activity in patients with schizophrenia and auditory hallucinations: A Proof-of-concept study.

Abstract Neurocognitive models and previous neuroimaging work posit that auditory verbal hallucinations (AVH) arise due to increased activity in speech-sensitive regions of the left posterior superior temporal gyrus (STG). Here, we examined if patients with schizophrenia (SCZ) and AVH could be trained to down-regulate STG activity using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF). We also examined the effects of rtfMRI-NF training on functional connectivity between the STG and other speech and language regions. Twelve patients with SCZ and treatment-refractory AVH were recruited to participate in the study and were trained to down-regulate STG activity using rtfMRI-NF, over four MRI scanner visits during a 2-week training period. STG activity and functional connectivity were compared pre- and post-training. Patients successfully learnt to down-regulate activity in their left STG over the rtfMRI-NF training. Post- training, patients showed increased functional connectivity between the left STG, the left inferior prefrontal gyrus (IFG) and the inferior parietal gyrus. The post-training increase in functional connectivity between the left STG and IFG was associated with a reduction in AVH symptoms over the training period. The speech-sensitive region of the left STG is a suitable target region for rtfMRI-NF in patients with SCZ and treatment-refractory AVH. Successful down-regulation of left STG activity can increase functional connectivity between speech motor and perception regions. These findings suggest that patients with AVH have the ability to alter activity and connectivity in speech and language regions, and raise the possibility that rtfMRI-NF training could present a novel therapeutic intervention in SCZ

ClassyFire: automated chemical classification with a comprehensive, computable taxonomy

Additional file 5. Use cases. Text-based search on the ClassyFire web server. (A) Building the query. (B) Sparteine, one of the returned compounds

Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.

The transforming growth factor β (TGFβ) superfamily includes TGFβ, activins, inhibins, and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by coordinately regulating cell proliferation, differentiation, and migration. Aberrant signaling of superfamily members, however, is associated with fibrosis as well as tumorigenesis, cancer progression, metastasis, and drug-resistance mechanisms in a variety of cancer subtypes. Given their involvement in human disease, the identification of novel selective inhibitors of TGFβ superfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context-specific roles depending on the ligand and the complex formation with the type 2 receptor. Here, we characterize the biologic effects of two transforming growth factor β receptor 1 (TGFBR1) kinase inhibitors designed to target TGFβ signaling. AZ12601011 [2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine]; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl)oxy]-2-pyridinyl}amino)benzenesulfonamide] (IC50 = 18 and 47 nM, respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC50 = 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC50 = 380 nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors activin A receptor type 1B (ALK4), TGFBR1, and activin A receptor type 1C (ALK7). AZ12799734, however, is a pan TGF/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by activin A receptor type 1L, bone morphogenetic protein receptor type 1A, and bone morphogenetic protein receptor type 1B and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFβ-induced migration of HaCaT keratinocytes and, furthermore, inhibited tumor growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFβ- and BMP-regulated signaling pathways to disease states

Breaking through an epigenetic wall: Re-activation ofOct4by KRAB-containing designer zinc finger transcription factors

The gene Oct4 encodes a transcription factor critical for the maintenance of pluripotency and self-renewal in embryonic stem cells. In addition, improper re-activation of Oct4 contributes to oncogenic processes. Herein, we describe a novel designer zinc finger protein (ZFP) capable of upregulating the endogenous Oct4 promoter in a panel of breast and ovarian cell lines carrying a silenced gene. In some ovarian tumor lines, the ZFP triggered a strong reactivation of Oct4, with levels of expression comparable with exogenous Oct4 cDNA delivery. Surprisingly, the reactivation of Oct4 required a KRAB domain for effective upregulation of the endogenous gene. While KRAB-containing ZFPs are traditionally described as transcriptional repressors, our results suggest that these proteins could, in certain genomic contexts, function as potent activators and, thus, outline an emerging novel function of KRAB-ZFPs. In addition, we document a novel ZFP that could be used for the epigenetic reprograming of cancer cells