Neurobiological mechanisms of electroconvulsive therapy for depression: Insights into hippocampal volumetric increases from clinical and preclinical studies.

Depression is a highly prevalent and disabling psychiatric disorder. The hippocampus, which plays a central role in mood regulation and memory, has received considerable attention in depression research. Electroconvulsive therapy (ECT) is the most effective treatment for severe pharmacotherapy-resistant depression. Although the working mechanism of ECT remains unclear, recent magnetic resonance imaging (MRI) studies have consistently reported increased hippocampal volumes following ECT. The clinical implications of these volumetric increases and the specific cellular and molecular significance are not yet fully understood. This narrative review brings together evidence from animal models and human studies to provide a detailed examination of hippocampal volumetric increases following ECT. In particular, our preclinical MRI research using a mouse model is consistent with human findings, demonstrating a marked increase in hippocampal volume following ECT. Notable changes were observed in the ventral hippocampal CA1 region, including dendritic growth and increased synaptic density at excitatory synapses. Interestingly, inhibition of neurogenesis did not affect the ECT-related hippocampal volumetric increases detected on MRI. However, it remains unclear whether these histological and volumetric changes would be correlated with the clinical effect of ECT. Hence, future research on the relationships between cellular changes, ECT-related brain volumetric changes, and antidepressant effect could benefit from a bidirectional translational approach that integrates human and animal models. Such translational research may provide important insights into the mechanisms and potential biomarkers associated with ECT-induced hippocampal volumetric changes, thereby advancing our understanding of ECT for the treatment of depression.

Separate optogenetic manipulation of Nerve/glial antigen 2 (NG2) glia and mural cells using the NG2 promoter.

Nerve/glial antigen 2 (NG2) is a protein marker of NG2 glia and mural cells, and NG2 promoter activity is utilized to target these cells. However, the NG2 promoter cannot target NG2 glia and mural cells separately. This has been an obstacle for NG2 glia-specific manipulation. Here, we developed transgenic mice in which either cell type can be targeted using the NG2 promoter. We selected a tetracycline-controllable gene induction system for cell type-specific transgene expression, and generated NG2-tetracycline transactivator (tTA) transgenic lines. We crossed tTA lines with the tetO-ChR2 (channelrhodopsin-2)-EYFP line to characterize tTA-dependent transgene induction. We isolated two unique NG2-tTA mouse lines: one that induced ChR2-EYFP only in mural cells, likely due to the chromosomal position effect of NG2-tTA insertion, and the other that induced it in both cell types. We then applied a Cre-mediated set-subtraction strategy to the latter case and eliminated ChR2-EYFP from mural cells, resulting in NG2 glia-specific transgene induction. We further demonstrated that tTA-dependent ChR2 expression could manipulate cell function. Optogenetic mural cell activation decreased cerebral blood flow, as previously reported, indicating that tTA-mediated ChR2 expression was sufficient to impact cellular function. ChR2-mediated depolarization was observed in NG2 glia in acute hippocampal slices. In addition, ChR2-mediated depolarization of NG2 glia inhibited their proliferation but promoted their differentiation in juvenile mice. Since the tTA-tetO combination is expandable, the mural cell-specific NG2-tTA line and the NG2 glia-specific NG2-tTA line will permit us to conduct observational and manipulation studies to examine in vivo function of these cells separately.

Region- and Cell Type-Specific Facilitation of Synaptic Function at Destination Synapses Induced by Oligodendrocyte Depolarization.

