The ventromedial prefrontal cortex and emotion regulation: lost in translation?

Neuroimaging studies implicate the ventromedial prefrontal cortex (vmPFC) in a wide range of emotional and cognitive functions, and changes in activity within vmPFC have been linked to the aetiology and successful treatment of depression. However, this is a large, structurally heterogeneous region and the extent to which this structural heterogeneity reflects functional heterogeneity remains unclear. Causal studies in animals should help address this question but attempts to map findings from vmPFC studies in rodents onto human imaging studies highlight cross-species discrepancies between structural homology and functional analogy. Bridging this gap, recent studies in marmosets - a species of new world monkey in which the overall organization of vmPFC is more like humans than that of rodents - have revealed that over-activation of the caudal subcallosal region of vmPFC, area 25, but not neighbouring area 32, heightens reactivity to negatively valenced stimuli whilst blunting responsivity to positively valenced stimuli. These co-occurring states resemble those seen in depressed patients, which are associated with increased activity in caudal subcallosal regions. In contrast, only reward blunting but not heightening of threat reactivity is seen following over-activation of the structurally homologous region in rodents. To further advance understanding of the role of vmPFC in the aetiology and treatment of depression, future work should focus on the behaviourally specific networks by which vmPFC regions have their effects, together with characterization of cross-species similarities and differences in function.

Is there a 'bipolar iceberg' in UK primary care psychological therapy services?

BACKGROUND: Improving Access to Psychological Therapies (IAPT) is a primary care therapy service commissioned by England's National Health Service (NHS) for people with unipolar depression and anxiety-related disorders. Its scope does not extend to 'severe mental illness', including bipolar disorders (BD), but evidence suggests there is a high BD prevalence in ostensibly unipolar major depressive disorder (uMDD) samples. This study aimed to indicate the prevalence and characteristics of people with BD in a naturalistic cohort of IAPT patients. METHODS: 371 participants were assessed before initiating therapy. Participants were categorised by indicated diagnoses: BD type-I (BD-I) or type-II (BD-II) as defined using a DSM diagnostic interview, bipolar spectrum (BSp, not meeting diagnostic criteria but exceeding BD screening thresholds), lifetime uMDD or other. Information about psychiatric history and co-morbidities was examined, along with symptoms before and after therapy. RESULTS: 368 patients provided sufficient data to enable classification. 10% of participants were grouped as having BD-I, 20% BD-II, 40% BSp, 25% uMDD and 5% other. BD and uMDD participants had similar demographic characteristics, but patients meeting criteria for BD-I/BD-II had more complex psychiatric presentations. All three 'bipolar' groups had particularly high rates of anxiety disorders. IAPT therapy receipt was comparable between groups, as was therapy response (F9704 = 1.113, p = 0.351). CONCLUSIONS: Notwithstanding the possibility that bipolar diathesis was overestimated, findings illustrate a high prevalence of BD in groups of people notionally with uMDD or anxiety. As well as improving the detection of BD, further substantive investigation is required to establish whether individuals affected by BD should be eligible for primary care psychological intervention.

Examining medical student volunteering during the COVID-19 pandemic as a prosocial behaviour during an emergency.

PURPOSE: Understanding the factors that influence prosocial behaviour during the COVID-19 pandemic is essential due to the disruption to healthcare provision. METHODS: We conducted an in-depth, mixed-methods cross-sectional survey, from 2 May 2020 to 15 June 2020, of medical students at medical schools in the United Kingdom. Data analysis was informed by Latané and Darley's theory of prosocial behaviour during an emergency. RESULTS: A total of 1145 medical students from 36 medical schools responded. Although 947 (82.7%) of students were willing to volunteer, only 391 (34.3%) had volunteered. Of the students, 92.7% understood they may be asked to volunteer; however, we found deciding one's responsibility to volunteer was mitigated by a complex interaction between the interests of others and self-interest. Further, concerns revolving around professional role boundaries influenced students' decisions over whether they had the required skills and knowledge. CONCLUSION: We propose two additional domains to Latané and Darley's theory that medical students consider before making their final decision to volunteer: 'logistics' and 'safety'. We highlight modifiable barriers to prosocial behaviour and provide suggestions regarding how the conceptual framework can be operationalized within educational strategies to address these barriers. Optimizing the process of volunteering can aid healthcare provision and may facilitate a safer volunteering process. Key messages  What is already known on this topic: There is a discrepancy between the number of students willing to volunteer during pandemics and disasters, and those who actually volunteer. Understanding the factors that influence prosocial behaviour during the current COVID-19 pandemic and future pandemics and disasters is essential. What this study adds: We expanded on Latané and Darley's theory of prosocial behaviour in an emergency and used this to conceptualize students' motivations to volunteer, highlighting a number of modifiable barriers to prosocial behaviour during the COVID-19 pandemic. How this study might affect research, practice, or policy: We provide suggestions regarding how the conceptual framework can be operationalized to support prosocial behaviours during emergencies for the ongoing COVID-19 pandemic and future crises.

Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset.

The ventromedial prefrontal cortex (vmPFC) is a key brain structure implicated in mood and anxiety disorders, based primarily on evidence from correlational neuroimaging studies. Composed of a number of brain regions with distinct architecture and connectivity, dissecting its functional heterogeneity will provide key insights into the symptomatology of these disorders. Focusing on area 14, lying on the medial and orbital surfaces of the gyrus rectus, this study addresses a key question of causality. Do changes in area 14 activity induce changes in threat- and reward-elicited responses within the nonhuman primate, the common marmoset, similar to that seen in mood and anxiety disorders? Area 14 overactivation was found to induce heightened responsivity to uncertain, low-imminence threat while blunting cardiovascular and behavioral anticipatory arousal to high-value food reward. Conversely, inactivation enhanced the arousal to high-value reward cues while dampening the acquisition of cardiovascular and behavioral responses to a Pavlovian threat cue. Basal cardiovascular activity, including heart rate variability and sympathovagal balance, which are dysfunctional in mood and anxiety disorders, are insensitive to alterations in area 14 activity as is the extinction of conditioned threat responses. The distinct pattern of dysregulation compared to neighboring region area 25 highlights the heterogeneity of function within vmPFC and reveals how the effects of area 14 overactivation on positive and negative reactivity mirror symptoms of anhedonia and anxiety that are so often comorbid in mood disorders.

Clinical support during COVID-19: An opportunity for service and learning? A cross-sectional survey of UK medical students.

PURPOSE: Medical students providing support to clinical teams during Covid-19 may have been an opportunity for service and learning. We aimed to understand why the reported educational impact has been mixed to inform future placements. METHODS: We conducted a cross-sectional survey of medical students at UK medical schools during the first Covid-19 'lockdown' period in the UK (March-July 2020). Analysis was informed by the conceptual framework of service and learning. RESULTS: 1245 medical students from 37 UK medical schools responded. 57% of respondents provided clinical support across a variety of roles and reported benefits including increased preparedness for foundation year one compared to those who did not (p < 0.0001). However, not every individual's experience was equal. For some, roles complemented the curriculum and provided opportunities for clinical skill development, reflection, and meaningful contribution to the health service. For others, the relevance of their role to their education was limited; these roles typically focused on service provision, with few opportunities to develop. CONCLUSION: The conceptual framework of service and learning can help explain why student experiences have been heterogeneous. We highlight how this conceptual framework can be used to inform clinical placements in the future, in particular the risks, benefits, and structures.[Box: see text].

COVIDReady2 study protocol: cross-sectional survey of medical student volunteering and education during the COVID-19 pandemic in the United Kingdom.

BACKGROUND: The coronavirus disease 2019 pandemic has led to global disruption of healthcare. Many students volunteered to provide clinical support. Volunteering to work in a clinical capacity was a unique medical education opportunity; however, it is unknown whether this was a positive learning experience or which volunteering roles were of most benefit to students. METHODS: The COVIDReady2 study is a national cross-sectional study of all medical students at medical schools in the United Kingdom. The primary outcome is to explore the experiences of medical students who volunteered during the pandemic in comparison to those who did not. We will compare responses to determine the educational benefit and issues they faced. In addition to quantitative analysis, thematic analysis will be used to identify themes in qualitative responses. DISCUSSION: There is a growing body of evidence to suggest that service roles have potential to enhance medical education; yet, there is a shortage of studies able to offer practical advice for how these roles may be incorporated in future medical education. We anticipate that this study will help to identify volunteer structures that have been beneficial for students, so that similar infrastructures can be used in the future, and help inform medical education in a non-pandemic setting. TRIAL REGISTRATION: Not Applicable.

