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A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies

Altmann, Andre; Ryten, Mina; Di Nunzio, Martina; Ravizza, Teresa; Tolomeo, Daniele; Reynolds, Regina H; Somani, Alyma; Bacigaluppi, Marco; Iori, Valentina; Micotti, Edoardo; Di Sapia, Rossella; Cerovic, Milica; Palma, Eleonora; Ruffolo, Gabriele; Botía, Juan A; Absil, Julie; Alhusaini, Saud; Alvim, Marina K M; Auvinen, Pia; Bargallo, Nuria; Bartolini, Emanuele; Bender, Benjamin; Bergo, Felipe P G; Bernardes, Tauana; Bernasconi, Andrea; Bernasconi, Neda; Bernhardt, Boris C; Blackmon, Karen; Braga, Barbara; Caligiuri, Maria Eugenia; Calvo, Anna; Carlson, Chad; Carr, Sarah J A; Cavalleri, Gianpiero L; Cendes, Fernando; Chen, Jian; Chen, Shuai; Cherubini, Andrea; Concha, Luis; David, Philippe; Delanty, Norman; Depondt, Chantal; Devinsky, Orrin; Doherty, Colin P; Domin, Martin; Focke, Niels K; Foley, Sonya; Franca, Wendy; Gambardella, Antonio; Guerrini, Renzo; Hamandi, Khalid; Hibar, Derrek P; Isaev, Dmitry; Jackson, Graeme D; Jahanshad, Neda; Kälviäinen, Reetta; Keller, Simon S; Kochunov, Peter; Kotikalapudi, Raviteja; Kowalczyk, Magdalena A; Kuzniecky, Ruben; Kwan, Patrick; Labate, Angelo; Langner, Soenke; Lenge, Matteo; Liu, Min; Martin, Pascal; Mascalchi, Mario; Meletti, Stefano; Morita-Sherman, Marcia E; O'Brien, Terence J; Pariente, Jose C; Richardson, Mark P; Rodriguez-Cruces, Raul; Rummel, Christian; Saavalainen, Taavi; Semmelroch, Mira K; Severino, Mariasavina; Striano, Pasquale; Thesen, Thomas; Thomas, Rhys H; Tondelli, Manuela; Tortora, Domenico; Vaudano, Anna Elisabetta; Vivash, Lucy; von Podewils, Felix; Wagner, Jan; Weber, Bernd; Wiest, Roland; Yasuda, Clarissa L; Zhang, Guohao; Zhang, Junsong; Leu, Costin; Avbersek, Andreja; Thom, Maria; Whelan, Christopher D; Thompson, Paul; McDonald, Carrie R; Vezzani, Annamaria; Sisodiya, Sanjay M
AIMS/OBJECTIVE:The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS:Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS:We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS:These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.
PMID: 34388852
ISSN: 1365-2990
CID: 5010892

Microscale Physiological Events on the Human Cortical Surface

Paulk, Angelique C; Yang, Jimmy C; Cleary, Daniel R; Soper, Daniel J; Halgren, Milan; O'Donnell, Alexandra R; Lee, Sang Heon; Ganji, Mehran; Ro, Yun Goo; Oh, Hongseok; Hossain, Lorraine; Lee, Jihwan; Tchoe, Youngbin; Rogers, Nicholas; Kiliç, Kivilcim; Ryu, Sang Baek; Lee, Seung Woo; Hermiz, John; Gilja, Vikash; Ulbert, István; Fabó, Daniel; Thesen, Thomas; Doyle, Werner K; Devinsky, Orrin; Madsen, Joseph R; Schomer, Donald L; Eskandar, Emad N; Lee, Jong Woo; Maus, Douglas; Devor, Anna; Fried, Shelley I; Jones, Pamela S; Nahed, Brian V; Ben-Haim, Sharona; Bick, Sarah K; Richardson, Robert Mark; Raslan, Ahmed M; Siler, Dominic A; Cahill, Daniel P; Williams, Ziv M; Cosgrove, G Rees; Dayeh, Shadi A; Cash, Sydney S
Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their "intermediate" microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit.
PMID: 33749727
ISSN: 1460-2199
CID: 4822312

Algebraic relationship between the structural network's Laplacian and functional network's adjacency matrix is preserved in temporal lobe epilepsy subjects