The axonal conduction of action potentials affects the absolute time it takes to transmit nerve impulses as well as temporal summation at destination synapses. At the physiological level, oligodendrocyte depolarization facilitates axonal conduction along myelinated fibers in the hippocampus; however, the functional significance of this facilitation is largely unknown. In this study, we examined the physiology of the facilitation of axonal conduction by investigating the changes in synaptic responses at destination synapses using male and female mice in which channelrhodopsin-2 expression was restricted to oligodendrocytes. The subiculum, one of the projection areas of the examined axons at the alveus of the hippocampus, is divided into three regions (proximal, mid, and distal) and contains two types of principal neurons: regular firing and bursting pyramidal cells. We found a significant increase in excitatory synaptic responses following optogenetic oligodendrocyte depolarization in bursting neurons at two of the three regions, but not in regular firing neurons at any region. The long-term potentiation (LTP) induced by theta burst stimulation at the synapses showing a significant increase was also enhanced after oligodendrocyte depolarization. Conversely, the reduction of oligodendrocyte depolarization during theta burst stimulation, which was achieved by photostimulation of archaerhodopsin-T expressed selectively on oligodendrocytes, reduced the magnitude of LTP. These results show that oligodendrocyte depolarization contributes to the fine control of synaptic activity between the axons they myelinate and targets subicular cells in a region- and cell type-specific manner, and suggest that oligodendrocyte depolarization during conditioning of stimuli is involved in the induction of LTP.SIGNIFICANCE STATEMENT All activity in the nervous system depends on the propagation of action potentials. Changes in the axonal conduction of action potentials influence the timing of synaptic transmission and information processing in neural circuits. At the physiological level, oligodendrocyte depolarization facilitates axonal conduction along myelinated fibers. In this study, we investigated the functional significance of the facilitation of axonal conduction induced by physiological oligodendrocyte depolarization. Using optogenetics and electrophysiological recordings, we demonstrated that oligodendrocyte depolarization in mice expressing channelrhodopsin-2 on oligodendrocytes increased excitatory synaptic responses and enhanced the induction of long-term potentiation at destination synapses in a region- and cell type-specific manner. This facilitation may have a hitherto unappreciated influence on the transfer of information between regions in the nervous system.

Diffusion functional MRI reveals global brain network functional abnormalities driven by targeted local activity in a neuropsychiatric disease mouse model.

Diffusion functional magnetic resonance imaging (DfMRI) has been proposed as an alternative functional imaging method to detect brain activity without confounding hemodynamic effects. Here, taking advantage of this DfMRI feature, we investigated abnormalities of dynamic brain function in a neuropsychiatric disease mouse model (glial glutamate transporter-knockdown mice with obsessive-compulsive disorder [OCD]-related behavior). Our DfMRI approaches consisted of three analyses: resting state brain activity, functional connectivity, and propagation of neural information. We detected hyperactivation and biased connectivity across the cortico-striatal-thalamic circuitry, which is consistent with known blood oxygen-level dependent (BOLD)-fMRI patterns in OCD patients. In addition, we performed ignition-driven mean integration (IDMI) analysis, which combined activity and connectivity analyses, to evaluate neural propagation initiated from brain activation. This analysis revealed an unbalanced distribution of neural propagation initiated from intrinsic local activation to the global network, while these were not detected by the conventional method with BOLD-fMRI. This abnormal function detected by DfMRI was associated with OCD-related behavior. Together, our comprehensive DfMRI approaches can successfully provide information on dynamic brain function in normal and diseased brains.

Water diffusion closely reveals neural activity status in rat brain loci affected by anesthesia.

Diffusion functional MRI (DfMRI) reveals neuronal activation even when neurovascular coupling is abolished, contrary to blood oxygenation level-dependent (BOLD) functional MRI (fMRI). Here, we show that the water apparent diffusion coefficient (ADC) derived from DfMRI increased in specific rat brain regions under anesthetic conditions, reflecting the decreased neuronal activity observed with local field potentials (LFPs), especially in regions involved in wakefulness. In contrast, BOLD signals showed nonspecific changes, reflecting systemic effects of the anesthesia on overall brain hemodynamics status. Electrical stimulation of the central medial thalamus nucleus (CM) exhibiting this anesthesia-induced ADC increase led the animals to transiently wake up. Infusion in the CM of furosemide, a specific neuronal swelling blocker, led the ADC to increase further locally, although LFP activity remained unchanged, and increased the current threshold awakening the animals under CM electrical stimulation. Oppositely, induction of cell swelling in the CM through infusion of a hypotonic solution (-80 milliosmole [mOsm] artificial cerebrospinal fluid [aCSF]) led to a local ADC decrease and a lower current threshold to wake up the animals. Strikingly, the local ADC changes produced by blocking or enhancing cell swelling in the CM were also mirrored remotely in areas functionally connected to the CM, such as the cingulate and somatosensory cortex. Together, those results strongly suggest that neuronal swelling is a significant mechanism underlying DfMRI.

Utility of Regular Management of Physical Activity and Physical Function in Hemodialysis Patients.

