Non-Pharmacological Interventions on Pain in Amyotrophic Lateral Sclerosis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs; thus, ALS is considered a multisystemic disorder. Pain is an important nonmotor symptom. Observational and case-control studies report high frequency of pain in ALS patients and it has been correlated with depression and quality of life. There are no specific scales for the assessment of pain and no randomized controlled trials (RCTs) regarding the drug management of pain in ALS. AIM: To systematically review the evidence for the nonpharmacological interventions (NPIs) in relieving pain in ALS, on March 2024, we searched the following databases: Pubmed, Scopus, Web of Science, and Cochrane. We also checked the bibliographies of trials identified to include further published or unpublished trials. MAIN RESULTS: A total of 1003 records were identified. Finally, five RCTs including 131 patients (64 in the intervention group and 67 in the control group) were included for meta-analysis. The interventions of the included RCTs consisted of muscle exercise, combined aerobics-strength intervention, and osteopathic manual treatment. The meta-analysis did not find a statistically significant difference in favor of NPIs for alleviating pain in ALS patients. CONCLUSIONS: ALS has a fulminant course and irreversibly leads to death. Pain in ALS patients, although a common nonmotor symptom, is often unrecognized and undertreated, and this is underlined by the lack of any RCTs on drug therapy for pain. Albeit NPIs are considered safe, as adverse effects are rarely reported, this systematic review did not provide sufficient evidence for a beneficial effect on pain. The scarceness of relevant literature highlights the need for future studies, with larger samples, more homogeneous in terms of interventions and population characteristics (stage of disease), and better choice of measurement scales to further investigate the efficacy, if any, of various pain interventions in ALS patients.

Impaired cerebral autoregulation in Fabry disease: A case-control study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls. METHODS: TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated. RESULTS: Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities. CONCLUSIONS: Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls.

Image analysis can reliably quantify median nerve echogenicity and texture changes in patients with carpal tunnel syndrome.

OBJECTIVE: To study the ability of image analysis measures to quantify echotexture changes of median nerve in order to provide a complementary diagnostic tool in CTS. METHODS: Image analysis measures (gray level co-occurrence matrix (GLCM), brightness, hypoechoic area percentage using max entropy and mean threshold) were calculated in normalized images of 39 (19 younger and 20 older than 65y) healthy controls and 95 CTS patients (37 younger and 58 older than 65y). RESULTS: Image analysis measures were equivalent or superior (older patients) to subjective visual analysis. In younger patients, GLCM measures showed equivalent diagnostic accuracy with cross sectional area (CSA) (Area Under Curve (AUC for inverse different moment = 0.97). In older patients all image analysis measures showed similar diagnostic accuracy to CSA (AUC for brightness = 0.88). Moreover, they had abnormal values in many older patients with normal CSA values. CONCLUSIONS: Image analysis reliably quantifies median nerve echotexture alterations in CTS and offers similar diagnostic accuracy to CSA measurement. SIGNIFICANCE: Image analysis may offer added value to existing measures in the evaluation of CTS, especially in older patients. Its clinical implementation would require incorporation of mathematically simple software code for online nerve image analysis in ultrasound machines.

Non-pharmacological Interventions on Pain and Quality of Life in Chemotherapy Induced Polyneuropathy: Systematic Review and Meta-Analysis.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN. MATERIALS AND METHODS: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol. RESULTS: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant. CONCLUSION: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms.

Primary Sjögren syndrome-related peripheral neuropathy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Primary Sjögren syndrome (pSS) is a chronic, systemic, autoimmune disorder characterized by lymphocytic infiltrates of the exocrine organs, leading to sicca symptoms and parotid enlargement. pSS has been linked to various neurological manifestations, including peripheral neuropathy (PN). We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS-related PN. METHODS: A literature search in the PubMed database was performed, and 49 papers were eligible to be included in this systematic review and meta-analysis. RESULTS: The pooled prevalence of PN in pSS is estimated to be 15.0% (95% confidence interval = 10.7%-20.7%). The mean age of pSS patients at PN diagnosis is 59 years. Among the patients with pSS and PN, 83% are females. Neuropathic symptoms usually precede or lead to the pSS diagnosis at a 2:1 ratio in patients with pSS-related PN. The commonest type of pSS-related PN is distal axonal polyneuropathy (80% of patients with pSS-related PN), followed by sensory ganglionopathy. Peripheral and cranial mononeuropathies-particularly trigeminal-are also frequent. Risk factors for developing PN include increasing age and presence of vasculitis. Immune-mediated pathogenetic mechanisms are discussed. Glucocorticoids are the most commonly used treatment option for managing pSS-related PN, when associated with vasculitis, followed by the use of intravenous immunoglobulin. CONCLUSIONS: PN is very common in pSS patients. Evidence on long-term prognosis of PN in pSS is limited, and further research is needed. Research into the use of immunosuppressive medication in nonvasculitic neuropathies in the context of pSS merits further consideration.

