Akihiro Shimotake

Direct Exploration of the Role of the Ventral Anterior Temporal Lobe in Semantic Memory: Cortical Stimulation and Local Field Potential Evidence From Subdural Grid Electrodes

Semantic memory is a crucial higher cortical function that codes the meaning of objects and words, and when impaired after neurological damage, patients are left with significant disability. Investigations of semantic dementia have implicated the anterior temporal lobe (ATL) region, in general, as crucial for multimodal semantic memory. The potentially crucial role of the ventral ATL subregion has been emphasized by recent functional neuroimaging studies, but the necessity of this precise area has not been selectively tested. The implantation of subdural electrode grids over this subregion, for the presurgical assessment of patients with partial epilepsy or brain tumor, offers the dual yet rare opportunities to record cortical local field potentials while participants complete semantic tasks and to stimulate the functionally identified regions in the same participants to evaluate the necessity of these areas in semantic processing. Across 6 patients, and utilizing a variety of semantic assessments, we evaluated and confirmed that the anterior fusiform/inferior temporal gyrus is crucial in multimodal, receptive, and expressive, semantic processing.

Neural correlates of mirth and laughter: A direct electrical cortical stimulation study

Laughter consists of both motor and emotional aspects. The emotional component, known as mirth, is usually associated with the motor component, namely, bilateral facial movements. Previous electrical cortical stimulation (ES) studies revealed that mirth was associated with the basal temporal cortex, inferior frontal cortex, and medial frontal cortex. Functional neuroimaging implicated a role for the left inferior frontal and bilateral temporal cortices in humor processing. However, the neural origins and pathways linking mirth with facial movements are still unclear. We hereby report two cases with temporal lobe epilepsy undergoing subdural electrode implantation in whom ES of the left basal temporal cortex elicited both mirth and laughter-related facial muscle movements. In one case with normal hippocampus, high-frequency ES consistently caused contralateral facial movement, followed by bilateral facial movements with mirth. In contrast, in another case with hippocampal sclerosis (HS), ES elicited only mirth at low intensity and short duration, and eventually laughter at higher intensity and longer duration. In both cases, the basal temporal language area (BTLA) was located within or adjacent to the cortex where ES produced mirth. In conclusion, the present direct ES study demonstrated that 1) mirth had a close relationship with language function, 2) intact mesial temporal structures were actively engaged in the beginning of facial movements associated with mirth, and 3) these emotion-related facial movements had contralateral dominance.

The 'when' and 'where' of semantic coding in the anterior temporal lobe: temporal representational similarity analysis of electrocorticogram data.

Electrocorticograms (ECoG) provide a unique opportunity to monitor neural activity directly at the cortical surface. Ten patients with subdural electrodes covering ventral and lateral anterior temporal regions (ATL) performed a picture naming task. Temporal representational similarity analysis (RSA) was used, for the first time, to compare spatio-temporal neural patterns from the ATL surface with pre-defined theoretical models. The results indicate that the neural activity in the ventral subregion of the ATL codes semantic representations from 250 msec after picture onset. The observed activation similarity was not related to the visual similarity of the pictures or the phonological similarity of their names. In keeping with convergent evidence for the importance of the ATL in semantic processing, these results provide the first direct evidence of semantic coding from the surface of the ventral ATL and its time-course.

Pre-SMA actively engages in conflict processing in human: a combined study of epicortical ERPs and direct cortical stimulation.

Previous non-invasive studies have proposed that the deeply seated region of the medial frontal cortex engages in conflict processing in humans, but its core region has remained to be elucidated. By means of direct cortical stimulation, which excels other techniques in temporal and spatial resolutions and in the capacity of producing transient, functional impairment even in the deeply located cortices, we attempted to obtain direct evidence that the pre-supplementary motor area (pre-SMA) actively engages in conflict processing. Subject was a patient with right frontal lobe epilepsy who underwent invasive presurgical evaluation with subdural electrodes placed on the medial and lateral frontal cortices. During a conflict task--modified Eriksen flanker task, direct cortical stimulation was delivered time-locked to the task at the inferior part of the medial superior frontal gyrus (inferior medial SFG), the superior part of the medial SFG, and the middle frontal gyrus. By adopting the session of sham stimulation that was employed as a within-block control, event-related potentials (ERPs) were recorded from the medial and lateral frontal cortices. The inferior medial SFG showed a significant ERP difference between trials with more and less conflict, while the other frontal cortices did not. Among the three stimulus sites, only stimulation of the inferior medial SFG significantly prolonged reaction time in trials with more conflict. Anatomically, the inferior medial SFG corresponded with the pre-SMA (Brodmann area 8). It was located 1-2 cm rostral to the vertical anterior commissure line where cortical stimulation elicited arrest of motion (the supplementary negative motor area). Functionally, this area corresponded to the dorso-rostral portion of the activation loci in previous neuroimaging studies focusing on conflict processing. By combining epicortical ERP recording and direct cortical stimulation in a human brain, this study, for the first time, presented one direct piece of evidence that the pre-SMA actively participates in conflict processing.

