Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Evaluating whole-brain tissue-property changes in MRI-negative pharmacoresistant focal epilepsies using MR fingerprinting.

OBJECTIVE: We aim to quantify whole-brain tissue-property changes in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant focal epilepsy by three-dimensional (3D) magnetic resonance fingerprinting (MRF). METHODS: We included 30 patients with pharmacoresistant focal epilepsy and negative MRI by official radiology report, as well as 40 age- and gender-matched healthy controls (HCs). MRF scans were obtained with 1 mm3 isotropic resolution. Quantitative T1 and T2 relaxometry maps were reconstructed from MRF and registered to the Montreal Neurological Institute (MNI) space. A two-sample t test was performed in Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) to evaluate significant abnormalities in patients comparing to HCs, with correction by the threshold-free cluster enhancement (TFCE) method. Subgroups analyses were performed for extra-temporal epilepsy/temporal epilepsy (ETLE/TLE), and for those with/without subtle abnormalities detected by morphometric analysis program (MAP), to investigate each subgroup's pattern of MRF changes. Correlation analyses were performed between the mean MRF values in each significant cluster and seizure-related clinical variables. RESULTS: Compared to HCs, patients exhibited significant group-level T1 increase ipsilateral to the epileptic origin, in the mesial temporal gray matter (GM) and white matter (WM), temporal pole GM, orbitofrontal GM, hippocampus, and amygdala, with scattered clusters in the neocortical temporal and insular GM. No significant T2 changes were detected. The ETLE subgroup showed a T1-increase pattern similar to the overall cohort, with additional involvement of the ipsilateral anterior cingulate GM. The subgroup of MAP+ patients also showed a T1-increase pattern similar to the overall cohort, with additional cluster in the ipsilateral lateral orbitofrontal GM. Higher T1 was associated with younger seizure-onset age, longer epilepsy duration, and higher seizure frequency. SIGNIFICANCE: MRF revealed group-level T1 increase in limbic/paralimbic structures ipsilateral to the epileptic origin, in patients with pharmacoresistant focal epilepsy and no apparent lesions on MRI, suggesting that these regions may be commonly affected by seizures in the epileptic brain. The significant association between T1 increase and higher seizure burden may reflect progressive tissue damage.

Novel noninvasive identification of patient-specific epileptic networks in focal epilepsies: Linking single-photon emission computed tomography perfusion during seizures with resting-state magnetoencephalography dynamics.

Single-photon emission computed tomography (SPECT) during seizures and magnetoencephalography (MEG) during the interictal state are noninvasive modalities employed in the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy (DRFE). The present study aims to investigate whether there exists a preferentially high MEG functional connectivity (FC) among those regions of the brain that exhibit hyperperfusion or hypoperfusion during seizures. We studied MEG and SPECT data in 30 consecutive DRFE patients who had resective epilepsy surgery. We parcellated each ictal perfusion map into 200 regions of interest (ROIs) and generated ROI time series using source modeling of MEG data. FC between ROIs was quantified using coherence and phase-locking value. We defined a generalized linear model to relate the connectivity of each ROI, ictal perfusion z score, and distance between ROIs. We compared the coefficients relating perfusion z score to FC of each ROI and estimated the connectivity within and between resected and unresected ROIs. We found that perfusion z scores were strongly correlated with the FC of hyper-, and separately, hypoperfused ROIs across patients. High interictal connectivity was observed between hyperperfused brain regions inside and outside the resected area. High connectivity was also observed between regions of ictal hypoperfusion. Importantly, the ictally hypoperfused regions had a low interictal connectivity to regions that became hyperperfused during seizures. We conclude that brain regions exhibiting hyperperfusion during seizures highlight a preferentially connected interictal network, whereas regions of ictal hypoperfusion highlight a separate, discrete and interconnected, interictal network.

Normative quantitative relaxation atlases for characterization of cortical regions using magnetic resonance fingerprinting.

Quantitative magnetic resonance (MR) has been used to study cyto- and myelo-architecture of the human brain non-invasively. However, analyzing brain cortex using high-resolution quantitative MR acquisition can be challenging to perform using 3T clinical scanners. MR fingerprinting (MRF) is a highly efficient and clinically feasible quantitative MR technique that simultaneously provides T1 and T2 relaxation maps. Using 3D MRF from 40 healthy subjects (mean age = 25.6 ± 4.3 years) scanned on 3T magnetic resonance imaging, we generated whole-brain gyral-based normative MR relaxation atlases and investigated cortical-region-based T1 and T2 variations. Gender and age dependency of T1 and T2 variations were additionally analyzed. The coefficient of variation of T1 and T2 for each cortical-region was 3.5% and 7.3%, respectively, supporting low variability of MRF measurements across subjects. Significant differences in T1 and T2 were identified among 34 brain regions (P < 0.001), lower in the precentral, postcentral, paracentral lobule, transverse temporal, lateral occipital, and cingulate areas, which contain sensorimotor, auditory, visual, and limbic functions. Significant correlations were identified between age and T1 and T2 values. This study established whole-brain MRF T1 and T2 atlases of healthy subjects using a clinical 3T scanner, which can provide a quantitative and region-specific baseline for future brain studies and pathology detection.

