Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein.

Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2-5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABAA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB.

Misguided presumptions: British Medical Association (BMA) and National Institute for Health and Clinical Excellence (NICE) guidance on organ retrieval and 'opt out' or 'presumed consent'.

Three documents have been produced in an attempt to increase the number of organs available for transplant: a National Institute for Health and Clinical Excellence (NICE) clinical guideline, a British Medical Association (BMA) report and a Welsh Government white paper. All three are ethically flawed: NICE and the BMA recommend that whenever there is intention to withdraw life-sustaining treatment and death is expected, patients should instead be stabilised to assess for donation. This is contrary to patients' best interests, the principles of mental capacity legislation and current criteria for accessing intensive care units. Regarding consent, the BMA and Welsh Government recommend an 'opt-out' policy, but consent in law requires information and cannot be 'presumed' or 'deemed' on the basis of failure to express or register 'opting out'. The language of all three proposals is manipulative, and patient trust may be undermined because the doctor's attention must move from the interests of the patient to those of the unknown organ recipients.

Treatment effects on event-related EEG potentials and oscillations in Alzheimer's disease.

Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.e., Aducanumab). Therefore, there is a need to identify and use biomarkers probing the neurophysiological underpinnings of human cognitive functions to test the clinical efficacy of that drug. In this regard, event-related electroencephalographic potentials (ERPs) and oscillations (EROs) are promising candidates. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association and Global Brain Consortium reviewed the field literature on the effects of the most used symptomatic drug against ADD (i.e., Acetylcholinesterase inhibitors) on ERPs and EROs in ADD patients with MCI and dementia at the group level. The most convincing results were found in ADD patients. In those patients, Acetylcholinesterase inhibitors partially normalized ERP P300 peak latency and amplitude in oddball paradigms using visual stimuli. In these same paradigms, those drugs partially normalize ERO phase-locking at the theta band (4-7 Hz) and spectral coherence between electrode pairs at the gamma (around 40 Hz) band. These results are of great interest and may motivate multicentric, double-blind, randomized, and placebo-controlled clinical trials in MCI and ADD patients for final cross-validation.

Are there consistent abnormalities in event-related EEG oscillations in patients with Alzheimer's disease compared to other diseases belonging to dementia?

Cerebrospinal and structural-molecular neuroimaging in-vivo biomarkers are recommended for diagnostic purposes in Alzheimer's disease (AD) and other dementias; however, they do not explain the effects of AD neuropathology on neurophysiological mechanisms underpinning cognitive processes. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association reviewed the field literature and reached consensus on the event-related electroencephalographic oscillations (EROs) that show consistent abnormalities in patients with significant cognitive deficits due to Alzheimer's, Parkinson's (PD), Lewy body (LBD), and cerebrovascular diseases. Converging evidence from oddball paradigms showed that, as compared to cognitively unimpaired (CU) older adults, AD patients had lower amplitude in widespread delta (>4 Hz) and theta (4-7 Hz) phase-locked EROs as a function of disease severity. Similar effects were also observed in PD, LBD, and/or cerebrovascular cognitive impairment patients. Non-phase-locked alpha (8-12 Hz) and beta (13-30 Hz) oscillations were abnormally reduced (event-related desynchronization, ERD) in AD patients relative to CU. However, studies on patients with other dementias remain lacking. Delta and theta phase-locked EROs during oddball tasks may be useful neurophysiological biomarkers of cognitive systems at work in heuristic and intervention clinical trials performed in AD patients, but more research is needed regarding their potential role for other dementias.

Fast oscillatory activity induced by kainate receptor activation in the rat basolateral amygdala in vitro.

The basolateral amygdala (BLA) has a fundamental role in affective processing. In vivo studies have revealed rhythmic population activity of a similar type to that seen in the hippocampus and cortical areas during learning tasks. The amygdala contains densely interconnected networks of inhibitory interneurons similar to those responsible for fast network activity generation in the hippocampus and other cortical structures. Here we report that neuronal networks of the BLA in isolation generate persistent, gamma frequency (30-80 Hz) oscillations upon kainate receptor activation with kainic acid. We show that, like other cortical structures, BLA oscillations are completely dependent upon γ-aminobutyric acid (GABA)ergic inhibition. GABA(A) receptor blockade abolished all oscillations, and the activity was also sensitive to the barbiturate, pentobarbital. Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-D-aspartate (NMDA) receptors had no significant effect on gamma activity. However, the GluR5-containing kainate receptor-specific antagonist (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl) pyrimidine-2,4-dione (UBP302) abolished oscillations-evidence that glutamatergic receptor involvement is predominantly kainate receptor mediated. The mixed AMPA/kainate receptor antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxalone-2,3-dione disodium (NBQX) abolished all oscillatory activity in 8/14 of slices tested. In the remaining slices, gamma frequency activity was abolished to reveal a low-amplitude, NMDA receptor-dependent, beta frequency (10-20 Hz) oscillation. Gamma oscillations are abolished by gap junction blockade. While these data show the BLA capable of generating gamma rhythms in common with other cortical areas studied to date, the network mechanisms appear to be different, suggesting a unique network structure underlies amygdala rhythmogenesis. Understanding how BLA networks produce synchronous activity is paramount to understanding how the BLA executes influence on important cognitive processes such as emotional learning.