Abdelnour, Farras; Dayan, Michael; Devinsky, Orrin; Thesen, Thomas; Raj, Ashish
The relationship between anatomic and resting state functional connectivity of large-scale brain networks is a major focus of current research. In previous work, we introduced a model based on eigen decomposition of the Laplacian which predicts the functional network from the structural network in healthy brains. In this work, we apply the eigen decomposition model to two types of epilepsy; temporal lobe epilepsy associated with mesial temporal sclerosis, and MRI-normal temporal lobe epilepsy. Our findings show that the eigen relationship between function and structure holds for patients with temporal lobe epilepsy as well as normal individuals. These results suggest that the brain under TLE conditions reconfigures and rewires the fine-scale connectivity (a process which the model parameters are putatively sensitive to), in order to achieve the necessary structure-function relationship.
PMID: 33385550
ISSN: 1095-9572
CID: 4732002

Dual mechanisms of ictal high frequency oscillations in human rhythmic onset seizures

Smith, Elliot H; Merricks, Edward M; Liou, Jyun-You; Casadei, Camilla; Melloni, Lucia; Thesen, Thomas; Friedman, Daniel J; Doyle, Werner K; Emerson, Ronald G; Goodman, Robert R; McKhann, Guy M; Sheth, Sameer A; Rolston, John D; Schevon, Catherine A
High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequency LFPs using multielectrode array recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. These multiscale recordings capture single cell, multiunit, and LFP activity from the human brain. We compare features of multiunit firing and high frequency LFP from microelectrodes and macroelectrodes during ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of high frequency LFP before and after local seizure invasion. Furthermore, we tie these time-domain differences to spatial domains of seizures, showing that penumbral discharges are more broadly distributed and less useful for seizure localization. These results describe the neuronal and synaptic correlates of two types of pathological HFOs in humans and have important implications for clinical interpretation of rhythmic onset seizures.
PMID: 33154490
ISSN: 2045-2322
CID: 4664412

Epilepsy surveillance in normocephalic children with and without prenatal Zika virus exposure

Blackmon, Karen; Waechter, Randall; Landon, Barbara; Noël, Trevor; Macpherson, Calum; Donald, Tyhiesia; Cudjoe, Nikita; Evans, Roberta; Burgen, Kemi S; Jayatilake, Piumi; Oyegunle, Vivian; Pedraza, Otto; Abdel Baki, Samah; Thesen, Thomas; Dlugos, Dennis; Chari, Geetha; Patel, Archana A; Grossi-Soyster, Elysse N; Krystosik, Amy R; LaBeaud, A Desiree
Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003-0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings.
PMID: 33253174
ISSN: 1935-2735
CID: 4709842

Forced conceptual thought induced by electrical stimulation of the left prefrontal gyrus involves widespread neural networks

Liu, Anli; Friedman, Daniel; Barron, Daniel S; Wang, Xiuyuan; Thesen, Thomas; Dugan, Patricia
BACKGROUND:Early accounts of forced thought were reported at the onset of a focal seizure, and characterized as vague, repetitive, and involuntary intellectual auras distinct from perceptual or psychic hallucinations or illusions. Here, we examine the neural underpinnings involved in conceptual thought by presenting a series of 3 patients with epilepsy reporting intrusive thoughts during electrical stimulation of the left lateral prefrontal cortex (PFC) during invasive surgical evaluation. We illustrate the widespread networks involved through two independent brain imaging modalities: resting state functional magnetic resonance imaging (fMRI) (rs-fMRI) and task-based meta-analytic connectivity modeling (MACM). METHODS:We report the clinical and stimulation characteristics of three patients with left hemispheric language dominance who demonstrate forced thought with functional mapping. To examine the brain networks underlying this phenomenon, we used the regions of interest (ROI) centered at the active electrode pairs. We modeled functional networks using two approaches: (1) rs-fMRI functional connectivity analysis, representing 81 healthy controls and (2) meta-analytic connectivity modeling (MACM), representing 8260 healthy subjects. We also determined the overlapping regions between these three subjects' rs-fMRI and MACM networks through a conjunction analysis. RESULTS:We identified that left PFC was associated with a large-scale functional network including frontal, temporal, and parietal regions, a network that has been associated with multiple cognitive functions including semantics, speech, attention, working memory, and explicit memory. CONCLUSIONS:We illustrate the neural networks involved in conceptual thought through a unique patient population and argue that PFC supports this function through activation of a widespread network.
PMID: 31951969
ISSN: 1525-5069
CID: 4264032

