Distinct roles of parvalbumin- and somatostatin-expressing neurons in flexible representation of task variables in the prefrontal cortex.

A hallmark of the prefrontal cortex (PFC) is flexible representation of task-relevant variables. To investigate roles of different interneuron subtypes in this process, we examined discharge characteristics and inactivation effects of parvalbumin (PV)- and somatostatin (SST)-expressing neurons in the mouse PFC during probabilistic classical conditioning. We found activity patterns and inactivation effects differed between PV and SST neurons: SST neurons conveyed cue-associated quantitative value signals until trial outcome, whereas PV neurons maintained valence signals even after trial outcome. Also, PV, but not SST, neuronal population showed opposite responses to reward and punishment. Moreover, inactivation of PV, but not SST, neurons affected outcome responses and activity reversal of pyramidal neurons. Modeling suggested opposite responses of PV neurons to reward and punishment as an efficient mechanism for facilitating rapid cue-outcome contingency learning. Our results suggest primary roles of mPFC PV neurons in rapid value updating and SST neurons in predicting values of upcoming events.

Dual Versus Mono Antiplatelet Therapy in Large Atherosclerotic Stroke.

Background and Purpose- Two large-scale randomized controlled trials of recurrent stroke prevention suggest that dual antiplatelet therapy with clopidogrel plus aspirin is beneficial for prevention of subsequent ischemic events. There is a paucity of data, however, on the efficacy or effectiveness of such an approach in the treatment of stroke patients with symptomatic large artery atherosclerotic occlusive disease. Methods- We used a multicenter stroke registry database (Clinical Research Collaboration for Stroke in Korea) to analyze acute ischemic stroke patients due to large artery atherosclerotic occlusive disease who were treated with aspirin alone or combination of clopidogrel and aspirin from May 2008 to May 2015. The results were analyzed by intention-to-treat, per-protocol, and as-treated methodologies. The primary end point was the 1-year composite outcome of stroke recurrence, myocardial infarction, and all-cause death. To balance the differences between groups, a frailty model using propensity scores and inverse probability of treatment weighting was used. Results- A total of 5934 patients with symptomatic large artery atherosclerotic occlusive disease were treated either with clopidogrel plus aspirin (n=2903, 49%) or aspirin (n=3031, 51%). The frequency of the primary outcome was 12% (n=353) in the clopidogrel-aspirin group and 14% (n=410) in the aspirin group. The hazards of the primary outcome with combination over aspirin only were significantly reduced in the per-protocol and as-treated analyses (hazard ratio, 0.71; 95% CI, 0.57-0.88; P=0.002 and hazard ratio, 0.81; 95% CI, 0.69-0.96; P=0.02, respectively), but there was borderline significance in the intention-to-treat analysis (hazard ratio, 0.86; 95% CI, 0.74-1.01; P=0.06). Combination therapy was beneficial for all-cause death in all analyses but did not reduce recurrent stroke. Conclusions- Compared with patients receiving aspirin monotherapy, the primary outcome seemed to occur less frequently in patients receiving dual antiplatelet therapy, which is explained mainly by the decrease of all-cause death. Since this is a nonrandomized, retrospective, observational study, our study should be cautiously interpreted.

Distinct Dynamics of Striatal and Prefrontal Neural Activity During Temporal Discrimination.

The frontal cortex-basal ganglia circuit plays an important role in interval timing. We examined neuronal discharges in the dorsomedial and dorsolateral striatum (DMS and DLS) in rats performing a temporal categorization task and compared them with previously recorded neuronal activity in the medial prefrontal cortex (mPFC). All three structures conveyed significant temporal information, but striatal neurons seldom showed the prolonged, full-interval spanning ramping activity frequently observed in the mPFC. Instead, the majority fired briefly during sample intervals. Also, the precision of neural time decoding became progressively worse with increasing time duration in the mPFC, but not in the striatum. With the caveat that mPFC and striatal units were recorded from different animals, our results suggest that the striatum and mPFC convey temporal information via distinct neural processes.

Differential coding of reward and movement information in the dorsomedial striatal direct and indirect pathways.

The direct and indirect pathways of the basal ganglia have long been thought to mediate behavioral promotion and inhibition, respectively. However, this classic dichotomous model has been recently challenged. To better understand neural processes underlying reward-based learning and movement control, we recorded from direct (dSPNs) and indirect (iSPNs) pathway spiny projection neurons in the dorsomedial striatum of D1-Cre and D2-Cre mice performing a probabilistic Pavlovian conditioning task. dSPNs tend to increase activity while iSPNs decrease activity as a function of reward value, suggesting the striatum represents value in the relative activity levels of dSPNs versus iSPNs. Lick offset-related activity increase is largely dSPN selective, suggesting dSPN involvement in suppressing ongoing licking behavior. Rapid responses to negative outcome and previous reward-related responses are more frequent among iSPNs than dSPNs, suggesting stronger contributions of iSPNs to outcome-dependent behavioral adjustment. These findings provide new insights into striatal neural circuit operations.

