ATPase N-ethylmaleimide-sensitive Fusion Protein: A Novel Key Player for Causing Spontaneous Network Excitation in Human Temporal Lobe Epilepsy.

The molecular basis for onset, maintenance and propagation of excitation along neuronal networks in epilepsy is still poorly understood. Besides different neurotransmitter receptors that control signal transfer at the synapse, one key regulator involved in all of these processes is the ATPase N-ethylmaleimide-sensitive fusion protein (NSF). Therefore, we analyzed receptor subunits and NSF levels in tissues from the medial temporal gyrus (MTG) of patients with pharmaco-resistant focal temporal lobe epilepsy resected during epilepsy surgery and autopsy controls. The resected tissues were further characterized by field potential recordings into tissues with and without spontaneous sharp wave activity. We detected increased levels of NSF, NMDA 1.1, 2A and GABAAγ2 receptor subunits associated with spontaneous sharp wave spiking activity. We further identified correlations between NSF, AMPA receptor subunit, metabotropic glutamate receptor and adenosine 1 receptor levels in the spontaneous sharp wave spiking tissues. Our findings suggest that NSF plays a key role in controlling spontaneous network excitation in epilepsy by two mechanisms of action: (1) directly via controlling transmitter release at the presynaptic side, and (2) indirectly via altering the function of possible receptor crosstalk and directing/integrating specific receptor compounds through/into the postsynaptic membrane

Directional spread of activity in synaptic networks of the human lateral amygdala.

Spontaneous epileptiform activity has previously been observed in lateral amygdala (LA) slices derived from patients with intractable-temporal lobe epilepsy. The present study aimed to characterize intranuclear LA synaptic connectivity and to test the hypothesis that differences in the spread of flow of neuronal activity may relate to spontaneous epileptiform activity occurrence. Electrical activity was evoked through electrical microstimulation in acute human brain slices containing the LA, signals were recorded as local field potentials combined with fast optical imaging of voltage-sensitive dye fluorescence. Sites of stimulation and recording were systematically varied. Following recordings, slices were anatomically reconstructed using two-dimensional unitary slices as a reference for coronal and parasagittal planes. Local spatial patterns and spread of activity were assessed by incorporating the coordinates of electrical and optical recording sites into the respective unitary slice. A preferential directional spread of evoked electrical signals was observed from ventral to dorsal, rostral to caudal and medial to lateral regions in the LA. No differences in spread of evoked activity were observed between spontaneously and non-spontaneously active LA slices, i.e. basic properties of evoked synaptic responses were similar in the two functional types of LA slices, including input-output relationship, and paired-pulse depression. These results indicate a directed propagation of synaptic signals within the human LA in spontaneously active epileptic slices. We suggest that the lack of differences in local and in systemic information processing has to be found in confined epileptiform circuits within the amygdala likely involving well-known 'epileptic neurons'

Oscillatory Dynamics Track Motor Performance Improvement in Human Cortex

<div><p>Improving performance in motor skill acquisition is proposed to be supported by tuning of neural networks. To address this issue we investigated changes of phase-amplitude cross-frequency coupling (paCFC) in neuronal networks during motor performance improvement. We recorded intracranially from subdural electrodes (electrocorticogram; ECoG) from 6 patients who learned 3 distinct motor tasks requiring coordination of finger movements with an external cue (serial response task, auditory motor coordination task, go/no-go). Performance improved in all subjects and all tasks during the first block and plateaued in subsequent blocks. Performance improvement was paralled by increasing neural changes in the trial-to-trial paCFC between theta (; 4–8 Hz) phase and high gamma (HG; 80–180 Hz) amplitude. Electrodes showing this covariation pattern (Pearson's r ranging up to .45) were located contralateral to the limb performing the task and were observed predominantly in motor brain regions. We observed stable paCFC when task performance asymptoted. Our results indicate that motor performance improvement is accompanied by adjustments in the dynamics and topology of neuronal network interactions in the and HG range. The location of the involved electrodes suggests that oscillatory dynamics in motor cortices support performance improvement with practice.</p></div

The amplitude of the HG oscillations is phase coupled to the -band (4–8 Hz) oscillations in all subjects across paradigms.

<p>A) Time courses of sine wave functions fitted to the single trial amplitude envelopes of the HG oscillations of one subjects collapsed over electrodes. B) Sine wave functions fitted to the trial-averaged HG oscillation amplitudes envelopes of each subject. Each solid line represents the fit for one subject. Each dot represents the individual trial average of the HG oscillation in one of 20 intervals equally spaced over a cycle. The black dashed line shows the averaged sine waves across subjects. The vertical blue dashed line denotes the averaged phase angle the HG amplitude peaks across subjects. The maximum of the cycle is at phase 0 and the minimum at .</p

Here we depict the separation of the whole experimental session into trial bins.

<p>The experimental session in each patient consisted of 2 blocks separated by a short break. In each block we defined two trial bins each containing 30 trials (blue). We compared the PLV across the four trial bins to assess the evolution of connectivity length of and HG activity during motor performance improvement.</p

Electrodes with significant trial-by-trial correlations of TPR with performance.

<p>The significance threshold was determined in a permutation procedure (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089576#s4" target="_blank">Methods</a>) A) Learning unrelated correlations of TPR with performance. B) Learning related correlations of TPR with performance. Darker colors indicate stronger correlations. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089576#s4" target="_blank">Methods</a> for calculations on separating performance and learning related effects. The blue shape in the first and second row show the outline of all superimposed square grids. The black shapes in the third row denotes the grid locations for the participant in the AMCT. Spatial distortions result from the projection onto the cortex (for details see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089576#pone.0089576.s003" target="_blank">Figure S2</a>).</p

Depiction of the results from the ROI-analysis.

<p>A) ROIs with significant performance improvement unrelated TPR/performance correlations. B) ROIs with significant performance improvement related TPR/performance correlations. ROIs with significant correlations (Bonferroni correct for six comparisons) are marked with an asterisk. The 6 ROIs are the anterior and posterior medial frontal gyrus, the anterior and the posterior inferior frontal gyrus, and the superior and posterior sensorimotor cortex. The blue margin shows the grid coverage across all subjects with a square grid implanted.</p