Neuronal activity patterns in the mediodorsal thalamus and related cognitive circuits are modulated by metabotropic glutamate receptors.

The mediodorsal thalamus (MD) likely plays an important role in cognition as it receives abundant afferent connections from the amygdala and prefrontal cortex (PFC). Indeed, disturbed activity within the MD is thought to precipitate cognitive deficits associated with schizophrenia. As compounds acting at the Group II metabotropic glutamate (mGlu) receptors (subtypes mGlu2/mGlu3) have efficacy in animal models of schizophrenia, we investigated whether a Group II agonist and an mGlu2 positive allosteric modulator (PAM) could modulate MD activity. Extracellular single-unit recordings were made in vivo from MD neurones in anaesthetised rats. Responses were elicited by electrical stimulation of the PFC and/or amygdala, with Group II compounds locally applied as required. The Group II agonist reduced inhibition evoked in the MD: an effect manifested as an increase in short-latency responses, and a decrease in long-latency burst-firing. This disinhibitory action of the Group II receptors in the MD represents a mechanism of potential therapeutic importance as increased inhibition in the MD has been associated with cognitive deficit-onset. Furthermore, as co-application of the mGlu2 PAM did not potentiate the Group II agonist effects in the MD, we suggest that the Group II disinhibitory effect is majority-mediated via mGlu3. This heterogeneity in Group II receptor thalamic physiology bears consequence, as compounds active exclusively at the mGlu2 subtype are unlikely to perturb maladapted MD firing patterns associated with cognitive deficits, with activity at mGlu3 receptors possibly more appropriate. Indeed, polymorphisms in the mGlu3, but not the mGlu2, gene have been detected in patients with schizophrenia

Group II metabotropic glutamate receptor modulation of sensory responses in the ventrobasal thalamus

The functional integrity of the thalamic reticular nucleus (TRN) is thought to be key in the control of selective attention (Crick, 1984; Pinault, 2004). This GABAergic structure (Houser et al., 1980) is responsible for ensuring synchronous activity within the appropriate thalamocortical circuits required for either sensory perception or for the preparation and execution of distinct motor and/or cognitive tasks. It is therefore imperative to ascertain the exact nature of how inhibitory innervation from the TRN to thalamic nuclei is controlled in order to understand how neurophysiological disease states associated with TRN malfunction (Huguenard, 1999; Rub et al., 2003; Barbas and Zikopoulos, 2007; Pinault, 2011) precipitate. I t has been previously demonstrated that the Group II metabotropic glutamate receptors (mGlu2/3) can modulate physiologically-evoked responses in the VB (Salt and Turner, 1998) by reducing inhibition from the TR N (Turner and Salt, 2003). However, it is not yet known what the relative contributions are of the two subtypes to this modulation, nor to what extent these receptors may be activated under physiological conditions during this process. Using single-neurone recording in the rat ventrobasal thalamus (VB) in vivo with local iontophoretic application of selective Group II mGlu receptor compounds, my findings were threefold. Firstly, I found that both mGlu2 and mGlu3 receptors contribute a component to the overall Group II mGlu receptor effect on sensory responses in the VB. Secondly, I was able to demonstrate that both Group II mGlu receptor subtypes are likely activated by endogenous ‘glutamate spillover’ from the synapses formed between excitatory sensory afferents and VB neurones following physiological sensory stimulation, and that this can lead to a reduction in sensory-evoked inhibition arising from the TRN. I propose that this potential Group II mGlu receptor modulation of inhibition could play an important role in discerning relevant information from background activity upon physiological sensory stimulation: a novel mechanism that could be of importance in attention and cognitive processes, whose malfunction could result in maladaption of sensory perception, such as that which can occur in psychiatric disease. Thirdly, I was able to provide evidence that mGlu2 receptors are likely located on astrocytic processes surrounding the VB- TR N synapse, and are able to mediate a n a st rocyti c mechanism of action that reduces inhibitory synaptic transmission from the TRN to the VB. To the best of my knowledge this provides the first evidence that mGlu2 receptors are able to activate astrocytes, and of the involvement of astrocytes in the modulation of heterosynaptic transmission. As VB astrocytes are able to respond to synaptic stimulation (Parri et al., 2010), maladaption of mGlu2 receptor-mediated endogenous astrocytic activation may therefore have functional implications for the processing of somatosensory information and for the preparation and execution of distinct motor and/or cognitive tasks. Finally, I also investigated the action of the putative endogenous selective Group II mGlu receptor agonist Xanthurenic Acid (XA), which is a metabolite of the kynurenine pathway. Changes in both of these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders, however little is known regarding the mechanism of action of XA. I therefore investigated the effects of XA in modulating inhibition in the VB from the TRN using the same in vivo electrophysiology preparation as described above, and also evaluated the ability of XA to bind to and activate mGlu2 receptors using in vitro molecular pharmacological methods. Selective Group II mGlu receptor compounds that exploit this novel mechanism of endogenous activation may therefore be of importance in the modulation of sensory, attentional and cognitive processes for therapeutic strategies

