Ameliorating effects of mirtazapine on visceral hypersensitivity in rats with neonatal colon sensitivity

Background The aim was to investigate the effects of mirtazapine on visceral hypersensitivity and gastric emptying in an established rodent model of colonic sensitization. Methods Twenty colonic sensitized rats and 20 matched controls were used. Visceral sensitivity during colorectal distension (CRD) was assessed by the measurement of abdominal electromyogram (EMG) with the pressures of 20, 40, and 60 mmHg. Mirtazapine with doses of 1, 5, and 10 mg kg⁻¹ were administered orally. Gastric emptying and small intestinal transit were performed in a separated experiment after gavage of 1.5 mL of phenol red solution. Key Results (i) Visceral hypersensitivity after neonatal colonic sensitization was confirmed. (ii) Mirtazapine dose‐dependently reduced visceral hypersensitivity in the colonic sensitized rats. The increases in EMG during CRD at 40, 60 mmHg were, 17.59 ± 6.49 and 26.04 ± 8.30, respectively, with saline session, and substantially reduced to 10.0 ± 5.95 (P = 0.02 vs corresponding saline) and 12.58 ± 7.43 (P < 0.001 vs saline) with mirtazapine at 10 mg kg⁻¹. Similar findings were noted at doses of 5 and 1 mg kg⁻¹ at a lesser degree. In the control rats, mirtazapine‐reduced visceral sensitivity only during CRD at 60 mmHg. (iii) Mirtazapine 10 mg kg⁻¹ significantly accelerated gastric emptying (P = 0.045) but slightly and marginally delayed intestinal transit (P = 0.058) the colonic sensitized rats. Conclusions & Inferences Mirtazapine dose‐dependently ameliorates visceral hypersensitivity in colonic sensitized rats. Mirtazapine at a high dose improves delayed gastric emptying in colonic sensitized rats but slightly and marginally delays small intestinal transit. Its roles in altering gastrointestinal motility need further investigation.     

A selective,high affinity 5‐HT2B receptor antagonist inhibits visceral hypersensitivity in rats

Background RS‐127445 is a selective, high affinity 5‐HT_2Breceptor antagonist. We investigated whether 5‐HT_2Breceptor antagonists can reduce colonic visceral hypersensitivity caused by restraint stress or by proximal colonic inflammation. Methods Visceral hypersensitivity was induced in rats by either restraint stress or injection of 2, 4, 6‐trinitrobenzene sulfonic acid (TNBS) into the proximal colon. Restraint stress produced a significant increase in numbers of abdominal contractions evoked by colorectal distension (CRD), measured as a quantitative index of visceral nociception in rats. Seven days after TNBS injection, the pain threshold to CRD at the non‐inflamed distal colon, that was determined as the minimum pressure required to evoke abdominal cramp, was significantly decreased. The effect of RS‐127445 on visceral hypersensitivity was assessed in either naïve or TNBS‐treated rats. Key Results Oral administration of a selective, high affinity 5‐HT_2Breceptor antagonist, RS‐127445, significantly inhibited visceral hypersensitivity provoked by restraint stress (35 to 74% inhibition at 1 to 10 mg kg^?1). Oral RS‐127445 produced a significant suppression of TNBS‐induced visceral hypersensitivity (15 to 62% inhibition at 3 to 30 mg kg^?1), although it was without significant effect on the visceral nociceptive threshold of naïve rats. RS‐127445 (1 to 30 mg kg^?1, p.o.) also dose‐dependently reduced the restraint stress‐induced defecation in naïve and TNBS‐treated rats. Conclusions & Inferences These results suggest that 5‐HT_2Breceptors are involved in signaling from the colon in rats in which there is visceral hypersensitivity and that a selective 5‐HT_2Breceptor antagonist could have therapeutic potential for the treatment of gut disorders characterized by visceral hypersensitivity.     

The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota

Background

Alterations of intestinal microbiota and hypersensitivity to colonic distension are two features of the irritable bowel syndrome (IBS). However, the role of intestinal microbiota in visceral hypersensitivity of IBS patients is far to be established. The aim of our study was to determine whether the intestinal microbiota is involved in the visceral hypersensitivity in IBS.

Methods

The painful response to colorectal distension and colonic mucosal parameters were assessed in gnotobiotic rats. Germfree (GF) rats were inoculated with the fecal microbiota from IBS patients characterized by hypersensitivity to colorectal distension (IBS HMA rats) or from non‐hypersensitive healthy volunteers (Healthy HMA rats). Conventional rats were studied as normosensitivity control. Fecal microbial analyses were carried out in human and HMA rats fecal samples using cultural and molecular approaches.

