Flattening plasma corticosterone levels increases the prevalence of serotonergic dorsal raphe neurons inhibitory responses to nicotine in adrenalectomised rats

Major depression is characterized by a diminished activity of the brain serotonergic system as well as by the flattening of plasma cortisol levels. Nicotine improves mood in patients with major depression and in experimentally depressed animals by increasing brain serotonin (5-HT), noradrenaline and dopamine levels. The present study was directed to determine if flattening plasma glucocorticoid levels changes nicotine's stimulatory effects upon 5-HT DRN neurons. The experiments were performed in brain slices obtained from rats previously (14 days) adrenalectomised and implanted subcutaneously with one pellet containing 75 mg of corticosterone (Adx + CSR rats). Whole cell voltage and current clamp techniques were used to study the activity of immunocitochemically identified 5-HT DRN neurons. Administration of nicotine (1 μM) in sham-operated animals produced stimulatory effects in all 5-HT DRN neurons studied. In Adx + CSR rats however, nicotine inhibited 75% of 5-HT DRN neurons and increased the potassium-dependent inward rectifying current. The inhibitory effect of nicotine upon 5-HT DRN neurons was dependent on serotonin release inside the DRN, since it was converted into a stimulatory response by the selective antagonist of 5-HT_1A receptors N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY100635, 25 nM). Adx + CSR rats also presented an increased function of 5-HT_1A autoreceptors, since, in these rats, serotonin (1–10 μM) produced a higher increase in the potassium dependent inward rectifying current in comparison with sham-operated animals. Serotonin release inside DRN was mediated by α4β2 nicotinic acetylcholine receptors since the selective antagonist of these receptors dihydro-β-erytroidine hydrobromide (DHβE, 100 nM) blocked the inhibitory effects of nicotine 5-HT DRN neurons. These data indicate that, in the experimental model of adrenalectomised rats implanted with corticosterone pellets, nicotine increases the function of 5-HT_1A receptors of 5-HT DRN neurons.     

Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes

PurposeTo further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8⁺ T lymphocytes in humans.MethodsIn 15 healthy subjects (9 female (60%), 35.7 ± 12.1 years), apoptosis and cytotoxic function of CD8⁺ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10 mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2 h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8⁺ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR).ResultsHigh concentration of LEV decreased perforin release of CD8⁺ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5–35.9%) vs. 16.6% (IQR 12–24.9%), p = 0.002). LEV had no influence on apoptosis and proliferation (p > 0.05). VPA (100 mg/L) slowed apoptosis of CD8⁺ T lymphocytes after 24 h (VPA 100 mg/L vs. control: 7.3% (IQR 5.4–9.5%) vs. 11.3% (IQR 8.2–15.1%), p < 0.001), but had no effects on perforin release (p > 0.05). SV2A protein was detected in CD8⁺ T lymphocytes.ConclusionLEV decreased degranulation of CD8⁺ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect.     

Stroke prediction with CHA2DS2-VASc score in patients with mesenteric ischemia without atrial fibrillation-insights from a nationwide cohort

BackgroundThe current study sought to evaluate the accuracy of CHA₂DS₂-VASc score for ischemic stroke prediction in patients with mesenteric ischemia without atrial fibrillation (AF).MethodsThe study participants included patients aged ≥18 years with a new diagnosis of mesenteric ischemia during hospitalization between January 1, 2000 and December 31, 2011. Individuals with atrial fibrillation (AF) or atrial flutter during the study period were excluded. The study participants were followed up until the ischemic stroke appeared or they were censored due to withdrawal from this program, mortality, or the end of the study period, whichever came first. Cox proportional hazards regression models were applied for ischemic stroke risk stratification in the study participants by CHA₂DS₂-VASc score. The c-statistic based on the receiver operating characteristic (ROC) analysis was applied to investigate the accuracy of CHA₂DS₂-VASc score for ischemic stroke risk discrimination.ResultsA total of 24039 study participants were enrolled. Ischemic stroke incidence increased from 1.54% in CHA₂DS₂-VASc score of 0 to 9.23% in CHA₂DS₂-VASc score of 6 or more. Moreover, the Kaplan–Meier curve with a log rank test demonstrated that patients with a higher CHA₂DS₂-VASc score were associated with an increased cumulative incidence rate of ischemic stroke during the follow-up period (p < 0.001). The discriminatory performance of the CHA2DS2-VASc score resulted in C-statistics of 0.65(95% CI = 0.63–0.66) for predicting ischemic stroke risk among patients with mesenteric ischemia without AF.ConclusionsA higher CHA₂DS₂-VASc score is demonstrated to be associated with an increased risk of ischemic stroke among patients with mesenteric ischemia without comorbid AF.     

