RATIONALE: Interictal spikes are brief (< 250 milliseconds), high-amplitude discharges observed in the EEG (scalp and intracranial) in patients who are predisposed to spontaneous seizures. The temporo-spatial distribution of spikes is variable and depends on states of vigilance (SOV) and seizure. In focal epilepsy, spikes are often found in regions beyond the seizure onset zone(SOZ) and are defined as “irritative zone”(IZ). Continuous dynamic interactions between SOZ and IZ are influenced by underlying synchronization that in turn is regulated by SOV. Studies demonstrating the variation in spike distribution are often constrained to cortical structures. Thalamus, a subcortical node interconnected to diverse cortical network including mesial temporal lobe, is implicated in regulation of SOV and in genesis of focal seizures. However to date, no study has explored the distribution of spike within the thalamo-cortical network in human focal epilepsy. We hypothesize, that the prevalence of spike within the SOZ and thalamus will vary with SOV and the spike count in thalamus will be higher during sleep than in wakefulness.
METHODS: Five adults with suspected temporal lobe epilepsy underwent stereoEEG (SEEG) investigation. Anterior thalamic nucleus (TH) ipsilateral to the SOZ was sampled with SEEG. The study was approved by IRB and written consent was obtained before surgery. Simultaneous scalp EEG was recorded that guided identification of NREM sleep (S) and wakefulness (A). Epileptogenic index was performed to identify SOZ. Spikes were analyzed during S and A from three channels :a) one within the SOZ; b) second from Th; and c) third outside the SOZ (control - C). Automated spike detection (P- operator) was validated by comparing the algorithm output to visual identification in 30 mins data per subject. For the spike count between SOV independent T-tests were performed to assess the bivariate relationships. Analysis of variance Welch ANOVA was used to analyze the differences in SOV as a function of three different independent samples (Channels). All statistical analyses were performed using IBM SPSS.
Auras (focal aware seizure; FAS) are subjective ictal events with retained consciousness. Epileptiform activities can disrupt cognitive tasks, but studies are limited to seizures with impaired awareness. As a proof of concept, we examined the cognitive effects of direct electrical stimulation to the left hippocampus which induced a habitual FAS in a patient with left mesial temporal lobe epilepsy. During the induced habitual FAS, verbal memory performance declined significantly as compared to pre-stimulation testing. Tasks measuring auditory working memory and psychomotor processing speed were not affected by the stimulation. The study confirms that FAS can impair episodic verbal memory and learning.
Keywords: Verbal memory, Aura, Focal aware seizure, Learning, Hippocampus, Epilepsy
RATIONALE: Most seizures self-terminate through complex interregional interactions. Increased synchrony (phase and amplitude correlation) just prior to termination is a common phenomenon. Generalized partial directed coherence (GPDC) measures directed functional connectivity (dFC) between brain regions . Indegree from a dFC provides valuable information to the state change affecting each region depending on synchrony in the local milieu. Here we measured indegree derived from windowed analysis of GPDC starting at 20 seconds before seizure termination and continued 20 seconds postictally, to quantify: 1) difference in the synchrony within the onset, spread and least involved channels (ON, SP and LI), 2) whether this interaction was significantly different between pre-termination (PrT) and post termination (PoT) states.
METHODS: Twenty seizures from 7 patients with intractable partial epilepsy underwent IEEG/SEEG placement for localizing the seizure onset zone (SOZ) were used for analysis. After the removal of artifactual channels, the data was converted to adjacency bipolar derivatives. GPDC was calculated using a window of 5 seconds with 50% overlap (SR: 2048Hz model order: 25) for each bandwidth (Delta:1-4Hz, Theta:4-8Hz, Alpha:8-13Hz, Beta:13-30Hz, Low Gamma:30-40Hz and High Gamma:45-95Hz) for all 3 types of channels. The indegree calculated across the stages and the bipolar derivations were tested with a two-way interaction ANOVA (LSD corrected p-value
RESULTS: It was found that the onset and spread channels had a significant difference between the PrT and PoT in all the band widths. However this difference was not very significant in the channels not involved. There was a significant decrease in indegree following seizure termination and this was maximum in the onset and spread channels but no on the least involved channels (p=0.041). The decrease in indegree was maximum at delta and
There is an unmet need to improve therapy for neuropsychiatric comorbidities that are highly prevalent in persons with epilepsy (PWE). However, diagnosing and monitoring the neurobehavioral symptoms is challenging as their presentation can overlap with seizures. In this retrospective study, we report the advantage of chronic ambulatory electrocorticography (ECoG) from implanted Responsive Neurostimulator System (RNS®) in characterizing these psychosomatic paroxysms as a possible ictal, postictal, or interictal phenomenon and how the diagnosis guided the therapy choices. Five out of 21 patients with RNS had neuropsychiatric symptoms (panic attack, psychosis, conversion, and somatization disorders) that overlapped with their seizure semiology and were found to benefit from the use of RNS ECoG data by timely diagnosing and titrating targeted therapies. The cases illustrate the use of RNS ECoG data in diagnosing and improving the management of comorbidities in PWE. The ability to access RNS ECoG data and correlate it with patient symptoms is unique among available therapeutic options for PWE.
Objective: Studies have demonstrated the utility of closed-loop neuromodulation in treating focal onset seizures. There is an utmost need of neurostimulation therapy for generalized tonic-clonic seizures. The study goals are to map the thalamocortical network dynamics during the generalized convulsive seizures and identify targets for reliable seizure detection.
Methods: Local field potentials were recorded from bilateral cortex, hippocampi, and centromedian thalami in Sprague-Dawley rats. Pentylenetetrazol was used to induce multiple convulsive seizures. The performances of two automated seizure detection methods (line length and P-operators) as a function of different cortical and subcortical structures were estimated. Multiple linear correlations-Granger's Causality was used to determine the effective connectivity.