Key Results

The microbial dysbiosis of the IBS gut microbiota (more sulfate‐reducing bacteria and Enterobacteriaceae and less bifidobacteria) could be maintained in gnotobiotic rats. The number of abdominal contractions in response to colorectal distensions was significantly higher in IBS HMA rats than in healthy HMA rats. No difference was observed between healthy HMA and conventional rats. Colorectal compliance, epithelial paracellular permeability, and density of colonic mucosal mast cells were similar in the three groups of rats.

Conclusions & Inferences

We herein showed that sensitivity to colonic distension of IBS patients can be transferred to rats by the fecal microbiota. Mucosal alterations associated with microbiota transfer are not involved in this hypersensitivity. The altered IBS microbiota may have important role in the hypersensitivity characterizing IBS patients through specific bacterial metabolites.     

Long-Term Trigeminal Nerve Stimulation as a Treatment for Ocular Pain

ObjectivesOcular pain symptoms (e.g., hypersensitivity to light and wind, “burning” sensations) can be debilitating and difficult to treat. Neuromodulatory therapies targeting sensory trigeminal and central pain pathways may help treat chronic ocular pain refractory to traditional therapies. The current study evaluates the long-term effects of a trigeminal neurostimulator (TNS) on ocular pain.Materials and MethodsRetrospective review of 18 individuals at the Miami Veterans Affairs Eye Clinic with chronic, severe ocular pain who were prescribed and used TNS at home for ≥3 months. The primary outcome measures were 1) ocular symptom intensity over a 24-hour recall period (dryness, pain, light sensitivity, wind sensitivity, burning; rated on 0–10 scales) captured pre-TNS and at monthly follow-up intervals and 2) side effects. The frequency and duration of TNS was a secondary outcome measure.ResultsThe mean age of the population (n = 18) was 57.5 years (range, 34–85 years) with a male majority (67%). Two individuals discontinued use due to lack of efficacy and one due to confounding health issues. Initial mean weekly frequency of TNS use was 3.7 ± 1.9 sessions of 25.8 min at month 1 and 2.7 ± 2.3 sessions of 28.0 min at month 6. At six months, pain intensity (↓ 31.4%), light sensitivity (↓ 36.3%), wind sensitivity (↓ 32.6%), and burning sensation (↓ 53.9%) were all decreased compared to baseline (p < 0.01 for all); greater decreases in ocular pain were noted in individuals with migraine (n = 10) than those without migraine (n = 8). No significant change was noted in mean dryness scores. Fifteen subjects experienced sedation with TNS use, persisting throughout the follow-up visits. No other adverse effects were communicated by any subjects.ConclusionOur study suggests TNS is a safe, adjunctive treatment option in individuals with severe, chronic ocular pain. Individuals demonstrated gradual, continual improvement in pain symptoms over time within a multimodal approach.     

The Effects of Electroacupuncture via Chronically Implanted Electrodes on Alcohol Drinking and Withdrawal Signs in Rats

BackgroundIn the United States, more than 14 million adults suffer from alcohol use disorder (AUD). We proposed a stress-free method of electroacupuncture (EA) using chronically implanted electrodes. We aimed to develop an effective method of EA for treating AUD by testing various stimulation locations and parameters, and then investigate the effects of the daily EA on alcohol consumption and withdrawal signs in rats.Materials and MethodsSprague-Dawley rats were trained to voluntarily drink ethanol under the intermittent access two-bottle choice procedure. By the end of four weeks, rats with ethanol consumption ≥1.5 g/kg/24 h were considered alcohol-dependent and included in an acute and prolonged experiments. The acute study was designed to investigate the effects of EA with different parameters and at different locations. EA treatment was applied at bilateral ST36 alone or bilateral ST36 and HT7 acupoints for 30 minutes. We investigated the effects of EA on 24-hour alcohol consumption, preference ratio (alcohol drink vs total drink), alcohol withdrawal signs (AWS), and prolonged alcohol consumption. Each animal served as its own control.Results1) By the end of week 4, 70% of rats became alcohol-dependent. 2) Following ethanol withdrawal, there was a gradual increase in AWS over time that peaked at two hours and dropped at six hours. Among the tested stimulation parameters and locations: 3) The best stimulation location was ST36 alone, and the best stimulation parameters were a combination of 100 and 2 Hz. EA at best stimulation location and parameters reduced ethanol intake by 27% (p < 0.05 vs baseline) and marginally reduced preference ratio by 23% (p = 0.05 vs baseline). 4) EA reduced AWS at two- and four-hours following ethanol withdrawal (p ≤ 0.03 each vs no EA). 5) Daily EA (for five consecutive days) resulted in a substantial reduction in ethanol intake and preference ratio by 44% and 47%, respectively (p = 0.002 each).ConclusionsThis work shows the potential of this novel method of EA for the treatment of AUD. Further studies are warranted to investigate the mechanisms through which EA exerts its effects.     