BACKGROUND/AIMS: Several clinical practice guidelines recommend regular assessment of physical activity and physical function as part of routine care in hemodialysis patients. However, there is no clear evidence to support these recommendations. We investigated whether the proportion of attendance at a regular program for management of physical activity and physical function can predict all-cause mortality and cardiovascular events in hemodialysis patients. METHODS: This retrospective cohort study consisted of 266 hemodialysis patients participating in the management program at least once. Participants were tracked for 3 years after their first attendance at the management program to determine their attendance proportion. The main study outcomes included all-cause mortality and a composite of fatal and nonfatal cardiovascular events. RESULTS: Median patient age was 64.5 (interquartile range, 56.8 - 72.0) years, 45% were women, and the median time on hemodialysis was 35.5 (interquartile range, 12.0 - 114.3) months at baseline. Sixty-five patients died over a median follow-up of 79 months. The incidence of cardiovascular events was 60 over a median follow-up of 68 months. Even after adjusting for any of the prognostic models, participants who attended ≤ 75% of sessions (n = 140) had higher risks of mortality (hazard ratio (HR), 1.79; 95% confidence interval (CI): 1.00 - 3.36; P = 0.049) and cardiovascular events (HR, 1.84; 95% CI: 1.07 - 3.48; P = 0.03) than those attending > 75% of sessions (n = 126). CONCLUSION: Hemodialysis patients in whom physical activity and physical function could be assessed more regularly had better prognosis than those with only intermittent assessment.

Neurogenesis-independent mechanisms of MRI-detectable hippocampal volume increase following electroconvulsive stimulation.

Electroconvulsive therapy (ECT) is one of the most effective psychiatric treatments but the underlying mechanisms are still unclear. In vivo human magnetic resonance imaging (MRI) studies have consistently reported ECT-induced transient hippocampal volume increases, and an animal model of ECT (electroconvulsive stimulation: ECS) was shown to increase neurogenesis. However, a causal relationship between neurogenesis and MRI-detectable hippocampal volume increases following ECT has not been verified. In this study, mice were randomly allocated into four groups, each undergoing a different number of ECS sessions (e.g., 0, 3, 6, 9). T2-weighted images were acquired using 11.7-tesla MRI. A whole brain voxel-based morphometry analysis was conducted to identify any ECS-induced brain volume changes. Additionally, a histological examination with super-resolution microscopy was conducted to investigate microstructural changes in the brain regions that showed volume changes following ECS. Furthermore, parallel experiments were performed on X-ray-irradiated mice to investigate the causal relationship between neurogenesis and ECS-related volume changes. As a result, we revealed for the first time that ECS induced MRI-detectable, dose-dependent hippocampal volume increase in mice. Furthermore, increased hippocampal volumes following ECS were seen even in mice lacking neurogenesis, suggesting that neurogenesis is not required for the increase. The comprehensive histological analyses identified an increase in excitatory synaptic density in the ventral CA1 as the major contributor to the observed hippocampal volume increase following ECS. Our findings demonstrate that modification of synaptic structures rather than neurogenesis may be the underlying biological mechanism of ECT/ECS-induced hippocampal volume increase.

Optogenetic activation of dorsal raphe serotonin neurons induces brain-wide activation.

Serotonin is a neuromodulator that affects multiple behavioral and cognitive functions. Nonetheless, how serotonin causes such a variety of effects via brain-wide projections and various receptors remains unclear. Here we measured brain-wide responses to optogenetic stimulation of serotonin neurons in the dorsal raphe nucleus (DRN) of the male mouse brain using functional MRI with an 11.7 T scanner and a cryoprobe. Transient activation of DRN serotonin neurons caused brain-wide activation, including the medial prefrontal cortex, the striatum, and the ventral tegmental area. The same stimulation under anesthesia with isoflurane decreased brain-wide activation, including the hippocampal complex. These brain-wide response patterns can be explained by DRN serotonergic projection topography and serotonin receptor expression profiles, with enhanced weights on 5-HT1 receptors. Together, these results provide insight into the DR serotonergic system, which is consistent with recent discoveries of its functions in adaptive behaviors.

Relationship among Falls, Fear of Falling, and Physical Activity Level in Patients on Hemodialysis.

