On the clinical utility of on-scalp MEG: A modeling study of epileptic activity source estimation.

OBJECTIVE: Epilepsy surgery requires localization of the seizure onset zone (SOZ). Today this can only be achieved by intracranial electroencephalography (iEEG). The iEEG electrode placement is guided by findings from non-invasive modalities that cannot themselves detect SOZ-generated initial seizure activity. On scalp magnetoencephalography (osMEG), with sensors placed on the scalp, demonstrates higher sensitivity than conventional MEG (convMEG) and could potentially detect early seizure activity. Here, we modeled EEG, convMEG and osMEG to compare the modalities' ability to localize SOZ activity and to detect epileptic spikes. METHODS: We modeled seizure propagation within ten epileptic networks located in the mesial and lateral temporal lobe; basal, dorsal, central and frontopolar frontal lobe; parietal and occipital lobe as well as insula and cingulum. The networks included brain regions often involved in focal epilepsy. 128-channel osMEG, convMEG, EEG and combined osMEG + EEG and convMEG + EEG were modeled, and the SOZ source estimation accuracy was quantified and compared using Student's t-test. RESULTS: OsMEG was significantly (p-value <0.01) better than both convMEG and EEG at detecting the earliest SOZ-generated seizure activity and epileptic spikes, and better at localizing seizure activity from all epileptic networks (p < 0.01). CONCLUSIONS: Our modeling results clearly show that osMEG has an unsurpassed potential to detect both epileptic spikes and seizure activity from all simulated anatomical sites. SIGNIFICANCE: No clinically available non-invasive technique can detect SOZ activity from all brain regions. Our study indicates that osMEG has the potential to become an important clinical tool, improving both non-invasive SOZ localization and iEEG electrode placement accuracy.

Interictal epileptiform discharges in focal epilepsy are preceded by increase in low-frequency oscillations.

OBJECTIVE: Interictal epileptiform discharges (IEDs) constitute a diagnostic signature of epilepsy. These events reflect epileptogenic hypersynchronization. Previous studies indicated that IEDs arise from slow neuronal activation accompanied by metabolic and hemodynamic changes. These might induce cortical inhibition followed hypersynchronization at IED onset. As cortical inhibition is mediated by low-frequency oscillations, we aimed to analyze the role of low-frequency oscillations prior the IED using magnetencephalography (MEG). METHODS: Low-frequency (1-8 Hz) oscillations pre-IED ([-1000 milliseconds (ms), IED onset]) were analyzed using MEG in 14 focal epilepsy patients (median age = 23 years, range = 7-46 age). Occurrence of local pre-IED oscillations was analyzed using Beamformer Dynamical Imaging of Coherent Sources (DICS) and event-related desynchronization/synchronization (ERD-ERS) maps constructed using cluster-based permutation tests. The development of pre-IED oscillations was characterized using Hilbert transformation. RESULTS: All patients exhibited statistically significant increase in delta (1-4 Hz) and/or theta (4-8 Hz) oscillations pre-IED compared to baseline [-2000 ms, -1000 ms]. Furthermore, all patients exhibited low-frequency power increase up to IED onset. CONCLUSIONS: We demonstrated consistently occurring, low-frequency oscillations prior to IED onset. SIGNIFICANCE: As low-frequency activity mediates cortical inhibition, our study demonstrates that a focal inhibition precedes hypersynchronization at IED onset.

Detection of interictal epileptiform discharges: A comparison of on-scalp MEG and conventional MEG measurements.

OBJECTIVE: Conventional MEG provides an unsurpassed ability to, non-invasively, detect epileptic activity. However, highly resolved information on small neuronal populations required in epilepsy diagnostics is lost and can be detected only intracranially. Next-generation on-scalp magnetencephalography (MEG) sensors aim to retrieve information unavailable to conventional non-invasive brain imaging techniques. To evaluate the benefits of on-scalp MEG in epilepsy, we performed the first-ever such measurement on an epilepsy patient. METHODS: Conducted as a benchmarking study focusing on interictal epileptiform discharge (IED) detectability, an on-scalp high-temperature superconducting quantum interference device magnetometer (high-Tc SQUID) system was compared to a conventional, low-temperature SQUID system. Co-registration of electroencephalopraphy (EEG) was performed. A novel machine learning-based IED-detection algorithm was developed to aid identification of on-scalp MEG unique IEDs. RESULTS: Conventional MEG contained 24 IEDs. On-scalp MEG revealed 47 IEDs (16 co-registered by EEG, 31 unique to the on-scalp MEG recording). CONCLUSION: Our results indicate that on-scalp MEG might capture IEDs not seen by other non-invasive modalities. SIGNIFICANCE: On-scalp MEG has the potential of improving non-invasive epilepsy evaluation.

Neurophysiological effects of continuous cortical stimulation in epilepsy - Spike and spontaneous ECoG activity.

