Ferruccio Panzica

Ionic mechanisms underlying burst firing in pyramidal neurons: intracellular study in rat sensorimotor cortex

In in vitro slices prepared from rat sensorimotor cortex, intracellular recordings were obtained from 107 layer V pyramidal neurons, subsequently injected with biocytin for morphological reconstruction. Of the 107 neurons, 59 (55.1%) were identified as adapting (45) or non-adapting (13) regular spiking neurons (RS), and 48 (44.9%) as intrinsically bursting (IB) neurons discharging with an initial cluster of action potentials, which tended to recur rhythmically in a subset of 19 cells. The block of IAR by extracellular Cs+ did not affect burst generation, but enhanced the tendency to reburst in IB neurons. A similar effect was induced by other procedures affecting K(+)-dependent post-burst hyperpolarization. In IB neurons Ca2+ spikes had a longer decay time than in RS neurons, however selective blockers of both low and high threshold Ca2+ conductances failed to impair bursting activity. On the contrary, the perfusion of the slices with 0.5-1 microM TTX suppressed bursting behaviour in a critical time interval preceding the complete block of Na(+)-dependent action potentials. It is concluded that the persistent Na+ current INAP is the most important intrinsic factor for the typical firing properties of IB neurons, while Ca2+ and K+ conductances appear to contribute towards shaping bursts and controlling their recurrence rate. The morphology, connectivity and physiological properties of adapting and non-adapting RS neurons are particularly suited to the processing of respectively phasic and tonic inputs, whereas the properties of IB neurons are consistent with their suggested role in cortical rhythmogenesis and in the pathophysiological synchronized activities underlying epileptogenesis.

The system epilepsies: a pathophysiological hypothesis.

We postulate that “system epilepsies” (SystE) are due to an enduring propensity to generate seizures of functionally characterized brain systems. Data supporting this hypothesis—that some types of epilepsy depend on the dysfunction of specific neural systems—are reviewed. The SystE hypothesis may drive pathophysiologic and clinical studies that can advance our understanding of epilepsies and can open up new therapeutic perspectives.

Movement-activated myoclonus in genetically defined progressive myoclonic epilepsies: EEG–EMG relationship estimated using autoregressive models

OBJECTIVE To study electroencephalography-electromyography (EEG-EMG) relationships in patients with different forms of progressive myoclonic epilepsies (PME). METHODS EEG-EMG auto-spectra, coherence and phase functions were estimated by means of bivariate and time varying autoregressive (AR) models in 15 patients: 8 with Unverricht-Lundborg, 4 with Lafora body disease, and 3 with sialidosis. RESULTS The coherence spectra of the EMG epochs including action myoclonus and contralateral frontocentral EEG derivations showed a main beta peak (average coherence: 0.60-0.79) in all patients, regardless of the type of PME. The time lag from cortex to muscle was 13.0-21.3 ms. Significantly, coherent gamma activity was consistently found only in the 3 patients with sialidosis; the most heterogeneous results were obtained in the patients with Lafora disease, who showed a more complex coherence profile. Periods of normal muscle contractions, which could be recorded in patients with Unverricht-Lundborg PME, were characterised by the presence of an EEG-EMG beta coherence peak on the same frequency as in the case of action myoclonus, but with a lower coherence value. CONCLUSIONS AR models were capable of describing EEG-EMG relationships in patients with PME, and indicated that coherent cortical and EMG beta oscillations are crucially involved in the generation of myoclonus. Moreover, they could detect the uneven spectral profiles characterising the different forms of PME.

Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease.

Objective: To investigate whether Unverricht–Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles. Methods: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated. Results: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency “giant” SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD. Conclusions: Patients with Unverricht–Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.