Network specific change in white matter integrity in mesial temporal lobe epilepsy

OBJECTIVES To identify the specific change of white matter integrity that occurs in the brain network related to epileptic activity in patients with mesial temporal lobe epilepsy (MTLE). METHODS We recruited 18 patients with MTLE and 18 healthy subjects. In MTLE patients, the remote functional-deficit zone was delineated using fluorodeoxyglucose positron emission tomography as an extratemporal region showing glucose hypometabolism. Using diffusion magnetic resonance imaging tractography, we defined a seizure propagation tract (PT) as a white matter pathway that connects the focus with a remote functional deficit zone. We also used the corticospinal tract (CST) and inferior longitudinal fasciculus (ILF) as control tracts in the hemisphere ipsilateral to the focus. Fractional anisotropy (FA), mean diffusivity (MD), and volume of the tracts were compared among PT, CST, and ILF. RESULTS Tractographic analysis identified the uncinate fasciculus, arcuate fasciculus, and fornix as PTs. A decrease in FA was found in MTLE patients compared with healthy subjects in all tracts, but PTs showed a more significant decrease in FA than did the two control tracts. Although the change in MD was also found in MTLE patients compared with healthy controls, a tract-specific change was not observed. Although white-matter damage was observed in all candidate tracts examined, the integrity of white matter was most significantly decreased in PTs in MTLE. CONCLUSION The change in white matter integrity occurs specifically in the pathways that connect the focus and remote functional deficit zones in patients with MTLE, i.e., the pathways that are assume to be associated with seizure propagation.

Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation.

Physiological high frequency activities (HFA) are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections), or different terminal layers (layer IV vs. layer II/III) affect its frequency, we, in the primary somatosensory cortex (SI), compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response) and N80 (late response) of somatosensory evoked potentials (HFASEP(N20) and HFASEP(N80)) and compared those overriding N1 and N2 (first and second responses) of cortico-cortical evoked potentials (HFACCEP(N1) and HFACCEP(N2)). HFASEP(N20) showed the power peak in the frequency above 200 Hz, while HFACCEP(N1) had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFACCEP(N1) and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions.

Clinical impact of intraoperative CCEP monitoring in evaluating the dorsal language white matter pathway.

In order to preserve postoperative language function, we recently proposed a new intraoperative method to monitor the integrity of the dorsal language pathway (arcuate fasciculus; AF) using cortico–cortical evoked potentials (CCEPs). Based on further investigations (20 patients, 21 CCEP investigations), including patients who were not suitable for awake surgery (five CCEP investigations) or those without preoperative neuroimaging data (eight CCEP investigations including four with untraceable tractography due to brain edema), we attempted to clarify the clinical impact of this new intraoperative method. We monitored the integrity of AF by stimulating the anterior perisylvian language area (AL) by recording CCEPs from the posterior perisylvian language area (PL) consecutively during both general anesthesia and awake condition. After tumor resection, single‐pulse electrical stimuli were also applied to the floor of the removal cavity to record subcortico‐cortical evoked potentials (SCEPs) at AL and PL in 12 patients (12 SCEP investigations). We demonstrated that (1) intraoperative dorsal language network monitoring was feasible even when patients were not suitable for awake surgery or without preoperative neuroimaging studies, (2) CCEP is a dynamic marker of functional connectivity or integrity of AF, and CCEP N1 amplitude could even become larger after reduction of brain edema, (3) a 50% CCEP N1 amplitude decline might be a cut‐off value to prevent permanent language dysfunction due to impairment of AF, (4) a correspondence (<2.0 ms difference) of N1 onset latencies between CCEP and the sum of SCEPs indicates close proximity of the subcortical stimulus site to AF (<3.0 mm). Hum Brain Mapp 38:1977–1991, 2017.