Assisted suicide and voluntary euthanasia: role contradictions for physicians.

It is widely assumed by the general public that if assisted suicide (AS) or euthanasia (VE) were legalised doctors must be essentially involved in the whole process including prescribing the medication and (in euthanasia) administering it. This paper explores some reasons for this assumption and argues that it flatly contradicts what it means to be a doctor. The paper is thus not mainly concerned with the ethics of AS/VE but rather with the concept of a doctor that has evolved since the time of Hippocrates to current professional guidance reflected in healthcare law. The paper argues that the most common recent argument for AS/VE--that patients have a right to control when and how they die--in fact points to the involvement not of doctors but of legal agencies as decision makers plus technicians as agents.

What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons.

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity, reflecting thalamocortical and corticocortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies.

Choice and responsibility in the NHS.

Patient choice is becoming the centre of health policy in the UK and other countries. But there is ambiguity about what choice means. As the term is used in everyday life, choice is the foundation of the doctrine of patient consent. The doctor is responsible for choosing appropriate treatment, and the patient is responsible for choosing (for consenting to or refusing) what is offered and accepts responsibility for that choice. That simple and ethically acceptable doctrine is being replaced politically by consumerist choice. But consumerism in healthcare is incompatible with a publicly funded service. Moreover, consumerism changes the locus of responsibility from the doctor to the consumer (the patient). The doctor will cease to have the values of a professional and will become simply an agent of the patient's demands.

Impaired Fast Network Oscillations and Mitochondrial Dysfunction in a Mouse Model of Alpha-synucleinopathy (A30P).

Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P). We found an age-dependent reduction in the power of the gamma (20-80 Hz) frequency oscillations in slices taken from mice aged 9-16 months (9+A30P), that was not present in either young 2-6 months old (2+A30P) mice, or in control mice at either age. The mitochondrial blockers potassium cyanide and rotenone both reduced network oscillations in a concentration-dependent manner in aged A30P mice and aged control mice but slices from A30P mice showed a greater reduction in the oscillations. Histochemical analysis showed an age-dependent reduction in cytochrome c oxidase (COX) activity, suggesting a mitochondrial dysfunction in the 9+A30P group. A deficit in COX IV expression was confirmed by immunohistochemistry. Overall, our data demonstrate an age-dependent impairment in mitochondrial function and gamma frequency activity associated with the abnormal expression of α-syn. These findings provide mechanistic insights into the consequences of over-expression of α-syn which might contribute to cognitive decline.

Attitudes toward antipsychotic medication: the impact of clinical variables and relationships with health professionals.

CONTEXT: Nonadherence to antipsychotic medication is a major cause of psychotic relapse and is strongly influenced by attitudes toward treatment. Although patient variables such as insight and symptoms that contribute toward attitudes have been identified, the contributions of relationship and service factors have not been adequately studied. OBJECTIVE: To determine relations between clinical and service variables and attitudes toward medication in people with a diagnosis of schizophrenia and schizoaffective disorder. DESIGN: Consecutively admitted patients were approached to take part; 23 refused. Measures included symptoms, insight, drug adverse effects, self-reported adherence, attitudes toward treatment, perceived relationship with the prescriber, ward atmosphere, and admission experience. Data were analyzed by a proportional odds model and structural equation modeling to test predicted paths between experience of admission, relationship variables, attitudes toward treatment, and self-reported adherence to medication. SETTING: Twenty-eight inpatient wards at 8 hospitals in North Wales and the Northwest of England. Sites included hospitals with inner-city and rural catchment areas. Patients Two hundred twenty-eight patients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder, assessed during acute admission. MAIN OUTCOME MEASURES: Attitudes toward treatment and self-reported adherence to medication. RESULTS: The data fit a model in which attitudes toward treatment were predicted by insight, relationship with staff (especially the physician-prescriber), and the patient's admission experience (maximum likelihood chi(2)(49) = 89.3, P<.001). A poor relationship with the prescriber, experience of coercion during admission, and low insight predicted a negative attitude toward treatment. CONCLUSIONS: The quality of relationships with clinicians during acute admission appears to be an important determinant of patients' attitudes toward treatment and adherence to medication. Enhancing such relationships may yield important clinical benefits.

A framework for making advance decisions on resuscitation.

Decisions about cardiopulmonary resuscitation (CPR) continue to cause difficulties for healthcare professionals. Current UK guidelines provide information on the underlying principles, but do not include a clear decision framework. The resulting confusion about when and who to ask about CPR can result in an inappropriate burden being placed on patients, partners or families. A simple clinical decision framework is presented, together with the underlying principles. This framework is offered as an aid for clinicians and patients in understanding the current ethical, clinical and legal guidance on decisions about CPR.

Delusional discourse: an investigation comparing the spontaneous causal attributions of paranoid and non-paranoid individuals.