Autonomic dysfunction in amyotrophic lateral sclerosis: A neurophysiological and neurosonology study.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Some ALS patients exhibit concomitant nonmotor signs, and thus ALS is considered a multisystem disorder. The aim of this study is to investigate autonomous nervous system involvement in ALS. METHODS: We investigated 21 ALS patients and 28 age-matched controls. ALS patients were assessed for disease severity with the Revised-ALS Functional Rating Scale (ALSFSR) and for the presence of autonomic symptoms with the Composite Autonomic Symptom Score scale. Sympathetic nervous system was evaluated by sympathetic skin response (SSR) and parasympathetic nervous system by ultrasonography of vagus nerve (VN) at the level of the thyroid gland. RESULTS: SSR latencies were shorter and SSR amplitudes were higher in controls compared to ALS patients. The cross-sectional area (CSA) of the VN was significantly smaller in ALS patients (mean CSA right/left: 1.73±0.62 mm2 /1.47±0.53 mm2 ) compared to controls (mean CSA right/left: 2.91±0.79 mm2 /2.30±0.80 mm2 ), right: p <. 001, left: p <. 001. There was a significant negative correlation between disease duration and CSA of left-VN (r = -0.493, p = .023). This correlation was attenuated between disease duration and CSA of right-VN (r = -0.419, p = .059). ALSFSR-R was positively correlated to CSA of right-VN (p = .006, r = 0.590). CSA of VN did not correlate with bulbar involvement. CONCLUSIONS: This study confirms the presence of autonomic dysfunction in ALS patients and provides evidence of VN atrophy that correlates with disease severity and duration and is independent of bulbar involvement. Degeneration of dorsal nucleus neurons of the VN is hypothesized.

Guillain-Barré syndrome and fulminant encephalomyelitis following Ad26.COV2.S vaccination: double jeopardy.

This correspondence comments on a published article presenting a case of rhombencephalitis following SARS-CoV-2-vaccination with the mRNA vaccine BNT162b2 (Pfizer/BioNTech). We also present the case of a 47-year-old man who developed Guillain-Barré-syndrome and a fulminant encephalomyelitis 28 days after immunization with Ad26.COV2.S (Janssen/Johnson & Johnson). Based on the presented cases, we underscore the importance of clinical awareness for early recognition of overlapping neuroimmunological syndromes following vaccination against SARS-CoV-2. Additionally, we propose that that role of autoantibodies against angiotensin-converting enzyme 2 (ACE2) and the cell-surface receptor neuropilin-1, which mediate neurological manifestations of SARS-CoV-2, merit further investigation in patients presenting with neurological disorders following vaccination against SARS-CoV-2.

Neurophysiological and ultrasonographic comparative study of autonomous nervous system in patients suffering from fibromyalgia and generalized anxiety disorder.

BACKGROUND: Fibromyalgia (FM) and generalized anxiety disorder (GAD) share common clinical features: they both affect women more than men, their diagnosis is based solely on clinical criteria, and some of the symptoms such as anxiety, aches and muscle tension, sleep disorders, and cognitive dysfunction occur in both diseases. For both conditions, an underlying dysregulation of the autonomic nervous system (ANS) has been proposed. OBJECTIVE: The aims of this study were to investigate ANS dysfunction in FM and GAD and compare them with controls. METHODS: Sympathetic skin response (SSR) from palm and sole and cross-sectional area (CSA) of bilateral vagus nerves (VN) were measured in 28 healthy controls, 21 FM patients, and 24 GAD patients. RESULTS: CSA of VN was significantly smaller in FM patients (right: 1.97 ± 0.74mm2, left: 1.75 ± 0.65 mm2) and GAD patients (right: 2.12 ± 0.97mm2, left: 1.71 ± 0.86 mm2) compared to controls (right: 3.21 ± 0.75 mm2, left: 2.65 ± 1.13 mm2, p < 0.001, but did not differ between the two patient groups. SSR parameters were similar between patients and controls. SSR latency correlated to clinical scales (FM Widespread Pain Index) in the FM group (r = 0.515, p = 0.02 and r = 0.447, p = 0.05) for the upper and lower limbs respectively, but no other correlation between clinical and neurophysiological parameters was identified. CONCLUSION: This study confirms similar ANS abnormalities in FM and GAD that fairly distinguish them from controls and support the hypothesis of a common pathophysiological substrate underlying both conditions.

