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The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19-49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed us-ing computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task ( t = 2.50, p = 0.02, d =-0.59), indicating that subjects on istradefylline interpreted social situations more positively. No other significant effects were observed on other cognitive tasks, nor in terms of cardiovascular measures (pulse and blood pressure). De-briefing indicated that blinding was successful, both for participants and the research team. Further exploration of the role of adenosine A2A receptors in emotional pro-cessing may be valuable, given that abnormalities in related cognitive functions are implicated in neuropsychiatric disorders. The role of adenosine systems in human cognition requires fur-ther clarification, including with different doses of istradefylline and over different schedules of administration.(c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Contains fulltext : 247514.pdf (Publisher’s version ) (Closed access) Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n = 35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomised, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms. 10 p.

AimsBackground and Aim: Psychodynamic psychiatry training seminars are a blended supervision and experiential style approach to training health care professionals in reflective practice and formulation. They apply psychodynamic theory through case formulations, seminars, and Balint groups so that health care staff can improve their communication style, formulation skills and enhance their appreciation for patients with complex mental health problems. Our aim is to evaluate the provision of our psychodynamic psychiatry training sessions for doctors in psychiatry, gastroenterology, and emergency medicine, and to evaluate the perceived benefits of attending in terms of personal and professional development.MethodsMethods: The evaluation used a standardized mixed-methods approach, with the sample consisting of psychiatry core trainees (n = 9), gastroenterology higher trainees (n = 4), and emergency medicine doctors (n = 10). The evaluation period was between October 2021 and January 2022. Data were gathered via a survey tool, adapted from the literature using Likert scales and free text questions to identify barriers and facilitators to the sessions.ResultsResults: All participants (n = 23) scored the group highly across the board in terms of acceptability, clinical impact, and fidelity measures. All participants reported that they have a better appreciation of group dynamics, the impact of the doctor's humanity and personality on their clinical work, and the symbolic meaning of the patient's symptoms. Notably, approximately 60% reported that the sessions were relevant to their ongoing training needs and that 95% of participants felt the sessions were a safe place to express and process anxieties and frustrations about their work. All participants either agreed or strongly agreed the group had changed the way they think and practice, and that they felt able to consider their clinical encounters in a new light.ConclusionConclusion: This evaluation reports early findings on psychodynamic psychiatry teaching for different medical groups. Overall, the participants felt the sessions were relevant to their training and improved their personal and professional development. Key benefits of the group were highlighted and included increased insight into the emotional and symbolic aspects of the patient's symptoms and clinical issues, team working through cohesion, and the humanity of the doctor in the clinical relationship with the patient. This suggests that the sessions provide a much-needed space to process and reflect on the often-intense demands of clinical work, individually and as a team. The main theme within barriers to the group processes was external in terms of other clinical demands requiring prioritization.

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n = 35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomised, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. Shackman and colleagues proposed this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral Anterior Cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy controls. Using the Ekman 60 Faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received Anterior Cingulotomy were impaired in recognising negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with hypotheses, we found that larger volume lesions predicted more impairment in recognising fear, disgust and anger, and no impairment in recognising facial expressions of surprise or happiness. However we found no impairment in recognising expressions of sadness. Also consistent with hypotheses, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman and colleague’s meta-analysis derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimising behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. Whilst the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes. Postprint

Our series on Prescribing challenges focuses on areas of therapeutics that can present a particular challenge in general practice. Here, the author considers the management options in treatment-refractory depression. Copyright © 2011 Wiley Interface Ltd

Background: The evidence base to guide therapeutic choices for patients with chronic and treatment-refractory depression (TRD) remains weak. There is limited comparative information available to guide the choice of intervention for patients with the most severe and disabling forms of illness. Objectives: The aim of this work was to describe the 12-month clinical outcomes of patients with chronic TRD treated with anterior capsulotomy (ACAPS; n = 5), anterior cingulotomy (ACING; n = 5) or vagus nerve stimulation (VNS; n = 5). Methods: We performed a retrospective, consecutive, case series comparison. Results: With clinical response defined as a ≥50% reduction from the baseline MADRS score, response rates were 40% for ACAPS, 60% for ACING and 20% for VNS. Adverse effects from all three procedures were relatively mild, consistent with previous reports and, in most cases, transient. Adverse effects from VNS were related to active stimulation, and were modifiable and diminished in severity over time. There were no deaths. Conclusions: Although based on a small sample, our data represent a unique comparison of ACAPS, ACING and VNS for chronic TRD. The three cohorts were broadly equivalent in terms of baseline clinical characteristics, indices of chronicity, illness severity and estimates of previous failed treatments. ACING and ACAPS, but not VNS, were associated with favourable response rates at 12 months.

The authors review contemporary indications for neurosurgical interventions in the management of chronic and refractory mental disorder, the procedures involved, their efficacy and known adverse effects. These data are presented within the context of a brief historical overview of the use of neurosurgery for mental disorder. In addition to a consideration of neurosurgical procedures that rely on the creation of putative therapeutic lesions, we also review two novel, non-destructive neurosurgical electrostimulation treatments that may represent viable alternatives to conventional ablative neurosurgery: vagus nerve stimulation and deep brain stimulation.