Meta-analysis of the association of the SLC6A3 3′-UTR VNTR with cognition

The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3′ untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k = 10 samples, N = 1193 subjects), inhibition (k = 8 samples, N = 829 subjects), executive functions including inhibition (k = 10 samples, N = 984 subjects), attention (k = 6 samples, N = 742 subjects) and declarative long-term memory (k = 5 samples, N = 251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p > 0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults.     

Pallidal low β-low γ phase-amplitude coupling inversely correlates with Parkinson disease symptoms

ObjectiveRecent discoveries suggest that it is most likely the coupling of β oscillations (13–30 Hz) and not merely their power that relates to Parkinson disease (PD) pathophysiology.MethodsWe analyzed power and phase amplitude coupling (PAC) in local field potentials (LFP) recorded from Pallidum after placement of deep brain stimulation (DBS) leads in nineteen PD patients and three patients with dystonia.ResultsWithin GPi, we identified PAC between phase of β and amplitude of high frequency oscillations (200–300 Hz) and distinct β-low γ (40–80 Hz) PAC both modulated by contralateral movement. Resting β-low γ PAC, also present in dystonia patients, inversely correlated with severity of rigidity and bradykinesia (R = −0.44, P = 0.028). These findings were specific to the low β band, suggesting a differential role for the two β sub-bands.ConclusionsPAC is present across distinct frequency bands within the GPi. Given the presence of low β-low γ PAC in dystonia and the inverse correlation with symptom severity, we propose that this PAC may be a normal pallidal signal.SignificanceThis study provides new evidence on the pathophysiological contribution of local pallidal coupling and suggests similar and distinct patterns of coupling within GPi and STN in PD.     

Maternal serum AGEs levels in pregnancies associated with neural tube defects

Advanced glycation end products (AGEs) plays an important role in diabetic embryopathy. AGE-mediated DNA damage could be a significant factor in the teratogenicity. The aim of the present study was to evaluate the association between the AGEs level and neural tube defects (NTDs) occurrence risk. Forty-eight mothers with NTD-affected pregnancies and 50 normal mothers were selected in this study. Blood were collected from the mothers and were assayed for serum AGEs, malondiadehyde (MDA) and hemoglobin A1c (HbA1c). Data were analyzed by logistic regression method. The study indicated that there were significant but modest lower prevalence for cases mothers on age, BMI and glucose levels compared with controls. NTD-affected mothers were significantly more likely to have higher AGEs levels (5.6 ± 0.48 AU vs. 4.6 ± 0.68 AU ρ < 0.01) than controls. The AGEs levels were not correlated with MDA and HbA1c in NTDs mothers (r² = 0.0006 p = 0.8691 and r² = 0.001 p = 0.8172, respectively). The conclusion is that AGEs might be associated with NTDs occurrence.     

Socio-Demographic Influences on Epilepsy Outcomes in an Inner-City Population

PurposePrevious studies show anti-epileptic drug compliance and seizure control in people with epilepsy (PWE) to be lower among low-income groups and African-Americans. We examined how socio-demographic factors influence seizure control in an inner-city population.MethodsThe clinic records of 193 PWE were analyzed. Good seizure control was defined as no seizures in the previous year. Bivariate and multivariate analyses were performed to examine the effects of race, age, gender, median household income, medication cost, and insurance status on good seizure control.ResultsThere were 69 Caucasians and 124 African-Americans (age 47.8 ± 16.5 years) in the study. African Americans had a significantly lower income than Caucasians (p < 0.001); but did not have inferior seizure control (p = 0.18). Seizure control was also not affected by gender (p = 0.82), AED costs (p = 0.06), insurance type (p = 0.20), or race-independent household income (p = 0.75).ConclusionContrary to prior literature, we find that in our population of PWE there were no significant effects of race or family income on seizure outcomes. Our findings add to the existing literature on socio-demographic disparities in PWE and merit further exploration by other groups     