Results: Of the 29 generalized tonic-clonic seizures analyzed, line length detected 100% of seizures in all the channels while the P-operator detected only 35% of seizures. The detection latencies were shortest in the thalamus in comparison to the cortex. There was a decrease in amplitude correlation within the thalamocortical network during the seizure, and flow of information was decreased from thalamus to hippocampal-parietal nodes.
Significance: The preclinical study confirms thalamus as a superior target for automated detection of generalized seizures and modulation of synchrony to increase coupling may be a strategy to abate seizures.
RATIONALE: Most seizures have the ability to self-terminate after a few seconds to minutes, suggesting that the brain possesses endogenous mechanisms to curtail excessive neuronal activation. Immediately following termination, myriads of changes are seen electro-clinically which are collectively classified as the POST ICTAL STATE. Most studies have characterized the EEG changes (suppression or delta/theta slowing), but these studies were limited to scalp EEG. Intracranial EEG recorded from cortical and subcortical structures provides rich information about the temporospatial changes in synchrony and spectral evolution at the post-ictal state. We hypothesize that the temporal evolution of synchrony and power spectrum is spatially heterogeneous and seizure onset zone is the last to recover. Furthermore, we posit that the pattern of changes in these two parameters will be different for synchronous ( seizure terminates at the same time in all recorded channels) versus asynchronous (seizure terminates at the different time among recorded channels) seizure offset.
METHODS: Thirty, post-ictal Stereo-EEG recordings were selected from 15 patients undergoing epilepsy surgical evaluation at the UAB Epilepsy Center. Video-EEG was sampled at 2 KHz, and all recording channels (range= 80-140 electrodes per patient) were included in the analysis. Two minutes of electrocorticogram starting from the earliest time of seizure offset was included for analysis. For synchronous offset, this was same for all channels while in asynchronous offset the EEG was clipped at the earliest offset. The 2 minute was then divided into 4, 30 seconds long segments, named P1, P2, P3, P4 and also a 30 s long baseline segment (B1) was chosen 5 minutes before the seizure started. The frequency was calculated with power spectrum density (PSD) in each post ictal segments, and the synchro-
Background and purpose: Focal seizures can arise from coordinated activity across large-scale epileptic networks and propagate to regions that are not functionally altered but are recruited by epileptiform discharges. In preclinical models of focal epilepsy, the thalamus is recruited by cortical onset seizures, but it remains to be demonstrated in clinical studies. In this pilot study, the authors investigate whether seizures with onset within and outside the mesial temporal structures are detected in the anterior thalamus (ATN).
Methods: After written consent, three subjects with suspected temporal lobe epilepsy undergoing stereotactic electrode implantation were recruited prospectively for thalamocortical depth EEG recordings. Three seizure detection metrics (line length-LL, Laplace operator-Lap; Teager energy-TE) were studied within the seizure onset zone and ATN.
Results: The LL, Lap, and TE metrics detected 40 (95%) seizures each in the ATN before the
behavioral manifestation. Rates of detection in the seizure onset zone were 40 (95%), 42 (100%), and 41 (98%), respectively. The mean detection latency in ATN from SOZ ranged from 0.25- 5.17 secs. Seizures were localized to amygdala-hippocampus, temporal pole, anterior insula and superior temporal gyrus.
Conclusions: The pilot study demonstrates that seizures in mesial temporal and temporal-plus epilepsies (i.e., temporoperisylvian) can be detected reliably in the ATN. Further studies are needed to validate these findings.
ny was defined as the mean phase lag index (PLI) between all channels from 2 s epochs derived from all segments (B1, P1-P4) in 7 frequency bands (delta:1-4 Hz, theta:4-7 Hz, alpha:8-12 Hz, beta:13-30 Hz, low gamma:30-40 Hz, high gamma:45-95 Hz, ripple band:95-150 Hz). PLI within the clinically identified seizure onset zone (SOZ) areas was calculated. Non parametric t-tests, Kruskal-Wallis analysis, multiple comparison test was applied on the mean PLI values.
RESULTS:The overall mean PLI values were significantly higher (p < 0.05) compared to the baseline in P1-P4 segments in delta and theta band, and in the P1 segment for the alpha band. Interestingly, P1 had higher mean PLI in the ripple band than P4. The synchronous and asynchronous offset were similar in the delta and theta band, but in the alpha, beta, gamma bands, the asynchronous mean PLI was higher at P1-P3 epochs. The emergence of theta or alpha frequencies were spatially heterogeneous and temporally the last within the SOZ. The PSD in the delta band was significantly (p < 0.05) higher after the synchronous termination compared to the asynchronous. This rate is reversed in the theta, alpha, beta, low gamma band, where the PSD is significantly higher (p < 0.05) in all the time segments.
CONCLUSIONS: Following seizure termination, patterns of synchronization differentiated between asynchronous and synchronous offset. For synchronous offset, synchrony in the delta and theta band while for asynchronous offset synchrony and frequency power in beta and low gamma bands were higher. These changes in the synchrony and frequency power after the seizure termination could lead us to characterize the level of excitability across the brain areas. Further analysis needed to investigate the connection between the frequency synchronization and the seizure duration, seizure subtype, or post ictal EEG and behavioral state. FUNDING:Supported by NSF grant OIA 1632891
FUNDING:This study was supported by NSF grant OIA 1632891
RATIONALE: After a seizure terminates, the ensuing electro-clinical changes that are often variable are collectively defined as the postictal state. This state is critically important as a cardio-respiratory compromise, and arousal dysfunction is often present and can contribute to mortality including SUDEP (Sudden Unexpected Death in Epilepsy). Prolonged loss of consciousness or confusion can contribute to poor quality of life. EEG changes in the postictal state are time variant and seizure dependent. It can range from continuous suppression to different degree of slowing (delta/theta) or epileptiform discharges (Periodic lateralized epileptiform discharges). Clinically patient can be obtunded or minimally responsive to external stimuli to confusion/agitation or with no/minimal loss of awareness. Interventions like closed loop brain stimulation that can accelerate recovery from the postictal state are attractive and might provide survival benefit. To develop such therapeutic intervention, the first important step is to quantify the behavioral state in the post-ictal period using electrocorticogram. Here we propose a novel strategy where automated detection of seizure termination and postictal behavioral changes are estimated using a single channel electrocorticogram recorded from seizure onset zone (SOZ).
METHODS:Twelve seizures recorded from five patients with intractable partial epilepsy undergoing intracranial EEG investigation were included in the study. The EEG recording was downsampled to 500 Hz from 2 KHz. A single channel with a minimal artifact from the SOZ was identified, and analysis was performed on that electrocorticogram(ECoG). Multiresolutional Teager energy was estimated from the ECoG (MTEO(k)) for each 1 second, and an adaptive threshold was developed for detection of seizure onset and termination. Shannon Permutation entropy (SPE) and Tsalis Permutation entropy (TPE) was performed initially to maximally parse sleep and awake ECoG. The three classifiers were then used to detect seizure termination and estimate behavioral changes (awake but confused/minimally responsive/awake without confusion) in the post-ictal period.
RESULTS:From video EEG analysis and clinical examination during post-ictal state, the following behavioral states were identified- awake but confused after CPS (N=5), minimally responsive after sGTC (N=4), awake without confusion after SPS (N=3). TPE and SPE were able to classify post-ictal behavioral changes accurately for the minimally responsive state, but there was overlap between two awake states. CONCLUSIONS:Estimating states of vigilance in the post-ictal state using single electrocorticogram is feasible. Further studies are required to develop this novel strategy.
FUNDING:This study was supported by NSF grant OIA 1632891
Figure 1A: An example of focal seizure with impaired awareness localized to right temporal pole, amygdala, anterior and posterior hippocampus (subject 3). Thalamogram highlighted in red. * represents the onset of oro-manual automatism. EEG visualized with input filter 1-100 Hz, Time base 15mm/sec, sensitivity 30 μV/mm.a=Amygdala, b-c=Anterior and Posterior Hippocampus, d= Temporal Pole, e-f=Anterior and Posterior Orbitofrontal, g-i=Anterior, Mid, Posterior Cingulate, j=Thalamoinsular. M represent mesial contacts while L for lateral contacts B-Receiver operator curves (ROC) for seizure detection using line length, Laplacian, and Teager energy within the anterior thalamic nuclei (left) and seizure onset zone (right). Areas under the ROC are presented. Note that the x- and y-axes have been adjusted to optimize presentation. CStereotactic placement of depth electrodes to sample right and left anterior thalamus. Points are displayed on the Talairach atlas in the axial slice.
RATIONALE: In partial epilepsy, seizures arise from brain regions that are thought to be fundamentally altered in their structure and function, leading to cognitive deficits observed during interictal (seizure-free) epochs. While the role of interictal spikes leading to transitory cognitive impairment is well recognized, the underlying mechanism of long-standing cognitive impairment seen in interictal periods is poorly understood. We hypothesized that recurrent neural interactions over longtime scales interictally will localize brain region/s that are functionally disconnected as evident from disruption of specific cognitive and metabolic networks. We have recently developed a focus localization algorithm (FLA) based on directed
METHODS: Five adults with intractable non-lesional partial epilepsy have undergone stereo depth EEG implantation targeting mesial and lateral temporal regions, cortical -subcortical structures in frontoparietal regions. Multivariate GPDC analysis (model order 7, 0.1-50 Hz and 70-110 Hz) was performed on the EEG sampled at 2KHz from all recording channels over 6 hrs awake and 6 hrs sleep EEG. Qualitative analysis of pre-operative FDG-PET scan and standard neuropsychological tests (WAIS-IV, BNT-60, CVLT-2, WRAT-3 Reading, Word Fluency, Digit span) performed interictally were analyzed and correlated with the identified maximum effective inflow brain region. RESULTS:Clinically identified seizure onset zones (SOZ) were non-dominant mesial temporal region (N=2), dominant mesial temporal region (N=1), anterior cingulate (N=1) and dorsolateral orbitofrontal (N=1). Regions identified by GPDC overlapped with clinically identified SOZ in 4/5 patients (80% overlap), and the results were more consistent with existence of higher gamma activity (70-110 Hz) during sleep. Hypometabolic regions identified by PET scan overlapped with all except one GPDC identified regions. There was also a correlation between cognitive deficits specific to regions identified by GPDC.
CONCLUSIONS: Inter-regional connectivity analysis over long time scales during seizure-free epochs successfully identified regions that are metabolically hypoactive and part of functional networks necessary for cognitive processing. Exploration of the relation between the ictal and the identified interictal network topology should add more value to the clinical utility of this novel quantitative analysis for epilepsy.
FUNDING:Acknowledgement: This study was supported by NSF grant OIA 1632891
RATIONALE: Localization of the epileptogenic focus from interictal periods remains a difficult problem to address in patients with focal epilepsy. Due to the involved ambiguities in assessment of the seizure onset zone (SOZ), patient discomfort and overly cost at the EMU, development of alternative robust and efficient ways to localize the focus has been more than desirable. We will present results from a new promising methodology for focus localization that we recently developed and applied to our first set of patients with temporal and frontal lobe epilepsy during their first hours of recovery from general anaesthesia following the implantation of the EEG electrodes and before tapering of their AEDs.
METHODS: The first set of 5 patients with focal epilepsy were recruited at the U. Alabama Birmingham site and consented for participation in our joint new NSF sponsored and IRB approved study on “Probing and Understanding the Brain: Micro and Macro Dynamics of Seizure and Memory Networks”. The implantation of depth electrodes was image-guided, robot-assisted (ROSA) and under general anesthesia using Propofol. Post-implantation patients were extubated and transferred to neuro ICU. The depth electrodes were connected to the Natus Xltek EEG machine and 120 EEG channel recording at 2KHz was initiated (Π period). We employed the Generalized Partial Direct Coherence (GPDC), a measure of directed causal interactions between brain sites over low (LFB: 0.1-50Hz) and high (HFB: 70-110Hz) frequency bands and a step of 0.1 Hz. The GPDC values were generated from a 7th order, 120-dimensional multivariate autoregressive model fitted to 100 sec successive and non-overlapping EEG segments for 1 hour in the Π period. We then estimated the percentage of time (POT) that each site showed the maximum cumulative incoming GPDC values from the other sites (effective inflow of information) .
RESULTS: The results of this analysis per electrode site, over low and high frequency bands, from one of our patients with left temporal epilepsy are shown in Figure 1. The clinically assessed focus in this patient in the HFB (right panel) coincided with the one from our analysis (left posterior hippocampus). In the remaining 4 patients with temporal and frontal lobe epilepsy, brain sites in the assessed SOZ also coincided with the largest POT in the HFB during period Π (see Table 1).
Despite numerous imaging studies highlighting the importance of the thalamus in a patient’s surgical prognosis, human electrophysiological studies involving the limbic thalamic nuclei are limited. The objective of this study was to evaluate the safety and accuracy of robot-assisted stereotactic electrode placement in the limbic thalamic nuclei of patients with suspected temporal lobe epilepsy (TLE).
After providing informed consent, 24 adults with drug-resistant, suspected TLE undergoing evaluation with stereoelectroencephalography (SEEG) were enrolled in the prospective study. The trajectory of one electrode planned for clinical sampling of the operculoinsular cortex was modified to extend it to the thalamus, thereby preventing the need for additional electrode placement for research. The anterior nucleus of the thalamus (ANT) (n = 13) and the medial group of thalamic nuclei (MED) (n = 11), including the mediodorsal and centromedian nuclei, were targeted. The postimplantation CT scan was coregistered to the preoperative MR image, and Morel’s thalamic atlas was used to confirm the accuracy of implantation.
CONCLUSIONS:The above results suggest that it is possible to accurately localize the focus early on in the post-surgical electrode implantation period Π in patients with focal epilepsy from: a) short (just 1 hour) periods before tapering of AEDs, and b) the high frequency EEG band. Finally, the performance of focus localization analysis may be explained by compartmentation of the brain networks under anesthesia .
 I. Vlachos, B. Krishnan, D. Treiman, K. Tsakalis, D. Kugiumtzis, L.D. Iasemidis, IEEE Trans. Biomed. Eng. (in press)
 L.D. Lewis et al., PNAS, E3377–E3386, Nov. 5, 2012.
FUNDING:This study was supported by NSF grant OIA 1632891.
The fornix, a salient white matter structure of the Papez circuit, plays a crucial role in memory consolidation. Low-frequency and theta-burst stimulations of the fornix improved memory and decreased epileptiform activity in temporal lobe epilepsy (TLE) (Koubeissi et al., 2013, Miller et al., 2015). The motivation for the present case study is the development of closed-loop stimulation of the fornix and other limbic structures in TLE. Sensing neural activity from the fornix is the first step towards such a therapy.
The fornix is a C-shaped structure formed by the output fibers of the hippocampus, and it connects the entorhinal cortex, amygdalae, and the cingulate gyrus (Thomas et al., 2011). Hence, the connectivity of the fornix should serve to sense the propagated neural activity from the limbic network. Local field potentials (LFPs) recorded from macro-electrodes is an attractive option for sensing in deep brain stimulation (DBS) for their ease of recording, signal reliability, and stability over protracted periods. The LFPs recorded at an electrode is a spatial average of current sources in the brain regions surrounding and interconnected to the recording electrode. Thus, we hypothesize that the forniceal LFPs, although from white matter, can detect epileptiform activities that originated in remote but interconnected structures within the limbic network. In a consenting patient undergoing stereo-EEG (SEEG) exploration for localization of TLE, we demonstrate changes in LFPs recorded from the fornix during a seizure and stimulation-induced after-discharges that originated outside the fornix.
To investigate dynamic changes in neural activity between the anterior nucleus of the thalamus (ANT) and the seizure onset zone (SOZ) in patients with drug‐resistant temporal lobe epilepsy (TLE) based on anatomic location, seizure subtype, and state of vigilance (SOV).
Eleven patients undergoing stereoelectroencephalography for seizure localization were recruited prospectively for local field potential (LFP) recording directly from the ANT. The SOZ was identified using line length and epileptogenicity index. Changes in power spectral density (PSD) were compared between the two anatomic sites as seizures (N = 53) transitioned from interictal baseline to the posttermination stage.
At baseline, the thalamic LFPs were significantly lower and distinct from the SOZ with the presence of higher power in the fast ripple band (P < 0.001). Temporal changes in ictal power of neural activity within ANT mimic those of the SOZ, are increased significantly at seizure onset (P < 0.05), and are distinct for seizures that impaired awareness or that secondarily generalized (P < 0.05). The onset of seizure was preceded by a decrease in the mean power spectral density (PSD) in ANT and SOZ (P < 0.05). Neural activity correlated with different states of vigilance at seizure onset within the ANT but not in the SOZ (P = 0.005).
The ANT can be recruited at the onset of mesial temporal lobe seizures, and the recruitment pattern differs with seizure subtypes. Furthermore, changes in neural dynamics precede seizure onset and are widespread to involve temporo‐thalamic regions, thereby providing an opportunity to intervene early with closed‐loop DBS.
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294-3410, USA.
Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bangalore, India.