Calculating Turns/Amplitude peak ratio of EMG interference pattern by using logistic curve fitting.

The aim of the study was to test whether logistic curve fitting (LCF) of Turns = f(Amplitude) plots of single muscle contractions can provide a reliable alternative method for peak-ratio calculation. EMG signals from 74 biceps and 62 triceps contractions were analyzed by applying LCF to Turns = f(Amplitude) plots. Peak-ratio (peak-ratio2) could then be calculated as the point of the fitted line with the highest Turn/Amplitude value. LCF yielded R2 values > 0.95 in the vast majority of contractions studied (68/74 biceps and 53/62 triceps). Peak-ratio2 values had a very strong linear relationship with the corresponding values calculated by the traditional method (peak-ratio1) in both normal and neurogenic conditions. Furthermore, ROC curve analysis showed that peak-ratio1 and peak-ratio2 had similar AUC values. Based on the LCF equation, peak-ratio = T2*(p - 1)/A0*p*(p - 1)1/p. Therefore, peak-ratio is proportional to the maximum number of turns (T2), positively correlated to the rate of turns' increment at the midpoint of the curve (p) and negatively correlated to the mean amplitude at the midpoint of the curve (A0). A0 is the variable that best discriminates between normal and neurogenic conditions. We provide an alternative method for peak-ratio calculation and show the variables that influence this sensitive marker of neurogenic disease.

Prevalence, clinical characteristics and outcomes of Guillain-Barré syndrome spectrum associated with COVID-19: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Mounting evidence supports an association between Guillain-Barré syndrome spectrum (GBSs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, GBSs in the setting of coronavirus disease 2019 (COVID-19) remains poorly characterized, whilst GBSs prevalence amongst COVID-19 patients has not been previously systematically evaluated using a meta-analytical approach. METHODS: A systematic review and meta-analysis of observational cohort and case series studies reporting on the occurrence, clinical characteristics and outcomes of patients with COVID-19-associated GBSs was performed. A random-effects model was used to calculate pooled estimates and odds ratios (ORs) with corresponding 95% confidence intervals (CIs), compared to non-COVID-19, contemporary or historical GBSs patients. RESULTS: Eighteen eligible studies (11 cohorts, seven case series) were identified including a total of 136,746 COVID-19 patients. Amongst COVID-19 patients, including hospitalized and non-hospitalized cases, the pooled GBSs prevalence was 0.15‰ (95% CI 0%-0.49‰; I2  = 96%). Compared with non-infected contemporary or historical controls, patients with SARS-CoV-2 infection had increased odds for demyelinating GBSs subtypes (OR 3.27, 95% CI 1.32%-8.09%; I2  = 0%). In SARS-CoV-2-infected patients, olfactory or concomitant cranial nerve involvement was noted in 41.4% (95% CI 3.5%-60.4%; I2  = 46%) and 42.8% (95% CI 32.8%-53%; I2  = 0%) of the patients, respectively. Clinical outcomes including in-hospital mortality were comparable between COVID-19 GBSs patients and non-infected contemporary or historical GBSs controls. CONCLUSION: GBSs prevalence was estimated at 15 cases per 100,000 SARS-CoV-2 infections. COVID-19 appears to be associated with an increased likelihood of GBSs and with demyelinating GBSs variants in particular.

The diagnostic accuracy of high-resolution ultrasound in screening for carpal tunnel syndrome and grading its severity is moderated by age.