Network hyperexcitability in a patient with partial reading epilepsy: Converging evidence from magnetoencephalography, diffusion tractography, and functional magnetic resonance imaging

OBJECTIVE The pathophysiological mechanisms of partial reading epilepsy are still unclear. We delineated the spatial-temporal characteristics of reading-induced epileptic spikes and hemodynamic activation in a patient with partial reading epilepsy. METHODS Magnetoencephalography (MEG) was recorded during silent letter-by-letter reading, and the source of reading-induced spikes was estimated using equivalent current dipole (ECD) analysis. Diffusion tractography was employed to determine if the white matter pathway connected spike initiation and termination sites. Functional magnetic resonance imaging (fMRI) was employed to determine the spatial pattern of hemodynamic activation elicited by reading. RESULTS In 91 spike events, ECDs were clustered in the left posterior basal temporal area (pBTA) during Katakana reading. In 8 of these 91 events, when the patient continued to read >30 min, another ECD cluster appeared in the left ventral precentral gyrus/frontal operculum with a time-difference of ∼24 ms. Probabilistic diffusion tractography revealed that the long segment of the arcuate fasciculus connected these two regions. fMRI conjunction analysis indicated that both Katakana and Kanji reading activated the left pBTA, but Katakana activated the left lateral frontal areas more extensively than Kanji. CONCLUSIONS Prolonged reading of Katakana induced hyper-activation of the cortical network involved in normal language function, concurrently serving as the seizure onset and symptomatogenic zones. SIGNIFICANCE Reflex epilepsy is believed to result from intrinsic hyper-excitability in the cortical regions recruited during behavioral states that trigger seizures. Our case shows that reading epilepsy can arise from a hyperexcitable network of cortical regions. Physiological activation of this network can have cumulative effects, resulting in greater reciprocal network propagation and electroclinical seizures. These effects, in turn, may give insights into the brain networks recruited by reading.

Epileptic network of hypothalamic hamartoma: An EEG-fMRI study

OBJECTIVE To investigate the brain networks involved in epileptogenesis/encephalopathy associated with hypothalamic hamartoma (HH) by EEG with functional MRI (EEG-fMRI), and evaluate its efficacy in locating the HH interface in comparison with subtraction ictal SPECT coregistered to MRI (SISCOM). METHODS Eight HH patients underwent EEG-fMRI. All had gelastic seizures (GS) and 7 developed other seizure types. Using a general linear model, spike-related activation/deactivation was analyzed individually by applying a hemodynamic response function before, at, and after spike onset (time-shift model=-8-+4s). Group analysis was also performed. The sensitivity of EEG-fMRI in identifying the HH interface was compared with SISCOM in HH patients having unilateral hypothalamic attachment. RESULTS EEG-fMRI revealed activation and/or deactivation in subcortical structures and neocortices in all patients. 6/8 patients showed activation in or around the hypothalamus with the HH interface with time-shift model before spike onset. Group analysis showed common activation in the ipsilateral hypothalamus, brainstem tegmentum, and contralateral cerebellum. Deactivation occurred in the default mode network (DMN) and bilateral hippocampi. Among 5 patients with unilateral hypothalamic attachment, activation in or around the ipsilateral hypothalamus was seen in 3 using EEG-fMRI, whereas hyperperfusion was seen in 1 by SISCOM. SIGNIFICANCE Group analysis of this preliminary study may suggest that the commonly activated subcortical network is related to generation of GS and that frequent spikes lead to deactivation of the DMN and hippocampi, and eventually to a form of epileptic encephalopathy. Inter-individual variance in neocortex activation explains various seizure types among patients. EEG-fMRI enhances sensitivity in detecting the HH interface compared with SISCOM.

P16-8 Parieto-frontal network in praxis of human: a combined study of high frequency cortical stimulation and CCEP study

Methods: Sixteen patients with refractory focal epilepsy were studied with TMS prior to and three months following epilepsy surgery. AED use in each patient did not change between the pre and post-operative TMS studies. Motor threshold (MT) at rest and recovery curve analysis using paired pulse stimulation at a number of short (2, 5, 10 and 15 ms) and long (50 300 ms) interstimulus intervals (ISIs) were measured. The patients were divided at the end of a one year follow-up period into seizure free (10/16) and ongoing seizure groups. Findings: A decrease in cortical excitability (p < 0.05), maximum at the long ISIs 250 and 300 ms was observed in both hemispheres postoperatively in the seizure free patients. This was not seen in patients who continued to have seizures. Conclusion: Successful surgical removal of the epileptic focus and postoperative seizure freedom is associated with bilateral decreased cortical excitability. This suggests that changes in cortical excitability associated with refractory epilepsy are not permanent and can be reversed if seizures are controlled.