Department of Mathematics, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
Direct electrical stimulation (DES) of the cortex is a clinically indispensable brain mapping technique that provides reliable information about the distribution of eloquent cortex and its connectivity to the white matter bundles (David et al., 2010). Apart from functional mapping, DES is also an efficient way to map neuroanatomical pathways connected to the stimulated node (Duffau, 2015, Lacruz et al., 2007, Martino et al., 2010, Matsumoto et al., 2007). The stimulated node act as an input gate into the large-scale network whose responses are mapped with high temporospatial precision using electrocorticography (ECoG). Evoked neural responses (called as cortico-cortical evoked potentials-CCEP) are measured as the variation in amplitude and first-peak latency (N1) that helps to estimate patient-specific neuroanatomical pathways in vivo (Duffau, 2015, Keller et al., 2014). Evoked cortical responses below 10 milliseconds (ms) reflect mono- or oligosynaptic connectivity while responses longer than 10 ms may reflect poly-synaptic connectivity (Keller et al., 2014, Logothetis et al., 2010). Unfortunately, most CCEP studies preclude mapping the early short-latencies (<10 ms) as the injected current saturates the amplifier of the clinical EEG acquisition system. Capitalizing on the improved clinical EEG acquisition system (Natus® Quantum®) that allows higher sampling (16 kHz) from 256 channels, we explored mapping short-latency cortical responses (<10 ms) to stimulation of ventral anterior nucleus of the thalamus (VA). Based on the known anatomical connectivity of the VA thalamus (often considered a part of the motor and limbic thalamus) (Aggleton et al., 1980, McFarland and Haber, 2000, Percheron et al., 1996), we hypothesize that short-latency evoked potentials (SLEP: <10 ms) can be mapped in cortices that receive afferents from the VA.
The study was performed on a 22-year old right-handed man with drug-resistant focal epilepsy who underwent stereo EEG (SEEG) exploration for localization of seizures. Post-SEEG, the seizures were localized to the left orbitofrontal region that was resected, and the patient remained seizure-free (>12 months). One of the depth electrodes sampling the frontal-operculum and insula was progressed medially to sample VA. The study was approved by IRB and written informed consent was obtained to record field potentials from the thalamus. Stimulation was performed (Nicolet® stimulator) when all antiseizure medications were discontinued to record seizure. Stimulation parameters were: bipolar stimulation (thalamic deepest contact as a cathode and the adjacent contact as anode), 1 Hz biphasic pulse wave with pulse width 300 µsec, current 3 mA and train of 40 seconds. The post-implant computed tomography (CT) image was co-registered with the pre-implant structural MRI using Advanced Normalization Tools (Avants et al., 2009). We then combined registration strategies in LeadDBS (Horn and Kuhn, 2015) and iElectrodes (Blenkmann et al., 2017) to map the electrode trajectory and the final thalamic target. The cortical regions implanted were confirmed with AAL2 atlas (Rolls et al., 2015), and the thalamic subnuclei were identified using the mean histological thalamic atlas (Krauth et al., 2010)
RESULTS: A total of 150 hours (15 hours of awake and 15 hours of sleep per subject X 5 subjects) was analyzed. SOZ were- temporo-insular, amygdala-hippocampus, temporo-perisylvian (N= 2) and hippocampal-anterior cingulate. Descriptive analyses included means, standard deviations, medians, and ranges of spikes were in table 1. For the SOZ the mean spike count for awake state were lower than sleep state (70.16 ± 22.36 compared to 97.52 ± 23.45, respectively; (t(df= 785)= -16.46, p0.001). For the TH channels the mean spike count for awake state were lower than sleep state (15.19 ± 11.29 compared to 72.43 ± 39.65, respectively; (t(df= 440.1)= -27.06, p0.001). Control channels did not show a significant difference between SOV. The differences between the channels (SOZ, TH and C) during different SOV were significantly different (Table 1 and Fig1). The ratio of spikes between SOZ:TH during awake and sleep were 4.6 and 1.6 respectively. The morphology of the spikes (duration, amplitude) was compared between SOZ and TH (Fig 1).
CONCLUSIONS:Following transition from awake to sleep, there was a- 1) significant increase in spike count in SOZ and TH; and 2) the increment in TH was significantly higher than in SOZ. Spikes in SOZ were faster than in TH.
FUNDING:This study was funded by the NSF EPSCoR OIA 1632891.
RATIONALE: Working memory (WM) describes a cognitive system which allows for the transient storage and utilization of information. Working memory describes multiple integrated processes. A stimulus is first encoded into working memory, stored and refreshed through rehearsal or maintenance of the memory trace, and ultimately utilized or retrieved to perform a goal-oriented action. Several functional MRI and PET studies highlighted a group of brain regions as critical to working memory including the dorsolateral prefrontal cortex (DLPFC), parietal and occipital regions, and the left supramarginal gyrus. Very few studies utilized neurophysiologic signals (MEG/EEG) to study sequential activation during WM tasks and some findings in the MEG/EEG working memory literature have been variable, although generally implicating theta activity to play a major role in working memory functions, in particular during encoding. There are no MEG data describing network working memory changes in patients with epilepsy.
METHODS:We recorded MEG data on 5 adult patients with temporal lobe epilepsy (two right, three left) and six healthy controls while performing a Sternberg working memory task using a 148-channel neuromagnetometer system, housed inside a magnetically- shielded room. In the Sternberg task, each trial comprised four phases, (1) a fixation phase which lasted 1.0 sec and functioned as the baseline; (2) an encoding phase which lasted 2.0 sec and consisted of 1, 3, 5 or 7 letters being presented simultaneously, (3) a maintenance phase that jittered 2-2.5 seconds where the six letters disappeared from the grid, and (4) a retrieval phase which lasted 4 sec and required participants to respond as to whether the single letter probe was included in the original encoding set. Each participant's MEG data were co-registered with structural T1-weighted MRI data prior to source space analysis. Cortical networks were imaged through a linearly constrained minimum variance vector (LCMV) beamformer which employs spatial filters in the frequency domain to calculate source power for the entire brain volume at different frequency bands (4-8 Hz, 8-13 Hz, 13-25 Hz and 25-50Hz). (http://neuroimage.usc.edu/brainstorm). Group images depicting sequential oscillatory changes were created during encoding, maintenance and retrieval in each frequency band.
RESULTS:Encoding, maintenance and retrieval activated bilateral network involving frontal, parietal and occipital regions in both patients and healthy subjects. Robust theta oscillatory response was seen during the maintenance/rehearsal phase once the letters disappeared (figure 1). The most robust activation is in the left inferior frontal gyrus in healthy subjects (figure 2a). Figure 2b shows oscillatory theta changes in healthy subjects during retrieval, particularly over the right supramarginal gyrus. Patients showed tendency to recruitment of additional frontal regions. There was no clear effect of the side of epilepsy likely due to small sample size.
CONCLUSIONS:Our study provided evidence for the role of theta oscillations during Sternberg working memory tasks. These oscillatory responses mediate the maintenance/rehearsal phase and are most prominent after the stimulus disappear. It also provides preliminary evidence of patterns of reorganization of working memory networks in temporal lobe epilepsy.
FUNDING:This data and research was partially funded through EPSCoR NeuroNEM as well as GRSP AL EPSCoR grants.
RATIONALE: Although intracranial electroencephalography (ICEEG) continues to be widely used in the surgical evaluation of refractory epilepsy, there remain inherent limitations associated with sufficient sampling for accurate seizure localization. Therefore, magnetoencephalography (MEG) provides a promising, non-invasive alternative. Both prospective and retrospective studies have shown the yield of seizure localization are comparable between ICEEG and MEG. Nevertheless, further investigation is required with larger sample sizes to fully determine the clinical utility and reliability of MEG evaluation prior to surgical intervention in comparison to ICEEG.
METHODS:A retrospective chart review was completed investigating 50 epilepsy patients who underwent intracranial EEG and had preoperative MEG between the years 2010 and 2017_. The MEG report was reviewed for those patients where epileptiform discharges were localized. The suspected seizure localization based upon MEG reports was then compared with expected seizure focus based on intracranial EEG monitoring. Single equivalent current dipole modeling was used to estimate source localization from the observed magnetic fields (at a single latency in the early phase of single spontaneous discharges with temporally and spatially stable magnetic flux patterns). Comparative statistical analysis was then completed to determine the correlation between seizure localization as predicted by ICEEG and MEG.
RESULTS: 50 patients (M: F 28:22), Age: 44±2 years, Onset age: 5 years .) with intractable partial epilepsy underwent IEEG/SEEG placement for localizing the EZ/SOZ. SOZ ranged between - mesial temporal/amygdala-hippocampus (N=24), mesial frontal (N=5), cingulate (N=2), perisylvian/insular (N=6), lateral frontal (N=13). The concordance between MEG detected spike, and icEEG detected SOZ was maximum between lateral temporal, perisylvian, intermediate for lateral frontal and mesial temporal and least with mesial frontal.
CONCLUSIONS: Magnetoencephalography provides a non-invasive technique for the localization of seizure focus in patients with medically refractory epilepsy prior to surgical intervention. An increasing number of studies have compared MEG with intracranial EEG monitoring for seizure focus, with promising results for the use of MEG. The results of our study show the benefit of MEG in surgical planning.
FUNDING:This study was supported by NSF grant OIA 1632891
RATIONALE: Recent studies using multi-modality brain-mapping techniques have elaborately elucidated epilepsy as a disease with anomalous network montages. Multiple studies in preclinical models of limbic/mesial Temporal lobe epilepsy (TLE) have indirectly supported the concept that thalamus intimately redefines the behavioral expression of limbic seizures. In a subset of patients with failed anterior temporal lobectomy (ATL), electrophysiological and imaging abnormalities in thalamo-temporal connectivity were significantly associated with failure to achieve adequate control of seizures. Among the different available pre-operative mapping techniques, stereoelectroencephalography (SEEG) allows simultaneous electrophysiological sampling of cortical and subcortical structures in three-dimensions and has been adopted in our Level-IV epilepsy center. Here we report our preliminary experience in the pre-surgical evaluation of cortico-thalamic dynamics using stereo depth EEG in a patient with failed ATL. The purpose of this study was to map the temporal dynamics of thalamic activity during transition from inter-ictal to simple and complex partial ictus states.
Figure 1. (A) Postimplant CT brain coregistered with MRI to demonstrate depth electrodes (highlighted with red dots) targeted toward the midline thalamus (highlighted with yellow dots) (B) Stereo EEG recording demonstrating spontaneous seizure (FIAS) localized to left amygdala (LA), anterior and posterior hippocampus (LAH, LPH), and midline thalamus (LTh). EEG changes low amplitude fast activity (LAFA). Included below is the time-frequency decomposition (1-100 Hz) of ictal thalamogram. Note the increase in power above 15 Hz following ictal recruitment. (C) Stereo EEG recording demonstrating induced seizure (FIAS) localized to the right amygdala (RA), anterior and posterior hippocampus (RAH, RPH), and midline thalamus (RTh). Electrical stimulation was applied to RAH. D- Stereo EEG recording demonstrating evoked seizure (FAS) localized to left amygdala (LA), anterior and posterior hippocampus (LAH, LPH). Electrical stimulation was applied to left midline thalamus (LTh). FIAS, Focal impaired awareness seizure; FAS, Focal aware seizure
The causal role of midline thalamus in the initiation and early organization of mesial temporal lobe seizures is studied. Three patients undergoing stereoelectroencephalography were enrolled for the placement of an additional depth electrode targeting the midline thalamus. The midline thalamus was recruited in all three patients at varying points of seizure initiation (0-13 seconds) and early propagation (9-60 seconds). Stimulation of either thalamus or hippocampus induced similar habitual seizures. Seizure-induced in the hippocampus rapidly recruited the thalamus. Evoked potentials demonstrated stronger connectivity from the hippocampus to the thalamus than in the opposite direction. The midline thalamus can be within the seizure initiation and symptomatogenic circuits.
