Monica Puligheddu

Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain

Vagus nerve stimulation therapy, effective for treatment-resistant epilepsy, has recently been approved also for treatment-resistant depression; nevertheless, the molecular mechanism(s) underlying its therapeutic action remains unclear. Given that neurotrophic factors and monoamines could play a crucial role in the pathophysiology of depression, we tested whether vagus nerve stimulation increases the expression of brain-derived neurotrophic factor, fibroblast growth factor, and nerve growth factor as well as the concentration of norepinephrine in the rat brain. Rats were implanted with a vagus nerve stimulator device and the effects of acute stimulation were evaluated on the growth factors mRNA levels and norepinephrine concentration by ribonuclease protection assay and microdialysis, respectively. We found that acute vagus nerve stimulation increased the expression of brain-derived neurotrophic factor and fibroblast growth factor in the hippocampus and cerebral cortex, decreased the abundance of nerve growth factor mRNA in the hippocampus, and, similar to the antidepressant drug venlafaxine, increased the norepinephrine concentration in the prefrontal cortex. This study demonstrates that acute vagus nerve stimulation triggers neurochemical and molecular changes in the rat brain involving neurotransmitters and growth factors known to play a crucial role in neuronal trophism. These new findings contribute to the elucidation of the molecular mechanisms underlying the therapeutic actions of vagus nerve stimulation in both treatment-resistant depression and epilepsy.

A single-question screen for rapid eye movement sleep behavior disorder: A multicenter validation study†

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinsons disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large‐scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single‐Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.

Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: A multicenter study

To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD).

Correlation between GABAA receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy

Vagus nerve stimulation (VNS) is an important option for the treatment of drug-resistant epilepsy. Through delivery of a battery-supplied intermittent current, VNS protects against seizure development in a manner that correlates experimentally with electrophysiological modifications. However, the mechanism by which VNS inhibits seizures in humans remains unclear. The impairment of gamma-aminobutyric acid (GABA)-mediated neuronal inhibition associated with epilepsy has suggested that GABA(A) receptors might contribute to the therapeutic efficacy of VNS. We have now applied single photon emission computed tomography (SPECT) with the benzodiazepine receptor inverse agonist [123I]iomazenil to examine cortical GABA(A) receptor density (GRD) before and 1 year after implantation of a VNS device in 10 subjects with drug-resistant partial epilepsy. VNS therapeutic responses resulted significantly correlated with the normalization of GRD. Moreover, a comparable control group, scheduled for a possible VNS implant, failed to show significant GRD variations after 1 year of a stable anti-epileptic treatment. These results suggest that VNS may modulate the cortical excitability of brain areas associated with epileptogenesis and that GABA(A) receptor plasticity contributes to this effect.

Environmental risk factors for REM sleep behavior disorder: A multicenter case-control study

Objective: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. Methods: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. Results: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). Conclusions: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Increase in 20-50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation

OBJECTIVE Though vagus nerve stimulation (VNS) is an important option in pharmaco-resistant epilepsy, its mechanism of action remains unclear. The observation that VNS desynchronised the EEG activity in animals suggested that this mechanism could be involved in VNS antiepileptic effects in humans. Indeed VNS decreases spiking bursts, whereas its effects on the EEG background remain uncertain. The objective of the present study is to investigate how VNS affects local and inter regional syncronization in different frequencies in pharmaco-resistant partial epilepsy. METHODS Digital recordings acquired in 11 epileptic subjects 1 year and 1 week before VNS surgery were compared with that obtained 1 month and 1 year after VNS activation. Power spectrum and synchronization were then analyzed and compared with an epileptic group of 10 patients treated with AEDs only. RESULTS VNS decreases the synchronization of theta frequencies (P < 0.01), whereas it increases gamma power spectrum and synchronization (< 0.001 and 0.01, respectively). CONCLUSIONS The reduction of theta frequencies and the increase in power spectrum and synchronization of gamma bands can be related to VNS anticonvulsant mechanism. In addition, gamma modulation could also play a seizure-independent role in improving attentional performances. SIGNIFICANCE These results suggest that some antiepileptic mechanisms affected by VNS can be modulated by or be the reflection of EEG changes.