Systematic review of medical student willingness to volunteer and preparedness for pandemics and disasters.

OBJECTIVE: This systematic review aimed to estimate the willingness of students to volunteer during a disaster, and how well-prepared medical students are for volunteering by assessing their knowledge and medical school curriculum of disaster and pandemic medicine. RESULTS: A total of 37 studies met inclusion criteria including 11 168 medical students and 91 medical schools. 24 studies evaluated knowledge (64.9%), 16 evaluated volunteering (43.2%) and 5 evaluated medical school curricula (13.5%). Weighted mean willingness to volunteer during a disaster was 68.4% (SD=21.7%, range=26.7%-87.8%, n=2911), and there was a significant difference between those planning to volunteer and those who actually volunteered (p<0.0001). We identified a number of modifiable barriers which may contribute to this heterogeneity. Overall, knowledge of disasters was poor with a weighted mean of 48.9% (SD=15.1%, range=37.1%-87.0%, n=2985). 36.8% of 76 medical schools curricula included teaching on disasters. However, students only received minimal teaching (2-6 hours). CONCLUSIONS: This study demonstrates that there is a large number of students who are willing to volunteer during pandemics. However, they are unlikely to be prepared for these roles as overall knowledge is poor, and this is likely due to minimal teaching on disasters at medical school. During the current COVID-19 pandemic and in future disasters, medical students may be required to volunteer as auxiliary staff. There is a need to develop infrastructure to facilitate this process as well as providing education and training to ensure students are adequately prepared to perform these roles safely.

Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety.

High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studies of high-trait anxiety reveals dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp) and rodent studies reveal the importance of aHipp glutamatergic hypofunction, the causal involvement of aHipp glutamate and its interaction with these areas in the primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety.SIGNIFICANCE STATEMENT High-trait anxiety predisposes sufferers to the development of anxiety and depression. Although neuroimaging of these disorders and rodent modeling implicate dysregulation in hippocampal glutamate and the subgenual/perigenual cingulate cortices (areas 25/32), the causal involvement of these structures in endogenous high-trait anxiety and their interaction are unknown. Here, we demonstrate that increased trait anxiety in marmoset monkeys correlates with reduced hippocampal glutamate and that increasing hippocampal glutamate release in high-trait-anxious monkeys normalizes the aberrant behavioral and cardiovascular responsivity to potential threats. This normalization was blocked by simultaneous inactivation of area 25, but not area 32. These findings provide casual evidence in primates that hippocampal glutamatergic hypofunction regulates endogenous high-trait anxiety and the hippocampal-area 25 circuit is a potential therapeutic target.

Opposing roles of primate areas 25 and 32 and their putative rodent homologs in the regulation of negative emotion.

Disorders of dysregulated negative emotion such as depression and anxiety also feature increased cardiovascular mortality and decreased heart-rate variability (HRV). These disorders are correlated with dysfunction within areas 25 and 32 of the ventromedial prefrontal cortex (vmPFC), but a causal relationship between dysregulation of these areas and such symptoms has not been demonstrated. Furthermore, cross-species translation is limited by inconsistent findings between rodent fear extinction and human neuroimaging studies of negative emotion. To reconcile these literatures, we applied an investigative approach to the brain-body interactions at the core of negative emotional dysregulation. We show that, in marmoset monkeys (a nonhuman primate that has far greater vmPFC homology to humans than rodents), areas 25 and 32 have causal yet opposing roles in regulating the cardiovascular and behavioral correlates of negative emotion. In novel Pavlovian fear conditioning and extinction paradigms, pharmacological inactivation of area 25 decreased the autonomic and behavioral correlates of negative emotion expectation, whereas inactivation of area 32 increased them via generalization. Area 25 inactivation also increased resting HRV. These findings are inconsistent with current theories of rodent/primate prefrontal functional similarity, and provide insight into the role of these brain regions in affective disorders. They demonstrate that area 32 hypoactivity causes behavioral generalization relevant to anxiety, and that area 25 is a causal node governing the emotional and cardiovascular symptomatology relevant to anxiety and depression.

