Physiological variables in association with spreading depolarizations in the late phase of ischemic stroke

Physiological effects of spreading depolarizations (SD) are only well studied in the first hours after experimental stroke. In patients with malignant hemispheric stroke (MHS), monitoring of SDs is restricted to the postoperative ICU stay, typically day 2-7 post-ictus. Therefore, we investigated the role of physiological variables (temperature, intracranial pressure, mean arterial pressure and cerebral perfusion pressure) in relationship to SD during the late phase after MHS in humans. Additionally, an experimental stroke model was used to investigate hemodynamic consequences of SD during this time window. In 60 patients with MHS, the occurrence of 1692 SDs was preceded by a decrease in mean arterial pressure (−1.04 mmHg; p = .02) and cerebral perfusion pressure (−1.04 mmHg; p = .03). Twenty-four hours after middle cerebral artery occlusion in 50 C57Bl6/J mice, hypothermia led to prolonged SD-induced hyperperfusion (+2.8 min; p < .05) whereas hypertension mitigated initial hypoperfusion (−1.4 min and +18.5%Δ rCBF; p < .01). MRI revealed that SDs elicited 24 hours after experimental stroke were associated with lesion progression (15.9 vs. 14.8 mm³; p < .01). These findings of small but significant effects of physiological variables on SDs in the late phase after ischemia support the hypothesis that the impact of SDs may be modified by adjusting physiological variables.     

Jugular venous and arterial concentrations of serum S-100B protein in patients with severe head injury: a pilot study

The objective of this study was to analyse the temporal courseof the jugular venous-arterial gradient of S-100B protein after severehead injury and the correlation between the absoluteconcentrations of serum S-100B protein and outcome, CTfindings, and clinical variables.
Fifteen patients were included in this pilot study. Allpatients were treated according to a standard therapy protocol targeted to maintain cerebral perfusion pressure. The serum concentration ofS-100 protein was measured daily for five consecutive days after injuryby a monoclonal two site immunoluminometric assay. Nine patients showedfavourable and six unfavourable outcome after 6 months with a mortalityrate of 33% (five patients). The mean gradient between jugular venousand arterial blood was 8.2% (p<0.05). Patients showing anunfavourable outcome had significantly higher jugular venous orarterial S-100 values compared with those with a favourable outcome(jugular venous S-100B 2.78 µg/l v 1.22 µg/l, p<0.05;arterial S-100B 2.48 µg/l v 1.19 µg/l, p<0.05). Allpatients with an initial or secondary increase in S-100B value of >2µg/l were found to have an unfavourable outcome. S-100B was found to be an independent predictor of outcome after severe head injury. Thepersisting increase of S-100B for three to five days even in patientswith favourable outcome and no signs of secondary insults might reflectcontinuing damage to the blood-brain barrier or ongoing glial cell death.

     

Reading skills deficits in people with mental illness: A systematic review and meta-analysis

BackgroundGood reading skills are important for appropriate functioning in everyday life, scholastic performance, and acquiring a higher socioeconomic status. We conducted the first systematic review and meta-analysis to quantify possible deficits in specific reading skills in people with a variety of mental illnesses, including personality disorders (PDs).MethodsWe performed a systematic search of multiple databases from inception until February 2020 and conducted random-effects meta-analyses.ResultsThe search yielded 34 studies with standardized assessments of reading skills in people with one or more mental illnesses. Of these, 19 studies provided data for the meta-analysis. Most studies (k = 27; meta-analysis, k = 17) were in people with schizophrenia and revealed large deficits in phonological processing (Hedge’s g = −0.88, p < 0.00001), comprehension (Hedge’s g = −0.96, p < 0.00001) and reading rate (Hedge’s g = −1.22, p = 0.002), relative to healthy controls; the single-word reading was less affected (Hedge’s g = −0.70, p < 0.00001). A few studies in affective disorders and nonforensic PDs suggested weaker deficits (for all, Hedge’s g < −0.60). In forensic populations with PDs, there was evidence of marked phonological processing (Hedge’s g = −0.85, p < 0.0001) and comprehension deficits (Hedge’s g = −0.95, p = 0.0003).ConclusionsPeople with schizophrenia, and possibly forensic PD populations, demonstrate a range of reading skills deficits. Future studies are needed to establish how these deficits directly compare to those seen in developmental or acquired dyslexia and to explore the potential of dyslexia interventions to improve reading skills in these populations.     

MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4

MicroRNA-29b (miR-29b) is involved in regulating ischemia process, but the molecular mechanism is unclear. In this work, we explored the function of miR-29b in cerebral ischemia. The level of miR-29b in white blood cells was evaluated in patients and mice after ischemic stroke. Brain infarct volume and National Institute of Health stroke scale (NIHSS) scores were analyzed to determine the relationship between miR-29b expression and the severity of stroke. The relationship of miR-29b and aquaporin-4 (AQP4) was further studied in mice. We found that miR-29b was significantly downregulated in stroke patients (P<0.05). MiR-29b level negatively associated with NIHSS scores (r=−0.349, P<0.01) and brain infarct volume (r=−0.321, P<0.05). In ischemic mice, miR-29b in the brain and blood were both downregulated (r=0.723, P<0.05). MiR-29b overexpression reduced infarct volume (49.50±6.55 versus 35.48±2.28 mm³, P<0.05), edema (164±4% versus 108±4%, P<0.05), and blood–brain barrier (BBB) disruption compared with controls (15±9% versus 7±3%, P<0.05). Aquaporin-4 expression greatly decreased after miR-29b overexpression (28±7% versus 11±3%, P<0.05). Dual-luciferase reporter system showed that AQP-4 was the direct target of miR-29b (P<0.05). We concluded that miR-29b could potentially predict stroke outcomes as a novel circulating biomarker, and miR-29b overexpression reduced BBB disruption after ischemic stroke via downregulating AQP-4.     

Effects of the combination of second-generation antipsychotics on serum concentrations of aripiprazole and dehydroaripiprazole in Chinese patients with schizophrenia

BackgroundAripiprazole (ARI) is often prescribed alone or in combination with other second-generation antipsychotics (SGAs) to treat patients with schizophrenia. However, this may increase the potential clinical significance of drug–drug interactions. Therapeutic drug monitoring (TDM) is an important and fundamental tool both when administering ARI alone and in combination with other SGAs to monitor ARI pharmacokinetics, adjust the dosage and thereby achieve more effective and safer treatment.AimsThis study retrospectively investigated the effects of four SGA comedications (clozapine, risperidone, quetiapine (QTP) and olanzapine) and other potential factors (sex, age and ARI dose) on the serum concentrations of ARI and dehydroaripiprazole (DARI) in Chinese patients with schizophrenia using TDM data.MethodsHigh-performance liquid chromatography was used to test the serum concentrations of ARI, DARI and ARI+DARI. In addition, steady-state dose-adjusted serum concentrations (ie, concentration-to-dose ratios, C:D ratios) of ARI, DARI and ARI+DARI; sex; age; ARI dose and SGA comedication dose between 299 inpatients with schizophrenia who received ARI or SGA comedication were all collected and analysed. Spearman’s correlation and multiple linear regression analysis were used to evaluate bivariate associations between ARI dose and serum ARI and DARI concentrations and describe the effect of independent variables on serum ARI and DARI concentrations, respectively.ResultsThere were significant differences in the C:D ratios of ARI (χ²=−3.21, p=0.001) and ARI+DARI (χ²=−2.50, p=0.01) between the ARI and SGA groups, as well as in the C:D ratios of ARI (χ²=−3.59, p<0.001) and ARI+DARI (χ²=−3.10, p=0.002) between the female patients in the two groups. Of the four SGAs, only QTP had significant effects on the C:D ratios of ARI (Z=−4.12, p<0.001) and ARI+DARI (Z=−3.62, p<0.001) when compared with the ARI group in the whole sample and on the C:D ratios of ARI, DARI and ARI+DARI (Z=−3.96, p<0.001; Z=−2.22, p=0.03; Z=−3.75, p<0.001, respectively) in women when compared with their counterparts in the ARI group.ConclusionComedication with SGAs resulted in lower C:D ratios of ARI and ARI+DARI compared with ARI monotherapy, and comedication with QTP resulted in lower C:D ratios of ARI and ARI+DARI than ARI monotherapy. Despite this statistical significance of our findings, whether the presently observed effect has clinical significance requires exploration by further research. TDM and dosage regulation of ARI should be performed in Chinese inpatients with schizophrenia who are receiving SGA comedication (especially QTP) to maintain a safe and effective dose-adjusted serum concentration of ARI and DARI.     