Figure 1 A: Intracranial EEG with recordings from left amygdala–hippocampus, orbitofrontal, insula and lateral temporal regions. Electrical stimulation artifact (highlighted) in hippocampal channels followed by an induced seizure. Co-registered MRI to demonstrate the orthogonal trajectory of left hippocampal depth electrode. B: Serial cognitive test performances in percentile. C: Spectrogram (1–100 Hz) showing seizure in the hippocampal channel and spread to orbitofrontal regions.
Epilepsy and Cognitive Neurophysiology Laboratory
CONCLUSIONS:In temporal lobe epilepsy, the thalamus can be recruited early in the seizure onset network, and temporal trends in recruitment relate to seizure subtypes and duration of epilepsy.
FUNDING:This study was funded by the NSF EPSCoR OIA 1632891.
connectivity between brain sites using the measure of generalized partial directed coherence (GPDC) over a broad frequency band. By exploring the concept of effective inflow, we subsequently correlated the identified focus with neuropsychological, and FDG-PET (Positron Emission Tomography) scans.
METHODS: A 27-year-old, right handed male with 8-year history of intractable simple (SPS),complex partial seizures (CPS) and MRI brain positive for right hippocampal sclerosis underwent standard right (non-dominant) anterior temporal lobectomy. He was seizure-free for two years, but subsequently there was resurgence of aura followed by frequent complex partial seizures. He then underwent stereo EEG investigation with ipsilateral implant targeting hippocampal remnant, lateral and basal temporal, anterior and posterior insular and posterior orbitofrontal regions. A multi-contact depth electrode with entry at the superior temporal gyrus was advanced medially to sample thalamus while the lateral contacts sampled lateral temporal neocortex (Fig 1). Seizures were identified using conventional visual analysis, HFO and ictal baseline shift. Matlab was used to analyze power spectrum, cross coherence, phase amplitude coupling and Directed transfer function analysis for substantiating functional connectivity between the seizure onset zone(s) and thalamus. Approval of the institutional review board was obtained for post-hoc analysis and publication.
RESULTS: Six seizures (2 SPS, 2 CPS and 2 secondarily generalized) with multi-focal origin were recorded during seven day SEEG monitoring and were selected for analysis. Visual analysis confirmed involvement of thalamus in CPS and sGTC seizures. Spectral analysis confirmed cortico-thalamic involvement between 100-400 Hz and the earliest involvement was within 10 seconds of seizure onset. Thalamic signatures at seizure onset differed from offset.CONCLUSIONS:In our preliminary analysis from a single patient, we can confirm that thalamus is involved in CPS and sGTC seizures. Further analysis is required to confirm the earliest time thalamus is involved with seizure onset and the directionality of cortico-thalamic interaction.
RATIONALE: Thalamus, with its reciprocal connectivity to the cortex, plays a critical role in the generation and behavioral expression of focal seizures. Thalamic subnuclei have distinct connectivity patterns with the cortex and determine variable functional significance. A recent study has demonstrated ventral posteromedial nuclei (VPM) interrupted information flow causing altered consciousness, while anterior thalamus (ATN) participates in the propagation of temporal lobe seizures. Limited clinical studies have demonstrated temporal lobe seizures recruit thalamus, but an in-depth investigation of the temporal trends and predictors of thalamic recruitment is lacking. Based on the rich connectivity of ATN with mesial temporal and perisylvian structures, we hypothesize that ATN will be recruited early at the onset of temporal lobe seizures. Under the supervision of IRB, during stereo-EEG (sEEG) exploration in suspected temporal lobe epilepsy, we sampled electrical activity from ventral lateral (VL) or AT nucleus.
METHODS: From 14 patient who had a thalamic sampling (N=5 ATN, 9 VL), multiple seizures (N=2-10/subject) were analyzed to determine -a) if thalamus (TH) is recruited early at seizure onset, and b) predictors of early recruitment. Epileptogenic index (EI) (Bartolomei 2008, Colombet 2015), a quantitative measure of the likelihood of regions involved in seizure onset was estimated with EI>0.25 (Roehri 2018) used to identify seizure onset channels (SOC) and if TH is within the seizure onset network. Line length (Esteller 2001)-an efficient method of automated seizure detection was calculated in 0.5 s windows, with 50% overlap. Latency (time difference between the beginning of the seizure on SOC and TH, and between clinical onset and TH involvement) and duration of TH involvement during a seizure were calculated (Figure 1). The results were grouped by the types of the seizure classification and the thalamic area (ATN, VL). Clinical features including duration of epilepsy, baseline seizure frequency, states of vigilance preceding seizure for every subject were collected. Logistic regression was used to assess the predictors of the thalamic involvement.
RESULTS: 69 focal seizures with semiology- 11 electrographic (E), 15 with awareness (FSA), 34 with awareness impaired (FSIA), 9 with bilateral tonic-clonic (TC) were analyzed. In the ATN cohort, 83.87% (26/31) of analyzed seizures had thalamus involved in seizure onset, while in VL this was 71.05% (27/38), with no statistically significant difference between the two cohorts (p=0.21). Overall average (SD) thalamic latency: 10.6s (24.3s); VL: 13.4s (29.6s), ATN: 7.8s (17.4s) and with respect to clinical onset in overall -13.1s, (24.2s); VL: -7.6s (27.9s), ANT: -18.8s (18.6). Seizures sustained in the thalamus over 66% of the total duration, and it was maximum in TC. Significant predictors for thalamic involvement are the number of TC seizures/month and the duration of epilepsy (p=0.001 and p=0.008 respectively).
Ten (77%) of 13 patients in the ANT group and 10 (91%) of 11 patients in the MED group had electrodes accurately placed in the thalamic nuclei. None of the patients had a thalamic hemorrhage. However, trace asymptomatic hemorrhages at the cortical-level entry site were noted in 20.8% of patients, who did not require additional surgical intervention. SEEG data from all the patients were interpretable and analyzable. The trajectories for the ANT implant differed slightly from those of the MED group at the entry point—i.e., the precentral gyrus in the former and the postcentral gyrus in the latter.