A Prospective Multicenter Case Series Utilizing Intraoperative Neuromonitoring With Evoked Compound Action Potentials to Confirm Spinal Cord Stimulation Lead Placement

ObjectivesThe use of intraoperative neuromonitoring (IONM) has been adapted to address issues of safety and proper lead positioning in spinal cord stimulation. This multicenter case series seeks to incorporate the use of evoked compound action potential (ECAP) and late response (LR) recording and compare it with the results obtained with IONM, specifically electromyography (EMG), for the confirmation of lead placement. This study aimed to establish a correlation between ECAPs, LR, and EMG and publish human recordings of ECAPs and LR during their use with IONM.Materials and MethodsStandard neuromonitoring protocols were followed at two institutions, with two separate physicians and with seven patients, as part of a larger ongoing study registered with ClinicalTrials.gov (NCT02924129). Stimulation and recording were performed, top and bottom, on each percutaneous lead. Stimulation amplitude was increased considering ECAP, LR, and EMG thresholds.ResultsECAPs, LRs, and EMG signals were observed in all patients. The onset of LR signals on implanted electrodes and EMG signal on subdermal electrodes was well correlated (rs = 0.94, p < 0.001), with a median LR:EMG value of 1.06 (N = 21). LR:EMG for the top (mean = 0.97, N = 8) vs bottom (mean = 1.15, N = 13) of the lead was compared using a paired Wilcoxon signed rank test and an independent samples Mann-Whitney test, revealing a marginally significant and a statistically significant difference (p = 0.078 and p = 0.015, respectively). Mean LR:ECAP was >2 in all locations and approximately 3.5 overall. LR:ECAP between the top and bottom of the lead was significantly different (Wilcoxon test, p < 0.01, N = 12).ConclusionsLR correlated with EMG; leads with bilateral (not necessarily symmetric) EMG activity showed LR:ECAP > 1.5. An LR:ECAP of <1, with LR/EMG generated before the ECAP, indicated that the lead is too lateral. The use of ECAP and LR has the potential of maintaining objective lead placement, without the need for needle placement with IONM.     

Guanylate cyclase C‐mediated antinociceptive effects of linaclotide in rodent models of visceral pain

Background Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation‐predominant irritable bowel syndrome (IBS‐C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS‐C. Therefore, we investigated the anti‐nociceptive properties of linaclotide in rodent models of inflammatory and non‐inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC‐C). Methods Orally administered linaclotide was evaluated in non‐inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)‐induced inflammatory model in Wistar rats and GC‐C null mice. Key Results In TNBS‐induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC‐C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post‐inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC‐C null mice. Conclusions & Inferences These findings indicate that linaclotide has potent anti‐nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC‐C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS‐C.     

Involvement of dopamine system in the regulation of the brain corticotropin-releasing hormone in paraventricular nucleus in a rat model of chronic visceral pain

Objective We aimed to investigate the mechanism of paraventricular nucleus (PVN) and ventral tegmental area (VTA) circuit in the pathogenesis of visceral pain-depression with a rat model induced by neonatal and adult colorectal distension (CRD).

Methods Neonate male Sprague-Dayley (SD) rats underwent CRD on postnatal days 8, 10, and 12, and when matured, were tested for adult abdominal withdrawal reflex (AWR) scores to assess visceral hypersensitivity. The forced swimming test was employed to evaluate depression-like behaviors. The rats exhibiting visceral pain-depressive behaviors underwent lidocaine injection in the VTA to explore the relationship between VTA and visceral pain. Moreover, double immunofluorescence was employed to evaluate the qualitative and quantitative expression of dopamine/ c-Fos in CRD rats. After verifying the existed fiber projection from PVN to VTA, the intra-PVN microinjection of CRH-RNAi lentivirus to inhibit corticotropin-releasing hormone (CRH) expression, behavioral changes were assessed by AWR score and FST. Thereafter, with the sacrifice of the rats, the variations of TH protein in rats were evaluated by immunofluorescence and Western blot.

