Insular seizures are great mimickers of seizures originating elsewhere in the brain. The insula is a highly connected brain structure. Seizures may only become clinically evident after ictal activity propagates out of the insula with semiology that reflects the propagation pattern. Insular seizures with perisylvian spread, for example, manifest first as throat constriction, followed next by perioral and hemisensory symptoms, and then by unilateral motor symptoms. On the other hand, insular seizures may spread instead to the temporal and frontal lobes and present like seizures originating from these regions. Due to the location of the insula deep in the brain, interictal and ictal scalp electroencephalogram (EEG) changes can be variable and misleading. Magnetic resonance imaging, magnetic resonance spectroscopy, magnetoencephalography, positron emission tomography, and single-photon computed tomography imaging may assist in establishing a diagnosis of insular epilepsy. Intracranial EEG recordings from within the insula, using stereo-EEG or depth electrode techniques, can prove insular seizure origin. Seizure onset, most commonly seen as low-voltage, fast gamma activity, however, can be highly localized and easily missed if the insula is only sparsely sampled. Moreover, seizure spread to the contralateral insula and other brain regions may occur rapidly. Extensive sampling of the insula with multiple electrode trajectories is necessary to avoid these pitfalls. Understanding the functional organization of the insula is helpful when interpreting the semiology produced by insular seizures. Electrical stimulation mapping around the central sulcus of the insula results in paresthesias, while stimulation of the posterior insula typically produces painful sensations. Visceral sensations are the next most common result of insular stimulation. Treatment of insular epilepsy is evolving, but poses challenges. Surgical resections of the insula are effective but risk significant morbidity if not carefully planned. Neurostimulation is an emerging option for treatment, especially for seizures with onset in the posterior insula. The close association of the insula with marked autonomic changes has led to interest in the role of the insula in sudden unexpected death in epilepsy and warrants additional study with larger patient cohorts.

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave ripples (SWRs) similar to those which in rodents mark memory replay. We show that while pHC generates SWRs, it also generates approximately as many spindle ripples (SSR: ripples phase-locked to local spindles). In contrast, SSRs are rare in aHC. Like SWRs, SSRs often co-occur with neocortical theta bursts (TBs), downstates (DSs), sleep spindles (SSs), and upstates (USs), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWRs co-occur with these waves in widespread cortical areas, especially frontocentral. These waves typically occur in the sequence TB-DS-SS-US, with SWRs usually occurring before SS-US. In contrast, SSRs occur ϳ350 ms later, with a strong preference for co-occurrence with posterior-parietal SSs. pHC-SSs were strongly phase-locked with parietal-SSs, and pHC-SSRs were phase-coupled with pHC-SSs and parietal-SSs. Human SWRs (and associated replay events, if any) are separated by ϳ5 s on average, whereas ripples on successive SSR peaks are separated by only ϳ80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex.

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The role of fast activity as a potential biomarker in localization of the epileptogenic zone (EZ) remains controversial due to recently reported unsatisfactory performance.We recently identified a "fingerprint" of the EZ as a time-frequency pattern that is defined by a combination of preictal spike(s), fast oscillatory activity, and concurrent suppression of lower frequencies. Here we examine the generalizability of the fingerprint in application to an independent series of patients (11 seizure-free and 13 nonseizure-free after surgery) and show that the fingerprint can also be identified in seizures with lower frequency (such as beta) oscillatory activity. In the seizure-free group, only 5 of 47 identified EZ contacts were outside the resection. In contrast, in the non-seizure-free group, 104 of 142 identified EZ contacts were outside the resection. We integrated the fingerprint prediction with the subject's MR images, thus providing individualized anatomical estimates of the EZ. We show that these fingerprint-based estimates in seizure-free patients are almost always inside the resection. On the other hand, for a large fraction of the nonseizure-free patients the estimated EZ was not well localized and was partially or completely outside the resection, which may explain surgical failure in such cases. We also show that when mapping fast activity alone onto MR images, the EZ was often over-estimated, indicating a reduced discriminative ability for fast activity relative to the full fingerprint for localization of the EZ. K E Y W O R D Sepileptogenic zone, high-frequency oscillations, localization-related epilepsy, partial seizure, stereo-EEG