Group cognitive behavioural treatment of youth anxiety in community based clinical practice: Clinical significance and benchmarking against efficacy

The efficacy of a group cognitive behavioural therapy (CBT) programme (Cool Kids) of youth anxiety has been demonstrated at university clinics in Australia and Denmark and similar CBT programmes have been found effective within community settings in other countries. However, most effectiveness studies of CBT for youth anxiety have either used a mixture of CBT guidelines, or translated protocols not previous tested in an efficacy trial. This study used a benchmarking strategy to compare outcomes from the same CBT programme used at a university research clinic (N = 87) and community centres (N = 82). There was a significant reduction on both clinical and self-report measures of youth anxiety over time with medium to large effect sizes within both samples. Treatment effects on self-report measures of youth anxiety were significantly larger within the university sample, while changes in clinical measures of youth anxiety were similar in the two samples. Overall these findings suggest that an efficacious CBT group treatment programme developed within research contexts is transportable to community centres. Despite being effective within the community, the results indicate that the treatment may lose some of its efficacy when disseminated to the community.     

Improvements in bimanual hand function after baby-CIMT in two-year old children with unilateral cerebral palsy: A retrospective study

The common assumption that early-onset intensive intervention positively affects motor development has rarely been investigated for hand function in children with unilateral cerebral palsy (CP). This retrospective study explored the possible impact of baby constraint-induced movement therapy (baby-CIMT) on hand function at two years of age. We hypothesized that baby-CIMT in the first year of life would lead to better bimanual hand use at two years of age than would not receiving baby-CIMT. The Assisting Hand Assessment (AHA) was administered at age 21 months (SD 2.4 months) in 72 children with unilateral CP, 31 of who received baby-CIMT. When dividing the children into four functional levels based on AHA, the proportional distribution differed between the groups in favour of baby-CIMT. Logistic regression analysis indicated that children in the baby-CIMT group were more likely than were children in the no baby-CIMT group to have a high functional level, even when controlling for the effect of brain lesion type (OR 5.83, 95% CI 1.44–23.56, p = 0.001). However, no difference was found between groups in the odds of having a very low functional level (OR 0.31, 95% CI 0.08–1.17, p = 0.084). The result shows that baby-CIMT at early age can have a positive effect. Children who received baby-CIMT were six times more likely to have a high functional level at two years of age than were children in the no baby-CIMT group.     

The clinimetric properties of aerobic and anaerobic fitness measures in adults with cerebral palsy: A systematic review of the literature

ObjectiveTo analyze the clinimetric properties of maximal aerobic and anaerobic fitness measurement protocols in adults with cerebral palsy (CP).Data SourcesA systematic search through March 2015 of databases PubMed, Embase, SPORTDiscus and PsycINFO was performed with medical subject heading terms for ‘cerebral palsy’ combined with search terms adults or adolescents and multiple text words for fitness and exercise tests that yielded 864 articles.Study SelectionAbstracts were screened by two reviewers to identify use of maximal fitness measurements in adolescents (14–18 yrs) or adults (>18 yrs) with CP of all abilities. Ninety-four articles were reviewed. No studies of adolescent (14–18 yrs) qualified. Eight articles reported clinimetric properties for adults with CP who walk or propel a wheelchair independently. Five articles reported on aerobic capacity, one reported on anaerobic capacity and two reported on both.Data ExtractionMethodological quality of the studies was rated using portions of the COSMIN (COnsensus-based Standards for the selection of health status Measurement INstruments) checklist. Quality of the measurement protocols was evaluated based on statistical strength of the clinimetrics. Synthesis of the overall evidence was based on the Cochrane review group guidelines which combine methodological quality and statistical strength.Data SynthesisEight articles reported on 4 aerobic and 1 anaerobic protocols. Overall synthesis revealed that for ambulatory adults with CP there is (i) moderate evidence for good reliability and good construct validity of maximal aerobic and anaerobic cycle tests, (ii) moderate evidence for good criterion validity of sub-maximal aerobic cycle tests, and (iii) strong evidence for poor criterion validity of the six-minute walk test as a maximal aerobic test. And for adults who propel a wheelchair there is limited evidence of good reliability for maximal aerobic wheelchair ergometer tests.ConclusionsLimited quality research exists on the clinimetric properties of aerobic and anaerobic capacity measures for adults with CP who have independent mobility. Quality aerobic and anaerobic measures for adults with more severe mobility impairments are absent.     

Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm

ObjectiveWe examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH.MethodsFifty-one HFS patients receiving BoNT/A therapy were recruited. Patients’ characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6-week follow-up after BoNT/A therapy.ResultsOf 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group-S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group-S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5–9] to 0 [0–5], p < 0.01) and HIT-6 (from 55 [54–64] to 44 [36–52], p < 0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95–629.39, p < 0.001) and history of chronic headache (odds ratio 28.53: 2.96–275.10, p < 0.001).ConclusionsPrimary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH.     

Quality of life for parents of children with autism spectrum disorders

This project describes health-related quality of life (HRQoL) of parents of children with autism spectrum disorders (ASDs) using mixed methods. Parents of children with ASDs (N = 224) reported on their HRQoL, depression, and caregiving burden using quantitative tools. HRQoL scores were slightly worse than from those in normative populations especially related to stress and mental health. For example, parents reported average HRQoL scores from SF-6D of 0.74, which was clinically significant lower than an average normative U.S. population. 40% of parents reported having clinical depression symptoms. Married parents reported lower depression symptoms than parents who were not. In addition, families with three or more children with special health care needs (CSHCN) reported lower HRQL and higher caregiving burden than families with less CSHCN. In the qualitative study, we conducted five focus groups to gain insight as to the reasons a child's ASD might influence a parent's HRQoL. Qualitative data further supports the notion that parental HRQoL was negatively influenced by their child's ASDs. Studies that seek to quantify the influence of ASDs and to assess the effect of interventions for children with ASDs may consider measuring the effects on family members as well.     

Evidence for Pretreatment LICI Deficits Among Depressed Children and Adolescents With Nonresponse to Fluoxetine

BackgroundResearch suggests that alterations in gamma-aminobutyric acid receptor functioning have a role in depression. Paired-pulse transcranial magnetic stimulation (TMS) paradigms are noninvasive measures of cortical inhibitory and excitatory circuits.Objective/hypothesisThe present study examined pretreatment short-interval intracortical inhibition (SICI), long-interval cortical inhibition (LICI), and intracortical facilitation (ICF) in children and adolescents with major depressive disorder who were initiating fluoxetine treatment. The primary objective was to examine the relationship of these measures with subsequent treatment response. It was hypothesized that alterations in pretreatment GABA and glutamate mediated neurotransmission, would be associated with fluoxetine nonresponse.MethodsSixteen children and adolescents with major depressive disorder underwent paired-pulse TMS testing before beginning fluoxetine treatment. Response was prospectively characterized by scores of 1 or 2 on the Clinical Global Impression Scale and less than 40 on the Children's Depression Rating Scale-Revised after 6 weeks of fluoxetine treatment (20–40 mg/day).ResultsEight patients responded to treatment. Least-squares mean LICI values were consistently higher bilaterally for treatment nonresponders. Higher LICI values indicate less inhibition and impaired GABA_B functioning. There was no significant effect of treatment response on the measures of SICI and ICF.ConclusionsOur findings suggest that deficits in pretreatment GABA_B may be related to fluoxetine nonresponse in depressed youth. This is congruent with prior work demonstrating that GABA_B interneurons have serotonergic input and antidepressants modulate GABA_B receptors. These findings also show that TMS paradigms have utility in studying the neurophysiology and treatment of childhood mood disorders.RegistrationsCortical Excitability and Inhibition in Children and Adolescents With Major Depressive Disorder, http://www.clinicaltrials.gov/ct2/show/NCT00896090?term=cortical+excitability+and+inhibition&rank=2, NCT00896090; Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse, http://www.clinicaltrials.gov/ct2/show/NCT00612313?term=Sequential+Treatment+and+MDD&rank=1, NCT00612313.     

Does early communication mediate the relationship between motor ability and social function in children with cerebral palsy?