A transdiagnostic systematic review and meta-analysis of ketamine's anxiolytic effects.

BACKGROUND: Ketamine may be effective in treating symptoms of anxiety, but the time profile of ketamine's anxiolytic effect is ill-defined. This systematic review and meta-analysis investigated the anxiolytic effect of ketamine at different time points across a range of clinical settings. METHODS: Electronic databases were searched to capture randomised control trials measuring the anxiolytic effects of ketamine in contexts including mood disorders, anxiety disorders and chronic pain. Meta-analyses were conducted using a random-effects model. The correlations between (1) improvements in mean anxiety and depression scores, and (2) peak dissociation and improvements in mean anxiety scores were also assessed. RESULTS: In all, 14 studies met inclusion criteria. Risk of bias was high in 11 studies. Ketamine significantly reduced anxiety scores compared to placebo at acute (<12 h; standard mean difference (SMD): -1.17, 95% confidence interval (CI) [-1.89, -0.44], p < 0.01), subacute (24 h; SMD: -0.44, 95% CI [-0.65, -0.22], p < 0.01) and sustained (7-14 days; SMD: -0.40, 95% CI [-0.63, -0.17], p < 0.01) time points. Exploratory analyses revealed improvements in anxiety and depression symptoms correlated at both subacute (R2 = 0.621, p = 0.035) and sustained time points (R2 = 0.773, p = 0.021). The relationship between peak dissociation and improvement in anxiety was not significant. CONCLUSIONS: Ketamine appears to offer rapid and sustained anxiety symptom relief across a range of clinical settings, with anxiolytic effects occurring within the first 12 h of administration and remaining effective for 1-2 weeks. Future studies could explore the effects of ketamine maintenance therapy on anxiety symptoms.

Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals.

Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine's effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine's antidepressant and anti-anhedonic action.

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets.

Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies.

The anterior cingulate cortex as a key locus of ketamine's antidepressant action.

The subdivisions of the anterior cingulate cortex (ACC) - including subgenual, perigenual and dorsal zones - are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine's anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine's action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network.

Quantifying anhedonia-like symptoms in marmosets using appetitive Pavlovian conditioning.

Blunted reward responsivity is associated with anhedonia in humans and is a core feature of depression. This protocol describes how to train the common marmoset, Callithrix jacchus, on an appetitive Pavlovian conditioning paradigm to measure behavioral and cardiovascular correlates of anticipatory and consummatory phases of reward processing. We describe how to use intracerebral infusions to manipulate brain regions whose activity is relevant to impaired reward processing in depression and how the paradigm can be used to test antidepressant efficacy. For complete details on the use and execution of this protocol, please refer to Alexander et al. (2019).

All hands on deck: early graduation of senior medical students in the COVID-19 pandemic.

This article was migrated. The article was marked as recommended. During the COVID-19 pandemic, early graduation of senior medical students simultaneously offers useful clinical experience in preparation for junior doctor posts, whilst helping address staffing shortages due to illness or self-isolation. Having recently graduated early from medical school, we offer our reflections on the obstacles and opportunities associated with working in an uncharted clinical environment. We are not the only ones on a steep learning curve at this time: this pandemic will challenge and provide learning for staff of all levels.

Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat.

Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat. 18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threat contrary to the beneficial effects we have previously demonstrated on over-activation induced reward blunting, illustrating the symptom-specificity of its actions.

A Focus on the Functions of Area 25.

Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the similarities between area 25 function in monkeys and IL function in rodents with respect to the regulation of reward-driven responses, but also the apparent inconsistencies in the regulation of threat responses, not only between the rodent and monkey literatures, but also within the rodent literature. Overall, we provide evidence for a causal role of area 25 in both the enhanced negative affect and decreased positive affect that is characteristic of affective disorders, and the cardiovascular and endocrine perturbations that accompany these mood changes. We end with a brief consideration of how future studies should be tailored to best translate these findings into the clinic.

Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex.

Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. 18F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine's modulation of an affective network to exert its action.