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences. During NREM sleep, the human hippocampus generates sharpwave-ripples (SWR) similar to those which in rodents mark memory replay. We show that while pHC generates SWR, it also generates about as many spindle-ripples (SSR: ripples phase-locked to local spindles). In contrast, SSR are rare in aHC. Like SWR, SSR often co-occur with neocortical theta bursts (TB), downstates (DS), spindles (SS) and upstates (US), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWR co-occur with these waves in widespread cortical areas, especially fronto-central. These waves typically occur in the sequence TB-DS-SS-US, with SWR usually occurring prior to SS-US. In contrast, SSR occur ~350 ms later, with a strong preference for cooccurrence with posterior-parietal SS. pHC-SS were strongly phase-locked with parietal-SS, and pHC-SSR were phase-coupled with pHC-SS and parietal-SS. Human SWR (and associated replay events, if any) are separated by ~5 s on average, whereas ripples on successive SSR peaks are separated by only ~80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex. Significance StatementRodent hippocampal neurons replay waking events during sharpwave-ripples in NREM sleep, facilitating memory transfer to a permanent cortical store. We show that human anterior hippocampus also produces sharpwave-ripples, but spindle-ripples predominate in posterior. Whereas sharpwave-ripples typically occur as cortex emerges from inactivity, spindle-ripples typically occur at peak cortical activity. Furthermore, posterior hippocampal spindle-ripples are tightly coupled to posterior parietal locations activated by conscious recollection. Finally, multiple spindle-ripples can recur within a second, whereas sharpwave-ripples are separated by about 5s. The human posterior hippocampus is considered homologous to rodent dorsal hippocampus, which is thought to be specialized for consolidation of specific memory details. We speculate that these distinct physiological characteristics of posterior hippocampal spindleripples may support a related function in humans.

OBJECT The frontal and insular fiber network in humans remains largely unknown. This study investigated the connectivity of the frontal and anterior insular network in humans using cortico-cortical evoked potential (CCEP). METHODS This retrospective analysis included 18 patients with medically intractable focal epilepsy who underwent stereoelectroencephalography and CCEP. Alternating 1-Hz electrical stimuli were delivered to parts of the frontal lobe and anterior insula (prefrontal cortex [PFC], ventrolateral and dorsolateral premotor area [vPM and dPM, respectively], presupplementary motor area [pre-SMA], SMA, frontal operculum, and anterior insula). A total of 40–60 stimuli were averaged in each trial to obtain CCEP responses. The distribution of CCEP was evaluated by calculating the root mean square of CCEP responses. RESULTS Stimulation of the PFC elicited prominent CCEP responses in the medial PFC and PMs over the ipsilateral hemisphere. Stimulation of the vPM and dPM induced CCEP responses in the ipsilateral frontoparietal areas. Stimulation of the pre-SMA induced CCEP responses in the ipsilateral medial and lateral frontal areas and contralateral pre-SMA, whereas stimulation of the SMA induced CCEP responses in the bilateral frontoparietal areas. Stimulation of the frontal operculum induced CCEP responses in the ipsilateral insula and temporal operculum. CCEPs were observed in the ipsilateral medial, lateral frontal, and frontotemporal operculum in the anterior insular stimulation. Stimulation of the vPM and SMA led to the network in the dominant hemisphere being more developed. CONCLUSIONS Various regions within the frontal lobe and anterior insula were linked to specific ipsilateral and contralateral regions, which may reflect distinct functional roles.

Patients with medically intractable epilepsy often undergo invasive evaluation and surgery, with a 50% success rate. The low success rate is likely due to poor identification of the epileptogenic zone (EZ), the brain area causing seizures. This work introduces a new method using functional magnetic resonance imaging (fMRI) with simultaneous direct electrical stimulation of the brain that could help localize the EZ, performed in five patients with medically intractable epilepsy undergoing invasive evaluation with intracranial depth electrodes. Stimulation occurred in a location near the hypothesized EZ and a location away. Electrical recordings in response to stimulation were recorded and compared to fMRI. Multiple stimulation parameters were varied, like current and frequency. The brain areas showing fMRI response were compared with the areas resected and the success of surgery. Robust fMRI maps of activation networks were easily produced, which also showed a significant but weak positive correlation between quantitative measures of blood-oxygen-level-dependent (BOLD) activity and measures of electrical activity in response to direct electrical stimulation (mean correlation coefficient of 0.38 for all acquisitions that produced a strong BOLD response). For four patients with outcome data at 6 months, successful surgical outcome is consistent with the resection of brain areas containing high local fMRI activity. In conclusion, this method demonstrates the feasibility of simultaneous direct electrical stimulation and fMRI in humans, which allows the study of brain connectivity with high resolution and full spatial coverage. This innovative technique could be used to better define the localization and extension of the EZ in intractable epilepsies, as well as for other functional neurosurgical procedures.