The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain ...disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders.
In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.
Background
Painful neuropathy is associated with plasticity changes in the nervous system. Standard repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive technique used to study ...changes in cortical excitability and to inhibit pain perception. Deep rTMS is a newer development that allows direct activation of deeper neuronal populations, by a unique coil design termed the H‐coil. This study was designed to assess whether deep rTMS applied over the motor cortical lower‐limb representation relieves pain in patients with diabetic neuropathy.
Methods
Patients were randomly assigned to receive daily real or sham H‐coil rTMS for 5 consecutive days. After a 5‐week washout period, they crossed over to the alternative treatment for additional 5 days (according to a crossover study design). Outcome measures were changes in the visual analogue scale (VAS) for pain and in area and threshold of RIII nociceptive flexion reflex (RIII reflex).
Results
Of the 25 patients randomized, 23 completed the study. After real rTMS, the VAS scores decreased significantly (p = 0.01), and so did RIII reflex area (p < 0.01), while no significant effects in these variables were induced by the sham rTMS treatment. The rTMS‐induced changes in the outcome measures disappeared about 3 weeks after stimulation. All patients tolerated stimulation well.
Conclusions
Deep H‐coil rTMS provides pain relief in patients with diabetic neuropathy. This innovative technique can induce a therapeutic effect on brain areas that otherwise remain difficult to target. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems.
We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated ...nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.
Oxygen is essential for human life. However, it could cause damaging effects on biological systems causing oxidative stress. Oxidative stress defined as "an alteration in the pro-oxidant-antioxidant ...balance in favor of the former that leads to potential damage" is characterized by the release of Reactive Oxygen Species (ROS). Oxidative stress is now recognized to play a central role in the pathophysiology of many different disorders, including complications of pregnancy such as placental pathology, PreEclampsia (PE), Intrauterine Growth Restriction (IUGR), gestational diabetes, and miscarriage. This narrative review aims to summarize pieces of evidence about the role of oxidative stress in the pathophysiology of the main obstetric complications with par-ticular interest in the neglected role of alcohol abuse.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes an impairment in both the upper and lower motor neurons. The recent description of numerous non-motor signs points to an ...involvement of the neocortex networks that is more complex than was previously believed. Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation, can enhance motor output in the contralateral hand through an NMDA-mediated sensorimotor mechanism.
To describe the effects of PAS on ALS patients before and after Riluzole intake compared with healthy subjects.
PAS was used to detect differences between 24 newly-diagnosed ALS patients and 25 age-matched healthy controls. MEP amplitude from the abductor pollicis brevis was considered before PAS, immediately after (T0) and after 10 (T10), 20 (T20), 30 (T30) and 60 (T60) minutes. Statistical significance was calculated using RM-ANOVA.
In healthy controls, PAS significantly increased MEP amplitude at T10, T20 and T30 (p < 0.05). In ALS patients, a significant increase in MEP amplitude was also observed after 60 min (p < 0.05), thus demonstrating NMDA-mediated enhanced facilitatory plasticity. After two weeks of riluzole intake, no MEP amplitude increase was evident after PAS at any time point. In three monomelic-onset ALS patients, a long lasting sensorimotor facilitation was evident only in the hemisphere corresponding to the affected side and appeared in the opposite hemisphere when the patients manifested contralateral symptoms.
PAS may be considered a useful tool when investigating NMDA-mediated neocortical networks in ALS patients and the modulation of such networks after anti-glutamatergic drug intake.
•Integrative networks in ALS are evaluable by paired associative stimulation (PAS).•The MEP amplitude increase after PAS lasts 1 h in ALS, 30 min in controls.•Riluzole assumption nullifies MEP increase in ALS patients.•Integrative networks are facilitated in ALS patients by glutamatergic mechanisms.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons that leads to progressive paralysis of skeletal muscle. Studies of ALS have revealed defects in expression ...of acetylcholine receptors (AChRs) in skeletal muscle that occur even in the absence of motor neuron anomalies. The endocannabinoid palmitoylethanolamide (PEA) modified the clinical conditions in one ALS patient, improving muscle force and respiratory efficacy. Clinically, ALS patients treated with PEA showed a lower decrease in their forced vital capacity (FVC) over time as compared with untreated ALS patients, suggesting that PEA can enhance pulmonary function in ALS. In the present work, data were collected from a cohort of 76 ALS patients and 17 denervated patients. Our results strengthen the evidence for the role of skeletal muscle in ALS pathogenesis and pave the way for the development of new drugs to hamper the clinical effects of the disease.
Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving upper and lower motor neurons. Paired associative stimulation (PAS) is an experimental method to investigate synaptic ...plasticity through LTP-like changes. Purpose of this study is to evaluate PAS effects on M1 excitability in ALS patients before and after two weeks of Riluzole intake. Eighteen ALS patients (nine pseudobulbar, nine spinal) have been recruited; we evaluated average amplitude of ten MEPs (120% of resting motor threshold -RMT-) before PAS protocol, right after (T0) and after 10 (T10), 20 (T20), 30 (T30) and 60 (T60) minutes. PAS protocol consisted in 200 electrical stimulus at 0.3 Hz, delivered on median nerve of non-dominant hand (300% sensitive threshold, 500 mcs), associated to a magnetic stimulus at 100% of RMT upon contralateral motor cortex. Interstimulus interval was decided according to latency of the component N20 of SEP, delayed by 2 ms. Repeated measures ANOVA showed a trend to significance in MEP amplitude increase in T20 and T30 ( p = 0.066 and 0.057 respectively) and a significant increase in T60 ( p = 0.047) in patients without Riluzole. In patients assuming Riluzole, no significant change in MEP amplitude was found. Riluzole could impair sensory-motor integrative circuits, as evaluated by PAS protocol.
COVID-19 is a complex syndrome caused by SARS-Cov-2. It mainly affects the respiratory system, but it could cause serious harm during pregnancy. An increase in stillbirths and preterm births has been ...highlighted by many authors. Although WHO and Royal College of Obstetrics and Gynecology don't recommend elective cesarean section in women with confirmed infection, cesarean sections were performed by many clinicians. This short narrative review aims to analyze pieces of evidence found in literature about the effectiveness of cesarean section in preventing stillbirths in COVID-19 positive mothers.
Studies included in the present review were retrieved searching MEDLINE (last access August 5th, 2021) with the following keywords: "pregnant woman with covid-19", "Caesarean section", "Ab-dominal Delivery" and "Stillbirth". Studies regarding the mode of delive-ry in pregnant women infected with COVID-19 and neonatal outcomes were included. Studies about biology, anesthesiology and necroscopy were excluded. Filters for "human" and "English" were applied.
Searching MEDLINE, 24 references were found. Other 103 articles were found searching bibliography. Two references were excluded after duplicate removal, 77 references after the title screen and 27 after the abstract screen. The final number of references included was 23. Most of the included studies were case reports. Most of them were from China.
Many authors highlighted the increased risk of fetal death in pregnancies complicated with SARS-Cov-2 infection, but it is not clear if Caesarean Section could reduce this risk. Pieces of evidence show that most clinicians choose to perform an elective cesarean section mostly because of maternal conditions or the fear of possible vertical transmission. Data show that mode of delivery doesn't affect the neonatal outcome and Caesarean Section doesn't reduce the positivity rate among neonates. Different opinions were found about the possible infection of amniotic fluid, cord blood and placenta. The risk of vertical transmission is considered moderate or low by most of the authors. Positivity to SARS-Cov-2 isn't an indication of elective cesarean section by itself, but this mode of delivery should be optioned in patients with other obstetrical indications or with severe conditions due to COVID. The recent increase in stillbirths could be related to the overall deterioration of maternal conditions.
The analgesic effects of cannabinoids are mediated through the activity on the endogenous cannabinoid system. (−)-trans-Δ9 -tetrahydrocannabinol (THC) is the principal psychoactive constituent of ...cannabis and it shows a partial agonist activity on cannabinoid receptors, in particular CB1 receptor, mainly expressed by neurons of the central and peripheral nervous system. Several studies demonstrate the effects of THC on pain perception. The aim of this study was to evaluate the effects of THC in 13 healthy volunteers (HV) through the analysis of Cutaneous Silent Period (CSP), a nociceptive spinal inhibitory reflex, considered a defense response, specific for the human upper limbs. CSP parameters have been recorded from the abductor digiti minimi (ADM) before and after an hour from the administration of a cannabis-based preparation. We recorded the same parameters before and after the administration of placebo in the same volunteers. The results showed that the CSP latency and amplitude left unchanged in HV after the drug administration at the dose commonly used to suppress nociceptive reflexes in humans. These differential effects of a narcotic-analgesic drug provide evidence that the Cutaneous Silent Period is not a THC-sensitive nociceptive reflex.
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