Giuseppe Capocchi

NMDA receptor-mediated long term modulation of electrically evoked field potentials in the rat medial vestibular nuclei.

SummaryThe effect of high frequency stimulation (HFS) of the primary vestibular afferents on field potentials recorded in the ipsilateral Medial Vestibular Nuclei (MVN) was studied. Our results show that potentiation and depression can be induced in different portions of MVN, which are distinguishable by their anatomical organization. HFS induces potentiation of the monosynaptic component in the ventral portion of the MVN, whereas it provokes depression of the polysynaptic component in the dorsal portion of the same nucleus. The induction of both potentiation and depression was blocked under AP5 perfusion, thus demonstrating that NMDA receptor activation mediates both phenomena. Furthermore, the finding that the field potentials were not modified during perfusion with DL-AP5, as previously reported, supports the hypothesis that NMDA receptors are not involved in the normal synaptic transmission from the primary vestibular afferent fibres, but are only activated following hyperstimulation of this afferent system. Our results suggest that the mechanisms of long term modification of synaptic efficacy observed in MVN may underlie the plasticity phenomena occurring in vestibular nuclei.

Theta burst stimulation is optimal for induction of LTP at both apical and basal dendritic synapses on hippocampal CA1 neurons

The efficacy of stimulation patterns consisting of brief high frequency bursts repeated at various intervals to induce long-term potentiation (LTP) at synapses on apical and basal dendrites of CA1 hippocampal neurons was tested in vitro. Both apical and basal dendritic synapses exhibited maximal LTP after bursts repeated at 5-10 Hz, i.e. close to the frequency of the endogenous hippocampal theta rhythm. As at apical dendritic synapses, LTP at basal dendritic synapses was blocked by an antagonist of NMDA receptors. Basal dendritic LTP was significantly greater in magnitude than apical dendritic LTP, although the reason for this is unknown.

The role of GABA in NMDA-dependent long term depression (LTD) of rat medial vestibular nuclei

The role of GABA in NMDA-dependent long term depression (LTD) in the medial vestibular nuclei (MVN) was studied on rat brainstem slices. High frequency stimulation (HFS) of the primary vestibular afferents induces a long lasting reduction of the polysynaptic (N2) component of the field potentials recorded in the dorsal portion of the MVN. The induction but not the maintenance of this depression was abolished by AP5, a specific blocking agent for glutamate NMDA receptors. The involvement of GABA in mediating the depression was checked by applying the GABAA and GABAB receptor antagonists, bicuculline and saclofen, before and after HFS. Under bicuculline and saclofen perfusion, HFS provoked a slight potentiation of the N2 wave, while the N2 depression clearly emerged after drug wash-out. This indicates that GABA is not involved in inducing the long term effect, but it is necessary for its expression. Similarly, the LTD reversed and a slight potentiation appeared when both drugs were administered after its induction. Most of these effects were due to the bicuculline, suggesting that GABAA receptors contribute to LTD more than GABAB do. According to our results, it is unlikely that the long lasting vestibular depression is the result of a homosynaptic LTD. On the contrary, our findings suggest that the depression is due to an enhancement of the GABA inhibitory effect, caused by an HFS dependent increase in gabaergic interneuron activity, which resets vestibular neuron excitability at a lower level.

Early admission to stroke unit influences clinical outcome.

An improvement in patient arrival time to stroke unit (SU) is recommended, since earlier stroke management seems to improve ‘per se’ functional outcome. The objective of this study was to determine if early admission influences the outcome, reduces disability and mortality at discharge and three months later independent of tlirombolytic treatment.

Glial cell line-derived neurotrophic factor and somatostatin levels in cerebrospinal fluid of patients affected by chronic migraine and fibromyalgia.

The aim of the present study was to verify cerebrospinal fluid (CSF) levels of glial cell line-derived neurotrophic factor (GDNF) and somatostatin, both measured by sensitive immunoassay, in: 16 chronic migraine (CM) patients, 15 patients with an antecedent history of migraine without aura diagnosed as having probable chronic migraine (PCM) and probable analgesic-abuse headache (PAAH), 20 patients affected by primary fibromyalgia syndrome (PFMS), and 20 control subjects. Significantly lower levels of GDNF and somatostatin were found in the CSF of both CM and PCM + PAAH patients compared with controls (GDNF = P < 0.001, P < 0.002; somatostatin = P < 0.002, P < 0.0003), without significant difference between the two groups. PFMS patients, with and without analgesic abuse, also had significantly lower levels of both somatostatin and GDNF (P < 0.0002, P < 0.001), which did not differ from those of CM and PCM + PAAH patients. A significant positive correlation emerged between CSF values of GDNF and those of somatostatin in CM (r = 0.70, P < 0.02), PCM + PAAH (r = 0.78, P < 0.004), and PFMS patients (r = 0.68, P < 0.008). Based on experimental findings, it can be postulated that reduced CSF levels of GDNF and somatostatin in both CM and PCM + PAAH patients can contribute to sustained central sensitization underlying chronic head pain. The abuse of simple or combination analgesics does not seem to influence the biochemical changes investigated, which appear to be more strictly related to the chronic pain state, as demonstrated also for fibromyalgia.