OBJECTIVE: To assess the effect of age on the accuracy of high-resolution ultrasound (HRUS) in the diagnosis and grading of carpal tunnel syndrome (CTS). METHODS: Patients with symptoms and signs of CTS (N = 527 wrists) were evaluated using electrodiagnostic studies (EDx) for CTS diagnosis and grading. Median nerve cross-sectional areas at carpal tunnel inlet (CSA) and at forearm level were measured by HRUS and the ratio of these values was calculated (WFR). Healthy controls underwent identical testing (N = 122 wrists). HRUS accuracy was assessed against the EDx standard by Receiver Operator Characteristic (ROC) curve analysis. RESULTS: In patients >65 y with moderate and severe CTS, disease-related increases in CSA and WFR were negatively correlated with increasing age. Subjects were grouped by age into younger (<65 y) and older (≥65 y). The c-statistics for CSA and WFR respectively were: For CTS diagnosis, younger group: 0.94 and 0.96 (excellent); older group: 0.85 and 0.86 (satisfactory). For CTS grading, younger group: differentiating mild CTS from controls: 0.90 and 0.92 (excellent); mild from moderate: 0.79 and 0.74 (satisfactory); moderate from severe: 0.82 and 0.78 (satisfactory). For CTS grading, older group: differentiating mild CTS from controls: 0.83 and 0.83 (satisfactory); mild from moderate: 0.53 and 0.61 (poor); moderate from severe: 0.65 and 0.53 (poor). CONCLUSIONS: For subjects aged <65 y, HRUS accuracy is excellent in CTS diagnosis and satisfactory in grading. For older subjects, accuracy is satisfactory in diagnosis but not in grading. SIGNIFICANCE: HRUS for CTS has diagnostic limitations selectively in older individuals.

Three new case reports of Arteriovenous malformation-related Amyotrophic Lateral Sclerosis.

Despite recent advances in genetics, in most cases of Amyotrophic Lateral Sclerosis (ALS) no etiological factor can be identified. Cerebral Arteriovenous Malformations (AVMs) have been associated with ALS development in a few studies, but the nature of this connection is unclear. We report here 3 additional cases of young adults, who had undergone repeated embolizations for complex AVMs, and who then developed, after many years, ALS symptoms and signs. In two of these cases Vascular Endothelial Growth Factor (VEGF) levels were found to be extremely high, in contrast to previous reports. Our 3 cases, together with the previously reported ones, suggest that a subgroup of patients with AVMs, with a particular profile of a complex nidus with repeated embolization procedures, are at increased risk of developing ALS. The reason for this association is unclear, but may relate to dysregulation of secreted vascular factors, as suggested by our VEGF results, or more broadly to the neurovascular hypothesis of ALS. Alternatively, a transneuronal type of neurodegeneration may be involved.

A strong linear relationship between Turns/Amplitude peak ratio and ratio at maximal effort.

In EMG interference pattern analysis, the peak value of turns to mean amplitude ratio [peak(T/A)] is an established clinically significant marker, but its calculation requires specific software available only in few EMG apparatuses. On the contrary, the turns to mean amplitude ratio obtained at maximal muscle contraction (T/Amax) is easily calculated but less well standardized. We aimed to quantitatively assess the association between T/Amax and peak(T/A). Data were derived from 642 muscle contractions (Nc) from 270 consecutive patients (Np) who underwent EMG at our laboratory (software Dantec Keypoint, QEMG) from May 2015 to September 2016 and had interference patterns obtained from at least one of the following muscles: triceps-lateral head, brachioradialis, extensor digitorum communis and biceps. Statistics were calculated separately for normal and neurogenic muscles. Peak(T/A) was calculated by the built-in "peak ratio" function. T/Amax was calculated by the built-in Interference Pattern analysis function. The ratio with the highest amplitude was selected as T/Amax. Linear regression models provided high Pearson correlation coeffficientscoefficients (R) between peak(T/A) and T/Amax for all 4 muscles, normal or neurogenic, except a subgroup of biceps in patients aged <40y. Specifically, R were: (A) triceps normal 0.79 (Nc = 99), neurogenic 0.83 (Nc = 50) (B) brachioradialis normal 0.81 (Nc = 84), neurogenic 0.78 (Nc = 66) (C) extensor digitorum communis normal 0.72 (Nc = 92), neurogenic 0.73 (Nc = 61) (D) biceps (age > 40y) normal 0.77 (Nc = 77), neurogenic 0.67 (Nc = 62). We conclude that T/Amax has a strong linear association with peak(T/A) and, therefore, the former may be further investigated as a potentially useful quantitative diagnostic marker, especially in cases where the latter is not available.

Differences in Pain Perception Between Men and Women of Reproductive Age: A Laser-Evoked Potentials Study.