BackgroundChildren diagnosed with neurodevelopmental conditions such as cerebral palsy (CP) are at risk of experiencing restrictions in social activities negatively impacting their subsequent social functioning. Research has identified motor and communication ability as being unique determinants of social function capabilities in children with CP, to date, no research has investigated whether communication is a mediator of the relationship between motor ability and social functioning.AimsTo investigate whether early communication ability at 24 months corrected age (ca.) mediates the relationship between early motor ability at 24 months ca. and later social development at 60 months ca. in a cohort of children diagnosed with cerebral palsy (CP).MethodA cohort of 71 children (43 male) diagnosed with CP (GMFCS I = 24, 33.8%, II = 9, 12.7%, III = 12, 16.9%, IV = 10, 14.1%, V = 16, 22.5%) were assessed at 24 and 60 months ca. Assessments included the Gross Motor Function Measure (GMFM), the Communication and Symbolic Behaviour Scales-Developmental Profile (CSBS-DP) Infant-Toddler Checklist and the Paediatric Evaluation of Disability Inventory (PEDI). A mediation model was examined using bootstrapping.ResultsEarly communication skills mediated the relationship between early motor abilities and later social functioning, b = 0.24 (95% CI = 0.08–0.43 and the mediation model was significant, F (2, 68) = 32.77, p < 0.001, R² = 0.49.Conclusions and implicationEarly communication ability partially mediates the relationship between early motor ability and later social function in children with CP. This demonstrates the important role of early communication in ongoing social development. Early identification of communication delay and enriched language exposure is crucial in this population.     

Sleep disorders,sleepiness, and near-miss accidents among long-distance highway drivers in the summertime

ObjectiveWe aimed to investigate sleepiness, sleep hygiene, sleep disorders, and driving risk among highway drivers.MethodsWe collected data using cross-sectional surveys, including the Epworth Sleepiness Scale (ESS) questionnaire, Basic Nordic Sleep Questionnaire (BNSQ), and a travel questionnaire; we also obtained sleep data from the past 24 h and information on usual sleep schedules. Police officers invited automobile drivers to participate.ResultsThere were 3051 drivers (mean age, 46 ± 13 y; 75% men) who completed the survey (80% participation rate). Eighty-seven (2.9%) drivers reported near-miss sleepy accidents (NMSA) during the trip; 8.5% of NMSA occurred during the past year and 2.3% reported sleepiness-related accidents occurring in the past year. Mean driving time was 181 ± 109 min and mean sleep duration in the past 24 h was 480 ± 104 min; mean sleep duration during workweeks was 468 ± 74 min. Significant risk factors for NMSA during the trip were NMSA in the past year, nonrestorative sleep and snoring in the past 3 months, and sleepiness during the interview. Neither sleep time in the past 24 h nor acute sleep debt (sleep time difference between workweeks and the past 24 h) correlated with the occurrence of near misses.ConclusionsUnlike previous studies, acute sleep loss no longer explains sleepiness at the wheel. Sleep-related breathing disorders or nonrestorative sleep help to explain NMSA more adequately than acute sleep loss.     

Maternal separation induces alterations of serotonergic system in different aged rats

Maternal separation (MS) induces profound behavioral and neurochemical dysregulations in adult rodents. In the present longitudinal study, we investigated the effects of repeated (4 h/day) maternal separation during postnatal days 1–21 on serotonergic synthesis and activity in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus of juvenile (post-natal day 21, PND 21), adolescent (PND 35) and early adult (PND 56) male Wistar rats. We found that MS increased 5-HT levels in the PFC of juvenile rats, and although MS increased 5-HT and 5-HIAA levels in the NAc of adolescent rats, the ratio between 5-HIAA and 5-HT decreased in the PFC. In addition, MS-treated adult rats showed increased levels of 5-HT in the PFC as well as 5-HT and 5-HIAA in the NAc. These data provided evidence that MS leads to profound and age-specific changes in serotonergic synthesis and activity in rodents. Our study also found that there are U-shaped and inverted U-shaped patterns for serotonergic synthesis and serotonergic activity from younger rats to adults, respectively. Together, our findings support the use of maternal separation as an animal model for studying the neurobiological pathogenesis of neurodevelopmental diseases.     