Many people might be confused about the term ‘placebo’ that is used in Baxendale et al ’s study.[1][1] The paper clearly refers to the low-intensity-light arm as receiving placebo treatment, and the clinical trial registration ([http://clinicaltrials.gov/show/[NCT01028456][3]][3]) also

International audience; Background: There is very limited evidence for the efficacy of any specific therapeutic intervention in chronic, treatment-refractory, Major Depression. Thermal Anterior Capsulotomy (ACAPS) is a rarely-performed but established therapeutic procedure for this patient group. Whilst benefit has been claimed, previous ACAPS reports have provided limited information. Detailed prospective reporting of therapeutic effects and side-effects is required. Objective: To report a prospective study of therapeutic effect, mental status, quality of life, social functioning, and neurocognitive functioning in individuals with chronic treatment-refractory Major Depression, treated with ACAPS. Method: A prospective case series of 20 patients treated by ACAPS between 1992 and 1999 were reassessed at a mean follow-up of 7.0 ± 3.4 years. Data were collected preoperatively and at long-term follow-up. Structural magnetic resonance imaging was performed in 14 participants. Results: According to a priori criteria, at long-term follow-up, 50% were classified as 'responders', 40% as 'remitters'. Fifty-five percent were classified as 'improved'; 35% were 'unchanged'; and 10% had 'deteriorated'. Neurocognitive and personality testing were not significantly different at follow up. A trend towards improvement in some aspects of executive neuropsychological functioning was observed. Significant adverse effects were infrequent and there were no deaths. Conclusions: ACAPS may represent an effective intervention for some patients with chronic, disabling, treatment-refractory Major Depression that has failed to respond to other therapeutic approaches. The adverse effect burden within this population was modest, with no evidence of generalised impairment of neurocognitive functioning.

One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms. Some of the previous studies of vagus nerve stimulation (VNS) have suggested antidepressant effects. Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant reduction (Por = 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score, the primary outcome measure. After 2 years, 53.1% (26/49) of the patients fulfilled the response criteria (or =50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scoresor = 10). The proportion of patients who fulfilled the remission criteria remained constant as the duration of VNS treatment increased. Voice alteration, cough, and pain were the most frequently reported adverse effects. Two patients committed suicide during the study; no other deaths were reported. No statistically significant differences were seen in the number of concomitant antidepressant medications. The results of this 2-year open-label trial suggest a clinical response and a comparatively benign adverse effect profile among patients with treatment-resistant depression.

BackgroundVagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression.MethodAn open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically.ResultsThe baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (⩾50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score ConclusionsVNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

Four patients that had received an anterior cingulotomy (ACING) and five patients that had received both an ACING and an anterior capsulotomy (ACAPS) as an intervention for chronic, treatment refractory depression were presented with a series of dynamic emotional stimuli and invited to identify the emotion portrayed. Their performance was compared with that of a group of non-surgically treated patients with major depression (n = 17) and with a group of matched, never-depressed controls (n = 22). At the time of testing, four of the nine neurosurgery patients had recovered from their depressive episode, whereas five remained depressed. Analysis of emotion recognition accuracy revealed no significant differences between depressed and non-depressed neurosurgically treated patients. Similarly, no significant differences were observed between the patients treated with ACING alone and those treated with both ACING and ACAPS. Comparison of the emotion recognition accuracy of the neurosurgically treated patients and the depressed and healthy control groups revealed that the surgically treated patients exhibited a general impairment in their recognition accuracy compared to healthy controls. Regression analysis revealed that participants' emotion recognition accuracy was predicted by the number of errors they made on the Stroop colour-naming task. It is plausible that the observed deficit in emotion recognition accuracy was a consequence of impaired attentional control, which may have been a result of the surgical lesions to the anterior cingulate cortex. © 2007 Elsevier Ltd. All rights reserved.

The application of machine learning techniques to psychiatric neuroimaging offers the possibility to identify robust, reliable and objective disease biomarkers both within and between contemporary syndromal diagnoses that could guide routine clinical practice. The use of quantitative methods to identify psychiatric biomarkers is consequently important, particularly with a view to making predictions relevant to individual patients, rather than at a group-level. Here, we describe predictions of treatment-refractory depression (TRD) diagnosis using structural T1-weighted brain scans obtained from twenty adult participants with TRD and 21 never depressed controls. We report 85% accuracy of individual subject diagnostic prediction. Using an automated feature selection method, the major brain regions supporting this significant classification were in the caudate, insula, habenula and periventricular grey matter. It was not, however, possible to predict the degree of 'treatment resistance' in individual patients, at least as quantified by the Massachusetts General Hospital (MGH-S) clinical staging method; but the insula was again identified as a region of interest. Structural brain imaging data alone can be used to predict diagnostic status, but not MGH-S staging, with a high degree of accuracy in patients with TRD.

Dr Persaud provides an ardent but ultimately flawed argument in favour of allowing neurosurgery for mental disorder (NMD) to die out ([Persaud/Crossley & Freeman, 2003][1]). Patients who are considered for NMD are among the most severely ill and disabled who come into contact with any branch of the