Yitzhak Schiller

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in Rats In Vivo

In epilepsy, the cortical network fluctuates between the asymptomatic interictal state and the symptomatic ictal state of seizures. Despite their importance, the network dynamics responsible for the transition between the interictal and ictal states are largely unknown. Here we used multielectrode single-unit recordings from the hippocampus to investigate the network dynamics during the development of seizures evoked by various chemoconvulsants in vivo. In these experiments, we detected a typical network dynamics signature that preceded seizure initiation. The preictal state preceding pilocarpine-, kainate-, and picrotoxin-induced seizures was characterized by biphasic network dynamics composed of an early desynchronization phase in which the tendency of neurons to fire correlated action potentials decreased, followed by a late resynchronization phase in which the activity and synchronization of the network gradually increased. This biphasic network dynamics preceded the initiation both of the initial seizure and of recurrent spontaneous seizures that followed. During seizures, firing of individual neurons and interneuronal synchronization further increased. These findings advance our understanding of the network dynamics leading to seizure initiation and may in future help in the development of novel seizure prediction algorithms.

Parkinson's disease tremor is diminished with relaxation guided imagery.

Patients with Parkinsons disease (PD) may have pronounced tremor that exacerbates during stress. To determine whether PD tremor improves with relaxation guided imagery (RGI) and relaxing music. Twenty patients with PD with moderate to severe tremor participated in sessions where relaxation techniques were implemented. Tremor was objectively monitored using an accelerometer. RGI dramatically decreased tremor in all 20 patients (baseline 270.38 ± 85.82 vs. RGI 35.57 ± 43.90 movements per minute P < 0.0001). In 15 patients, RGI completely abolished tremor for 1–13 min. Average tremor activity remained significantly bellow baseline both 15 min and 30 min after RGI was discontinued (P < 0.001). Patients reported improvement lasting 2–14 hours (mean 6.8 ± 3.8). Relaxing music significantly reduced tremor but to a lesser degree than RGI (220.04 ± 106.53 movements per minute P = 0.01). Self‐relaxation had no significant effect on tremor. RGI can supplement conventional medical treatments for tremor in patients with PD on best medical treatment.

Development of hypersynchrony in the cortical network during chemoconvulsant-induced epileptic seizures in vivo.

The prevailing view of epileptic seizures is that they are caused by increased hypersynchronous activity in the cortical network. However, this view is based mostly on electroencephalography (EEG) recordings that do not directly monitor neuronal synchronization of action potential firing. In this study, we used multielectrode single-unit recordings from the hippocampus to investigate firing of individual CA1 neurons and directly monitor synchronization of action potential firing between neurons during the different ictal phases of chemoconvulsant-induced epileptic seizures in vivo. During the early phase of seizures manifesting as low-amplitude rhythmic β-electrocorticography (ECoG) activity, the firing frequency of most neurons markedly increased. To our surprise, the average overall neuronal synchronization as measured by the cross-correlation function was reduced compared with control conditions with ~60% of neuronal pairs showing no significant correlated firing. However, correlated firing was not uniform and a minority of neuronal pairs showed a high degree of correlated firing. Moreover, during the early phase of seizures, correlated firing between 9.8 ± 5.1% of all stably recorded pairs increased compared with control conditions. As seizures progressed and high-frequency ECoG polyspikes developed, the firing frequency of neurons further increased and enhanced correlated firing was observed between virtually all neuronal pairs. These findings indicated that epileptic seizures represented a hyperactive state with widespread increase in action potential firing. Hypersynchrony also characterized seizures. However, it initially developed in a small subset of neurons and gradually spread to involve the entire cortical network only in the later more intense ictal phases.

Texture coarseness responsive neurons and their mapping in layer 2–3 of the rat barrel cortex in vivo

Texture discrimination is a fundamental function of somatosensory systems, yet the manner by which texture is coded and spatially represented in the barrel cortex are largely unknown. Using in vivo two-photon calcium imaging in the rat barrel cortex during artificial whisking against different surface coarseness or controlled passive whisker vibrations simulating different coarseness, we show that layer 2–3 neurons within barrel boundaries differentially respond to specific texture coarsenesses, while only a minority of neurons responded monotonically with increased or decreased surface coarseness. Neurons with similar preferred texture coarseness were spatially clustered. Multi-contact single unit recordings showed a vertical columnar organization of texture coarseness preference in layer 2–3. These findings indicate that layer 2–3 neurons perform high hierarchical processing of tactile information, with surface coarseness embodied by distinct neuronal subpopulations that are spatially mapped onto the barrel cortex. DOI: http://dx.doi.org/10.7554/eLife.03405.001

The antiepileptic and ictogenic effects of optogenetic neurostimulation of PV-expressing interneurons.

Parvalbumin (PV)-expressing interneurons exert powerful inhibitory effects on the normal cortical network; thus optogenetic activation of PV interneurons may also possess antiepileptic properties. To investigate this possibility we expressed channelrhodopsin 2 in PV interneurons by locally injecting the Cre-dependent viral vector AAV2/1-EF1a-DIO-ChETA-EYFP into the S1 barrel cortex of PV-Cre mice. Approximately 3-4 wk later recurrent electrographic seizures were evoked by local application of the chemoconvulsant 4-aminopyridine (4-AP); the ECoG and unit activity were monitored with extracellular silicone electrodes; and PV interneurons were activated optogenetically during the ictal and interictal phases. Five- to ten-second optogenetic activation of PV interneurons applied during electrographic seizures (ictal phase) terminated 33.7% of electrographic seizures compared with only 6% during sham stimulation, and the average electrographic seizure duration shortened by 38.7 ± 34.2% compared with sham stimulation. In contrast, interictal optogenetic activation of PV interneurons showed powerful and robust ictogenic effects. Approximately 60% of interictal optogenetic stimuli resulted in electrographic seizure initiation. Single-unit recordings revealed that presumptive PV-expressing interneurons markedly increased their firing during optogenetic stimulation, while many presumptive excitatory pyramidal neurons showed a biphasic response, with initial suppression of firing during the optogenetic pulse followed by a synchronized rebound increase in firing at the end of the laser pulse. Our findings indicated that ictal activation of PV-expressing interneurons possesses antiepileptic properties probably due to suppression of firing in pyramidal neurons during the laser pulse. However, in addition interictal activation of PV-expressing interneurons possesses powerful ictogenic properties, probably due to synchronized postinhibition rebound firing of pyramidal neurons.