Examining the association between exposome score for schizophrenia and functioning in schizophrenia,siblings, and healthy controls: Results from the EUGEI study

BackgroundA cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls.MethodsThis cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate.ResultsES-SCZ was associated with the GAF dimensions in patients (symptom: B = −1.53, p-value = 0.001; disability: B = −1.44, p-value = 0.001), siblings (symptom: B = −3.07, p-value < 0.001; disability: B = −2.52, p-value < 0.001), and healthy controls (symptom: B = −1.50, p-value < 0.001; disability: B = −1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group.ConclusionsOur findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.     

Brain temperature regulation in poor-grade subarachnoid hemorrhage patients – A multimodal neuromonitoring study

Elevated body temperature (T_core) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (T_brain) is usually higher than T_core. However, the implication of this difference (T_delta) remains unclear. We aimed to study factors associated with higher T_delta and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of T_core, T_brain, cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. T_brain was tightly correlated with T_core (r = 0.948, p < 0.01), and was higher in 73.7% of neuromonitoring time (T_delta +0.18°C, IQR −0.01 – 0.37°C). A higher T_delta was associated with better metabolic state, indicated by lower CMD-glutamate (p = 0.003) and CMD-lactate (p < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2, p < 0.001). During MD, T_delta was significantly lower (0°C, IQR −0.2 – 0.1; p < 0.001). A higher T_delta was associated with improved outcome (OR = 7.7, p = 0.002). Our study suggests that T_brain is associated with brain metabolic activity and exceeds T_core when mitochondrial function is preserved. Further studies are needed to understand how T_delta may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.     

Ischemic lesion water homeostasis after thrombectomy for large vessel occlusion stroke within the anterior circulation: The impact of age

The effect of age on lesion pathophysiology in the context of thrombectomy has been poorly investigated. We aimed to investigate the impact of age on ischemic lesion water homeostasis measured with net water uptake (NWU) within a multicenter cohort of patients receiving thrombectomy for anterior circulation large vessel occlusion (LVO) stroke. Lesion-NWU was quantified in multimodal CT on admission and 24 h for calculating Δ-NWU as their difference. The impact of age and procedural parameters on Δ-NWU was analyzed. Multivariable regression analysis was performed to identify significant predictors for Δ-NWU. Two hundred and four patients with anterior circulation stroke were included in the retrospective analysis. Comparison of younger and elderly patients showed no significant differences in NWU on admission but significantly higher Δ-NWU (p = 0.005) on follow-up CT in younger patients. In multivariable regression analysis, higher age was independently associated with lowered Δ-NWU (95% confidence interval: −0.59 to −0.16, p < 0.001). Although successful recanalization (TICI ≥ 2b) significantly reduced Δ-NWU progression by 6.4% (p < 0.001), younger age was still independently associated with higher Δ-NWU (p < 0.001). Younger age is significantly associated with increased brain edema formation after thrombectomy for LVO stroke. Younger patients might be particularly receptive targets for future adjuvant neuroprotective drugs that influence ischemic edema formation.     

Analyzing the Significance of T1 Slope minus Cervical Lordosis in Patients with Anterior Cervical Discectomy and Fusion Surgery

