Intracranial Neurofeedback Modulating Neural Activity in the Mesial Temporal Lobe During Memory Encoding: A Pilot Study.

Removal of the mesial temporal lobe (MTL) is an established surgical procedure that leads to seizure freedom in patients with intractable MTL epilepsy; however, it carries the potential risk of memory damage. Neurofeedback (NF), which regulates brain function by converting brain activity into perceptible information and providing feedback, has attracted considerable attention in recent years for its potential as a novel complementary treatment for many neurological disorders. However, no research has attempted to artificially reorganize memory functions by applying NF before resective surgery to preserve memory functions. Thus, this study aimed (1) to construct a memory NF system that used intracranial electrodes to feedback neural activity on the language-dominant side of the MTL during memory encoding and (2) to verify whether neural activity and memory function in the MTL change with NF training. Two intractable epilepsy patients with implanted intracranial electrodes underwent at least five sessions of memory NF training to increase the theta power in the MTL. There was an increase in theta power and a decrease in fast beta and gamma powers in one of the patients in the late stage of memory NF sessions. NF signals were not correlated with memory function. Despite its limitations as a pilot study, to our best knowledge, this study is the first to report that intracranial NF may modulate neural activity in the MTL, which is involved in memory encoding. The findings provide important insights into the future development of NF systems for the artificial reorganization of memory functions.

A pacing-controlled protocol for frequency-diastolic relations distinguishes diastolic dysfunction specific to a mouse HFpEF model.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant NG-nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/dtmax) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model.NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

An Unusual Case of Left Ventricular Outflow Tract Obstruction after Aortic Valve Replacement.

Surgical valve replacement improves the symptoms and prognosis of patients with valvular heart diseases. Aortic regurgitation elicits volume overload that causes enlargement of the left ventricle (LV), while the LV size often shrinks to near normal after aortic valve replacement (AVR), which is referred to as "reverse remodeling". We experienced a case in which LV outflow tract (LVOT) obstruction became apparent after AVR, resulting in worsening of heart failure. A 65-year-old man who had undergone surgical AVR for aortic valve regurgitation 15 months previously exhibited dyspnea on effort accompanied with severe LVOT obstruction. With double pressure catheters, we directly recorded an augmented pressure gradient in the LVOT and rapid relief of the obstruction by intravenous administration of the anti-arrhythmic drug cibenzoline. Since the considerable LV hypertrophy had been indicated by an electrocardiogram and echocardiography before AVR, we suspected that dilation of the LV chamber due to aortic valve regurgitation could have masked the subclinical LVOT obstruction, which became clinically evident after LV size reduction due to reverse remodeling after AVR.

Overview of the 83rd Annual Scientific Meeting of the Japanese Circulation Society　- Renaissance of Cardiology for the Creation of Future Medicine.

The 83rdAnnual Scientific Meeting of the Japanese Circulation Society was held in Yokohama, Japan, on March 29-31, 2019, just as the cherry blossoms came into full bloom. Because the environment around cardiovascular healthcare is rapidly changing, it becomes highly important to make a breakthrough at the dawn of a new era. The main theme of this meeting was "Renaissance of Cardiology for the Creation of Future Medicine". The meeting benefited from the participation of 18,825 people, and there were in-depth and extensive discussions at every session, focusing on topics covering clinical and basic research, medical care provision system, human resource development, and public awareness in cardiovascular medicine. The meeting was completed with great success, and we greatly appreciate the tremendous cooperation and support from all affiliates.

Various Cardiac Abnormalities Caused by Bacterial Myocarditis.

A 69-year-old woman without any past disease history was hospitalized for heart failure. After hospitalization, she showed myocardial infarction, atrioventricular dissociation, and cardiac dysfunction, and finally she passed away despite intensive care. Autopsy revealed that the cardiac abnormalities were due to bacterial myocarditis possibly resulting from urinary tract infection by E. coli. Although bacterial myocarditis is rare in developed countries, we should consider its possibility when patients show various cardiac abnormalities with bacterial infection.

Adrenal insufficiency causes life-threatening arrhythmia with prolongation of QT interval.

A 63-year-old woman who had hypopituitarism was re-admitted to our hospital because of fever, diarrhea and disturbance of consciousness with life-threatening arrhythmia due to prolongation of the QT interval. She has been treated with hydrocortisone consequently, and has shown few ventricular arrhythmias with normalization of the QT interval. There have been several reports showing the case of prolonged QT interval with adrenal insufficiency, but there are few reports of isolated adrenocorticotropic hormone deficiency without any electrolytes imbalance that showed polymorphic ventricular tachycardia associated with QT prolongation. We discuss some possible mechanisms of how adrenal insufficiency causes life-threatening arrhythmia. Since lack of glucocorticoid hormone might induce prolongation of the QT interval, patients with adrenal insufficiency should be paid attention as candidates of lethal arrhythmias particularly when exposed to excessive stresses.

Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation.

OBJECTIVE: The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases, such as atherosclerosis and restenosis, after percutaneous coronary intervention. Many studies have shown that estrogen inhibits VSMC proliferation in response to vascular injury in the mouse carotid injury model. However, the mechanisms that mediate these effects remain unclear. Here, we investigated the mechanisms by which estrogen inhibits VSMC proliferation. APPROACH AND RESULTS: We established a novel transgenic mouse line, referred to as the disrupting peptide mice, in which rapid estrogen receptor (ER)-mediated signaling is abolished by overexpression of a peptide that prevents the ER from forming a signaling complex necessary for rapid signaling. Carotid artery VSMCs from disrupting peptide mice or littermate wild-type female mice were obtained by the explant method. In VSMCs derived from wild-type mice, estrogen significantly inhibited VSMC proliferation. Phosphorylation levels of Akt and extracellular regulated kinase induced by platelet derived growth factor were significantly inhibited by estrogen pretreatment. Estrogen enhanced complex formation between ERα and protein phosphatase 2A (PP2), and enhanced PP2A activity. The blockade of PP2A activity abolished the estrogen-induced antiproliferative effect on VSMCs. In contrast, none of these effects of estrogen observed in the wild-type VSMCs were observed in VSMCs derived from disrupting peptide mice. These results support that rapid, non-nuclear ER signaling is required for estrogen-induced inhibition of VSMC proliferation, and further that PP2A activation by estrogen mediates estrogen-induced antiproliferative effects. CONCLUSIONS: These findings support that PP2A activation via rapid, non-nuclear ER signaling may be a novel target for therapeutic approaches to inhibit VSMC proliferation, which plays a central role in atherosclerosis and restenosis.

[Brain mechanisms of depression--preliminary evidence from fMRI studies].

Although brain monoamines serotonin, noradrenaline, and dopamine have been repeatedly shown to be linked to depression, it remains unclear how monoamine dysfunction is mechanistically related to symptoms of depression. We hypothesized that imbalances in the networks of regions innervated by monoamines disrupt patients' learning and decision-making abilities, and this disruption could, in turn, lead to symptoms of depression. We have conducted functional magnetic resonance imaging (fMRI) studies on learning and decision-making, mainly focusing on the role of serotonin. Our results suggest that parallel organization for reward prediction at different time scales in the striatum is under differential modulation by serotonin, and that depression is associated with a diminished recruitment of the dorsal striatum, involved in long-term reward prediction. Based on these findings, the brain mechanisms of depression are discussed.

Inhibitory effects of naringenin on estrogen deficiency-induced obesity via regulation of mitochondrial dynamics and AMPK activation associated with white adipose tissue browning.

AIMS: Post-ovariectomy (OVX) changes in hormones induce obesity and white adipose tissue (WAT) inflammation. Increased energy expenditure via WAT browning is a novel therapeutic strategy for treating obesity. Naringenin (NAR) reduces inflammation and lipogenesis in obesity and attenuates estrogen deficiency-associated metabolic disorders; however, its role in WAT browning remains unclear. MATERIALS AND METHODS: We investigated NAR ability to inhibit estrogen deficiency-associated obesity in vivo using a rat model and in vitro using 3T3-L1 adipocytes. KEY FINDINGS: NAR significantly decreased the body weight and WAT mass of rats. O2 consumption, CO2 production, and energy expenditure were significantly lower in the OVX group than in the sham group, but NAR treatment reversed these effects of OVX. NAR treatment markedly improved glucose intolerance and lipid profiles as well as leptin, adiponectin, and irisin levels. NAR upregulated markers of browning and mitochondrial biogenesis in inguinal WAT. Moreover, it enhanced markers of mitochondrial fusion and inhibited fission via activating the AMP-activated protein kinase pathway. Similar results were observed in 3T3-L1 adipocytes. Moreover, NAR-induced mitochondrial biogenesis and fusion were suppressed by dorsomorphin (an AMP-activated protein kinase inhibitor). SIGNIFICANCE: NAR alleviates obesity and metabolic dysfunction through the induction of WAT browning achieved via the modulation of AMP-activated protein kinase-regulated mitochondrial dynamics in WATs. NAR supplementation may therefore represent a potential intervention for preventing postmenopausal adipose tissue dysregulation.