Results Intra-VTA microinjection of lidocaine increased the pain threshold of CRD group. After intra-VTA microinjection of green retrograde tracer, immunofluorescence photomicrographs visualized the PVN with a typical green retrograde tracer. Intra-PVN microinjection of CRH-RNAi lentivirus alleviated the visceral pain-depression behaviors and decreased the TH protein expression in the VTA.

Conclusion These data demonstrated that the VTA played a functional role in chronic visceral pain and depression, and the CRH-containing neurons in hypothalamic PVN may be implicated in the onset and maintenance of the chronic visceral pain and depression via the activation of dopamine in the VTA.     

Electroacupuncture diminishes P2X2 and P2X3 purinergic receptor expression in dorsal root ganglia of rats with visceral hypersensitivity

Electroacupuncture at Shangjuxu (ST37) and Tianshu (ST25) can improve visceral hypersensitivity in rats. Colorectal distension was used to establish a rat model of chronic visceral hypersensitivity. Immunohistochemistry was used to detect P2X2 and P2X3 receptor expression in dorsal root ganglia from rats with chronic visceral hypersensitivity. Results demonstrated that abdominal withdrawal reflex scores obviously increased following establishment of the model, indicating visceral hypersensitivity. Simultaneously, P2X2 and P2X3 receptor expression increased in dorsal root ganglia. After bilateral electroacupuncture at Shangjuxu and Tianshu, abdominal withdrawal reflex scores and P2X2 and P2X3 receptor expression decreased in rats with visceral hypersensitivity. These results indicated that electroacupuncture treatment improved visceral hypersensitivity in rats with irritable bowel syndrome by reducing P2X2 and P2X3 receptor expression in dorsal root ganglia.     

Gender differences in REM sleep behavior disorder: a clinical and polysomnographic study in China

ObjectiveRapid eye movement (REM) sleep behavior disorder (RBD) has been considered a male-predominant parasomnia, and there is little comparative data on potential differences between males and females. Therefore, the aim of our study was to examine and characterize gender difference in RBD.MethodsNinety patients diagnosed with RBD were consecutively recruited from a sleep medicine clinic. All patients were assessed by a RBD questionnaire and overnight video polysomnography. Demographic, clinical data, presence of dreams and dream-enacting behaviors, sleep parameters and electromyographic (EMG) activity were compared for male and female patients with RBD.ResultsFemales were significantly younger than males, both in the mean age of RBD onset (45.3 ± 19.3 vs. 56.2 ± 14.1; p = 0.027) and the mean age at diagnosis (50.4 ± 18.2 vs. 61.1 ± 14.1; p = 0.022). Secondary RBD was 21% in males and 44% in females (p = 0.021). Antidepressant use was more common among females (22%) than males (2%; p = 0.003). There was no significant gender difference in dream content (eg, violent and frightening dreams) of RBD patients. However, females had less dream-enacting behaviors, especially in movement related dreams and falling out of bed. Interestingly, no significant difference was found in the quantification of EMG activity during REM sleep between male and female patients.ConclusionsWe found significant gender differences in demographics, associated comorbidities, and dream-related behaviors in patients with RBD. Female RBD patients reported significantly less behavior during dreams, but there was no significant gender difference in EMG activity during REM sleep.     

The effects of repetitive transcranial magnetic stimulation on body weight and food consumption in obese adults: A randomized controlled study

BackgroundAlthough some studies have reported significant reductions in food cravings following the single-session of repetitive transcranial magnetic stimulation (rTMS), there is little research on the effects of multi-session of rTMS on food consumption and body weight in obese subjects.ObjectiveWe conducted 4-week randomized, sham-controlled, single-blind, parallel-group trial to examine the effect of rTMS on body weight in obese adults.MethodsForty-three obese patients (body mass index [BMI] ≥25 kg/m²) aged between 18 and 70 years were randomized to the sham or real treatment group (21 in the TMS group and 22 in the sham treatment group). A total of 8 sessions of rTMS targeting the left dorsolateral prefrontal cortex (DLPFC) was provided over a period of 4 weeks. The primary outcome measure was weight change in kilograms from baseline to 4 weeks. Secondary endpoints included changes in anthropometric measures, cardiovascular risk factors, food intake, and appetite.ResultsParticipants in the rTMS group showed significantly greater weight loss from baseline following the 8 session of rTMS (−2.75 ± 2.37 kg vs. 0.38 ± 1.0 kg, p < 0.01). Consistent with weight loss, there was a significant reduction in fat mass and visceral adipose tissue at week 4 in the rTMS group compared with the control group (p < 0.01). After the 8 sessions of rTMS, the TMS group consumed fewer total kilocalories and carbohydrates per day than the control group (p < 0.05).Conclusions8 sessions of HF rTMS delivered to the left DLPFC were effective in inducing weight loss and decreasing food intake in obese patients.Trial registrationClinical trial registered with the Clinical Trials Registry at http://cris.cdc.go.kr (KCT0002548).     