An extension of the FRI framework for calcium transient detection

Two-photon calcium imaging of the brain allows the spatiotemporal activity of neuronal networks to be monitored at cellular resolution. In order to analyse this activity it must first be possible to detect, with high temporal resolution, spikes from the time series corresponding to single neurons. Previous work has shown that finite rate of innovation (FRI) theory can be used to reconstruct spike trains from noisy calcium imaging data. In this paper we extend the FRI framework for spike detection from calcium imaging data to encompass data generated by a larger class of calcium indicators, including the genetically encoded indicator GCaMP6s. Furthermore, we implement least squares model-order estimation and perform a noise reduction procedure ('pre-whitening') in order to increase the robustness of the algorithm. We demonstrate high spike detection performance on real data generated by GCaMP6s, detecting 90% of electrophysiologically-validated spikes

Opioid-related deaths during hospital admissions or shortly after discharge in the United Kingdom: A thematic framework analysis of coroner reports

BACKGROUND: People who use heroin and other illicit opioids are at high risk of fatal overdose in the days after hospital discharge, but the reasons for this risk have not been studied. METHODS: We used the National Programme on Substance Abuse Deaths, a database of coroner reports for deaths following psychoactive drug use in England, Wales, and Northern Ireland. We selected reports where the death occurred between 2010 and 2021, an opioid was detected in toxicology testing, the death was related to nonmedical opioid use, and death was either during an acute medical or psychiatric hospital admission or within 14 days after discharge. We used thematic framework analysis of factors that may contribute to the risk of death during hospital admission or after discharge. RESULTS: We identified 121 coroners’ reports; 42 where a patient died after using drugs during hospital admission, and 79 where death occurred shortly after discharge. The median age at death was 40 (IQR 34–46); 88 (73%) were male; and sedatives additional to opioids were detected at postmortem in 88 cases (73%), most commonly benzodiazepines. In thematic framework analysis, we categorised potential causes of fatal opioid overdose into three areas: (a) hospital policies and actions. Zero-tolerance policies mean that patients conceal drug use and use drugs in unsafe places such as locked bathrooms. Patients may be discharged to locations such as temporary hostels or the street while recovering. Some patients bring their own medicines or illicit opioids due to expectations of low-quality care, including undertreated withdrawal or pain; (b) high-risk use of sedatives. People may increase sedative use to manage symptoms of acute illness or a mental health crisis, and some may lose tolerance to opioids during a hospital admission; (c) declining health. Physical health and mobility problems posed barriers to post-discharge treatment for substance use, and some patients had sudden deteriorations in health that may have contributed to respiratory depression. CONCLUSION: Hospital admissions are associated with acute health crises that increase the risk of fatal overdose for patients who use illicit opioids. Hospitals need guidance to help them care for this patient group, particularly in relation to withdrawal management, harm reduction interventions such as take-home naloxone, discharge planning including continuation of opioid agonist therapy during recovery, management of poly-sedative use, and access to palliative care

Astrocytes modulate thalamic sensory processing via mGlu2 receptor activation.