Distinct Roles of Parvalbumin- and Somatostatin-Expressing Interneurons in Working Memory.

Inhibitory interneurons are thought to play crucial roles in diverse brain functions. However, roles of different inhibitory interneuron subtypes in working memory remain unclear. We found distinct activity patterns and stimulation effects of two major interneuron subtypes, parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons, in the medial prefrontal cortex of mice performing a spatial working memory task. PV interneurons showed weak target-dependent delay-period activity and were strongly inhibited by reward. By contrast, SOM interneurons showed strong target-dependent delay-period activity, and only a subtype of them was inhibited by reward. Furthermore, optogenetic stimulation of PV and SOM interneurons preferentially suppressed discharges of putative pyramidal cells and interneurons, respectively. These results indicate different contributions of PV and SOM interneurons to prefrontal cortical circuit dynamics underlying working memory.

Effect of Long-Term Treatment with Fimasartan on Transient Focal Ischemia in Rat Brain.

Fimasartan is a newly developed angiotensin receptor blocker, which may have protective effects during myocardial infarction or atherosclerosis. In this context, we investigated the effects of long-term treatment with low-dose fimasartan on focal ischemia in rat brain. We induced focal ischemia in brain by transient intraluminal occlusion of middle cerebral artery (MCA) and administered low-dose (0.5 mg/kg) or regular doses (1 or 3 mg/kg) of fimasartan via intravenous routes. After the administration of low-dose (0.5 mg/kg) fimasartan, blood pressure did not decrease compared to the phosphate-buffered saline- (PBS-) control with MCA occlusion (MCAO) group. The infarct volume and ischemic cell death were reduced in the low-dose fimasartan-treated group (46 ± 41 mm(3) for 0.5 mg/kg and 153 ± 47 mm(3) for PBS-control with MCAO; P < 0.01) but not in the regular-dose groups. Low-dose fimasartan treatment improved functional recovery after ischemia and significantly decreased mortality. In our study, fimasartan reduced the degradation of IκB and the formation of an inflammatory end-product, COX-2. As a result, the recruitment of inflammatory cells in the peri-infarct area decreased in fimasartan-treated group. We have demonstrated that long-term, low-dose fimasartan treatment improved outcomes after focal ischemia in the brain via a reduction of inflammation.

Secondary prevention by stroke subtype: a nationwide follow-up study in 46 108 patients after acute ischaemic stroke.

AIMS: Although use of antithrombotic agents is recommended after ischaemic stroke or transient ischaemic attack (TIA), long-term outcome of secondary prevention between stroke subtypes has not yet been explored. METHODS AND RESULTS: We used data from the Korean Stroke Registry (KSR), a nationwide, multicentre, prospective registry for acute stroke patients. Patients with acute ischaemic stroke or TIA within 7 days of onset were consecutively enrolled between January 2002 and September 2010. A total of 46 108 patients with ischaemic stroke and TIA were included in this study. Among the major stroke subtypes, stroke due to small vessel occlusion (SVO) showed the lowest mortality, whereas cardioembolic stroke (CE) was associated with the fatal prognosis during the follow-up [for SVO: hazard ratio (HR) 0.66, 95% CI 0.62-0.71; for CE: HR 1.41, 95% CI 1.30-1.53; large artery atherosclerosis (LAA) group as a reference]. Regarding secondary prevention, antiplatelet polytherapy was better than monotherapy in the patients with LAA-related stroke in prognosis [HR 0.89, 95% CI 0.80-0.98]. Anticoagulant therapy was associated with better outcome than antiplatelet monotherapy in CE-related stroke [HR 0.66, 95% CI 0.59-0.74]. In SVO-related stroke group, antiplatelet polytherapy failed to show benefits over monotherapy. Additionally, the risk of death was higher with anticoagulant therapy in the patients with SVO-related stroke [HR 1.44, CI 95% 1.06-1.97]. CONCLUSIONS: Our study demonstrated that stroke subtype affects prognosis and also determines the effectiveness of secondary prevention.

Extents of white matter lesions and increased intraventricular extension of intracerebral hemorrhage.

OBJECTIVES: To determine whether the extent of white matter lesions on a CT scan of acute intracerebral hemorrhage patients is associated with the prevalence and severity of intraventricular extension of hemorrhage. DESIGN AND SETTING: A post hoc analysis of Acute Brain Bleeding Analysis-IntraCerebral Hemorrhage cohort, a nationwide prospective cohort of acute intracerebral hemorrhage patients (total number of cohort subjects, 1,604). PATIENTS: Spontaneous intracerebral hemorrhage patients (n = 1,262). INTERVENTIONS: None. MEASUREMENTS: The authors analyzed CT scan images taken within 48 hours after stroke onset. Extent of white matter lesions, volume of intracerebral hemorrhage, presence of intraventricular extension of hemorrhage, and intraventricular extension of hemorrhage score (approximation of intraventricular extension of hemorrhage volume) were measured using CT scans, and demographic, laboratory, clinical, and mortality data were also gathered through review of medical records and retrieval from the governmental statistical archive. MAIN RESULTS: The frequency of intraventricular extension of hemorrhage in our population was 27.2% (343 subjects). The proportion of extensive white matter lesions in intraventricular extension of hemorrhage subjects (33.8%) was higher than that of non-intraventricular extension of hemorrhage cases (16.3%; p < 0.01). Multivariable analysis showed that mild (odds ratio, 1.48; 95% confidence interval 1.05- 0.09; p < 0.01) and extensive (odds ratio, 2.73; 95% confidence interval 1.88-3.98; p < 0.01) white matter lesions were significantly associated with the presence of intraventricular extension of hemorrhage in spontaneous intracerebral hemorrhage patients. The estimated mean of the intraventricular extension of hemorrhage score from the extensive white matter lesions group (9.09 ± 0.76) was significantly higher than that of the no white matter lesions group (6.72 ± 0.78; p < 0.01 from analyses of covariances) after adjustment for relevant covariates. CONCLUSIONS: We documented that the severity of white matter lesions is related to the occurrence and amount of intraventricular extension of hemorrhage in spontaneous intracerebral hemorrhage cases.

Excessive work and risk of haemorrhagic stroke: a nationwide case-control study.

BACKGROUND: Adverse effect of excessive work on health has been suggested previously, but it was not documented in cerebrovascular diseases. AIM: The authors investigated whether excessive working conditions would associate with increased risk of haemorrhagic stroke. METHODS: A nationwide matched case-control study database, which contains 940 cases of incident haemorrhagic stroke (498 intracerebral haemorrhages and 442 sub-arachnoid haemorrhages) with 1880 gender- and age- (± 5-year) matched controls, was analysed. Work-related information based on the regular job situation, including type of occupation, regular working time, duration of strenuous activity during regular work and shift work, was gathered through face-to-face interviews. Conditional logistic regression analyses were used for the multivariable analyses. RESULTS: Compared with white-collar workers, blue-collar workers had a higher risk for haemorrhagic stroke (odds ratio, 1.33 [95% confidence interval, 1.06-1.66]). Longer regular working time was associated with increased risk of haemorrhagic stroke [odds ratio, 1.38 (95% confidence interval, 1.05-1.81) for 8-12 h/day; odds ratio, 1.95 (95% confidence interval, 1.33-2.86) for ≥ 13 h/day; compared with ≤ 4 h/day]. Exposure to ≥ 8 h/week of strenuous activity also associated haemorrhagic stroke risk [odds ratio, 1.61 (95% confidence interval, 1.26-2.05); compared with no strenuous activity]. Shift work was not associated with haemorrhagic stroke (P = 0.98). Positive associations between working condition indices and haemorrhagic stroke risk were consistent regardless of haemorrhagic stroke sub-types and current employment status. CONCLUSIONS: Blue-collar occupation, longer regular working time and extended duration of strenuous activity during work may relate to an increased risk of haemorrhagic stroke.

Ceria nanoparticles that can protect against ischemic stroke.

Uniform 3 nm-sized ceria nanoparticles can protect against ischemic stroke by scavenging reactive oxygen species (ROS) and reducing apoptosis. PEGylated ceria nanoparticles showed protective effects against ROS-induced cell death in vitro. Optimal doses of ceria nanoparticles reduced infarct volumes and the rate of ischemic cell death in vivo.

Impact of CHADS(2) Score on Neurological Severity and Long-Term Outcome in Atrial Fibrillation-Related Ischemic Stroke.

BACKGROUND AND PURPOSE: The CHADS(2) (an acronym for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack or thromboembolism) score is a widely used system for estimating the risk of stroke in patients with atrial fibrillation. However, how the CHADS(2) score is related to stroke severity and outcome in patients with strokes due to atrial fibrillation has not yet been elucidated. METHODS: We enrolled patients with atrial fibrillation who visited our stroke center within 7 days after the onset of acute ischemic stroke between October 2002 and September 2008. CHADS(2) scores were categorized into three groups: 0 points, low risk; 1 or 2 points, intermediate risk; and 3-6 points, high risk. Poor neurological state was defined as follows: a National Institutes of Health Stroke Scale (NIHSS) score of ≥2, and a modified Rankin Scale (mRS) score of ≥3 at discharge. Mortality information was ascertained as at December 2008. RESULTS: A cohort of 298 patients with atrial-fibrillation-related stroke was included in this study. A high-risk CHADS(2) score at admission was a powerful predictor of poor neurological outcome [for NIHSS: odds ratio (OR), 4.17; 95% confidence interval (CI), 1.76-9.87; for mRS: OR, 2.97; 95% CI, 1.23-7.16] after controlling for all possible confounders. In addition, a high-risk CHADS(2) score was an independent predictor of all causes of death during the follow-up [hazard ratio (HR), 3.01; 95% CI, 1.18-7.65] and vascular death (HR, 12.25; 95% CI, 1.50-99.90). CONCLUSIONS: Although the CHADS(2) score was originally designed to distinguish patients with a future risk of stroke, our study shows that it may also be used to predict poor neurological outcome after atrial-fibrillation-related stroke.