Multicentre analysis of 178,992 type 2 diabetes patients revealed better metabolic control despite higher rates of hypertension,stroke, dementia and repeated inpatient care in patients with comorbid Parkinson's disease

BackgroundEspecially in older people, physicians are faced with the coexistence of type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). Therefore, this research aimed to compare diabetes endpoints between T2DM with and without PD.MethodsBased on the standardized, multicenter, prospective DPV database, 178,992 T2DM patients (≥40 years) were analyzed. 1579 were diagnosed with PD and/or received specific treatment. Hierarchical multivariable regression models were used for group comparisons; adjusted estimates based on observed marginal frequencies were calculated.ResultsPD patients were significantly older (77.9 vs. 70.0 years; p < 0.0001) and had a longer diabetes duration (10.3 vs. 8.4 years; p < 0.0001). In young PD patients (<50 years), percentage of females was significantly higher compared to age-matched T2DM patients without PD or people of the German population (66.7 vs. 38.1 vs. 49.0%; p < 0.0001, p < 0.02).After demographic adjustment, T2DM patients with PD showed a significantly lower HbA1c (58.0 vs. 60.3 mmol/mol; p < 0.0001), OAD/GLP-1 treatment (41.9 vs. 45.9%; p < 0.01) and frequency of dyslipidemia (62.0 vs. 64.5%; p < 0.05). In contrast, rates of insulin therapy (57.8 vs. 54.8%; p < 0.05), hypertension (73.3 vs. 68.6%; p < 0.001), antihypertensive medication (60.4 vs. 56.1%; p < 0.01), stroke (12.0 vs. 7.3%; p < 0.0001), dementia (9.2 vs. 2.6%; p < 0.0001) and repeated inpatient care (15.7 vs. 12.0%; p < 0.0001) were significantly higher and duration of hospital stay (6.2 vs. 4.7 days; p < 0.0001) was significantly longer in T2DM with PD.ConclusionClear demographic and clinical differences were observed between T2DM with and without PD. In PD patients, metabolic control is better, potentially due to more intensive medical care.     

Central nervous system abnormalities in vaginismus

ObjectiveTo investigate possible altered CNS excitability in vaginismus.MethodsIn 10 patients with primary idiopathic lifelong vaginismus, 10 with vulvar vestibulitis syndrome accompanied by vaginismus and healthy controls we recorded EMG activity from the levator ani (LA) and external anal sphincter (EAS) muscles and tested bulbocavernosus reflex (BCR). Pudendal-nerve somatosensory evoked potentials (SEPs) were tested after a single stimulus. Pudendal-nerve SEP recovery functions were assessed using a paired conditioning-test paradigm at interstimulus intervals (ISIs) of 5, 20 and 40 ms.ResultsEMG in patients showed muscular hyperactivity at rest and reduced inhibition during straining. The BCR polysynaptic R2 had larger amplitude (p < 0.01) and longer duration (p < 0.01) in patients from both groups than in controls. In controls, paired-pulse SEPs were suppressed at the 5 ms ISI for N35–P40 (p < 0.05) and P40–N50 ms (p < 0.001) and facilitated at the 20 ms ISI for N35–P40 (p < 0.05) and P40–N50 (p < 0.05). No significant differences were found in the paired-pulse N35–P40 in patients and controls but the cortical P40–N50 at 20 ISI was facilitated in patients (p < 0.05).ConclusionsEMG activity is enhanced and the cortical SEP recovery cycle and BCR are hyperexcitable in vaginismus.SignificanceThe neurophysiological abnormalities in patients with vaginismus indicate concomitant CNS changes in this disorder.     