Comorbidity and medication in REM sleep behavior disorder A multicenter case-control study

Objective: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. Methods: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. Results: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3–2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4–3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8–7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1–3.3; depression: OR 1.6, 95% CI 1.0–2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1–3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3–3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8–15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0–118.8; nonsmoking: OR 2.4, 95% CI 0.4–13.2) and consequent pulmonary disease. Conclusions: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case-control study

Patients with idiopathic REM sleep behavior disorder (iRBD) are at very high risk of developing neurodegenerative synucleinopathies, which are disorders with prominent autonomic dysfunction. Several studies have documented autonomic dysfunction in iRBD, but large-scale assessment of autonomic symptoms has never been systematically performed. Patients with polysomnography-confirmed iRBD (318 cases) and controls (137 healthy volunteers and 181 sleep center controls with sleep diagnoses other than RBD) were recruited from 13 neurological centers in 10 countries from 2008 to 2011. A validated scale to study the disorders of the autonomic nervous system in Parkinsons disease (PD) patients, the SCOPA-AUT, was administered to all the patients and controls. The SCOPA-AUT consists of 25 items assessing the following domains: gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual dysfunction. Our results show that compared to control subjects with a similar overall age and sex distribution, patients with iRBD experience significantly more problems with gastrointestinal, urinary, and cardiovascular functioning. The most prominent differences in severity of autonomic symptoms between our iRBD patients and controls emerged in the gastrointestinal domain. Interestingly, it has been reported that an altered gastrointestinal motility can predate the motor phase of PD. The cardiovascular domain SCOPA-AUT score in our study in iRBD patients was intermediate with respect to the scores reported in PD patients by other authors. Our findings underline the importance of collecting data on autonomic symptoms in iRBD. These data may be used in prospective studies for evaluating the risk of developing neurodegenerative disorders.

Family history of idiopathic REM behavior disorder: A multicenter case-control study

Objective: To compare the frequency of proxy-reported REM sleep behavior disorder (RBD) among relatives of patients with polysomnogram-diagnosed idiopathic RBD (iRBD) in comparison to controls using a large multicenter clinic-based cohort. Methods: A total of 316 patients with polysomnography-confirmed iRBD were recruited from 12 RBD study group centers, along with 316 controls matched on sex and age group. All subjects completed a self-administered questionnaire that collected proxy-reported information on family history of tremor, gait trouble, balance trouble, Parkinson disease, memory loss, and Alzheimer disease. The questionnaire also included a single question that asked about possible symptoms of RBD among first-degree relatives (siblings, parents, and children). Results: A positive family history of dream enactment was reported in 13.8% of iRBD cases compared to 4.8% of controls (odds ratio [OR] = 3.9, 95% confidence interval [CI] 2.0–7.7). ORs were increased for both siblings (OR = 6.1, 95% CI 2.1–18.1) and parents (OR = 3.2, 95% CI 1.4–7.8). We found no significant difference in sex, current age (65.3 ± 10.2 vs 66.9 ± 10.2 years), or age at self-reported RBD onset (55.2 ± 11.7 vs 56.6 ± 15.1 years) in possible familial vs sporadic iRBD. No differences were found in family history of tremor, walking and balance troubles, Parkinson disease, memory loss, or Alzheimer disease. Conclusion: We found increased odds of proxy-reported family history of presumed RBD among individuals with confirmed iRBD. This suggests the possibility of a genetic contribution to RBD.

Beta and Gamma Range EEG Power‐Spectrum Correlation with Spiking Discharges in DBA/2J Mice Absence Model: Role of GABAB Receptors

Summary:  Purpose: To describe the correlations between spiking pattern and EEG power spectrum frequency in DBA/2J mice, a model for murine absence seizures, after γ‐aminobutyric acid (GABA)B modulation.