Termination of Chemoconvulsant-Induced Seizures by Synchronous and Asynchronous Electrical Stimulation of the Hippocampus In-Vivo

BACKGROUND Neurostimulation has been proposed as a potential new treatment modality for pharmacoresistant epilepsy. Yet the effect of the different stimulation parameters on the efficacy of stimulation is not sufficiently known. OBJECTIVE Investigate the effect of different stimulation parameters on the efficacy of neurostimulation in terminating acute chemoconvulsant-induced hippocampal seizures in-vivo. METHODS Seizures were induced in rats in-vivo either by systemic or local intra hippocampal application of chemoconvulsants, and bipolar electrical stimulation was applied during seizures by stimulating the perforant pathway of the hippocampus. The stimulus intensity, frequency, and duration were altered. RESULTS Increasing the stimulus intensity and train duration increased the probability for seizure termination. The efficacy of stimulus intensity peaked at 250-300 μA. Low stimulation frequencies (≤13 Hz) were inefficient in terminating seizures. Increasing the stimulation frequency (up to 250 Hz) enhanced seizure termination, reaching a plateau effect at frequencies of 50-100 Hz. When we simultaneously applied the same stimulation frequency in two adjacent electrodes (synchronous stimulation) the probability for seizure termination did not significantly change. In contrast when the two stimulating electrodes were simultaneously activated with different asynchronous stimulation frequencies (30 and 100 Hz or 60 and 200 Hz, asynchronous stimulation) the probability for terminating seizures more than doubled. Similar results were also observed with local intra hippocampal-induced seizures. CONCLUSIONS Asynchronous stimulation paradigms enhanced the antiepileptic efficacy of neurostimulation, possibly by desynchronizing and functionally subdividing the network.

Atrial Fibrillation Associated With Epileptic Seizures—Reply

Background Epileptic seizures are often associated with changes in cardiac autonomic function. Yet atrial fibrillation (AFib) or atrial flutter (AFlu) following epileptic seizures has only rarely been reported in the past. Objectives To describe and characterize patients who experienced lone AFib or AFlu as a consequence of epileptic seizures. Design Case reports. Setting University teaching hospital. Patients We describe 4 patients who developed transient AFib following epileptic seizures and 1 patient who developed transient AFlu following epileptic seizures. Results In all patients, AFib and AFlu followed a generalized tonic-clonic seizure. The arrhythmia usually lasted a few hours and converted spontaneously to a normal sinus rhythm. In 3 patients, AFib or AFlu developed during the first seizure they experienced, and none of the patients developed drug-resistant epilepsy. Moreover, none of the patients had a known cardiac disease, yet, in 2 patients, the cardiological workup demonstrated mild abnormalities on the cardiac stress test. Conclusions Atrial fibrillation is the most common type of arrhythmia, with an estimated prevalence of 1%. Despite the fact that AFib can cause syncope, it is important to consider the possibility of AFib developing secondary to an epileptic seizure in cases of AFib and transient loss of consciousness.

Prolonged ictal aphasia: A diagnosis to consider

Aphasia is a common symptom encountered by clinical neurologists. It is usually caused by strokes or lesions involving language regions of the brain, yet prolonged aphasia is rarely the sole manifestation of a simple partial status epilepticus. We report six patients, who suffered from prolonged ictal aphasia. All but one patient had a structural lesion in the left hemisphere, only three suffered from clinical seizures during or shortly prior to the aphasic episode. All patients had ictal patterns on the electroencephalogram (EEG), four of whom had periodic lateralized epileptiform discharges, and five showed frequent recurrent electrographic seizures during the aphasic state. The aphasia lasted several days in all patients, and it resolved after administration of antiepileptic drug treatment. In conclusion, prolonged ictal aphasia is a rare but important treatable cause of aphasia. Surface EEG recordings should be obtained in all patients with unexplained prolonged aphasia to diagnose this rare but treatable entity.

Feedforward motor information enhances somatosensory responses and sharpens angular tuning of rat S1 barrel cortex neurons

The primary vibrissae motor cortex (vM1) is responsible for generating whisking movements. In parallel, vM1 also sends information directly to the sensory barrel cortex (vS1). In this study, we investigated the effects of vM1 activation on processing of vibrissae sensory information in vS1 of the rat. To dissociate the vibrissae sensory-motor loop, we optogenetically activated vM1 and independently passively stimulated principal vibrissae. Optogenetic activation of vM1 supra-linearly amplified the response of vS1 neurons to passive vibrissa stimulation in all cortical layers measured. Maximal amplification occurred when onset of vM1 optogenetic activation preceded vibrissa stimulation by 20 ms. In addition to amplification, vM1 activation also sharpened angular tuning of vS1 neurons in all cortical layers measured. Our findings indicated that in addition to output motor signals, vM1 also sends preparatory signals to vS1 that serve to amplify and sharpen the response of neurons in the barrel cortex to incoming sensory input signals. DOI: http://dx.doi.org/10.7554/eLife.21843.001