Effects of transcranial magnetic stimulation on the human brain recorded with intracranial electrocorticography.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the neurophysiological effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 22 neurosurgical participants with no adverse events. We next evaluated intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N = 10, 1414 electrodes). We demonstrate that TMS is capable of inducing evoked potentials both locally within the dlPFC and in downstream regions functionally connected to the dlPFC, including the anterior cingulate and insular cortex. These downstream effects were not observed when stimulating other distant brain regions. Intracranial dlPFC electrical stimulation had similar timing and downstream effects as TMS. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

Association of socioeconomic status with 30- and 90-day readmission following open and laparoscopic hernia repair: a nationwide readmissions database analysis.

BACKGROUND: Socioeconomic disparities have been associated with outcomes in many medical conditions. The association of socioeconomic status (SES) with readmissions after ventral and inguinal hernia repair has not been well studied on a national level. This study aims to evaluate the association of SES with readmission as a significant outcome in patients undergoing ventral and inguinal hernia repair. METHODS: A retrospective cohort study was performed evaluating patients undergoing ventral hernia and inguinal hernia repair with 1:1 propensity score matching using the Nationwide Readmissions Database (2016-2017). Both 30- and 90-day readmissions were examined. After matching, a multivariate logistic regression analysis was performed using confounding variables including hospital setting, comorbidities, urgency of repair, sociodemographic status, and payer. Likelihood of readmission was reported in odds ratio form. RESULTS: Readmission rates were 11.56% (24,323 out of 210,381) and 17.94% (30,893 out of 172,210) for 30- and 90-day readmissions, respectively. Patients with Medicaid and in the lower income quartile were more likely to present in an emergent fashion for hernia repair. After matching, a multivariate logistic regression analysis showed socioeconomic status (OR 1.250 and 1.229) was a statistically significant independent predictor of readmission at 30 and 90 days, respectively. Inversely, factors associated with the least likely chance of readmission were a laparoscopic approach (OR 0.646 and 0.641), elective admission (OR 0.824 and 0.779), and care in a teaching hospital (OR 0.784 and 0.798). CONCLUSION: SES is an independent predictor of readmission at 30 and 90 days following open and laparoscopic ventral and inguinal hernia repair. Patients with a lower socioeconomic status were more likely to undergo hernia repair in the emergent setting. Efforts toward mitigating SES disparities by potentially promoting MIS techniques, enhancing access to elective cases, and systematic approaches to perioperative care for this disadvantaged population can potentially enhance overall hernia outcomes.

Rapid eye movement sleep patterns of brain activation and deactivation occur within unique functional networks.

Rapid eye movement (REM) sleep is a paradoxical state where the individual appears asleep while the electroencephalogram pattern resembles that of wakefulness. Regional differences in brain metabolism have been observed during REM sleep compared to wakefulness, but it is not known whether the spatial distribution of metabolic differences corresponds to known functional networks in the brain. Here, we use a combination of techniques to evaluate the networks associated with sites of REM sleep activation and deactivation from previously published positron emission tomography studies. We use seed-based functional connectivity from healthy adults acquired during quiet rest to show that REM-activation regions are functionally connected in a network that includes retrosplenial cingulate cortex, parahippocampal gyrus, and extrastriate visual cortices, corresponding to components of the default mode network and visual networks. Regions deactivated during REM sleep localize to right-lateralized fronto-parietal and salience networks. A negatively correlated relationship was observed between REM-activation and deactivation networks. Together, these findings show that regional activation and deactivation patterns of REM sleep tend to occur in distinct functional connectivity networks that are present during wakefulness, providing insights regarding the differential contributions of brain regions to the distinct subjective experiences that occur during REM sleep (dreaming) relative to wakefulness.

Classical monocytes maintain ex vivo glycolytic metabolism and early but not later inflammatory responses in older adults.