Neural correlates of unstructured motor behaviors

Gabriel, Paolo Gutierrez; Chen, Kenny; Alasfour, Abdulwahab; Pailla, Tejaswy; Doyle, Werner; Devinsky, Orrin; Friedman, Daniel; Dugan, Patricia; Melloni, Lucia; Thesen, Thomas; Gonda, David; Sattar, Shifteh; Wang, Sonya; Gilja, Vikash
We studied the relationship between uninstructed, unstructured movements and neural activity in three epilepsy patients with intracranial electroencephalographic (iEEG) recordings. We used a custom system to continuously record high definition video precisely time-aligned to clinical iEEG data. From these video recordings, movement periods were annotated via semi-automatic tracking based on dense optical flow. We found that neural signal features (8--32 Hz and 76--100 Hz power) previously identified from task-based experiments are also modulated before and during a variety of movement behaviors. These movement behaviors are coarsely labeled by time period and movement side (e.g. `Idle' and `Move', `Right' and `Left'); movements within a label can include a wide variety of uninstructed behaviors. A rigorous nested cross-validation framework was used to classify both movement onset and lateralization with statistical significance for all subjects. We demonstrate an evaluation framework to study neural activity related to natural movements not evoked by a task, annotated over hours of video. This work further establishes the feasibility to study neural correlates of unstructured behavior through continuous recording in the epilepsy monitoring unit. The insights gained from such studies may advance our understanding of how the brain naturally controls movement, which may inform the development of more robust and generalizable brain-computer interfaces.
PMID: 31342926
ISSN: 1741-2552
CID: 3987402

Cortical gray-white matter blurring and declarative memory impairment in MRI-negative temporal lobe epilepsy

Blackmon, Karen; Barr, William B; Morrison, Chris; MacAllister, William; Kruse, Michelle; Pressl, Christina; Wang, Xiuyuan; Dugan, Patricia; Liu, Anli A; Halgren, Eric; Devinsky, Orrin; Thesen, Thomas
Magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) may be a distinct syndrome from TLE with mesial temporal sclerosis (TLE-MTS). Imaging and neuropsychological features of TLE-MTS are well-known; yet, these features are only beginning to be described in MRI-negative TLE. This study examined whether a quantitative measure of cortical gray and white matter blurring (GWB) was elevated in the temporal lobes ipsilateral to the seizure onset zone of individuals with MRI-negative TLE relative to TLE-MTS and healthy controls (HCs) and whether GWB elevations were associated with neuropsychological comorbidity. Gray-white matter blurring from 34 cortical regions and hippocampal volumes were quantified and compared across 28 people with MRI-negative TLE, 15 people with TLE-MTS, and 51 HCs. Declarative memory was assessed with standard neuropsychological tests and the intracarotid amobarbital procedure (IAP). In the group with MRI-negative TLE (left and right onsets combined), hippocampal volumes were within normal range but GWB was elevated, relative to HCs, across several mesial and lateral temporal lobe regions ipsilateral to the seizure onset zone. Gray-white matter blurring did not differ between the groups with TLE-MTS and HC or between the groups with TLE-MTS and MRI-negative TLE. The group with MRI-negative TLE could not be distinguished from the group with TLE-MTS on any of the standard neuropsychological tests; however, ipsilateral hippocampal volumes and IAP memory scores were lower in the group with TLE-MTS than in the group with MRI-negative TLE. The group with left MRI-negative TLE had lower general cognitive abilities and verbal fluency relative to the HC group, which adds to the characterization of neuropsychological comorbidities in left MRI-negative TLE. In addition, ipsilateral IAP memory performance was reduced relative to contralateral memory performance in MRI-negative TLE, indicating some degree of ipsilateral memory dysfunction. There was no relationship between hippocampal volume and IAP memory scores in MRI-negative TLE; however, decreased ipsilateral IAP memory scores were correlated with elevated GWB in the ipsilateral superior temporal sulcus of people with left MRI-negative TLE. In sum, GWB elevations in the ipsilateral temporal lobe of people with MRI-negative TLE suggest that GWB may serve as a marker for reduced structural integrity in regions in or near the seizure onset zone. Although mesial temporal abnormalities might be the major driver of memory dysfunction in TLE-MTS, a loss of structural integrity in lateral temporal lobe regions may contribute to IAP memory dysfunction in MRI-negative TLE.
PMID: 31181427
ISSN: 1525-5069
CID: 3927662