Objective: We investigated differences in pain perception between men and women of reproductive age by using Laser-Evoked Potentials (LEPs). Design, Setting, Subjects: Forty-four right-handed healthy volunteers (19 males/25 females), aged 30­40 years were studied. A CO2 laser generated three series of 10 thermal pulses (4.5 W) on the radial aspect of the dorsum of the left hand. A recording montage for late LEPs was used, and the potentials of each series of stimuli were averaged to calculate mean latency and amplitude for each subject. Volunteers scored verbally pain intensity (Numerical rating scale [NRS]; 0­10). Three series of 10 numbers were averaged for calculation of mean NRS score. Methods: LEP peak-to-peak amplitude, latency, and NRS scoring were compared between genders, and correlations between LEP amplitude/latency and NRS scores were assessed. Results: Data from 44 subjects were analyzed. LEP amplitudes differed significantly (P < 0.001) between men (24.2 ± 6.0 µV) and women (38.9 ± 15.28 µV), while no difference was found for latency (156.5 ± 8.6 versus 160.4 ± 19.8 ms, P = 0.42) or NRS score (2.6 ± 1.5 versus 2.4 ± 1.4, P = 0.63), respectively. Menstrual cycle phase did not influence LEP parameters (P = 0.59 for amplitude and P = 0.69 for latency) or NRS score (P = 0.95). No significant correlation was found between latency or amplitude and NRS score (P = 0.43 and P = 0.90, respectively). Conclusions: Our results demonstrate a significant gender-related difference in LEP amplitudes with lower mean values in men, while no difference was found in LEP latencies or in subjective pain ratings. Further research is required to clarify the clinical significance of the above experimental findings.

Unilateral suppression of P/N13' potential amplitude in young patients with persistent numbness due to cervical monoradiculopathy. A case-control study.

OBJECTIVE: The utility of Dermatomal Somatosensory Evoked Potentials (DSEPs) in the diagnostic workup of suspected cervical monoradiculopathy has been limited by significant overlap between measurements obtained from affected versus unaffected roots. In a case-control study, we explored whether, under certain conditions, asymmetry in DSEP parameters may offer significant help in the diagnosis of monoradiculopathy. METHODS: DSEPs were obtained bilaterally from patients with persistent (age range 33-55, n = 10) or intermittent (age range 31-55, n = 7) unilateral sensory symptoms of less than one month duration due to MRI-confirmed cervical monoradiculopathy. DSEPs were also obtained bilaterally from aged-matched asymptomatic volunteers (age range 31-54, n = 8) and older asymptomatic volunteers (age range 57-77, n = 8). Amplitude and latency of the P/N13' potential (negative peak at 13 ms) were measured. RESULTS: In all ten patients with persistent symptoms, the P/N13' amplitude ratio, defined as P/N13' amplitude on the symptomatic side divided by P/N13' amplitude on the contralateral asymptomatic side, ranged between 0.0 and 0.50 (unilateral suppression). In all seven patients with intermittent symptoms, P/N13' amplitude ratios ranged between 0.60 and 1.00. In all age-matched asymptomatic controls, P/N13' amplitude ratio (side with lower divided by side with higher amplitude) was always at least 0.80. Among older asymptomatic subjects, DSEPs had inconsistent characteristics. CONCLUSIONS: Cervical monoradiculopathy with persistent numbness in young patients (aged up to 55 years) is very strongly associated with unilateral suppression of P/N13' DSEP amplitude. No significant asymmetry is observed in cases of monoradiculopathy with intermittent numbness. SIGNIFICANCE: In young patients with unilateral upper extremity persistent sensory complaints, DSEP amplitude asymmetry, as quantified by the P/N13' ratio, may offer significant help in the diagnosis of monoradiculopathy.

The L-type voltage-dependent calcium channel long-term potentiation is higher in the dorsal compared with the ventral associational/commissural CA3 hippocampal synapses.

The diversification between dorsal (DH) and ventral (VH) hippocampus includes the different ability to support NMDA receptor-dependent long-term synaptic potentiation (LTP). In this study, we assessed the ability of associational/commissural connections in the CA3 hippocampal field to show NMDA receptor-independent LTP. We found that high-frequency stimulation under blockade of NMDA receptors induced greater LTP in DH (40.7±8.5%) than in VH (17.1±4.6%). The blocker of L-type voltage-dependent calcium channels (VDCC) nifedipine prevented the induction of LTP. We hypothesize that the different ability for VDCC-LTP between DH and VH might have important implications in the memory-related information processing performed by the circuits of the two hippocampal segments.

Endogenous adenosine induces NMDA receptor-independent persistent epileptiform discharges in dorsal and ventral hippocampus via activation of A2 receptors.