Astrocytes possess many of the same signalling molecules as neurons. However, the role of astrocytes in information processing, if any, is unknown. Using electrophysiological and imaging methods, we report the first evidence that astrocytes modulate neuronal sensory inhibition in the rodent thalamus. We found that mGlu2 receptor activity reduces inhibitory transmission from the thalamic reticular nucleus to the somatosensory ventrobasal thalamus (VB): mIPSC frequencies in VB slices were reduced by the Group II mGlu receptor agonist LY354740, an effect potentiated by mGlu2 positive allosteric modulator (PAM) LY487379 co-application (30 nM LY354740: 10.0 ± 1.6% reduction; 30 nM LY354740 & 30 μM LY487379: 34.6 ± 5.2% reduction). We then showed activation of mGlu2 receptors on astrocytes: astrocytic intracellular calcium levels were elevated by the Group II agonist, which were further potentiated upon mGlu2 PAM co-application (300 nM LY354740: ratio amplitude 0.016 ± 0.002; 300 nM LY354740 & 30 μM LY487379: ratio amplitude 0.035 ± 0.003). We then demonstrated mGlu2-dependent astrocytic disinhibition of VB neurons in vivo: VB neuronal responses to vibrissae stimulation trains were disinhibited by the Group II agonist and the mGlu2 PAM (LY354740: 156 ± 12% of control; LY487379: 144 ± 10% of control). Presence of the glial inhibitor fluorocitrate abolished the mGlu2 PAM effect (91 ± 5% of control), suggesting the mGlu2 component to the Group II effect can be attributed to activation of mGlu2 receptors localised on astrocytic processes within the VB. Gating of thalamocortical function via astrocyte activation represents a novel sensory processing mechanism. As this thalamocortical circuitry is important in discriminative processes, this demonstrates the importance of astrocytes in synaptic processes underlying attention and cognition

Potentiation of sensory responses in ventrobasal thalamus in vivo via selective modulation of mGlu1 receptors with a positive allosteric modulator.

Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes

Methadone and buprenorphine-related deaths among people prescribed and not prescribed Opioid Agonist Therapy during the COVID-19 pandemic in England

BACKGROUND: The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths. METHODS: This was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System. RESULTS: We found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05). CONCLUSIONS: Methadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference

Factors associated with alcohol reduction in harmful and hazardous drinkers following alcohol brief intervention in Scotland: a qualitative enquiry

Background: Alcohol Brief Intervention (ABI) uses a motivational counselling approach to support individuals to reduce excessive alcohol consumption. There is growing evidence on ABI’s use within various health care settings, although how they work and which components enhance success is largely unknown. This paper reports on the qualitative part of a mixed methods study. It explores enablers and barriers associated with alcohol reduction following an ABI. It focuses on alcohol’s place within participants’ lives and their personal perspectives on reducing consumption. There are a number of randomised controlled trials in this field though few ABI studies have addressed the experiences of hazardous/harmful drinkers. This study examines factors associated with alcohol reduction in harmful/hazardous drinkers following ABI. Methods: This qualitative study was underpinned by a realist evaluation approach and involved semistructured interviews with ten harmful or hazardous alcohol drinkers. Participants (n = 10) were from the intervention arm of a randomised controlled trial (n = 124). All had received ABI, a 20 min motivational counselling interview, six months previously, and had reduced their alcohol consumption. Interviews were recorded, transcribed verbatim and thematically analysed. Results: Participants described their views on alcohol, its’ place in their lives, their personal perspectives on reducing their consumption and future aspirations. Conclusions: The findings provide an insight into participants’ views on alcohol, ABI, and the barriers and enablers to change. Participants described a cost benefit analysis, with some conscious consideration of the advantages and disadvantages of reducing intake or abstaining from alcohol. Findings suggest that, whilst hospital admission can act as a catalyst, encouraging individuals to reflect on their alcohol consumption through ABI may consolidate this, turning this reflective moment into action. Sustainability may be enhanced by the presence of a ‘significant other’ who encourages and experiences benefit. In addition having a purpose or structure with activities linked to employment and/or social and leisure pursuits offers the potential to enhance and sustain reduced alcohol consumption. Trial registration: Trial registration number TRN NCT00982306 September 22nd 200

Synthetic Cannabinoid-Related Deaths in England, 2012-2019.

Aim: To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Design: Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012-2019). Findings: One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; p<0.01), and lived in more deprived areas (p<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all p<0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). Conclusions: This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970–2010

Purpose Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. Methods We analyzed all available mean State–Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. Results Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. Conclusions Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys