Richard A. Wennberg

Chronic anterior thalamus stimulation for intractable epilepsy.

Summary: u2002Purpose: A significant number of patients with epilepsy remain poorly controlled despite antiepileptic medication (AED) treatment and are not eligible for resective surgery. Novel therapeutic methods are required to decrease seizure burden in this population. Several observations have indicated that the anterior thalamic region plays an important role in the maintenance and propagation of seizures. We investigated neuromodulation of the anterior thalamus by using deep‐brain stimulation (DBS) in patients with intractable seizures.

Memory enhancement induced by hypothalamic/fornix deep brain stimulation.

Bilateral hypothalamic deep brain stimulation was performed to treat a patient with morbid obesity. We observed, quite unexpectedly, that stimulation evoked detailed autobiographical memories. Associative memory tasks conducted in a double‐blinded “on” versus “off” manner demonstrated that stimulation increased recollection but not familiarity‐based recognition, indicating a functional engagement of the hippocampus. Electroencephalographic source localization showed that hypothalamic deep brain stimulation drove activity in mesial temporal lobe structures. This shows that hypothalamic stimulation in this patient modulates limbic activity and improves certain memory functions. Ann Neurol 2008;63:119–123

Performance reassessment of a real-time seizure-detection algorithm on long ECoG series

Summary: u2002Purpose: Automated seizure detection and blockage requires highly sensitive and specific algorithms. This study reassessed the performance of an algorithm by using a more extensive database than that of a previous study and its suitability for safety/efficacy closed‐loop studies to block seizures in humans.

Enhanced Synchrony in Epileptiform Activity? Local versus Distant Phase Synchronization in Generalized Seizures

Synchronization is a fundamental characteristic of complex systems and a basic mechanism of self-organization. A traditional, accepted perspective on epileptiform activity holds that hypersynchrony covering large brain regions is a hallmark of generalized seizures. However, a few recent reports have described substantial fluctuations in synchrony before and during ictal events, thus raising questions as to the widespread synchronization notion. In this study, we used magnetoencephalographic recordings from epileptic patients with generalized seizures and normal control subjects to address the extent of the phase synchronization (phase locking) in local (neighboring) and distant cortical areas and to explore the ongoing temporal dynamics for particular ranges of frequencies at which synchrony occurs, during interictal and ictal activity. Synchronization patterns were found to differ somewhat depending on the epileptic syndrome, with primary generalized absence seizures displaying more long-range synchrony in all frequency bands studied (3–55 Hz) than generalized tonic motor seizures of secondary (symptomatic) generalized epilepsy or frontal lobe epilepsy. However, all seizures were characterized by enhanced local synchrony compared with distant synchrony. There were fluctuations in the synchrony between specific cortical areas that varied from seizure to seizure in the same patient, but in most of the seizures studied, regardless of semiology, there was a constant pattern in the dynamics of synchronization, indicating that seizures proceed by a recruitment of neighboring neuronal networks. Together, these data indicate that the concept of widespread “hypersynchronous” activity during generalized seizures may be misleading and valid only for very specific neuronal ensembles and circumstances.

H215O or 13NH3 PET and electromagnetic tomography (LORETA) during partial status epilepticus

The authors evaluated the feasibility and source localization utility of H215O or 13NH3 PET and low-resolution electromagnetic tomography (LORETA) in three patients with partial status epilepticus (SE). Results were correlated with findings from intraoperative electrocorticographic recordings and surgical outcomes. PET studies of cerebral blood flow and noninvasive source modeling with LORETA using statistical nonparametric mapping provided useful information for localizing the ictal activity in patients with partial SE.

Source localization of mesial temporal interictal epileptiform discharges : Correlation with intracranial foramen ovale electrode recordings

OBJECTIVEnWe have investigated the localization accuracy of low-resolution electromagnetic tomography (LORETA) for mesial temporal interictal epileptiform discharges (IED) on a statistical basis by using clinical electroencephalographic (EEG) data of simultaneous scalp and intracranial foramen ovale (FO) electrode recordings.nnnMETHODSnWe retrospectively analyzed the IED of 15 patients who underwent presurgical assessment for intractable temporal lobe epilepsy. All patients have subsequently undergone amygdalohippocampectomy. The scalp signals were averaged time-locked to the peak activity in bilateral 10-contact FO electrode recordings. Source modeling was carried out by using statistical non-parametric mapping (SNPM) of LORETA values and by calculating raw LORETA values of averaged IED. The results were compared to intracranial data obtained from FO electrode recordings.nnnRESULTSnTwo thousand six hundred and fifteen discharges could be attributed to 19 different patterns of intracranial mesial temporal IED. SNPM of LORETA revealed confined ipsilateral mesial temporal solutions for 14 (73.7%) and no significant solutions for five (26.3%) of these patterns. Raw LORETA current density distributions of the 19 averaged IED patterns revealed ipsilateral basal to lateral temporal solutions for the 14 IED patterns with a sufficient signal to noise ratio (SNR), but spurious results for those five IED with a low SNR.nnnCONCLUSIONSnSNPM of LORETA but not LORETA analysis of averaged IED patterns accurately localizes the source generators of mesial temporal IEDs.nnnSIGNIFICANCEnSNPM of raw LORETA values might be appropriate for localizing restricted mesial temporal lobe sources.

Cortical activation with deep brain stimulation of the anterior thalamus for epilepsy

OBJECTIVEnWe studied the relation between thalamic stimulation parameters and the morphology, topographic distribution and cortical sources of the cerebral responses in patients with intractable epilepsy undergoing deep brain stimulation (DBS) of the thalamus.nnnMETHODSnBipolar and monopolar stimuli were delivered at a rate of 2 Hz to the anterior (AN, four patients), the dorsomedian (DM, four patients), and the centromedian nucleus (CM, one patient) using the programmable stimulation device (Medtronic ITREL II). Source modeling was carried out by using statistical non-parametric mapping of low-resolution electromagnetic tomography (LORETA) values.nnnRESULTSnAll patients demonstrated reproducible time-locked cortical responses (CRs) consisting of a sequence of components with latencies between 20 and 320 ms. The morphology of these CRs, however, was very heterogeneous, depending primarily on the site of stimulation. Following AN stimulation, cortical activation was most prominent in ipsilateral cingulate gyrus, insular cortex and lateral neocortical temporal structures. Stimulation of the DM mainly showed activation of the ipsilateral orbitofrontal and mesial and lateral frontal areas, but also involvement of mesial temporal structures. Stimulation of the CM showed a rather diffuse (though still mainly ipsilateral) increase of cortical activity. The magnitude of cortical activation was positively related to the strength of the stimulus and inversely related to the impedance of the electrode.nnnCONCLUSIONSnThe pattern of cortical activation corresponded with the hodology of the involved structures and may underscore the importance of optimal localization of DBS electrodes in patients with epilepsy.nnnSIGNIFICANCEnThe method of analyzing sources of CRs could potentially be a useful tool for titration of DBS parameters in patients with electrode contacts in clinically silent areas. Furthermore, the inverse relation of the cortical activation and the impedance of the electrode contacts might suggest that these impedance measurements should be taken into consideration when adjusting DBS parameters in patients with epilepsy.

Propagation of interictal discharges in temporal lobe epilepsy: Correlation of spatiotemporal mapping with intracranial foramen ovale electrode recordings

OBJECTIVEnWe have investigated intracerebral propagation of interictal epileptiform discharges (IED) in patients with mesial temporal lobe epilepsy (MTLE) by using spatiotemporal source maps based on statistical nonparametric mapping (SNPM) of low resolution electromagnetic tomography (LORETA) values.nnnMETHODSnWe analyzed 30 patterns of IED recorded simultaneously with scalp and intracranial foramen ovale (FO) electrodes in 15 consecutive patients with intractable MTLE. The scalp EEG signals were averaged time-locked to the peak activity in bilateral 10-contact FO electrode recordings. SNPM was applied to LORETA values and spatiotemporal source maps were created by allocating the t-values over time to their corresponding Brodmann areas. Propagation was defined as secondary statistically significant involvement of distinct cortical areas separated by >15 ms. The results were correlated with intracranial data obtained from FO electrode recordings and with scalp EEG recordings. All patients underwent subsequent amygdalo-hippocampectomy and outcome was assessed one year after surgery.nnnRESULTSnWe found mesial to lateral propagation in 6/30 IED patterns (20%, four patients), lateral to mesial propagation in 4/30 IED patterns (13.3%, four patients) and simultaneous (within 15 ms) activation of mesial and lateral temporal areas in 6/30 IED patterns (20%, five patients). Propagation generally occurred within 30 ms and was always limited to ipsilateral cortical regions. Nine/30 IED patterns (30%) showed restricted activation of mesial temporal structures and no significant solutions were found in 5/30 IED patterns (16.7%). There was no clear association between the number or characteristics of IED patterns and the postsurgical outcome.nnnCONCLUSIONSnSpatiotemporal mapping of SNPM LORETA accurately describes mesial to lateral temporal propagation of IED, and vice versa, which commonly occur in patients with MTLE.nnnSIGNIFICANCEnIntracerebral propagation must be considered when using non-invasive source algorithms in patients with MTLE. Spatiotemporal mapping might be useful for visualizing this propagation.

Depth electrode recorded cerebral responses with deep brain stimulation of the anterior thalamus for epilepsy

OBJECTIVEnWe investigated the relation between anterior thalamic stimulation and the morphology of the evoked cerebral responses (CRs) using intracerebral depth electrodes in patients with intractable epilepsy undergoing deep brain stimulation (DBS) of the thalamus.nnnMETHODSnMonopolar cathodic and bipolar stimuli were delivered at a rate of 2 or 1 Hz to the anterior nucleus (AN) and the dorsomedian nucleus (DM) of two patients using the programmable stimulation device (Medtronic ITREL II) or a GRASS stimulation device (S12). CRs were recorded from depth or DBS electrodes, situated bilaterally in mesial temporal (hippocampus, both patients), lateral temporal (one patient), orbitofrontal (Brodmann area 11, one patient) and anterior thalamic sites (one patient).nnnRESULTSnThe distribution and morphology of the CRs depended primarily on the site of stimulation within the anterior thalamic region. Overall, monopolar cathodic and bipolar stimulation of the AN elicited CRs mainly in ipsilateral mesial temporal cortical areas, whereas stimulation of the DM evoked high-amplitude CRs predominantly in ipsilateral orbitofrontal areas. The amplitude of the CR was positively related to the strength of the stimulus and generally higher with monopolar than with bipolar stimulation. The differences between CRs elicited during wakefulness or slow wave sleep were minimal.nnnCONCLUSIONSnThe distribution of the CRs corresponded with the intracerebral pathways of the involved structures and the findings are in good accordance with those of our previous study investigating the sources of CRs using statistical non-parametric mapping of low resolution electromagnetic tomography (LORETA) values.nnnSIGNIFICANCEnOur findings indicate a certain degree of point-to-point specificity within the thalamocortical circuitry, which may make optimal localization of DBS electrodes important in patients with epilepsy.

Intracranial volume conduction of cortical spikes and sleep potentials recorded with deep brain stimulating electrodes.

OBJECTIVEnTo examine interictal epileptiform and sleep potentials recorded intracranially from deep brain stimulation (DBS) electrodes in patients treated with DBS for epilepsy. Specifically, this study sought to determine whether the DBS-recorded potentials represent: (a) volume conduction from surface neocortical discharges or (b) transsynaptic propagation along cortical-subcortical pathways with local generation of the subcortical potentials near the DBS targets.nnnMETHODSnSix patients with intractable epilepsy treated with thalamic DBS of the central median nucleus (CM; one patient) or anterior thalamus (5 patients) who had focal interictal spikes were studied. Sleep potentials were also studied in a 7th patient with Parkinson disease treated with DBS of the subthalamic nucleus (STN).nnnRESULTSnFocal interictal cortical spikes recorded by scalp electroencephalography (EEG) were recorded synchronously, but with opposite polarity, from the DBS electrodes in CM as well as the more superficial anterior thalamic contacts situated in the anterior nucleus (AN) and dorsal medial nucleus (DM). In referential montages, the subcortical potentials were of highest amplitude ipsilateral to the focal cortical spikes, with a small but reproducible amplitude decrement present at each electrode contact more distant from the cortical source, irrespective of the specific DBS target. Subcortical sleep potentials (K-complexes and sleep spindles) were also recorded synchronously and with inverse polarity compared to the corresponding scalp potentials, and appeared in a similar fashion at all subcortical sites sampled by the DBS electrodes. Amplitude attenuation in the thalamus of intracranial volume conducted potentials with increasing distance from their cortical spike sources was measured at approximately 5-10 microV/mm.nnnDISCUSSIONnRecent reports on scalp-CM or scalp-STN EEG recordings in patients treated with DBS for epilepsy have interpreted the intracranial waveforms as evidence of transsynaptic cortical-subcortical transmission across neuroanatomical pathways presumed to be involved in the generation of sleep potentials (Clin. Neurophysiol. 113 (2002) 25) and epileptiform activity (Clin. Neurophysiol. 113 (2002) 1391). However, our results show that the intracranial spikes recorded from DBS electrodes in various regions of the thalamus (CM, AN and DM) represent subcortical volume conduction of the synchronous cortical spikes recorded with scalp EEG. The same is true for the intracranial reflections of scalp EEG sleep potentials recorded from DBS electrodes in CM, AN, DM and STN. These interictal DBS waveforms thus cannot be used to support hypotheses of specific cortical-subcortical pathways of neural propagation or subcortical generation of the DBS-recorded potentials associated with scalp EEG interictal spikes and sleep potentials.nnnSIGNIFICANCEnDetailed analysis of the intracranial potentials recorded from DBS electrodes in association with scalp EEG spikes and sleep discharges shows that the intracranial waveforms represent volume conduction from discharges generated in the neocortex and not, as has been suggested, locally generated activity resulting from cortical-subcortical neural propagation.