The effects of preweaning manganese exposure on spatial learning ability and p-CaMKIIα level in the hippocampus

BackgroundThe effects and mechanisms of preweaning Manganese (Mn) exposure on cognitive dysfunction remain unclear.ObjectiveThis study evaluated the effects of preweaning Mn exposure on spatial learning and memory as well as the protein expression of CaMKIIα and p-CaMKIIα.MethodsWe treated neonate rats with Mn²⁺ doses of 0 (control group), 10, 20 and 30 mg of Mn²⁺ per kg body weight (Mn-exposed groups) over postnatal day (PND) 1–21 by intraperitoneal injection. The ability of spatial learning and memory was tested on PND 22 using the Morris water maze (MWM), while the protein expressions of CaMKIIα and p-CaMKIIα in the hippocampus were evaluated by Western blotting. The levels of Mn in the blood and hippocampus were measured by inductively coupled plasma-mass spectrometry (ICP-MS).ResultsThe rats in Mn-exposed groups showed a significant delay in spatial learning ability on the third day of the MWM without dose-dependent differences, but there was no effect on the spatial memory ability. p-CaMKIIα, but not CaMKIIα protein expression significantly reduced in the Mn-exposed group.ConclusionThese findings suggested that the inhibition of p-CaMKIIα could be one of the mechanisms involved in the occurrence of Mn-induced cognitive impairments.     

Characterizing the Mechanisms of Central and Peripheral Forms of Neurostimulation in Chronic Dysphagic Stroke Patients

BackgroundSwallowing problems following stroke may result in increased risk of aspiration pneumonia, malnutrition, and dehydration.Objective/hypothesisOur hypothesis was that three neurostimulation techniques would produce beneficial effects on chronic dysphagia following stroke through a common brain mechanism that would predict behavioral response.MethodsIn 18 dysphagic stroke patients (mean age: 66 ± 3 years, 3 female, time-post-stroke: 63 ± 15 weeks [±SD]), pharyngeal electromyographic responses were recorded after single-pulse transcranial magnetic stimulation (TMS) over the pharyngeal motor cortex, to measure corticobulbar excitability before, immediately, and 30 min, after real and sham applications of neurostimulation. Patients were randomized to a single session of either: pharyngeal electrical stimulation (PES), paired associative stimulation (PAS) or repetitive TMS (rTMS). Penetration-aspiration scores and bolus transfer timings were assessed before and after both real and sham interventions using videofluoroscopy.ResultsCorticobulbar excitability of pharyngeal motor cortex was beneficially modulated by PES, PAS and to a lesser extent by rTMS, with functionally relevant changes in the unaffected hemisphere. Following combining the results of real neurostimulation, an overall increase in corticobulbar excitability in the unaffected hemisphere (P = .005, F_1,17 = 10.6, ANOVA) with an associated 15% reduction in aspiration (P = .005, z = −2.79) was observed compared to sham.ConclusionsIn this mechanistic study, an increase in corticobulbar excitability the unaffected projection was correlated with the improvement in swallowing safety (P = .001, rho = −.732), but modality-specific differences were observed. Paradigms providing peripheral input favored change in neurophysiological and behavioral outcome measures in chronic dysphagia patients. Further larger cohort studies of neurostimulation in chronic dysphagic stroke are imperative.     

Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity

BackgroundVagus nerve stimulation (VNS) is currently used to treat refractory epilepsy and is being investigated as a potential therapy for a range of conditions, including heart failure, tinnitus, obesity and Alzheimer's disease. However, the invasive nature and expense limits the use of VNS in patient populations and hinders the exploration of the mechanisms involved.ObjectiveWe investigated a non-invasive method of VNS through electrical stimulation of the auricular branch of the vagus nerve distributed to the skin of the ear – transcutaneous VNS (tVNS) and measured the autonomic effects.MethodsThe effects of tVNS parameters on autonomic function in 48 healthy participants were investigated using heart rate variability (HRV) and microneurography. tVNS was performed using a transcutaneous electrical nerve stimulation (TENS) machine and modified surface electrodes. Participants visited the laboratory once and received either active (200 μs, 30 Hz; n = 34) or sham (n = 14) stimulation.ResultsActive tVNS significantly increased HRV in healthy participants (P = 0.026) indicating a shift in cardiac autonomic function toward parasympathetic predominance. Microneurographic recordings revealed a significant decrease in frequency (P = 0.0001) and incidence (P = 0.0002) of muscle sympathetic nerve activity during tVNS.ConclusiontVNS can increase HRV and reduce sympathetic nerve outflow, which is desirable in conditions characterized by enhanced sympathetic nerve activity, such as heart failure. tVNS can therefore influence human physiology and provide a simple and inexpensive alternative to invasive VNS.