Using judiciously planned robot-assisted SEEG, the authors demonstrate the safety of electrophysiological sampling from various thalamic nuclei for research recordings, presenting a technique that avoids implanting additional depth electrodes or compromising clinical care. With these results, we propose that if patients are fully informed of the risks involved, there are potential benefits of gaining mechanistic insights to seizure genesis, which may help to develop neuromodulation therapies.
Arousal is the most primitive, powerful instinct with survival benefit present in all vertebrates. Even though the arousal systems are classically viewed as "ascending" brainstem phenomena, there is a "descending" cortical feedback system that maintains consciousness. In this study, we provide electrophysiological confirmation that seizures localized to the anterior cingulum can behaviorally manifest as paroxysms of arousal from sleep.
Methods: Temporal dynamics of arousal induced by anterior cingulate seizures were analyzed by using multiple modalities including stereoelectroencephalography (phase lag index and phase amplitude coupling), lead-1 ECG (point-process heart rate variability analysis) and diffusion tractography (DTI).
Results: The ictal arousal was associated with an increase in synchronization in the alpha band and an increase in local theta or alpha-gamma phase-amplitude coupling. In comparison to seizures that lacked clinical manifestations, ictal arousal was associated with an increase in heart rate but not heart rate variability. Finally, DTI demonstrated degeneration in white fiber tracts passing between the anterior cingulum and anterior thalamus ipsilateral to the epileptogenic cortex. The patient underwent resection of the anterior cingulum, and histopathology confirmed focal cortical dysplasia type II.
Conclusion: Anterior cingulate seizures inducing behavioral arousal have identifiable autonomic and EEG signatures.
Keywords: Anterior cingulate; Arousal; Heart rate variability; Hypnopompic seizure; Phase lag index; Phase-amplitude coupling
Risk of sudden unexpected death in epilepsy increases with frequent generalized tonic-clonic seizures and response to therapy can be monitored with a responsive neurostimulation device.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality in patients with refractory epilepsy, but the underlying mechanisms and the predictors of patient risk remain an active area of research.1,2 At present, risk assessment is based on disease severity accrued over the preceding years, but how the risk changes with therapy and disease progression have been poorly understood.3 To establish the pathophysiology of SUDEP, studies have capitalized on experimental models4 and rare terminal events recorded in the epilepsy monitoring unit.5 In these settings, the seizures are either induced or precipitated by weaning off medications and hence the electrophysiologic changes should be validated with spontaneous seizures recorded over longer time scale. Here we report progressive electrophysiologic changes in ambulatory electrocorticography preceding sudden death in a 38-year-old, right-handed woman who had intractable bitemporal epilepsy.
Fig. 1 Phase-lag index (PLI), heart rate (HR), heart rate variability (HRV), Diffusion Tractography and Phase-amplitude coupling (PAC) results: a average PLI (μPLI) is higher in TCW in all frequency bandwidths with ictal arousal (A+, blue line) except theta band (* p < 0.017, t test with Bonferroni correction) (* The significance of the rmANOVA model, blue lines- significance of post hoc analysis of A+ seizures, red lines—significance of post hoc analysis of A− seizures), b Left panel contains average HR (bpm), right shows average HRV (σHR-bpm) from all the seizures. Ictal tachycardia was evident with arousal (A+ seizures), but not with electrographic seizures (A−, grey circles). c Mean fractional anisotropy (meanFA) was lower ipsilateral to seizure onset (right) compared to the contralateral side (left). d Phase-amplitude coupling representations with overlaid thresholds (outer threshold line: mean + 1SD, middle threshold line: mean + 2SD, inner threshold line: mean + 3SD). The window around the arousal shows increased MI (yellow blobs) theta-gamma, and alpha-gamma coupling.
gamma band in the onset and spread channels. When we tested the interaction between the seizure state and the onset channel type it was found that the indegree showed a significant reduction (Table 1)(Figure 1).
CONCLUSIONS: PrT is a state of heightened synchronization with increased cross talk between the different electrodes, following which there is a catastrophic drop in synchronization in a wide range of brain electrical activity with all cannels a similar post ictal state with little variance between them.
 “The Concept of Effective Inflow: Application to Interictal Localization of the Epileptogenic Focus from iEEG.” IVlachos I, Krishnan B, Treiman D, Tsakalis K, Kugiumtzis D, Iasemidis LD. IEEE Transactions on Biomedical Engineering (2016)
FUNDING:This study was supported by NSF grant OIA 1632891.
Systems Science and Informatics Unit, Indian Statistical Institute, Kolkata, India
Department of Clinical Neurosciences, NIMHANS, Bangalore 560029, India
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA
Targeted stimulation of white matter has opened newer perspectives in the field of neuromodulation, towards an attempt to improve memory or as a therapy for epilepsy. Stimulation of the fornix, being a part of the Papez circuit, is likely to modulate the limbic network excitability. However, the stimulation-frequency dependent variability in network excitability is unknown. In the case study, which involved stereo electroencephalographic (SEEG) recording of field potentials in a 48-year old left-handed woman with suspected temporal lobe epilepsy, we demonstrated the network effects of acute low (1 and 10 Hz) and high (50 Hz) frequency electrical stimulation of fornix. Mapping the short-latency evoked responses to forniceal stimulation confirmed the SEEG target localization within the Papez circuit. Low and high-frequency stimulation of the fornix produced opposite effects in the post-stimuli excitability, with the latter causing increased excitability in the limbic network that culminated in a clinical seizure. A distinct spectral peak around 8 Hz confirmed that sensing field potentials from the forniceal white matter is feasible. This is the first case study that provided an insight into how the temporal patterning of forniceal stimulation altered the downstream limbic network excitability.