ObjectiveAccurate measurement of T1 slope (a component of T1s minus cervical lordosis [CL]) is often constrained by anatomical limitations. In this situation, efforts should be made to find the exact meaning of T1s-CL and whether there are any alternatives to it. MethodsWe enrolled 117 patients who received two-level anterior cervical discectomy and fusion (ACDF). Occipital slope, C2 slope (C2s), C7 slope (C7s), T1, O-C2 angle (O-C2A), C2-7 angle (C2-7A), O-C7 angle (O-C7A), T1s-CL, C7-T1 angle (C7-T1A), and C2-7 sagittal vertical axis were measured. We determined 16° (T1s-CL) as the reference point for dividing subjects into the mismatch group and the balance group, and a comparative analysis was performed. ResultsThe mean value of C7-T1A was constantly maintained within 2.6° peri-operatively. In addition, C2s and T1s-CL showed the same absolute change (Δ|0.8|°). The mean values of T1s-CL of the mismatch and balance groups were 23.0° and 7.6°, respectively. The five factors with the largest differences between the two groups were as follows : C2s (Δ13.3°), T1s-CL (Δ15.4°), O-C2A (Δ8.7°), C2-7A (Δ14.7°), and segmental angle (Δ7.9°) before surgery. Only four factors showed statistically significant change between the two groups after ACDF : T1s-CL (Δ4.0° vs. Δ0.2°), C2s (Δ3.2° vs. Δ0.7°), O-C2A (Δ2.6° vs. Δ1.3°), C2-7A (Δ6.3° vs. Δ1.3°). A very strong correlation between T1s-CL and C2s was also found (r=|0.88–0.96|). ConclusionC2s itself may be the essential key to represent T1s-CL. The amounts and directions of change of these two factors (T1s-CL and C2s) were also almost identical. The above phenomenon was re-confirmed once again through the correlation analysis.     

The additive impact of cardio‐metabolic disorders and psychiatric illnesses on accelerated brain aging

Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio‐metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning “BrainAge” index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD− (N = 964), SMI−/CMD+ (N = 3,765), SMI−/CMD− (N = 8,083). SMI (F = 40.47, p = 2.06 × 10⁻¹⁰) and CMD (F = 24.69, p = 6.82 × 10⁻⁷) significantly, independently impacted whole‐brain QRI in SMI+. SSD had the largest effect (Cohen’s d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI− (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole‐brain QRI was significantly (p < 10⁻¹⁶) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p < 10⁻¹⁶). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio‐metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age‐related cognitive decline.     

Preliminary study of associative stigma among trainee psychiatrists in Flanders,Belgium

AIM: To study the degree of stigmatization among trainee psychiatrists, individual characteristics potentially leading to higher associative stigma, and coping mechanisms.METHODS: Two hundred and seven trainee psychiatrists in Flanders(Belgium), all member of the Flemish Association of Trainee Psychiatrists, were approached to participate in the survey. A non-demanding questionnaire that was specifically designed for the purpose of the study was sent by mail. The questionnaire consisted of three parts, each emphasizing a different aspect of associative stigma: devaluing and humiliating interactions, the focus on stigma during medical train-ing, and identification with negative stereotypes in the media. Answers were scored on a Likert scale ranging from 0 to 3. The results were analyzed using SPSS Version 18.0. RESULTS: The response rate of the study was 75.1%. The internal consistency of the questionnaire was good, with a Cronbach's α of 0.71. Seventy-five percent of all trainee psychiatrists confirmed hearing denigrating or humiliating remarks about the psychiatric profession more than once. Additionally, more than half of them had had remarks about the incompetence of psychiatrists directed at them. Only 1.3% remembered having stigma as a topic during their psychiatric training. Trainees who had been in training for a longer period of time had experienced a significantly higher level of stigmatization than trainees with fewer years of experience(mean total stigma scores of 16.93 ± SD 7.8 vs 14.45 ± SD 6.1, t =-2.179 and P 0.05). In addition, senior trainees effectively kept quiet about their profession significantly more often than their junior colleagues(mean item score 0.44 ± SD 0.82 vs 0.13 ± SD 0.48, t = 2.874, P 0.01). Comparable results were found in trainees working in adult psychiatry as were found in those working in child or youth psychiatry(mean item score 0.38 ± SD 0.77 vs 0.15 ± SD 0.53, t =-2.153, P 0.05). Biologically oriented trainees were more inclined to give preventive explanations about their profession, which can be seen as a coping mechanism used to deal with this stigma(mean item score 2.05 ± SD 1.05 vs 1.34 ± SD 1.1, t =-3.403, P 0.01).CONCLUSION: Associative stigma in trainee psychiatrists is underestimated. More attention should be paid to this potentially harmful phenomenon in training.     