OBJECTIVE: Patients on hemodialysis are highly susceptible to falls and fractures. Amplified apprehension regarding the fear of falling (FOF) constitutes a risk factor that restricts physical activity and escalates the probability of falls among the elderly population. This study aimed to elucidate the association between falls and FOF and physical activity in patients on hemodialysis. METHODS: A prospective cohort study was conducted across 9 centers. FOF was assessed using the Falls Efficacy Scale-International (FES-I). Physical activity was assessed using the Japanese version of the International Physical Activity Questionnaire short form. Subsequently, falls were monitored over a duration of 1 year. Logistic regression analysis was performed to evaluate the relationship between falls and FOF and physical activity. In addition, in the receiver operating characteristic analysis, the cutoff value of FES-I that predicts falls was determined using the Youden Index. A restricted cubic spline curve was utilized to analyze the nonlinear association between falls and the FES-I. RESULTS: A total of 253 patients on hemodialysis (70.0 [59.0-77.0] years old; 105 female [41.5%]) were included in the analysis. During the 1-year observation period, 90 (35.6%) patients experienced accidental falls. The median FES-I score was 36.0 (24.0-47.0) points, and patients with higher FES-I scores had more falls. Following adjusted logistic regression analysis, FES-I exhibited an independent association with falls (OR = 1.04; 95% CI = 1.01-1.06), but physical activity was not. The area under the receiver operating characteristic curve was 0.70 (95% CI = 0.64-0.77), and the FES-I threshold value for distinguishing fallers from non-fallers was determined as 37.5 points (sensitivity 65.6%, specificity 35.0%). A nonlinear relationship between falls and FES-I was observed. CONCLUSION: FOF was associated with the incidence of falls in patients on hemodialysis. IMPACT: The evaluation and implementation of interventions targeting the FOF may mitigate the risk of falls.

Involvement of glial P2Y1 receptors in cognitive deficit after focal cerebral stroke in a rodent model.

BACKGROUND: Neuroinflammation is associated with many conditions that lead to dementia, such as cerebrovascular disorders or Alzheimer's disease. However, the specific role of neuroinflammation in the progression of cognitive deficits remains unclear. To understand the molecular mechanisms underlying these events we used a rodent model of focal cerebral stroke, which causes deficits in hippocampus-dependent cognitive function. METHODS: Cerebral stroke was induced by middle cerebral artery occlusion (MCAO). Hippocampus-dependent cognitive function was evaluated by a contextual fear conditioning test. The glial neuroinflammatory responses were investigated by immunohistochemical evaluation and diffusion tensor MRI (DTI). We used knockout mice for P2Y1 (P2Y1KO), a glial ADP/ATP receptor that induces the release of proinflammatory cytokines, to examine the links among P2Y1-mediated signaling, the neuroinflammatory response, and cognitive function. RESULTS: Declines in cognitive function and glial neuroinflammatory response were observed after MCAO in both rats and mice. Changes in the hippocampal tissue were detected by DTI as the mean diffusivity (MD) value, which corresponded with the cognitive decline at 4 days, 1 week, 3 weeks, and 2 months after MCAO. Interestingly, the P2Y1KO mice with MCAO showed a decline in sensory-motor function, but not in cognition. Furthermore, the P2Y1KO mice showed neither a hippocampal glial neuroinflammatory response (as assessed by immunohistochemistry) nor a change in hippocampal MD value after MCAO. In addition, wild-type mice treated with a P2Y1-specific antagonist immediately after reperfusion did not show cognitive decline. CONCLUSION: Our findings indicate that glial P2Y1 receptors are involved in the hippocampal inflammatory response. The findings from this study may contribute to the development of a therapeutic strategy for brain infarction, targeting the P2Y1 receptor.

Association of habitual physical activity measured by an accelerometer with high-density lipoprotein cholesterol levels in maintenance hemodialysis patients.

After confirming the relationship between high-density lipoprotein cholesterol (HDL-C) levels and mortality in hemodialysis patients for study 1, we investigated the effect of physical activity on their HDL-C levels for study 2. In study 1, 266 hemodialysis patients were monitored prospectively for five years, and Cox proportional hazard regression confirmed the contribution of HDL-C to mortality. In study 2, 116 patients were recruited after excluding those with severe comorbidities or requiring assistance from another person to walk. Baseline characteristics, such as demographic factors, physical constitution, primary kidney disease, comorbid conditions, smoking habits, drug use, and laboratory parameters, were collected from patient hospital records. An accelerometer measured physical activity as the number of steps per day over five consecutive days, and multiple regression evaluated the association between physical activity and HDL-C levels. Seventy-seven patients died during the follow-up period. In study 1, we confirmed that HDL-C level was a significant predictor of mortality (P = 0.03). After adjusting for patient characteristics in study 2, physical activity was independently associated with HDL-C levels (adjusted R (2) = 0.255; P = 0.005). In conclusion, physical inactivity was strongly associated with decreased HDL-C levels in hemodialysis patients.

Optogenetic demonstration of the involvement of SMA-negative mural cells in the regulation of cerebral blood flow.

Mural cells are critical components of the cerebral vasculature. They are categorized into three primary subsets: arteriole smooth muscle cells (aSMCs), pericytes (PCs) and venule smooth muscle cells (vSMCs). It is well known that aSMCs can directly regulate cerebral blood flow (CBF) with their own contraction and dilation mechanisms. On the other hand, the direct involvement of PCs or vSMCs in CBF regulation is controversial. This ambiguity is largely due to the lack of specifically manipulable tools to isolate their function. To address this issue, we employed a set-subtraction approach by using a combination of tTA-mediated gene induction and Cre-mediated gene excision. We developed transgenic mice expressing optical actuators, channelrhodopsin-2 (ChR2) and photoactivated adenylyl cyclase (PAC) in smooth muscle actin (SMA)-negative mural cells that lack the machinery for SMA-mediated vasoregulation. Using these mouse models, we assessed CBF alterations in response to optical stimulation using laser Doppler techniques. Our results showed that optical stimulation induced notable CBF changes in both models. This study provides evidence for the potential regulatory role of PCs and vSMCs in cerebral hemodynamics and introduces powerful tools to specifically manipulate these cell types in vascular neurobiology.

Brain Response to Interferential Current Compared with Alternating Current Stimulation.

Temporal interference (TI) stimulation, which utilizes multiple external electric fields with amplitude modulation for neural modulation, has emerged as a potential noninvasive brain stimulation methodology. However, the clinical application of TI stimulation is inhibited by its uncertain fundamental mechanisms, and research has previously been restricted to numerical simulations and immunohistology without considering the acute in vivo response of the neural circuit. To address the characterization and understanding of the mechanisms underlying the approach, we investigated instantaneous brainwide activation patterns in response to invasive interferential current (IFC) stimulation compared with low-frequency alternative current stimulation (ACS). Results demonstrated that IFC stimulation is capable of inducing regional neural responses and modulating brain networks; however, the activation threshold for significantly recruiting a neural response using IFC was higher (at least twofold) than stimulation via alternating current, and the spatial distribution of the activation signal was restricted. A distinct blood oxygenation level-dependent (BOLD) response pattern was observed, which could be accounted for by the activation of distinct types of cells, such as inhibitory cells, by IFC. These results suggest that IFC stimulation might not be as efficient as conventional brain modulation methods, especially when considering TI stimulation as a potential alternative for stimulating subcortical brain areas. Therefore, we argue that a future transcranial application of TI on human subjects should take these implications into account and consider other stimulation effects using this technique.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

Correlation between antibiotic use and antibiotic resistance: A multicenter study using the Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system in Hokkaido, Japan.

BACKGROUND: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan. METHODS: Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro. RESULTS: The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = .015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = .023), ρ = 0.76 (P < .001), and ρ = 0.502 (P = .029), respectively]. CONCLUSIONS: This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures.

Walking speed in patients with first acute myocardial infarction who participated in a supervised cardiac rehabilitation program after coronary intervention.

This study aimed to evaluate the degree of reduction in walking speed in patients with acute myocardial infarction (AMI) compared to age-matched community-dwelling people and identify factors associated with walking speed. The subjects were 210 middle-aged and 188 elderly patients with a first AMI (AMI group) and 198 age-matched community-dwelling people with no medical events (non-AMI group). We measured maximum walking speed in all subjects and collected clinical data, including that related to motor function, at the end of a supervised cardiac rehabilitation program in the AMI group. Data were analyzed based on age and sex. Walking speed in men and women in the middle-aged AMI subgroup decreased to 77.9% and 75.7% relative to that of the non-AMI subgroup matched by sex, respectively; walking speed in men and women in the elderly AMI subgroup decreased to 78.7% and 74.2% relative to that of the non-AMI subgroup matched by sex, respectively. Moreover, 6.4% of men and 23.8% of women in the middle-aged AMI subgroup, and 28.8% of men and 43.5% of women in the elderly AMI subgroup, had a slower walking speed compared to their respective non-AMI groups, which may contribute to an increased risk for cardiovascular mortality. Stepwise multiple regression analysis for motor function revealed that only leg strength in the middle-aged AMI subgroup, and both leg strength and standing balance in the elderly AMI subgroup, were associated with walking speed, regardless of sex after adjusting for clinical characteristics. These results suggest that evaluation and management of walking speed are necessary in implementing effective disease management for patients with first AMI.

Oligodendrocytic Na+-K+-Cl- co-transporter 1 activity facilitates axonal conduction and restores plasticity in the adult mouse brain.