OBJECTIVE: The effect of continuous subthreshold cortical stimulation (CSCS) over the seizure onset zone (SOZ) in epilepsy was analyzed to delineate the affected physiological processes. METHOD: ECoG data was recorded over SOZ and adjacent regions in patients (n = 7) with refractory-epilepsy. Data was reviewed before and during 2 Hz cortical electrical stimulation. Group differences were estimated using ANOVA and correlation with Pearson's r. RESULTS: CSCS reduced background ECoG power at SOZ (p < 0.05), increased spectral coherence (p < 0.05) and reduced spike rate (p < 0.01) over all recorded sites. Spectral power and coherence (p < 0.01) correlated with spike rate at SOZ but not with each other at any location. Spike morphology correlated with spike-rate over all recorded sites (p < 0.0001) and with spectral power and coherence at SOZ (p < 0.01). CONCLUSION: This study shows changes in cortical electrophysiology during CSCS over the SOZ where spike rate reduction correlated with two independent electrophysiological parameters, background power and coherence. These results suggest the possibility of a causal relationship between spectral power, coherence and interictal spikes which may be related to seizure rate. SIGNIFICANCE: Improved understanding of the effect of electrical stimulation on epileptic tissue could suggest improvements in stimulation paradigms to reduce seizure frequency.

CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer's disease.

Chemokine (C-C motif) receptor 2 (CCR2)-signaling can mediate accumulation of microglia at sites affected by neuroinflammation. CCR2 and its main ligand CCL2 (MCP-1) might also be involved in the altered metabolism of beta-amyloid (Aß) underlying Alzheimer's disease (AD). We therefore measured the levels of CCL2 and three other CCR2 ligands, i.e. CCL11 (eotaxin), CCL13 (MCP-4) and CCL26 (eotaxin-3), in the cerebrospinal fluid (CSF) and plasma of 30 controls and 119 patients with mild cognitive impairment (MCI) at baseline. During clinical follow-up 52 MCI patients were clinically stable for five years, 47 developed AD (i.e. cases with prodromal AD at baseline) and 20 developed other dementias. Only CSF CCL26 was statistically significantly elevated in patients with prodromal AD when compared to controls (p = 0.002). However, in patients with prodromal AD, the CCL2 levels in CSF at baseline correlated with a faster cognitive decline during follow-up (r(s) = 0.42, p = 0.004). Furthermore, prodromal AD patients in the highest tertile of CSF CCL2 exhibited a significantly faster cognitive decline (p<0.001) and developed AD dementia within a shorter time period (p<0.003) compared to those in the lowest tertile. Finally, in the entire MCI cohort, CSF CCL2 could be combined with CSF Tau, P-tau and Aß42 to predict both future conversion to AD and the rate of cognitive decline. If these results are corroborated in future studies, CCL2 in CSF could be a candidate biomarker for prediction of future disease progression rate in prodromal AD. Moreover, CCR2-related signaling pathways might be new therapeutic targets for therapies aiming at slowing down the disease progression rate of AD.

Detection of Alzheimer peptides and chemokines in the aqueous humor.

PURPOSE: Alzheimer disease (AD) and age-related ocular diseases are characterized by inflammation and accumulation of insoluble proteins. We aimed to investigate the detectability and clinical relevance of a panel of AD-related markers, such as Alzheimer peptides and chemokines, in the aqueous humor (AH) samples taken from patients with cataract only, or cataract and 1 other ocular disease. METHODS: The AH samples were obtained during cataract surgery from patients with cataract only (n=162), cataract and glaucoma (n=21), cataract and exfoliation (PEX) (n=31), cataract and macular degeneration (n=36), and cataract and diabetic retinopathy (n=16). The AD peptides (Aß1-42, Aß1-40, Aß1-38) and chemokines (eotaxin, eotaxin 3, interleukin [IL]-8, inducible protein-10, monocyte chemotactic protein [MCP]-1, MCP-4, macrophage-derived chemokine, macrophage inflammatory protein-1ß, thymus and activation-regulated chemokine) were quantified by using multiplex immunoassays. RESULTS: The levels of the AH peptides (Aß1-38, Aß1-40, Aß1-42) did not differ between disease groups. Independently of disease group, the Aß1-38 levels correlated with Aß1-40 and Aß1-42 (p<0.001, n=277). Notably, the ratio Aß1-42 to Aß1-38 differed between PEX and macular degeneration (mean 95% confidence interval [CI] = 8.12 [11.3-3.99] vs 2.23 [2.67-0.52], p=0.003). Among chemokines examined, only MCP-1 and IL-8 were detected in about 90% to 46% of all analyzed (n=266) samples. Higher levels of AH IL-8 were found in the glaucoma group than in cataract only (p=0.011). Independently of disease group, a correlation was observed between AH MCP-1 and IL-8 (rho=0.275, p<0.001, n=266) and between MCP-1 and Aß1-40 (rho=0.239, p<0.001, n=266). CONCLUSIONS: Our findings highlight pathologic similarities between AD and eye diseases, and show the potential of modern technologies to detect AD biomarkers in age-related eye diseases.