Haemostatic changes during surgery for primary brain tumours

OBJECTIVE—Primary brain tumours may be associatedwith coagulation disorders which can pose intraoperative andpostoperative management difficulties. The aim was to evaluate thecoagulation profile of patients with brain tumours undergoing surgeryusing thromboelastography (TEG) in combination with simple laboratory tests.
METHODS—Fifty adult patients with primary braintumours larger than 4 cm in maximum diameter and no history ofcoagulation disorders were studied in a prospective, observationalmanner over a one year period. Preoperative, intraoperative, andpostoperative measurements included haemoglobin concentration, plateletcount, prothrombin and partial thromboplastin times, fibrin(ogen)degradation product concentration, D-dimer concentration, and TEG.
RESULTS—Eleven patients (22%) had abnormalintraoperative TEGs, of whom six (12%) subsequently developedhaematomas requiring surgical evacuation. The coagulopathy seemed to behyperfibrinolysis in two cases (4%) and disseminated intravascularcoagulation in four (8%). There was no preoperative difference inreaction time (R time) for clot formation between the non-haematoma andhaematoma groups(mean 11.44 (SD 3.42) v 12.33 (2.50) min,P= 0.46). However, when other preoperative indices were compared, inthe non-haematoma group, K time (time to reach a clot amplitude of 20 mm) was shorter (6.72 (2.15) v 10.56 (3.50) min, P=0.001),rate of clot growth (å) was faster (43.67°(7.53) v27.11° (5.42) , P<0.0001) and maximum amplitude of clot strength(MA) was greater (52.64 (7.85) v 40.33(6.59) mm, P<0.001). Intraoperatively, R time was significantly shortened in thenon-haematoma group, (7.67 (1.78) min, P<0.0001) unlike the haematomagroup (10.67 (1.58) minutes, P=0.11).
CONCLUSIONS—Although these results indicate ageneral hypercoagulability during brain tumour surgery, in certaincases, a predisposition towards hypocoagulability may exist even beforesurgery, detectable only when the physical characteristics of clotformation are studied by TEG. Judicious replacement of clottingfactors, platelets, and antifibrinolytic agents should be consideredintraoperatively if the TEG is abnormal, without waiting for laboratorytest results.

     

Motor Function in School-Aged Children with Attention-Deficit/Hyperactivity Disorder in Korea

Objective

Motor function critically influences daily activities and academic performance. We compared motor function in school-aged children with Attention-Deficit/Hyperactivity Disorder (ADHD) to that of normal children.

Methods

Participants were 58 children with ADHD [51 males, 7 females; mean age 9 years 6 months±2 years 0 months (SD)] and 70 normal controls [56 males, 14 females; mean age 9 years 2 months±1 years 7 months (SD)]. We assessed motor function with the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition.

Results

The ADHD group had a significantly lower total motor composite score (t=-9.32, p<0.001) than that of the control group. Standard scores of four motor-area composites such as fine manual control (t=-3.76, p<0.001), manual coordination (t=-6.87, p<0.001), body coordination (t=-7.14, p<0.001), and strength and agility (t=-8.54, p<0.1) were significantly lower in the ADHD group than those in the control group. Among the subtests, scores on fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, running speed and agility, and strength were significantly lower in the ADHD group than those in the controls, whereas upper-limb coordination was not significantly different between the groups.

Conclusion

School-aged children with ADHD in Korea had significantly lower motor function compared to that of controls. Thus, it is suggested that appropriate target intervention for motor function is important in children with motor impairment in addition to pharmacotherapy or psychosocial therapy for improving the core symptoms.     