Effects of Multimodal Analgesia on Recovery From Percutaneous Spinal Cord Stimulator Implantation

ObjectiveWe aimed to determine the relationship between number and type of analgesic modalities utilized and postoperative pain after percutaneous spinal cord stimulator implantation. Secondary measures include opioid requirements, discharge times, and effects of specific modalities.Materials and MethodsThis single-center retrospective cohort at Brooke Army Medical Center from April 2008 through July 2017 reviewed 70 patients undergoing stimulator implantation by a pain specialist. Data included: home opioid regimen; preoperative/postoperative medications and pain; intraoperative medications; and discharge times. Analysis utilized a Wilcoxon nonparametric mode, and chi-square testing for specific modalities. We compared outcomes based on the number of modalities administered and whether patients received specific medications.ResultsPatients averaged receiving 3.8 modalities (standard deviation 1.4). Patients receiving ≥5 modalities had increased pain from preoperative to postoperative scores by two points, while those who received ≤4 had no increase (p < 0.01). Patients receiving ketamine had a median three point increase in pain scores from their baseline vs no change for others (p < 0.05). Patients receiving four modalities had shorter phase one recovery times vs ≤ 2 (median 66 vs 91.5 min; p = 0.01). Patients receiving ≥4 modalities had shorter times vs ≤3 (median 74 vs 88.5 min; p < 0.01). Patients receiving NSAIDs had shorter times than others (median 78 vs 87 min; p < 0.05).ConclusionsKetamine administration and use of ≥5 analgesic modalities were associated with more postoperative pain for unclear reasons. Patients receiving NSAIDs or ≥4 analgesic modalities had shorter recovery times. These data may lead to further work that could optimize ambulatory practices for stimulator implantation. More work is warranted on this subject.     

Visual complaints and visual hallucinations in Parkinson's disease

BackgroundVisual symptoms are common in Parkinson's disease (PD) and are frequently under-diagnosed. The detection of visual symptoms is important for differential diagnosis and patient management.AimTo establish the prevalence of recurrent visual complaints (RVC) and recurrent visual hallucinations (RVH) and to investigate their interaction in PD patients and controls.MethodsThis cross-sectional study included 88 PD patients and 90 controls. RVC and RVH were assessed with a visual symptom questionnaire and the North-East-Visual-Hallucinations-Interview (NEVHI).ResultsDouble vision (PD vs. Controls: 18.2% vs. 1.3%; p < 0.001), misjudging objects when walking (PD vs. Controls: 12.5% vs. 1.3%; p < 0.01), words moving whilst reading (PD vs. Controls: 17.0% vs. 1.3%; p < 0.001) and freezing in narrow spaces (PD vs. Controls: 30.7% vs. 0%; p < 0.001) were almost exclusively found in PD patients. The same was true for recurrent complex visual hallucinations and illusions (PD vs. Controls: both 17.0% vs. 0%; p < 0.001). Multiple RVC (43.2% vs. 15.8%) and multiple RVH (29.5% vs. 5.6%) were also more common in PD patients (both p < 0.001). RVC did not predict recurrent complex visual hallucinations; but double vision (p = 0.018, R² = 0.302) and misjudging objects (p = 0.002, R² = 0.302) predicted passage hallucinations. Misjudging objects also predicted the feeling of presence (p = 0.010, R² = 0.321).ConclusionsMultiple and recurrent visual symptoms are common in PD. RVC emerged as risk factors predictive of the minor forms of hallucinations, but not recurrent complex visual hallucinations.     

Association Between CT Angiogram Collaterals and CT Perfusion in Delayed Time Windows for Large Vessel Occlusion Ischemic Strokes