BACKGROUND: Inflammaging is a condition of chronic low-grade inflammation due to the aging process and is associated with a variety of chronic diseases. Monocytes are innate immune cells which contribute to inflammation and are dysregulated during aging, demonstrated reduced phagocytosis, increased inflammation, and alterations in subset proportions. Metabolism is known to determine immune cell function, with quiescent and anti-inflammatory cells primarily relying on fatty acid oxidation, while activated and inflammatory cells primarily rely on glycolysis. We have previously shown an age-related decrease in mitochondrial respiratory capacity in monocytes, so we hypothesized here that a compensatory shift toward glycolysis would occur which would also exacerbate inflammation. RESULTS: Using Seahorse assays, we profiled glycolysis in classical monocytes isolated from older (60-80 yr) and younger (18-35 yr) adults. Aging did not affect parameters of basal glycolysis in the glycolysis stress test, nor did it alter glycolytic activation early (2 h) or later (24 h) post-LPS stimulation. Cytokine gene expression was unchanged between aged and young subjects at 2 h post-LPS but was reduced in older subjects at 24 h post-LPS either significantly (IL1B) or near-significantly (IL6, IL10). CONCLUSIONS: Aging appears not to affect glycolytic metabolism ex vivo in classical monocytes, but may reduce cytokine expression at later timepoints. Studies examining monocytes stimulated with age-altered circulating factors or with other pattern recognition receptor agonists may shed further light on monocyte metabolism as a determinant of immunosenescence and inflammaging.

CD14+ monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression.

The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1ß release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for "drivers" of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets.

TCR+CD3+CD4-CD8- effector T cells in psoriasis.

The autoimmune/inflammatory disorder psoriasis is characterized by keratinocyte proliferation and immune cell infiltration of the skin. TCR+CD3+CD4-CD8- "double negative" (DN) T cells can derive from CD8+ T cells through the down-regulation of CD8. The inhibitory molecule programmed death (PD-)1 is expressed on activated T cells and plays a role in the maintenance of peripheral tolerance. A subset of DN T cells, characterized by the expression of PD-1, has recently been demonstrated to be self-reactive. We demonstrate that a majority of DN T cells exhibits effector memory phenotypes, express IFN-γ, and fail to proliferate. DN T cells from psoriasis patients are characterized by reduced DNA methylation of the IFNG gene and increased PD-1 expression. Furthermore, PD-1 positive DN T cells infiltrate the epidermis in psoriatic skin lesions. Our observations offer additional insight into the molecular pathophysiology of plaque psoriasis and show promise as potential disease biomarkers and/or therapeutic targets for future interventions.

Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training.

There is robust evidence that habitual physical activity is anti-inflammatory and protective against developing chronic inflammatory disease. Much less is known about the effects of habitual moderate exercise in the gut, the compartment that has the greatest immunological responsibility and interactions with the intestinal microbiota. The link between the two has become evident, as recent studies have linked intestinal dysbiosis, or the disproportionate balance of beneficial to pathogenic microbes, with increased inflammatory disease susceptibility. Limited animal and human research findings imply that exercise may have a beneficial role in preventing and ameliorating such diseases by having an effect on gut immune function and, recently, microbiome characteristics. Emerging data from our laboratory show that different forms of exercise training differentially impact the severity of intestinal inflammation during an inflammatory insult (for example, ulcerative colitis) and may be jointly related to gut immune cell homeostasis and microbiota-immune interactions. The evidence we review and present will provide data in support of rigorous investigations concerning the effects of habitual exercise on gut health and disease.

Effects of exercise in a relapsing-remitting model of experimental autoimmune encephalomyelitis.

Previous research has examined the effects of exercise in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. However, all previous studies have utilized a chronic model of EAE, with exercise delivered prior to or immediately after induction of EAE. To our knowledge, no study has examined the effects of exercise delivered during a remission period after initial disease onset in a relapsing-remitting model of EAE (RR-EAE). The current study examines the effects of both voluntary wheel running and forced treadmill exercise on clinical disability and hippocampal brain-derived neurotrophic factor (BDNF) in SJL mice with RR-EAE. The results demonstrate no significant effects of exercise delivered during remission after initial disease onset on clinical disability scores or levels of hippocampal BDNF in mice with RR-EAE. Furthermore, our results demonstrate no significant increase in citrate synthase activity in the gastrocnemius and soleus muscles of mice in the running wheel or treadmill conditions compared with the sedentary condition. These results suggest that the exercise stimuli might have been insufficient to elicit differences in clinical disability or hippocampal BDNF among treatment conditions. © 2016 Wiley Periodicals, Inc.

First direct limits on lightly ionizing particles with electric charge less than e/6.

While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200.

Search for low-mass weakly interacting massive particles with SuperCDMS.

We report a first search for weakly interacting massive particles (WIMPs) using the background rejection capabilities of SuperCDMS. An exposure of 577 kg days was analyzed for WIMPs with mass <30 GeV/c(2), with the signal region blinded. Eleven events were observed after unblinding. We set an upper limit on the spin-independent WIMP-nucleon cross section of 1.2×10(-42) cm(2) at 8 GeV/c(2). This result is in tension with WIMP interpretations of recent experiments and probes new parameter space for WIMP-nucleon scattering for WIMP masses <6 GeV/c(2).

