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ABSTRACTPsychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the aetiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens ofGria1-/-mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons inGria1-/-mice. Furthermore, dopamine signals were initially similar inGria1-/-mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations inGria1-/-mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.
\n \n\n \n \nPharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3\u0394Fb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3\u0394Fb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3\u0394Fb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.
\n \n\n \n \nRATIONALE: Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation. OBJECTIVES: We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice. METHODS: Male mice received paroxetine (10\u00a0mg/kg/day, s.c.) for 12\u00a0days, then were swapped to saline injections for a 13\u00a0day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system. RESULTS: Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24\u00a0h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation. CONCLUSIONS: This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.
\n \n\n \n \nPurpose: To explore the utility of phosphorus magnetic resonance spectroscopy (31P MRS) in identifying anthracycline-induced cardiac toxicity in patients with breast cancer. Methods: Twenty patients with newly diagnosed breast cancer receiving anthracycline-based chemotherapy had cardiac magnetic resonance assessment of left ventricular ejection fraction (LVEF) and 31P MRS to determine myocardial Phosphocreatine/Adenosine Triphosphate Ratio (PCr/ATP) at three time points: pre-, mid-, and end-chemotherapy. Plasma high sensitivity cardiac troponin-I (cTn-I) tests and electrocardiograms were also performed at these same time points. Results: Phosphocreatine/Adenosine Triphosphate did not change significantly between pre- and mid-chemo (2.16 \u00b1 0.46 vs. 2.00 \u00b1 0.56, p = 0.80) and pre- and end-chemo (2.16 \u00b1 0.46 vs. 2.17 \u00b1 0.86, p = 0.99). Mean LVEF reduced significantly by 5.1% between pre- and end-chemo (61.4 \u00b1 4.4 vs. 56.3 \u00b1 8.1 %, p = 0.02). Change in PCr/ATP ratios from pre- to end-chemo correlated inversely with changes in LVEF over the same period (r = -0.65, p = 0.006). Plasma cTn-I increased progressively during chemotherapy from pre- to mid-chemo (1.35 \u00b1 0.81 to 4.40 \u00b1 2.64 ng/L; p = 0.01) and from mid- to end-chemo (4.40 \u00b1 2.64 to 18.33 \u00b1 13.23 ng/L; p = 0.001). Conclusions: In this small cohort pilot study, we did not observe a clear change in mean PCr/ATP values during chemotherapy despite evidence of increased plasma cardiac biomarkers and reduced LVEF. Future similar studies should be adequately powered to take account of patient drop-out and variable changes in PCr/ATP and could include T1 and T2 mapping.
\n \n\n \n \nBACKGROUND AND OBJECTIVES: Directional deep brain stimulation (DBS) electrodes are increasingly used, but conventional computed tomography (CT) is unable to directly image segmented contacts owing to physics-based resolution constraints. Postoperative electrode segment orientation assessment is necessary because of the possibility of significant deviation during or immediately after insertion. Photon-counting detector (PCD) CT is a relatively novel technology that enables high resolution imaging while addressing several limitations intrinsic to CT. We show how PCD CT can enable clear in\u00a0vivo imaging of DBS electrodes, including segmented contacts and markers for all major lead manufacturers. MATERIALS AND METHODS: We describe postoperative imaging and reconstruction protocols we have developed to enable optimal lead visualization. PCD CT images were obtained of directional leads from the three major manufacturers and fused with preoperative 3T magnetic resonance imaging (MRI). Radiation dosimetry also was evaluated and compared with conventional imaging controls. Orientation estimates from directly imaged leads were compared with validated software-based reconstructions (derived from standard CT imaging artifact analysis) to quantify congruence in alignment and directional orientation. RESULTS: High-fidelity images were obtained for 15 patients, clearly indicating the segmented contacts and directional markers both on CT alone and when fused to MRI. Our routine imaging protocol is described. Ionizing radiation doses were significantly lower than with conventional CT. For most leads, the directly imaged lead orientations and depths corresponded closely to those predicted by CT artifact-based reconstructions. However, unlike direct imaging, the software reconstructions were susceptible to 180\u00b0 error in orientation assessment. CONCLUSIONS: High-resolution photon-counting CT can very clearly image segmented DBS electrode contacts and directional markers and unambiguously determine lead orientation, with lower radiation than in conventional imaging. This obviates the need for further imaging and may facilitate anatomically tailored directional programming.
\n \n\n \n \nBACKGROUND: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. METHODS: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms \"stroke\", \"endovascular treatment\", \"intravenous thrombolysis\", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0\u00b782 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986. FINDINGS: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0\u00b789, 95% CI 0\u00b776-1\u00b704). Any intracranial haemorrhage (0\u00b782, 0\u00b768-0\u00b799) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly. INTERPRETATION: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment. FUNDING: Stryker and Amsterdam University Medical Centers, University of Amsterdam.