ObjectivesRecent endovascular trials have established the use of CT perfusion (CTP) in endovascular treatment selection for patients with large vessel occlusions (LVO). However, the relationship between CTP and collateral circulation is unclear in delayed time windows. We explored the relationship between CT Angiogram (CTA) collaterals and CTP parameters in delayed time windows (6-24 hours).Materials and MethodsWe utilized a single institutional, retrospective stroke registry of consecutive patients between May 2016 and May 2018 with anterior LVO with CTA and CTP imaging within 6-24 hours of stroke onset. We graded baseline collaterals on single phase CTA using modified Tan collateral score (0-3) and dichotomized into good (2-3) and poor (0-1) collaterals. We recorded automated CTP parameters, including estimated ischemic core (cerebral blood flow (CBF)<30%), penumbra (T_max>6 s), and mismatch ratio. We used Mann-Whitney test and linear regression to assess associations.ResultsWe included 48 patients with median age of 62 years (IQR= 52-72), median core of 17.5 mL (IQR=0-47), and median penumbra of 117.5 mL (IQR= 62-163.5). Patients with good collaterals had smaller median core (0 mL, IQR=0-12 mL vs. 40.5 mL, IQR=15-60 mL) (p < 0.001), smaller median penumbra (83.5 mL, IQR=43-135 mL vs. 142.5 mL, IQR=77-190 mL) (p = 0.04), larger median mismatch ratio (13.7, IQR=5.7-58.0 vs. 3.1, IQR=2.1-5.0) (p < 0.001), and lower median hypoperfusion intensity ratio (0.23, IQR=0-0.44 vs. 0.52, IQR=0.45-0.63) (p < 0.001) than patients with poor collaterals.ConclusionsIn delayed time window LVO patients, good CTA collaterals are significantly associated with smaller CTP core, smaller penumbra, larger mismatch ratio, and lower hypoperfusion intensity ratio. CTA collateral assessment could be a potential valuable surrogate to perfusion imaging, particularly in stroke centers where CTP is unavailable.     

Dexmedetomidine Relieves Acute Inflammatory Visceral Pain in Rats through the ERK Pathway,Toll-Like Receptor Signaling,and TRPV1 Channel

Dexmedetomidine (DEX) is a highly selective α2 adrenergic receptor agonist. In this study, we aimed to characterize the antinociceptive effects of DEX in acute inflammatory visceral pain (AIVP) induced by acetic acid in rats and to evaluate whether antinociception was regulated by the extracellular signal-regulated protein kinase (ERK) pathway, Toll-like receptor (TLR) signaling, and transient receptor potential (TRP) channel. Acetic acid was administered to 30 male rats with or without DEX. Rats were divided into six groups, as follows: control, disease (received no treatment before acetic acid administration), vehicle-treated, low-dose DEX (lDEX), medium-dose DEX (mDEX), and high-dose DEX (hDEX)-treated groups. Thermal withdrawal latency (TWL), mechanical withdrawal threshold (MWT), and abdominal withdrawal reflex (AWR) were measured to assess pain. We detected electromyographic (EGM) responses in the rectus abdominis muscle and measured the average arterial blood pressure. Levels of interleukin 1 (IL-1), IL-2, and IL-6 in the serum, as well as tumor necrosis factor α (TNF-α) and prostaglandin E₂ (PGE₂) in the peritoneal fluid, were measured by ELISA. The expression levels of phospho(p)CREB, pERK1/2, pMEK1, and TRP cation channel subfamily V member 1 (TRPV1), as well as the activation state of TLR4, were determined in the spinal cord of rats by real-time polymerase chain reaction and western blot analysis. TWL and MWT scores were elevated (P?<?0.05) in the hDEX and mDEX groups, whereas AWR scores decreased (P?<?0.01), compared to those in the disease group. The medium and high doses of DEX suppressed IL-1, IL-6, TNF-α, and PGE₂ release, and increased IL-2 release. In addition, protein and mRNA levels of MEK, ERK, and CREB were reduced in the mDEX and hDEX groups. Moreover, TLR4 and its downstream target, nuclear factor kappa B, along with calcitonin gene-related peptide release through the TRPV1 channel, were suppressed by mDEX and hDEX treatment. Taken together, our results suggest that DEX might exert an antinociceptive effect in AIVP in rats through the MEK/ERK pathway, TLR signaling, and TRPV1 channel, resulting in suppression of visceral hypersensitivity.     

Activation of corticotropin-releasing factor neurons and microglia in paraventricular nucleus precipitates visceral hypersensitivity induced by colorectal distension in rats