Search for low-mass weakly interacting massive particles using voltage-assisted calorimetric ionization detection in the SuperCDMS experiment.

SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170 eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6 GeV/c2.

Exercise training increases size of hippocampus and improves memory.

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

BACKGROUND: Transcranial magnetic stimulation (TMS) is believed to alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach generally evaluates low-frequency neural activity at the cortical surface. However, TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct assessment of deeper and more localized oscillatory responses across the frequency spectrum. OBJECTIVE/HYPOTHESIS: Our study used iEEG to understand the effects of TMS on human neural activity in the spectral domain. We asked (1) which brain regions respond to cortically-targeted TMS, and in what frequency bands, (2) whether deeper brain structures exhibit oscillatory responses, and (3) whether the neural responses to TMS reflect evoked versus induced oscillations. METHODS: We recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at either the dorsolateral prefrontal cortex (DLPFC) or parietal cortex. iEEG signals were analyzed using spectral methods to understand the oscillatory responses to TMS. RESULTS: Stimulation to DLPFC drove widespread low-frequency increases (3-8 Hz) in frontolimbic cortices and high-frequency decreases (30-110 Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with phase-locked evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. CONCLUSIONS: By combining TMS with intracranial EEG recordings, our results suggest that TMS is an effective means to perturb oscillatory neural activity in brain-wide networks, including deeper structures not directly accessed by stimulation itself.

Silicon detector dark matter results from the final exposure of CDMS II.

We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July 2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41(-0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to <0.13 and <0.08 events at the 90% confidence level, respectively. The exposure of this analysis is equivalent to 23.4 kg day for a recoil energy range of 7-100 keV for a WIMP of mass 10 GeV/c2. The probability that the known backgrounds would produce three or more events in the signal region is 5.4%. A profile likelihood ratio test of the three events that includes the measured recoil energies gives a 0.19% probability for the known-background-only hypothesis when tested against the alternative WIMP+background hypothesis. The highest likelihood occurs for a WIMP mass of 8.6 GeV/c2 and WIMP-nucleon cross section of 1.9×10(-41) cm2.

Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis.

The purpose of this study was to examine whether exercise training reduced inflammation and symptomology in a mouse model of colitis. We hypothesized that moderate forced treadmill running (FTR) or voluntary wheel running (VWR) would reduce colitis symptoms and colon inflammation in response to dextran sodium sulfate (DSS). Male C57Bl/6J mice were randomized to sedentary, moderate intensity FTR (8-12 m/min, 40 min, 6 weeks, 5x/week), or VWR (30 days access to wheels). DSS was given at 2% (w/v) in drinking water over 5 days. Mice discontinued exercise 24 h prior to and during DSS treatment. Colons were harvested on Days 6, 8 and 12 in FTR and Day 8 post-DSS in VWR experiments. Contrary to our hypothesis, we found that moderate FTR exacerbated colitis symptomology and inflammation as measured by significant (p<0.05) increases in diarrhea and IL-6, IL-1ß, IL-17 colon gene expression. We also observed higher mortality (3/10 died vs. 0/10, p=0.07) in the FTR/DSS group. In contrast, VWR alleviated colitis symptoms and reduced inflammatory gene expression in the colons of DSS-treated mice (p<0.05). While DSS treatment reduced food/fluid intake and body weight, there was a tendency for FTR to exacerbate, and for VWR to attenuate, this effect. FTR (in the absence of DSS) increased gene expression of the chemokine and antibacterial protein CCL6 suggesting that FTR altered gut homeostasis that may be related to the exaggerated response to DSS. In conclusion, we found that FTR exacerbated, whereas VWR attenuated, symptoms and inflammation in response to DSS.

Effects of voluntary wheel running on LPS-induced sickness behavior in aged mice.

Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged sickness behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and sickness in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced sickness behavior and proinflammatory cytokine gene expression in ~22-month-old C57BL/6J mice. Mice were housed with a running wheel (VWR), locked-wheel (Locked), or no wheel (Standard) for 10 weeks, after which they were intraperitoneally injected with LPS across a range of doses (0.02, 0.08, 0.16, 0.33 mg/kg). VWR mice ran on average 3.5 km/day and lost significantly more body weight and body fat, and increased their forced exercise tolerance compared to Locked and Shoebox mice. VWR had no effect on LPS-induced anorexia, adipsia, weight-loss, or reductions in locomotor activity at any LPS dose when compared to Locked and Shoebox groups. LPS induced sickness behavior in a dose-dependent fashion (0.33>0.02 mg/kg). Twenty-four hours post-injection (0.33 mg/kg LPS or Saline) we found a LPS-induced upregulation of whole brain TNFα, IL-1ß, and IL-10 mRNA, and increased IL-1ß and IL-6 in the spleen and liver; these effects were not attenuated by VWR. We conclude that VWR does not reduce LPS-induced exaggerated or prolonged sickness behavior in aged animals, or 24h post-injection (0.33 mg/kg LPS or Saline) brain and peripheral proinflammatory cytokine gene expression. The necessity of the sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.

Neurobiological markers of exercise-related brain plasticity in older adults.

The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age=66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.

Mitochondrial dysfunction at the cornerstone of inflammatory exacerbation in aged macrophages.

Immunosenescence encompasses multiple age-related adaptations that result in increased susceptibility to infections, chronic inflammatory disorders, and higher mortality risk. Macrophages are key innate cells implicated in inflammatory responses and tissue homeostasis, functions progressively compromised by aging. This process coincides with declining mitochondrial physiology, whose integrity is required to sustain and orchestrate immune responses. Indeed, multiple insults observed in aged macrophages have been implied as drivers of mitochondrial dysfunction, but how this translates into impaired immune function remains sparsely explored. This review provides a perspective on recent studies elucidating the underlying mechanisms linking dysregulated mitochondria homeostasis to immune function in aged macrophages. Genomic stress alongside defective mitochondrial turnover accounted for the progressive accumulation of damaged mitochondria in aged macrophages, thus resulting in a higher susceptibility to excessive mitochondrial DNA (mtDNA) leakage and reactive oxygen species (ROS) production. Increased levels of these mitochondrial products following infection were demonstrated to contribute to exacerbated inflammatory responses mediated by overstimulation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and cyclic GMP-ATP synthase (cGAS)-stimulator of interferon genes (STING) pathways. While these mechanisms are not fully elucidated, the present evidence provides a promising area to be explored and a renewed perspective of potential therapeutic targets for immunological dysfunction.

TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

Transcranial magnetic stimulation (TMS) is increasingly deployed in the treatment of neuropsychiatric illness, under the presumption that stimulation of specific cortical targets can alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach is most useful for evaluating low-frequency neural activity at the cortical surface. As such, little is known about how TMS perturbs rhythmic activity among deeper structures - such as the hippocampus and amygdala - and whether stimulation can alter higher-frequency oscillations. Recent work has established that TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct neural recordings at sufficient spatiotemporal resolution to examine localized oscillatory responses across the frequency spectrum. To that end, we recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at several cortical sites. Stimulation to the dorsolateral prefrontal cortex (DLPFC) drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices, as well as high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with brief evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. Taken together, we established that non-invasive stimulation can (1) provoke a mixture of low-frequency evoked power and induced theta oscillations and (2) suppress high-frequency activity in deeper brain structures not directly accessed by stimulation itself.

Dietary whole glucan particles do not affect antibody or cell-mediated immune responses to influenza virus vaccination in mice.

Influenza virus is a serious health concern. ß-glucans derived from plants, bacteria, and fungi have been shown to potentiate immune system responses including those elicited by vaccination. However, in these studies ß-glucan was administered as an adjuvant in the vaccine preparation. We hypothesized that addition of a commercially available whole glucan particle supplement to the diet would improve immune response to primary and secondary influenza vaccination in mice. ß-glucan was added to pelleted diet and fed to mice at concentrations designed to deliver 0 (control), 1.8 or 90 mg·kg(-1)·day(-1) to each mouse. Influenza vaccine was given intramuscularly in the left hindlimb and primary and secondary responses were assessed. Supplementation with ß-glucan was not effective in boosting immune responses to the vaccine, either in the primary or secondary vaccination experiments. Surprisingly, addition of particulate ß-glucan to the vaccine itself also failed to elicit a greater antibody response. These observations suggest that this particular form of ß-glucan is ineffective in boosting immune response to intramuscular influenza vaccination. Further study is warranted to determine if the use of different mouse models, different vaccine delivery systems, or ß-glucans purified from different strains of bacteria, fungi, or plants could improve outcomes using this or similar protocols.