Endothelial estrogen - myocardial cGMP axis critically determines angiogenesis and cardiac performance during pressure-overload.

AIM: Estrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Estrogen receptor α (ERα) non-nuclear signaling confers protection against heart failure remodeling, involving myocardial cyclic guanosine monophosphate (cGMP) - cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examined the cell type-specific role of ERα non-nuclear signaling in estrogen-conferred protection against heart failure. METHODS AND RESULTS: We first assessed the tissue-specific impacts of ERα in estrogen's cardiac benefits, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3week pressure-overload (TAC). E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signaling in endothelial cells, employing animals with endothelial-specific inactivation of ERα non-nuclear signaling (ERαKI/KI/Tie2Cre+). Female OVX mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+ TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which was associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed with CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+ was rescued by myocardial PKG activation from chronic treatment with soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required co-existence of intact endothelial ERα signaling in a NOS-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of endothelial cells. CONCLUSIONS: An endothelial estrogen - myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure-overload.

Rapid estrogen receptor signaling is essential for the protective effects of estrogen against vascular injury.

BACKGROUND: Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which, when bound to estrogen, can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a rapid nonnuclear signaling cascade. However, the biological significance of this rapid signaling pathway has been unclear. METHODS AND RESULTS: In the present study, we develop a novel transgenic mouse in which rapid signaling is blocked by overexpression of a peptide that prevents ERs from interacting with the scaffold protein striatin (the disrupting peptide mouse). Microarray analysis of ex vivo treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the disrupting peptide mouse after carotid artery wire injury. CONCLUSIONS: Taken together, these results support the concept that rapid, nonnuclear ER signaling contributes to the transcriptional regulatory functions of ER and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents.

Perivascular adipose tissue in vascular pathologies-a novel therapeutic target for atherosclerotic disease?

Most blood vessels are surrounded by adipose tissues known as perivascular adipose tissue (PVAT). Emerging experimental data have implicated the potential involvement of PVAT in the pathogenesis of cardiovascular disease: PVAT might be a source of inflammatory mediators under pathological conditions such as metabolic disorders, chronic inflammation, and aging, leading to vascular pathologies, while having vasculo-protective roles in a healthy state. PVAT has been also gaining attention in human disease conditions. Recent integrative omics approaches have greatly enhanced our understanding of the molecular mechanisms underlying the diverse functions of PVAT. This review summarizes recent progress in PVAT research and discusses the potential of PVAT as a target for the treatment of atherosclerosis.

The emerging role of estrogen's non-nuclear signaling in the cardiovascular disease.

Sexual dimorphism exists in the epidemiology of cardiovascular disease (CVD), which indicates the involvement of sexual hormones in the pathophysiology of CVD. In particular, ample evidence has demonstrated estrogen's protective effect on the cardiovascular system. While estrogen receptors, bound to estrogen, act as a transcription factor which regulates gene expressions by binding to the specific DNA sequence, a subpopulation of estrogen receptors localized at the plasma membrane induces activation of intracellular signaling, called "non-nuclear signaling" or "membrane-initiated steroid signaling of estrogen". Although the precise molecular mechanism of non-nuclear signaling as well as its physiological impact was unclear for a long time, recent development of genetically modified animal models and pathway-selective estrogen receptor stimulant bring new insights into this pathway. We review the published experimental studies on non-nuclear signaling of estrogen, and summarize its role in cardiovascular system, especially focusing on: (1) the molecular mechanism of non-nuclear signaling; (2) the design of genetically modified animals and pathway-selective stimulant of estrogen receptor.

Effects of inhaling essential oils of Citrus limonum L., Santalum album, and Cinnamomum camphora on human brain activity.

INTRODUCTION: Essential oil inhalation has various effects on the human body. However, its effects on cognitive function and the neural basis remain unclear. We aimed to investigate the effects of inhaling lemon, sandalwood, and kusunoki essential oils on human brain activity and memory function using multichannel electroencephalography and brain source activity estimation. METHODS: Participants performed a letter 2-back working memory task during electroencephalography measurements before and after essential oil inhalation. Brain activation, task difficulty, concentration degree, and task performance were compared among the essential oils and a fragrance-free control. RESULTS: Task performance significantly improved after lemon essential oil inhalation. Lemon essential oil inhalation resulted in delta and theta band activation in the prefrontal cortex, including the anterior cingulate gyrus and orbitofrontal cortex, superior temporal gyrus, parahippocampal gyrus, and insula. During inhalation, persistent alpha band activation was observed in the prefrontal cortex, including the anterior cingulate gyrus. Sandalwood essential oil inhalation led to beta and gamma band activation in the prefrontal cortex, including the anterior cingulate gyrus. CONCLUSION: Our findings demonstrate that different essential oils have specific effects on brain activity related to emotion and memory processing.