Giant axonal neuropathy with subclinical involvement of the central nervous system : Case report

The case of a 17-year-old girl with slowly progressive sensory-motor neuropathy is described. Sural nerve biopsy showed abnormally enlarged exons filled with neurofilaments. Neurofilament accumulation was limited to the axons and was not found in other cells of the skin or peripheral nerve. The patient showed EEG and brain MRI abnormalities, but there was no clinical evidence of central nervous system involvement. Although these findings suggest an atypical attenuated form of giant axonal neuropathy, a new nosological entity cannot be excluded.

Narcolepsy is a common phenotype in HSAN IE and ADCA-DN

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.

Efficacy of Thrombolytic (rt-PA) Therapy in Old Stroke Patients: The Perugia Stroke Unit Experience

The use of intravenous recombinant tissue plasminogen activator (rt-PA) administered within 3 hrs from symptom onset is beneficial in selected patients independent of age; although oldest patients (≥80 years) are excluded a priori. We report an experience relative to rt-PA treatment in the oldest patients including outcome at 3 months. Data were from the hospital-based Perugia Stroke Registry. Seventy-two consecutive acute stroke patients, fulfilling NINDS and EUSI-criteria were treated with rt-PA Of these 23 patients (30.5%) were ≥80 years. The median and mean age were, respectively, 72.5 and 71.1 ± 12.7 years (range 35–94). The proportion of favorable outcome at 3-months did not differ between groups (55% elderly versus 51.1% of younger patients). Proportions of unfavorable outcome and death from baseline were similar in both groups of patients. Age did not influence prognosis in patients treated with rt-PA. The oldest stroke patients should not be excluded from rt-PA treatment on the basis of age per se.

Complexity of Motor Sequences and Cortical Reorganization in Parkinson's Disease: A Functional MRI Study

Motor impairment is the most relevant clinical feature in Parkinsons disease (PD). Functional imaging studies on motor impairment in PD have revealed changes in the cortical motor circuits, with particular involvement of the fronto-striatal network. The aim of this study was to assess brain activations during the performance of three different motor exercises, characterized by progressive complexity, using a functional fMRI multiple block paradigm, in PD patients and matched control subjects. Unlike from single-task comparisons, multi-task comparisons between similar exercises allowed to analyse brain areas involved in motor complexity planning and execution. Our results showed that in the single-task comparisons the involvement of primary and secondary motor areas was observed, consistent with previous findings based on similar paradigms. Most notably, in the multi-task comparisons a greater activation of supplementary motor area and posterior parietal cortex in PD patients, compared with controls, was observed. Furthermore, PD patients, compared with controls, had a lower activation of the basal ganglia and limbic structures, presumably leading to the impairment in the higher levels of motor control, including complexity planning and execution. The findings suggest that in PD patients occur both compensatory mechanisms and loss of efficiency and provide further insight into the pathophysiological role of distinct cortical and subcortical areas in motor dysfunction.

Characteristics of Delayed Admission to Stroke Unit

Early admission to stroke unit (SU) and factors that may cause admission delay represent relevant issues to obtain an optimal management of acute stroke. This study was aimed at recording timing from clinical onset to admission to our SU and to identify the reasons for delay. We prospectively examined acute stroke patients consecutively admitted to the Perugia SU. Baseline characteristics of stroke patients, stroke type and etiology, time from symptom onset to arrival in the SU were obtained from the Hospital-Based Perugia Stroke Registry. 60.8% of 2,213 consecutive stroke patients admitted to the SU arrived within 6 hrs and 39.2% after 6 hrs. Underestimation of symptoms was the cause of delay in 48.7% of cases. Younger age, especially for females, ischemic stroke, mild and/or unspecific symptoms and the underestimation of symptoms seem to be the main reasons for delayed arrival in the SU. To increase the proportion of stroke patients arriving in the SU within 3 hr of symptom onset, it is necessary to improve public and general practitioner awareness of stroke through educational programs.