Friedhelm C. Schmitt

Radiofrequency lesioning for epileptogenic periventricular nodular heterotopia: a rational approach.

Periventricular nodular heterotopias (PNHs) are frequently associated with pharmacoresistant epilepsy. They are considered part of a dysfunctional network, connected to the overlying cortex. Therefore, removal of the PNHs and additional cortectomy or lobectomy seem to be essential for significant and long‐lasting seizure reduction. These procedures, however, can have considerable limitations, especially in patients with functional eloquent cortex adjacent to the PNH. Alternatively, stereotactic neurosurgery can reduce the surgical trauma. Presented is a 56‐year‐old man who became seizure‐free after stereotactically guided radiofrequency lesioning of a solitary PNH.

Memory signals from the thalamus: Early thalamocortical phase synchronization entrains gamma oscillations during long-term memory retrieval

The thalamus is believed to be a key node in human memory networks, however, very little is known about its real-time functional role. Here we examined the dynamics of thalamocortical communication during long-term episodic memory retrieval in two experiments. In experiment 1, intrathalamic and surface EEG was recorded in an epileptic patient implanted with depth electrodes for brain stimulation therapy. In a recognition memory test, early (300-500 ms) stimulus-linked oscillatory synchrony between mediodorsal thalamic and frontal surface electrodes at beta frequency (20 Hz) was enhanced for correctly remembered old compared to correctly rejected new items. Directionality measures (Granger causality) indicated that the thalamus was the sender, and the neocortex the receiver, of this beta signal, which also modulated the power of neocortical gamma (55-80 Hz) oscillations (cross-frequency coupling). Experiment 2 validated the cross-frequency coupling effects in a healthy participant sample. Confirming the findings from experiment 1, significantly increased cross-frequency coupling was found over frontal scalp electrodes during successful recognition. Extending anatomical knowledge on thalamic connectivity with frontal neocortex, these results suggest that the thalamus sends an early memory signal to frontal regions, triggering further memory search processes.

Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation

The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding. DOI:http://dx.doi.org/10.7554/eLife.05352.001

Clinical relevance of source location in frontal lobe epilepsy and prediction of postoperative long-term outcome

PURPOSE To evaluate the value of magnetoencephalography (MEG) source localization in localization of epileptic activities and predicting surgical outcome in frontal lobe epilepsies (FLE). METHODS Forty-six patients with presurgical MEG evaluation and intractable FLE surgery (28 male patients) were analyzed retrospectively with a mean follow-up of 5 years. Dipole analysis was performed for MEG source imaging (MSI). The localization of dipole clusters in relation to the dominant hemisphere, lesions, resection cavity and functional cortex were analyzed. The predictive value of MSI in respect to clinical outcome with long-term postoperative follow up was evaluated. RESULTS Interictal focal epileptic activities were found in 82.6% (38/46) patients with monofocal activity 81.6% (31/38) and multifocal activities 18.4% (7/38). Seizure free rate was 47.9% at the mean follow-up of 5.0 ± 4.0 years (median 11.5, range 2-57). Seizure recurrence mainly occurred in the first 1 year after surgery. In the monofocal epileptic activity group, 58.1% (18/31) of the patients were seizure free, predicitng postoperative seizure freedom better than multifocal localization 0% (0/7) (p=0.028). Dipole clusters were completely resected in 70.9% of monofocal activity patients, which had higher seizure free rates compared to partial resection (p=0.002). In patients with surgery in the dominant hemisphere, seizure control was less likely (p=0.006). CONCLUSION MSI contributes to the clinical prediction of postoperative outcome in FLE patients. MSI may non-invasively disclose early epileptogenic lesions, pointing to a resectable lesion, and it then facilitates shortcut route of presurgical evaluation.

Deep hypothermia terminates status epilepticus - an experimental study

In search for novel treatment approaches in status epilepticus, the anticonvulsant effect of moderate and deep hypothermia was assessed in a rodent model. Self-sustaining status epilepticus (SSSE) characterized by spontaneous high-amplitude discharges recorded from the dentate gyrus was induced in male adult rats by electrical stimulation of the perforant path. After the end of stimulation, rats underwent cooling to 30 °C (n=7) and 20 °C (n=10) for 120 min and rewarming to 37 °C for another 60 min. Control SSSE animals (n=6) remained untreated for 180 min. Frequency of epileptiform discharges was assessed every 10 min. At the target temperature of 20 °C, SSSE was completely suppressed in four rats, this effect was not observed in any animal of the other two groups (p=0.043). On rewarming, seizure activity did not reoccur. Discharge frequency was significantly lower in the 20 °C group at most time points after 60 min of cooling. Following deep hypothermia, eight animals were rewarmed, all survived and moved spontaneously at 37 °C. These experimental data indicate the strong and enduring anticonvulsant and obviously safe properties of cooling down to 20 °C. Patients with status epilepticus refractory to first- and second-line anticonvulsants may benefit from deep cooling as an effective non-pharmacological adjunct to anesthetic anticonvulsants.

Nucleus accumbens stimulation in partial epilepsy--a randomized controlled case series.