Free energy model of emotional valence in dual-process perceptions.

An appropriate level of arousal induces positive emotions, and a high arousal potential may provoke negative emotions. To explain the effect of arousal on emotional valence, we propose a novel mathematical framework of arousal potential variations in the dual process of human cognition: automatic and controlled. A suitable mathematical formulation to explain the emotions in the dual process is still absent. Our model associates free energy with arousal potential and its variations to explain emotional valence. Decreasing and increasing free energy consequently induce positive and negative emotions, respectively. We formalize a transition from the automatic to the controlled process in the dual process as a change of Bayesian prior. Further, we model emotional valence using free energy increase (FI) when one tries changing one's Bayesian prior and its reduction (FR) when one succeeds in recognizing the same stimuli with a changed prior and define three emotions: "interest," "confusion," and "boredom" using the variations. The results of our mathematical analysis comparing various Gaussian model parameters reveals the following: (1) prediction error (PR) increases FR (representing "interest") when the first prior variance is greater than the second prior variance, (2) PR decreases FR when the first prior variance is less than the second prior variance, and (3) the distance between priors' means always increases FR. We also discuss the association of the outcomes with emotions in the controlled process. The proposed mathematical model provides a general framework for predicting and controlling emotional valence in the dual process that varies with viewpoint and stimuli, as well as for understanding the contradictions in the effects of arousal on the valence.

Vertebral osteomyelitis secondary to infective endocarditis detected by repeated magnetic resonance imaging: a case report.

Background: Patients with infective endocarditis (IE) experience various symptoms, a major one being back pain, which is occasionally caused by concomitant vertebral osteomyelitis (VO). Magnetic resonance imaging (MRI) is generally used to detect VO; however, the sensitivity of detection using MRI is very low in the early stages of VO. Case summary: A 60-year-old man visited our hospital with complaints of fever and persistent back pain over the past 7 days. A holosystolic heart murmur was auscultated, and an echocardiography revealed a vegetation on the posterior mitral leaflet. Blood cultures were positive for Streptococcus sanguinis. He was diagnosed with IE and treated with antimicrobials. A lumbar spine MRI on Day 1 showed no clear signs of vertebral infection, but the back pain continued and gradually worsened. Magnetic resonance imaging retest on Day 8 showed high signal intensity within the lumbar vertebral bodies and the disk on T2-weighted sequences, indicating VO. Intravenous antimicrobial therapy was extended, followed by oral antimicrobials, and a corset was put on to protect the lumbar spine to prevent bone degradation. Discussion: For persistent back pain in IE patients, repeat MRIs at regular intervals of time can detect possible vertebral infection even if signs of vertebral infection were absent on the initial MRI.

Paving the Way for Memory Enhancement: Development and Examination of a Neurofeedback System Targeting the Medial Temporal Lobe.

Neurofeedback (NF) shows promise in enhancing memory, but its application to the medial temporal lobe (MTL) still needs to be studied. Therefore, we aimed to develop an NF system for the memory function of the MTL and examine neural activity changes and memory task score changes through NF training. We created a memory NF system using intracranial electrodes to acquire and visualise the neural activity of the MTL during memory encoding. Twenty trials of a tug-of-war game per session were employed for NF and designed to control neural activity bidirectionally (Up/Down condition). NF training was conducted with three patients with drug-resistant epilepsy, and we observed an increasing difference in NF signal between conditions (Up-Down) as NF training progressed. Similarities and negative correlation tendencies between the transition of neural activity and the transition of memory function were also observed. Our findings demonstrate NF's potential to modulate MTL activity and memory encoding. Future research needs further improvements to the NF system to validate its effects on memory functions. Nonetheless, this study represents a crucial step in understanding NF's application to memory and provides valuable insights into developing more efficient memory enhancement strategies.

Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report.

Glycogen storage disease type III (GSD-III) is an autosomal recessive metabolic disorder caused by mutations in the AGL gene, and may develop various types of pulmonary hypertension (PH). Here, we report a case of 24-year-old man with GSD-IIIb with two novel null variants in AGL (c.2308 + 2T>C and c.3045_3048dupTACC). He developed multi-drug-resistant pulmonary veno-occlusive disease (PVOD) and was registered as a candidate for lung transplantation. No pathogenic variants were detected in previously known causative genes for pulmonary hypertension and the underlying mechanism of coincidence of two rare diseases was unknown. We discuss the association of the loss of glycogen-debranching enzyme with incident PVOD.