Research into the nature of attributional reasoning in paranoia has for the most part been restricted to questionnaire-based approaches. This fails to address the issue of whether a distinctive attributional style underpins the everyday talk of paranoid individuals. This study aimed to investigate whether attributional models of paranoid delusions applied to spontaneous attributions generated in the discourse of 12 paranoid and 12 non-paranoid speakers. Causal attributions for negative and positive life experiences were extracted from interview transcripts and rated using the Content Analysis of Verbatim Explanations (CAVE) technique. It was found that, as a proportion, paranoids made more attributions for negative events that were of an external-personal, stable and global nature (as attributional models would predict). They also made significantly more external-personal attributions for negative events and, in one of two datasets, showed a more external mean CAVE rating for negative events than the non-paranoid controls. This paper highlights important issues underlying the extraction of attributions from paranoid talk, and discusses the implications for attributional models of paranoia and future discourse-based research in this area.

Advance care planning: ethical and clinical implications for hospital medicine.

Advance care planning takes place 'in advance of' anticipated loss of capacity with the aim of informing the best interests judgments required when capacity is later lost. It is an ethically and clinically distinct subset of general care planning.

The corticostriatal system in dissociated cell culture.

The sparse connectivity within the striatum in vivo makes the investigation of individual corticostriatal synapses very difficult. Most studies of the corticostriatal input have been done using electrical stimulation under conditions where it is hard to identify the precise origin of the cortical input. We have employed an in vitro dissociated cell culture system that allows the identification of individual corticostriatal pairs and have been developing methods to study individual neuron inputs to striatal neurons. In mixed corticostriatal cultures, neurons had resting activity similar to the system in vivo. Up/down states were obvious and seemed to encompass the entire culture. Mixed cultures of cortical neurons from transgenic mice expressing green fluorescent protein with striatal neurons from wild-type mice of the same developmental stage allowed visual identification of individual candidate corticostriatal pairs. Recordings were performed between 12 and 37 days in vitro (DIV). To investigate synaptic connections we recorded from 69 corticostriatal pairs of which 44 were connected in one direction and 25 reciprocally. Of these connections 41 were corticostriatal (nine inhibitory) and 53 striatocortical (all inhibitory). The observed excitatory responses were of variable amplitude (-10 to -370 pA, n = 32). We found the connections very secure - with negligible failures on repeated stimulation (approximately 1 Hz) of the cortical neuron. Inhibitory corticostriatal responses were also observed (-13 to -314 pA, n = 9). Possibly due to the mixed type of culture we found an inhibitory striatocortical response (-14 to -598 pA, n = 53). We are now recording from neurons in separate compartments to more closely emulate neuroanatomical conditions but still with the possibility of the easier identification of the connectivity.

The ethical basis of making decisions about cardiopulmonary resuscitation.

This article outlines the clinical ethical concerns around decision making regarding cardiopulmonary resuscitation and how they resulted from lack of clarity in the formulation of the previous guidance. It then reviews new guidance and discusses its wider implications for doctors and patients.

Patients' understanding and participation in a trial designed to improve the management of anti-psychotic medication: a qualitative study.

BACKGROUND: Combining qualitative methods alongside randomised controlled trials in the health field has been advocated but has only been used rarely in mental health services research. The aim of this study was to illuminate patients' understanding of the nature and purpose and outcomes of a trial designed to improve the management of neuroleptic medication. METHODS: Qualitative interviews were carried out with a group of patients participating in a trial comparing a psycho-educational and therapeutic alliance intervention in managing anti-psychotic medication. RESULTS: Our findings highlighted aspects of the experience, process and outcome of the trial, which remain latent in the quantitative assessment. The issue of enlarged selfefficacy emerging when patients were involved in communications with professionals in the trial was important. Whilst the participants provided positive feedback about their involvement in the trial, they struggled to recall the details of the intervention to which they had been exposed. Patients did not readily identify the content and concepts characterising each condition; rather they prioritised the opportunity for communication and contact with the researchers. CONCLUSIONS: Qualitative research accompanying trials illuminates and adds to the quantitative outcomes. The key to interpreting participants' accounts of the process and outcomes of this trial suggests the need to give greater emphasis to participants' past and current experience of service contact.

Attention, theory of mind, and causal attributions in people with persecutory delusions: A preliminary investigation.

INTRODUCTION: Abnormal attributions and deficits in theory of mind (ToM) skills have been implicated in paranoid delusions. Bentall and Kinderman (1998) have proposed that ToM deficits tend to prevent individuals from making situational attributions and therefore increase the probability of external-personal attributions, which in turn lead to paranoid beliefs. They further suggested that more fundamental information-processing deficits, by affecting theory of mind skills, increase the probability of paranoid attributions. METHODS: Relationships between attention, ToM and attributions were assessed in acute and remitted paranoid patients and normal controls. Participants performed the digit span with distraction task, false belief and deception tasks, and a measure of attributional style. RESULTS: Compared to the controls, acute patients were distractible, performed poorly on ToM, and made more attributions that were judged external-personal by independent raters (but not as judged by self-ratings). ToM scores predicted the number of external-personal attributions as expected, but the effect of distraction on ToM was equivocal. CONCLUSIONS: Preliminary support was found for the hypotheses, but further studies are required using a range of executive, attentional, ToM, and attribution measures.