Although adenosine is widely assumed to be an endogenous anticonvulsant its role in epileptogenesis is still contradictory. Using slices from the dorsal (DH) and the vental (VH) rat hippocampus and extracellular recordings from the CA3 field we aimed to determine the effects of endogenous adenosine on the expression and long-term maintenance of epileptiform activity induced by blockade of adenosine receptors types A(1) (A(1)R) and A(2) (A(2)R) under conditions of low magnesium. We found that the A(1)Rs blockade induced persistent epileptiform discharges (PED) more frequently in VH (by 52%) than in DH (by 31%). The induction of PED upon an additional blockade of A(2)Rs increased in VH (by 48%) but decreased in DH (by 74%). Remarkably, the increment in VH was prevented by a blockade of NMDARs. A blockade of A(2)Rs increased the NMDAR-mediated component of evoked synaptic potential in both VH and DH (by ~100%) but suppressed the non-NMDAR-mediated component in DH but not VH. A blockade of A(1)Rs induced PED equally in DH (76%) and VH (80%) via a NMDAR-independent mechanism. A blockade of A(2)Rs under blockade of A(1)Rs and NMDARs reduced the PED to 17% in DH and to 38% in VH. These findings show that A(2)Rs play a different role in the long-term maintenance of epileptiform activity between DH and VH and suggest that endogenous activation of A(2)Rs facilitates NMDAR-independent induction of PED in both hippocampal poles, but suppresses NMDAR-dependent induction of PED in VH.

Effects of morning melatonin administration on electroencephalographic theta to alpha power ratio in reproductive versus postmenopausal healthy female volunteers.

OBJECTIVE: The aim of the present study was to investigate the effect of exogenous morning melatonin administration on the electroencephalogram of reproductive versus postmenopausal women. METHODS: Twenty-six female, reproductive and postmenopausal healthy volunteers were randomly assigned to receive melatonin or placebo at 9:00 in the morning. Twelve electroencephalographic recording sessions were performed before the intake of melatonin or placebo and at 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, and 300 min. Theta to alpha ratios for every subject, channel and session were mathematically processed to yield the logarithm (base 10) of the spectral (theta power)/(alpha power) ratio for the 12 electroencephalographic sessions, weighted to the baseline ratio (LwRs). The LwRs were compared between melatonin groups (reproductive versus postmenopausal women) and also between melatonin and control groups. RESULTS: Data from 24 women were analyzed. The LwRs in the reproductive women were significantly lower than the LwRs in postmenopausal women at 60, 180, 240 and 300 min after melatonin consumption (p=0.007, 0.041, 0.008 and 0.040 respectively). In reproductive women, the LwRs of subjects who received melatonin were significantly lower compared to their controls at 60, 240 and 300 min after melatonin or placebo intake (p=0.005, 0.006 and 0.019 respectively). In postmenopausal women, no significant differences in the LwRs were calculated for any time point between melatonin and control groups. CONCLUSIONS: Our results show that morning melatonin administration produces no electroencephalographic changes in postmenopausal women. In contrast, electroencephalographic changes suggesting a possible awaking effect were observed in reproductive women.

Long-term potentiation of high-frequency oscillation and synaptic transmission characterize in vitro NMDA receptor-dependent epileptogenesis in the hippocampus.

The implication of high-frequency network oscillations (HFOs) in brain pathology resides in as yet unclear mechanisms. Employing field recordings from ventral hippocampal slices and two models of epileptogenesis (i.e. establishment of interictal-like persistent bursts), we found that HFOs associated with epileptiform bursts and excitatory synaptic transmission were co-modulated during epileptogenesis. NMDA receptor-dependent epileptogenesis in CA3 was consistently accompanied by long-lasting strengthening in synaptic transmission (by 94+/-17%, n=5) and HFOs (frequency, power and duration increased by 24+/-8%, 57+/-18% and 33+/-10%, respectively). Co-modulation of synaptic transmission and HFOs was also observed in NMDA receptor-independent epileptogenesis, although in individual experiments either enhancement or depression of both phenomena was observed. Pathological HFOs >200 Hz were unequivocally present in persistent bursts induced by NMDA receptor-dependent but not NMDA receptor-independent mechanisms. The duration of pathological HFOs associated with persistent bursts but not of HFOs associated with bursts before the establishment of epileptogenesis was linearly and strongly correlated with the duration of bursts (r=0.58, P<0.0001). We propose that interplay between spontaneous synchronous bursting and long-lasting synaptic potentiation accompanying certain forms of epileptogenesis may underlie long-lasting potentiation of HFOs, whose quantitative aspects may reliably signal the degree of network changes involved in epileptogenesis.