\n \n\n \n \nBACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. \u00a9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
\n \n\n \n \nTranscranial direct current stimulation (tDCS) can enhance motor and language rehabilitation after stroke. Though brain lesions distort tDCS-induced electric field (E-field), systematic accounts remain limited. Using electric field modelling, we investigated the effect of 630 synthetic lesions on E-field magnitude in the region of interest (ROI). Models were conducted for two tDCS montages targeting either primary motor cortex (M1) or Broca's area (BA44). Absolute E-field magnitude in the ROI differed by up to 42% compared to the non-lesioned brain depending on lesion size, lesion-ROI distance, and lesion conductivity value. Lesion location determined the sign of this difference: lesions in-line with the predominant direction of current increased E-field magnitude in the ROI, whereas lesions located in the opposite direction decreased E-field magnitude. We further explored how individualised tDCS can control lesion-induced effects on E-field. Lesions affected the individualised electrode configuration needed to maximise E-field magnitude in the ROI, but this effect was negligible when prioritising the maximisation of radial inward current. Lesions distorting tDCS-induced E-field, is likely to exacerbate inter-individual variability in E-field magnitude. Individualising electrode configuration and stimulator output can minimise lesion-induced variability but requires improved estimates of lesion conductivity. Individualised tDCS is critical to overcome E-field variability in lesioned brains.
\n \n\n \n \nFast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABAARs). Despite their fundamental role, it is still not known how GABAARs signal in the intact brain. Here, we use in\u00a0vivo gramicidin recordings to investigate synaptic GABAAR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anesthetized cortex, synaptic GABAARs exert classic hyperpolarizing effects. In contrast, GABAAR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABAAR equilibrium potentials (EGABAAR), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. Synaptic EGABAAR observed in awake cortex facilitates the desynchronizing effects of inhibitory inputs upon local networks, which increases the flexibility of spiking responses to external inputs. Our findings therefore suggest that GABAAR signaling adapts to optimize cortical functions.
\n \n\n \n \nBrain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on \"Best Practices & Tools for Diffusion MR Spectroscopy\" held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.
\n \n\n \n \nThe use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N\u2009=\u200978 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.
\n \n\n \n \nBACKGROUND: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients' clinical phenotypes and analyse the differential clinical course. METHODS: We performed a hierarchical cluster analysis based on Ward's Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. RESULTS: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients' prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5\u2009months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P < .001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27-3.62; HR 3.42, 95%CI 2.72-4.31; HR 2.79, 95%CI 2.32-3.35), and Cluster 1 (HR 1.88, 95%CI 1.48-2.38; HR 2.50, 95%CI 1.98-3.15; HR 2.09, 95%CI 1.74-2.51) reported a higher risk for the three outcomes respectively. CONCLUSIONS: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes.
\n \n\n \n \nBehavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, we tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition. Thirty-three participants with a syndrome associated with FTLD (15 patients with behavioural variant frontotemporal dementia and 18 with progressive supranuclear palsy, including both Richardson's syndrome and progressive supranuclear palsy-frontal subtypes) and 20 healthy control subjects were included. Participants undertook ultra-high field (7 T) magnetic resonance spectroscopy and a stop-signal task of response inhibition. We measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter. We conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.
\n \n\n \n \nThe brain's capacity to adapt to sensory inputs is key for processing sensory information efficiently and interacting in new environments. Following repeated exposure to the same sensory input, brain activity in sensory areas is known to decrease as inputs become familiar, a process known as adaptation. Yet, the brain-wide mechanisms that mediate adaptive processing remain largely unknown. Here, we combine multimodal brain imaging (functional magnetic resonance imaging [fMRI], magnetic resonance spectroscopy) with behavioral measures of orientation-specific adaptation (i.e., tilt aftereffect) to investigate the functional and neurochemical mechanisms that support adaptive processing. Our results reveal two functional brain networks: 1) a sensory-adaptation network including occipital and dorsolateral prefrontal cortex regions that show decreased fMRI responses for repeated stimuli and 2) a perceptual-memory network including regions in the parietal memory network (PMN) and dorsomedial prefrontal cortex that relate to perceptual bias (i.e., tilt aftereffect). We demonstrate that adaptation relates to increased occipito-parietal connectivity, while decreased connectivity between sensory-adaptation and perceptual-memory networks relates to GABAergic inhibition in the PMN. Thus, our findings provide evidence that suppressive interactions between sensory-adaptation (i.e., occipito-parietal) and perceptual-memory (i.e., PMN) networks support adaptive processing and behavior, proposing a key role of memory systems in efficient sensory processing.
\n \n\n \n \nCultural differences in visual perceptual learning (VPL) could be attributed to differences in the way that people from individualistic and collectivistic cultures preferentially attend to local objects (analytic) or global contexts (holistic). Indeed, individuals from different cultural backgrounds can adopt distinct processing styles and learn to differentially construct meaning from the environment. Therefore, the present work investigates if cross-cultural differences in VPL can vary as a function of holistic processing. A shape discrimination task was used to investigate whether the individualistic versus collectivistic backgrounds of individuals affected the detection of global shapes embedded in cluttered backgrounds. Seventy-seven participants-including Asian (collectivistic background) and European (individualistic background) students-were trained to discriminate between radial and concentric patterns. Singelis's self-construal scale was also used to assess whether differences in learning could be attributed to independent or interdependent self-construal. Results showed that collectivists had faster learning rates and better accuracy performance than individualists following training-thereby reflecting their tendency to attend holistically when learning to extract global forms. Further, we observed a negative association between independent self-construal-which has previously been linked to analytic processing-with performance. This study provides insight into how socio-cultural backgrounds affect VPL.
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