Neuromodulative treatment options are warranted in patients with difficult‐to‐treat epilepsy. However, acquisition of controlled data on deep brain stimulation has so far been achieved only for the centromedian and anterior thalamic nucleus. In a case series of four patients with intractable partial epilepsy, a randomized controlled cross‐over protocol was used to get insight into efficacy and safety of 3‐month nucleus accumbens stimulation. Seizure frequency, neurocognitive testing, “Liverpool Seizure Severity Score,” “Quality of Life in Epilepsy Inventory,” “Beck Depression Inventory,” and “Mini International Neuropsychiatric Interview” were obtained at every visit. In a subsequent open‐label phase, nucleus accumbens stimulation responders underwent concomitant anterior thalamic nucleus stimulation, whereas nonresponders received solely thalamic stimulation. Under nucleus accumbens stimulation, three of four patients had ≥50% reduction in frequency of disabling seizures without further improvement with additional anterior thalamic nucleus stimulation. Patient‐reported outcome and neurocognitive testing remained unchanged. Accumbens stimulation is safe and seems to be a suitable option in intractable partial epilepsy. The current findings require substantiation by an adequately powered multicenter study.

Direct Targeting of the Thalamic Anteroventral Nucleus for Deep Brain Stimulation by T1-Weighted Magnetic Resonance Imaging at 3 T

Background: The thalamic anteroventral nucleus (AV) is a promising target structure for deep brain stimulation (DBS) in patients suffering from refractory epilepsy. Direct visualization of the AV would improve spatial accuracy in functional stereotactic neurosurgery for treatment of this disease. Methods: On 3-tesla magnetic resonance imaging (MRI), acquisition parameters were adjusted for optimal demarcation of the AV in 1 healthy subject. Reliability of AV visualization was then evaluated in 5 healthy individuals and 3 patients with refractory epilepsy. Results: In all individuals, an adjusted T1-weighted sequence allowed for demarcation of the AV. It was clearly distinguishable from hyperintense myelin-rich lamellae surrounding it ventrally and laterally and appeared hypo-intense compared to the adjacent thalamic nuclei. Image resolution and contrast facilitated direct stereotactic targeting of the AV prior to DBS surgery in all 3 patients. Conclusions: Direct targeting of the AV can be achieved, which has immediate implications for the accuracy of MRI-guided DBS in patients with refractory epilepsy.

MEG in frontal lobe epilepsies: Localization and postoperative outcome

Purpose:  This study aimed to analyze magnetoencephalography (MEG) localizations of epileptic clusters in different cortical regions of the frontal lobe and relate these findings to postoperative outcomes associated with frontal lobe epilepsy (FLE).

Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients

In view of the regulatory function of the thalamus in the sleep‐wake cycle, the impact of deep brain stimulation (DBS) of the anterior nucleus thalami (ANT) on sleep was assessed in a small consecutive cohort of epilepsy patients with standardized polysomnography (PSG). In nine patients treated with ANT‐DBS (voltage 5 V, frequency 145 Hz, cyclic mode), the number of arousals during stimulation and nonstimulation periods, neuropsychiatric symptoms (npS), and seizure frequency were determined. Electroclinical arousals were triggered in 14.0 to 67.0% (mean 42.4 ± SD 16.8%) of all deep brain stimuli. Six patients reported npS. Nocturnal DBS voltages were reduced in eight patients (one patient without npS refused) and PSGs were repeated. Electroclinical arousals occurred between 1.4 and 6.7 (mean 3.3 ± 1.7) times more frequently during stimulation periods compared to nonstimulation periods; the number of arousals positively correlated with the level of DBS voltage (range 1 V to 5 V) (Spearman′s rank coefficient 0.53121; p < 0.05). No patient experienced seizure deterioration and four patients reported remission of npS. This case‐cohort study provides evidence that ANT‐DBS interrupts sleep in a voltage‐dependent manner, thus putatively resulting in an increase of npS. Reduction of nocturnal DBS voltage seems to lead to improvement of npS without hampering efficacy of ANT‐DBS.

Phase-Amplitude Cross-Frequency Coupling in the Human Nucleus Accumbens Tracks Action Monitoring during Cognitive Control

The Nucleus Accumbens (NAcc) is an important structure for the transfer of information between cortical and subcortical structures, especially the prefrontal cortex and the hippocampus. However, the mechanism that allows the NAcc to achieve this integration is not well understood. Phase-amplitude cross-frequency coupling (PAC) of oscillations in different frequency bands has been proposed as an effective mechanism to form functional networks to optimize transfer and integration of information. Here we assess PAC between theta and high gamma oscillations as a potential mechanism that facilitates motor adaptation. To address this issue we recorded intracranial field potentials directly from the bilateral human NAcc in three patients while they performed a motor learning task that varied in the level of cognitive control needed to perform the task. As in rodents, PAC was observable in the human NAcc, transiently occurring contralateral to a movement following the motor response. Importantly, PAC correlated with the level of cognitive control needed to monitor the action performed. This functional relation indicates that the NAcc is engaged in action monitoring and supports the evaluation of motor programs during adaptive behavior by means of PAC.