The juvenile brain presents plasticity. Oligodendrocytes are the myelinating cells of the central nervous system and myelination can be adaptive. Plasticity decreases from juvenile to adulthood. The mechanisms involving oligodendrocytes underlying plasticity are unclear. Here, we show Na+-K+-Cl- co-transporter 1 (NKCC1), highly expressed in the juvenile mouse brain, regulates the oligodendrocyte activity from juvenile to adulthood in mice, as shown by optogenetic manipulation of oligodendrocytes. The reduced neuronal activity in adults was restored by Nkcc1 overexpression in oligodendrocytes. Moreover, in adult mice overexpressing Nkcc1, long-term potentiation and learning were facilitated compared to age-matched controls. These findings demonstrate that NKCC1 plays a regulatory role in the age-dependent activity of oligodendrocytes, furthermore inducing activation of NKCC1 in oligodendrocytes can restore neuronal plasticity in the adult mouse brain.

Direct Impact of Motor Cortical Stimulation on the Blood Oxygen-level Dependent Response in Rats.

PURPOSE: Neuropathic pain is a complex and distressing chronic illness in modern medicine. Since 1990s, motor cortex stimulation (MCS) has emerged as a potential treatment for chronic neuropathic pain; however, the precise mechanisms underlying analgesia induced by MCS are not completely understood. The purpose of the present study was to investigate the blood oxygen-level dependent (BOLD) response in the brain during MCS. METHODS: We inserted a bipolar tungsten electrode into the primary motor cortex (M1) of adult male Wistar rats. Functional magnetic resonance imaging (fMRI) scans were implemented simultaneously with the electrical stimulation of M1 and the BOLD signals taken from the fMRI were used as an index to reflect the response against MCS. RESULTS: Our results demonstrated that the bilateral M1, ipsilateral caudate-putamen, and ipsilateral primary somatosensory cortex to the stimulation spot were activated after the onset of MCS. The BOLD signal time courses were analysed in these regions and similar temporal characteristics were found. CONCLUSION: By conducting direct cortical stimulation of the rodent brain to investigate its instant effect using fMRI, we identified encephalic regions directly involved in the instant motor cortical stimulation effects in healthy rat models. This result may be essential in establishing a foundation for further research on the underlying neuropathways associated with the MCS effects.

Effect of Layer Directions on Internal Structures and Tensile Properties of 17-4PH Stainless Steel Parts Fabricated by Fused Deposition of Metals.

17-4PH stainless steel specimens were fabricated by fused deposition of metals (FDMet) technology, which combines 17-4PH particles with an organic binder. FDMet promises a low-cost additive manufacturing process. The present research aims to clarify the influence of layer directions in the 3D printing process on the mechanical and shrinkage properties of as-sintered and as-aged specimens. All specimens (the as-sintered and as-aged specimens printed in three layer directions) exhibited high relative density (97.5-98%). The highest ultimate strengths (880 and 1140 MPa in the as-sintered and as-aged specimens, respectively) were obtained when the layer direction was perpendicular to the tensile direction. Conversely, the specimens printed with their layer direction parallel to the tensile direction presented a low ultimate strength and low strain at breakage. The fact that the specimens with their layer direction parallel to the tensile direction presented a low ultimate strength and low strain at breakage is a usual behavior of parts obtained by means of FDM. The SEM images revealed oriented binder domains in the printed parts and oriented voids in the sintered parts. It was assumed that large binder domains in the filament were oriented perpendicular to the layer directions during the fused deposition modeling printing, and remained as oriented voids after sintering. Stress concentration in the oriented void defects was likely responsible for the poor tensile properties of these specimens.

Optical manipulation of local cerebral blood flow in the deep brain of freely moving mice.

An artificial tool for manipulating local cerebral blood flow (CBF) is necessary for understanding how CBF controls brain function. Here, we generate vascular optogenetic tools whereby smooth muscle cells and endothelial cells express optical actuators in the brain. The illumination of channelrhodopsin-2 (ChR2)-expressing mice induces a local reduction in CBF. Photoactivated adenylyl cyclase (PAC) is an optical protein that increases intracellular cyclic adenosine monophosphate (cAMP), and the illumination of PAC-expressing mice induces a local increase in CBF. We target the ventral striatum, determine the temporal kinetics of CBF change, and optimize the illumination intensity to confine the effects to the ventral striatum. We demonstrate the utility of this vascular optogenetic manipulation in freely and adaptively behaving mice and validate the task- and actuator-dependent behavioral readouts. The development of vascular optogenetic animal models will help accelerate research linking vasculature, circuits, and behavior to health and disease.