Hippocampal volumetric integrity in mesial temporal lobe epilepsy: A fast novel method for analysis of structural MRI

Hakimi, Mathew; Ardekani, Babak A; Pressl, Christina; Blackmon, Karen; Thesen, Thomas; Devinsky, Orrin; Kuzniecky, Ruben I; Pardoe, Heath R
OBJECTIVE:We investigate whether a rapid and novel automated MRI processing technique for assessing hippocampal volumetric integrity (HVI) can be used to identify hippocampal sclerosis (HS) in patients with mesial temporal lobe epilepsy (mTLE) and determine its performance relative to hippocampal volumetry (HV) and visual inspection. METHODS:We applied the HVI technique to T1-weighted brain images from healthy control (n = 35), mTLE (n = 29), non-HS temporal lobe epilepsy (TLE, n = 44), and extratemporal focal epilepsy (EXTLE, n = 25) subjects imaged using a standardized epilepsy research imaging protocol and on non-standardized clinically acquired images from mTLE subjects (n = 40) to investigate if the technique is translatable to clinical practice. Performance of HVI, HV, and visual inspection was assessed using receiver operating characteristic (ROC) analysis. RESULTS:mTLE patients from both research and clinical groups had significantly reduced ipsilateral HVI relative to controls (effect size: -0.053, 5.62%, p =  0.002 using a standardized research imaging protocol). For lateralizing mTLE, HVI had a sensitivity of 88% compared with a HV sensitivity of 92% when using specificity equal to 70%. CONCLUSIONS:The novel HVI approach can effectively detect HS in clinical populations, with an average image processing time of less than a minute. The fast processing speed suggests this technique could have utility as a quantitative tool to assist with imaging-based diagnosis and lateralization of HS in a clinical setting.
PMID: 31153104
ISSN: 1872-6844
CID: 3922132

Coarse behavioral context decoding

Alasfour, Abdulwahab; Gabriel, Paolo; Jiang, Xi; Shamie, Isaac; Melloni, Lucia; Thesen, Thomas; Dugan, Patricia; Friedman, Daniel; Doyle, Werner; Devinsky, Orin; Gonda, David; Sattar, Shifteh; Wang, Sonya; Halgren, Eric; Gilja, Vikash
OBJECTIVE:Current brain-computer interface (BCI) studies demonstrate the potential to decode neural signals obtained from structured and trial-based tasks to drive actuators with high performance within the context of these tasks. Ideally, to maximize utility, such systems will be applied to a wide range of behavioral settings or contexts. Thus, we explore the potential to augment such systems with the ability to decode abstract behavioral contextual states from neural activity. APPROACH/METHODS:To demonstrate the feasibility of such context decoding, we used electrocorticography (ECoG) and stereo-electroencephalography (sEEG) data recorded from the cortical surface and deeper brain structures, respectively, continuously across multiple days from three subjects. During this time, the subjects were engaged in a range of naturalistic behaviors in a hospital environment. Behavioral contexts were labeled manually from video and audio recordings; four states were considered: engaging in dialogue, rest, using electronics, and watching television. We decode these behaviors using a factor analysis and support vector machine (SVM) approach. MAIN RESULTS/RESULTS:We demonstrate that these general behaviors can be decoded with high accuracies of 73% for a four-class classifier for one subject and 71% and 62% for a three-class classifier for two subjects. SIGNIFICANCE/CONCLUSIONS:To our knowledge, this is the first demonstration of the potential to disambiguate abstract naturalistic behavioral contexts from neural activity recorded throughout the day from implanted electrodes. This work motivates further study of context decoding for BCI applications using continuously recorded naturalistic activity in the clinical setting.
PMID: 30523860
ISSN: 1741-2552
CID: 3642332