Did we learn something positive out of the COVID-19 pandemic? Post-traumatic growth and mental health in the general population

BackgroundWhen facing a traumatic event, some people may experience positive changes, defined as posttraumatic growth (PTG).MethodsUnderstanding the possible positive consequences of the pandemic on the individual level is crucial for the development of supportive psychosocial interventions. The present paper aims to: 1) evaluate the levels of PTG in the general population; 2) to identify predictors of each dimension of post-traumatic growth.ResultsThe majority of the sample (67%, N = 13,889) did not report any significant improvement in any domain of PTG. Participants reported the highest levels of growth in the dimension of “appreciation of life” (2.3 ± 1.4), while the lowest level was found in the “spiritual change” (1.2 ± 1.2). Female participants reported a slightly higher level of PTG in areas of personal strength (p < .002) and appreciation for life (p < .007) compared to male participants, while no significant association was found with age. At the multivariate regression models, weighted for the propensity score, only the initial week of lockdown (between 9-15 April) had a negative impact on the dimension of “relating to others” (B = −.107, 95% CI = −.181 to −.032, p < .005), while over time no other effects were found. The duration of exposure to lockdown measures did not influence the other dimensions of PTG.ConclusionsThe assessment of the levels of PTG is of great importance for the development of ad hoc supportive psychosocial interventions. From a public health perspective, the identification of protective factors is crucial for developing ad-hoc tailored interventions and for preventing the development of full-blown mental disorders in large scale.     

Pre‐ and post‐conditioning with poly I:C exerts neuroprotective effect against cerebral ischemia injury in animal models: A systematic review and meta‐analysis

BackgroundToll‐like receptor (TLR) agonist polyinosinic–polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear.MethodsWe evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion.ResultsPoly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre‐ and post‐conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor‐κB (NF‐κB) [SMD = −1.78; CIs (−2.67, −0.88); p = 0.0)], and tumor necrosis factor alpha (TNF‐α) [SMD = −16.83; CIs (−22.63, −11.02); p = 0.00].ConclusionWe showed that poly I:C is neuroprotective and acts via the TLR3/NF‐κB/TNF‐α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.     

Blood flow distribution during heat stress: cerebral and systemic blood flow

The purpose of the present study was to assess the effect of heat stress-induced changes in systemic circulation on intra- and extracranial blood flows and its distribution. Twelve healthy subjects with a mean age of 22±2 (s.d.) years dressed in a tube-lined suit and rested in a supine position. Cardiac output (Q), internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) blood flows were measured by ultrasonography before and during whole body heating. Esophageal temperature increased from 37.0±0.2°C to 38.4±0.2°C during whole body heating. Despite an increase in Q (59±31%, P<0.001), ICA and VA decreased to 83±15% (P=0.001) and 87±8% (P=0.002), respectively, whereas ECA blood flow gradually increased from 188±72 to 422±189 mL/minute (+135%, P<0.001). These findings indicate that heat stress modified the effect of Q on blood flows at each artery; the increased Q due to heat stress was redistributed to extracranial vascular beds.     

Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine

Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain‐wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = −0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = −0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL‐ and MRP‐DA release patterns (ΔR ² >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL‐ and MRP‐induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern‐based characterization of drug‐induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.     

Changes in striatal dopamine transporters in bipolar disorder and valproate treatment

BackgroundPrevious studies suggested that a disturbance of the dopamine system underlies the pathophysiology of bipolar disorder (BD). In addition, the therapeutic action of medications for treating BD, such as valproate (VPA), might modulate dopamine system activity, but it remains unclear. Here, we aimed to investigate the role of the striatal dopamine transporter (DAT) in BD patients and in social defeat (SD) mice treated with VPA.MethodsWe enrolled community-dwelling controls (N = 18) and BD patients (N = 23) who were treated with VPA in a euthymic stage. The striatal DAT availabilities were approached by TRODAT-1 single photon emission computed tomography. We also established a chronic SD mouse model and treated mice with 350 mg/kg VPA for 3 weeks. Behavioral tests were administered, and striatal DAT expression levels were determined.ResultsIn humans, the level of striatal DAT availability was significantly higher in euthymic BD patients (1.52 ± 0.17 and 1.37 ± 0.23, p = 0.015). Moreover, the level of striatal DAT availability was also negatively correlated with the VPA concentration in BD patients (r = −0.653, p = 0.003). In SD mice, the expression of striatal DAT significantly increased (p < 0.001), and the SD effect on DAT expression was rescued by VPA treatment.ConclusionsThe striatal DAT might play a role in the pathophysiology of BD and in the therapeutic mechanism of VPA. The homeostasis of DAT might represent a new therapeutic strategy for BD patients.     