Spectral properties of EEG fast activity ictal discharges associated with infantile spasms

OBJECTIVE The aim of this study was to evaluate the characteristics of the ictal EEG event accompanying infantile spasms. METHODS Quantitative analysis was used, based on the application of a bivariate autoregressive (AR) parametric model; autospectra, coherence, phase functions and inter-hemispheric time differences were estimated on homologous EEG channels in 18 infants presenting with either cryptogenic or symptomatic West syndrome. RESULTS The AR analysis of the 500 ms EEG epochs preceding spasm onset revealed the presence of a short discharge of fast activity restricted to a narrow frequency band in 13 of the 18 cases included in the study. The fast discharge peaked at 17.5+/-2.1 Hz, with rather low inter-hemispheric coherence values (0.52+/-0.17) and asymmetric amplitude on homologous EEG derivations. It persisted briefly after spasm onset, reaching a higher coherence value (0.71+/-0.16). The inter-hemispheric time difference, estimated in those cases with the coherence values significantly different from zero, ranged from 9.1 to 14.3 ms (11.4+/-1.9) in the epoch preceding spasm onset. CONCLUSION The data obtained from the analysis of the ictal EEG events, compared with clinical and interictal EEG features, indicate that an asymmetric EEG pattern (mainly consisting of a rhythmic burst of fast activity) consistently preceded both symmetric and asymmetric spasms, thus suggesting a localized cortical origin of the ictal discharge giving rise to the spasms.

Progressive myoclonic epilepsies Definitive and still undetermined causes

Objective: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. Methods: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. Results: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. Conclusions: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Cortical myoclonus in Janz syndrome.

OBJECTIVE To evaluate the characteristics of EEG paroxysms and the relationship between EEG spikes and ictal myoclonic jerks in patients with juvenile myoclonic epilepsy (JME). METHODS Six patients with a typical form of JME entered the study and underwent computerized polygraphic recordings. In each patient, the inter-peak spike interval was measured on repeated EEG bursts, and jerk-locked back averaging was performed on ictal epochs using a time window including the 100 ms before and the 100-200 ms after the point at which the jerk-related EMG potential diverged from baseline. RESULTS In all cases, the myoclonic jerks were associated with polyspike waves (PSW) complexes. The frequency of repeated spikes within the PSW complex ranged from 16 to 27 Hz. Jerk-locked averaging revealed a positive-negative EEG transient with maximal amplitude on the frontal leads, which preceded the myoclonic jerk by 10.25+/-0.96 ms. A delay of 9.50+/-1.73 ms was measured between the jerk-locked positive peak detected on the frontal EEG leads of the two hemispheres; a comparable time lag was observed between the onset of myoclonic jerks in the two deltoid muscles. CONCLUSIONS Our data suggest that the ultimate mechanism responsible for ictal myoclonic jerks in JME is largely similar to that sustaining cortical myoclonus in more severe pathological conditions such as progressive myoclonus epilepsies, despite the different pathogenic substrate and triggering mechanisms.

A neurophysiological study of myoclonus in patients with DYT11 myoclonus-dystonia syndrome

Mutations in the ϵ‐sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus‐dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11‐MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 ± 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo‐rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a “startle‐like” muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long‐loop reflexes were normal, as was silent period and long‐term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short‐term intracortical inhibition revealed subtle impairment, and event‐related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11‐MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11‐MDS may justify the involvement of different brain areas.

Expression of intrinsic bursting properties in neurons of maturing sensorimotor cortex.

Intrinsically bursting (IB) neurons, responding with a burst of action potentials to just threshold intracellular depolarizing current pulses, are encountered in layer V of mature rodent sensorimotor cortex. We report the results of intracellular recordings performed on neocortical slices obtained from immature rats between postnatal day (P) 7 and P21, as compared to adult animals (above P60). The bursting properties are here reported to mature abruptly around P14. After this time a subpopulation of IB neurons was recognizable on the basis of both physiological and morphological characteristics (i.e. extensive apical and basal dendrites arborization, axon collaterals limited to layers V-VI). Maturational changes in number and distribution of Ca2+/K+ channels may account for this developmental step. The immaturity of IB neurons may be correlated with the poorly synchronized character of cortical activities in the very young animals.

Enhanced frontocentral EEG connectivity in photosensitive generalized epilepsies: a partial directed coherence study.

Purpose:  Photosensitive epilepsy (PSE) is the most common form of reflex epilepsy presenting with electroencephalography (EEG) paroxysms elicited by intermittent photic stimulation (IPS). To investigate whether the neuronal network undergoes dynamic changes before and during the transition to an EEG epileptic discharge, we estimated EEG connectivity patterns in photosensitive (PS) patients with idiopathic generalized epilepsy.