Visceral hypersensitivity is a major contributor to irritable bowel syndrome and other disorders with visceral pain. Substantial evidence has established that glial activation and neuro-glial interaction play a key role in the establishment and maintenance of visceral hypersensitivity. We recently demonstrated that activation of spinal microglial toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor κB (NF-κB) signaling facilitated the development of visceral hypersensitivity in a rat model developed by neonatal and adult colorectal distensions (CRDs). Hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of chronic pain. In this study, we examined the mechanism by which microglia and neurons in PVN establish and maintain visceral hypersensitivity and the involvement of TLR4 signaling. Visceral hypersensitivity was precipitated by adult colorectal distension (CRD) only in rats that experienced neonatal CRDs. Visceral hypersensitivity was associated with an increase in the expression of c-fos, corticotropin-releasing factor (CRF) protein and mRNA in PVN, which could be prevented by intra-PVN infusion of lidocaine or small interfering RNA targeting the CRF gene. These results suggest PVN CRF neurons modulate visceral hypersensitivity. Adult CRD induced an increase in the expression of Iba-1 (a microglial marker), TLR4 protein, and its downstream effectors MyD88, NF-κB, as well as proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) only in rats that experienced neonatal CRDs. Intra-PVN infusion of minocycline, a nonselective microglial inhibitor, attenuated the hyperactivity of TLR4 signaling cascade, microglial activation, and visceral hypersensitivity. Taken together, these data suggest that neonatal CRDs induce a glial activation in PVN. Adult CRD potentiates the glial and CRF neuronal activity, and precipitates visceral hypersensitivity and pain. TLR4 signaling and proinflammatory cytokines TNF-α and IL-1β may participate in neuro-glial interaction during the pathogenesis of visceral hypersensitivity.     

Sleep and libido in men with obstructive sleep apnea syndrome

ObjectivesThe objectives of this study were to investigate the relationship between a low libido and objective sleep parameters as well as mood disturbances in patients with obstructive sleep apnea syndrome (OSA).MethodsWe enrolled 436 untreated patients who were newly diagnosed with OSA (all male, mean age 42.8 years). Patients completed the Symptom checklist-90-Revised (SCL-90-R), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI), and Beck Anxiety Inventory (BAI). Patients were divided into low-libido and normal-libido groups according to their response to the statement “Loss of sexual interest or pleasure” on the SCL-90-R.ResultsApproximately 23% of patients reported a low libido. Patients with a low libido were older (47.5 ± 9.0 vs. 41.4 ± 11.1 years; p < 0.001), had more nocturia (33.3% vs. 16.6%; p < 0.001), higher BDI (9.0 (5.0–14.0) vs. 5.0 (2.0–9.0); p < 0.001) and BAI score (11.0 (6.3–16.8) vs. 5.0 (2.0–10.0); p < 0.001). These patients had a lower non-REM sleep stage 3 (N3) % (0.1 (0–4.0) vs. 2.3 (0.1–7.9); p < 0.001). Multivariate analysis revealed that older age and higher BDI score were independent factors associated with a low libido.ConclusionsMen with untreated OSA suffered from a low libido. Older age and depressed mood were the most important factors of low libido in middle-aged men with OSA.     

Advanced therapies in Parkinson’s disease: Long-term retrospective study

BackgroundLevodopa/carbidopa intestinal gel infusion (LCIG) and subthalamic nucleus deep brain stimulation (STN-DBS) are approved therapies for advanced Parkinson’s disease (PD) whose long-term comparability remains unclear.MethodsWe reviewed the 5-year data on activities of daily living (ADL) and motor complications (OFF time, dyskinesia duration, and dyskinesia severity), as measured by the Unified Parkinson Disease Rating Scale (UPDRS) section-II and section-IV (items 39, 32, and 33, respectively) in 60 PD patients exposed to STN-DBS (n = 20), LCIG (n = 20), and oral medical therapy (OMT) (n = 20) at similar baseline disability and cognitive state.ResultsSTN-DBS and LCIG showed a similar magnitude of deterioration in ADL (+6.1 vs. +5.7 UPDRS-II; p = 0.709), but lesser than with OMT (+13.7 UPDRS-II; p = 0.005). OFF time also improved to the same extent in STN-DBS and LCIG (−62% vs. −54.5%; p = 0.830), while worsened with OMT (+78.6%; p < 0.001). STN-DBS and LCIG yielded greater improvement on dyskinesia compared to OMT (dyskinesia duration: −66.1% vs. −9.0% vs. +24.2% [p = 0.001]; dyskinesia severity: −68.8% vs. −18.0% vs. +16.2% [p = 0.002]), with relative superiority of STN-DBS over LCIG (p = 0.004 for duration; p = 0.014 for severity). The annualized rate of complication was lower in STN-DBS vs. LCIG (0.13 vs. 0.68; p < 0.001) but not different between STN-DBS and OMT (0.13 vs. 0.10; p = 0.795).ConclusionsSTN-DBS and LCIG showed comparable efficacy in ADL and OFF time, superior to OMT. STN-DBS yielded greater improvement in dyskinesia and lower long-term rate of complications than LCIG.