Chronological Changes of C-Reactive Protein Levels Following Uncomplicated,Two-Staged,Bilateral Deep Brain Stimulation

ObjectiveThe occurrence of acute cerebral infection following deep brain stimulation (DBS) is currently being reported with elevation of C-reactive protein (CRP) level. The aim of the present study was to establish normal range of the magnitude and time-course of CRP increases following routine DBS procedures in the absence of clinical and laboratory signs of infection.MethodsA retrospective evaluation of serial changes of plasma CRP levels in 46 patients undergoing bilateral, two-staged DBS was performed. Because DBS was performed as a two-staged procedure involving; implantation of lead and internal pulse generator (IPG), CRP was measured preoperatively and postoperatively every 2 days until normalization of CRP (post-lead implantation day 2 and 4, post-IPG implantation day 2, 4, and 6).ResultsCompared with preoperative CRP levels (0.12±0.17 mg/dL, n=46), mean CRP levels were significantly elevated after lead insertion day 2 and 4 (1.68±1.83 mg/dL, n=46 and 0.76±0.38 mg/dL, n=16, respectively, p<0.001). The mean CRP levels at post-lead implantation day 2 were further elevated at post-IPG implantation day 2 (3.41±2.56 mg/dL, n=46, respectively, p<0.01). This elevation in post-IPG day 2 rapidly declined in day 4 (1.24±1.29 mg/dL, n=46, p<0.05) and normalized to preoperative value at day 6 (0.42±0.33 mg/dL, n=46, p>0.05). Mean CRP levels after IPG implantation were significantly higher in patients whose IPGs were implanted at post-lead day 3 than those at post-lead day 5-6 (3.99±2.80 mg/dL, n=30, and 2.31±1.56 mg/dL, n=16, respectively, p<0.05). However, there was no difference in post-IPG day 2 and 4 between them (p>0.05).ConclusionThe mean postoperative CRP levels were highest on post-IPG insertion day 2 and decreased rapidly, returning to the normal range on post-IPG implantation day 6. The duration of post-lead implantation period influenced the magnitude of CRP elevation at post-IPG insertion day 2. Information about the normal response of CRP following DBS could help to avoid unnecessary diagnostic and therapeutic efforts.     

Impact of the Coronavirus Disease Pandemic on Patients with Head Injuries in South Korea

ObjectiveThe coronavirus disease 2019 (COVID-19) pandemic is affecting the characteristics of patients with head injuries. This study aimed to evaluate the effect of the COVID-19 pandemic on patients with head injuries at a regional emergency medical center in South Korea. MethodsFrom April 2019 to November 2020, 350 patients with head injuries were admitted to our hospital. The study period was divided into the pre-COVID-19 (n=169) and COVID-19 (n=181) eras (10 months each). Patients with severe head injuries requiring surgery (n=74) were categorized into those who underwent surgery (n=41) and those who refused surgery (n=33). ResultsHead injuries in pediatric patients (<3 years) were more frequent in the COVID-19 era than in the pre-COVID-19 era (8.8% vs. 3.6%, p=0.048). More patients refused surgery in the COVID-19 era than in the pre-COVID-19 era (57.9% vs. 30.6%, p=0.021). Refusal of surgery was associated with old age (67.7±14.5 vs. 52.4±19.1, p<0.001), marital status (married, 84.8% vs. 61.0%, p=0.037), unemployment (42.4% vs. 68.3%, p=0.034), COVID-19 era (66.7% vs. 39.0%, p=0.021), and lower Glasgow coma scale scores (6.12±3.08 vs. 10.6±3.80, p<0.001). Multivariable logistic regression analysis revealed that refusal of surgery was independently associated with old age (adjusted odds ratio [OR], 1.084; 95% confidence interval [CI], 1.030–1.140; p=0.002), COVID-19 era (adjusted OR, 6.869; 95% CI, 1.624–29.054; p=0.009), and lower Glasgow coma scale scores (adjusted OR, 0.694; 95% CI, 0.568–0.848; p<0.001). ConclusionWe observed an increased prevalence of head injuries in pediatric patients (<3 years) during the COVID-19 pandemic. Additionally, among patients with severe head injuries requiring surgery, more patients refused to undergo surgery during the COVID-19 pandemic.