Black Line Sign in Focal Cortical Dysplasia IIB: A 7T MRI and Electroclinicopathologic Study.

BACKGROUND AND OBJECTIVES: We aim to provide detailed imaging-electroclinicopathologic characterization of the black line sign, a novel MRI marker for focal cortical dysplasia (FCD) IIB. METHODS: 7T T2*-weighted gradient-echo (T2*w-GRE) images were retrospectively reviewed in a consecutive cohort of patients with medically intractable epilepsy with pathology-proven FCD II, for the occurrence of the black line sign. We examined the overlap between the black line region and the seizure-onset zone (SOZ) defined by intracranial EEG (ICEEG) and additionally assessed whether complete inclusion of the black line region in the surgical resection was associated with postoperative seizure freedom. The histopathologic specimen was aligned with the MRI to investigate the pathologic underpinning of the black line sign. Region-of-interest-based quantitative MRI (qMRI) analysis on the 7T T1 map was performed in the black line region, entire lesional gray matter (GM), and contralateral/ipsilateral normal gray and white matter (WM). RESULTS: We included 20 patients with FCD II (14 IIB and 6 IIA). The black line sign was identified in 12/14 (85.7%) of FCD IIB and 0/6 of FCD IIA on 7T T2*w-GRE. The black line region was highly concordant with the ICEEG-defined SOZ (5/7 complete and 2/7 partial overlap). Seizure freedom was seen in 8/8 patients whose black line region was completely included in the surgical resection; in the 2 patients whose resection did not completely include the black line region, both had recurring seizures. Inclusion of the black line region in the surgical resection was significantly associated with seizure freedom (p = 0.02). QMRI analyses showed that the T1 mean value of the black line region was significantly different from the WM (p < 0.001), but similar to the GM. Well-matched histopathologic slices in one case revealed accumulated dysmorphic neurons and balloon cells in the black line region. DISCUSSION: The black line sign may serve as a noninvasive marker for FCD IIB. Both MRI-pathology and qMRI analyses suggest that the black line region was an abnormal GM component within the FCD. Being highly concordant with ICEEG-defined SOZ and significantly associated with seizure freedom when included in resection, the black line sign may contribute to the planning of ICEEG/surgery of patients with medically intractable epilepsy with FCD IIB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in individuals with intractable focal epilepsy undergoing resection who have a 7T MRI with adequate image quality, the presence of the black line sign may suggest FCD IIB, be concordant with SOZ from ICEEG, and be associated with more seizure freedom if fully included in resection.

Characterizing thalamic and basal ganglia nuclei in medically intractable focal epilepsy by MR fingerprinting.

OBJECTIVES: Magnetic resonance fingerprinting (MRF) is a novel, quantitative, and noninvasive technique to measure brain tissue properties. We aim to use MRF for characterizing normal-appearing thalamic and basal ganglia nuclei in the epileptic brain. METHODS: A three-dimensional (3D) MRF protocol (1 mm3 isotropic resolution) was acquired from 48 patients with unilateral medically intractable focal epilepsy and 39 healthy controls (HCs). Whole-brain T1 and T2 maps (containing T1 and T2 relaxation times) were reconstructed for each subject. Ten subcortical nuclei in the thalamus and basal ganglia were segmented as regions of interest (ROIs), within which the mean T1 and T2 values, as well as their coefficient of variation (CV) were compared between the patients and HCs at the group level. Subgroup and correlation analyses were performed to examine the relationship between significant MRF measures and various clinical characteristics. Using significantly abnormal MRF measures from the group-level analyses, support vector machine (SVM) and logistic regression machine learning models were built and tested with 5-fold and 10-fold cross-validations, to separate patients from HCs, and to separate patients with left-sided and right-sided epilepsy, at the individual level. RESULTS: MRF revealed increased T1 mean value in the ipsilateral thalamus and nucleus accumbens; increased T1 CV in the bilateral thalamus, bilateral pallidum, and ipsilateral caudate; and increased T2 CV in the ipsilateral thalamus in patients compared to HCs (p < .05, false discovery rate [FDR] corrected). The SVM classifier produced 78.2% average accuracy to separate individual patients from HCs, with an area under the curve (AUC) of 0.83. The logistic regression classifier produced 67.4% average accuracy to separate patients with left-sided and right-sided epilepsy, with an AUC of 0.72. SIGNIFICANCE: MRF revealed bilateral tissue-property changes in the normal-appearing thalamus and basal ganglia, with ipsilateral predominance and thalamic preference, suggesting subcortical involvement/impairment in patients with medically intractable focal epilepsy. The individual-level performance of the MRF-based machine-learning models suggests potential opportunities for predicting lateralization.

Using magnetic resonance fingerprinting to characterize periventricular nodular heterotopias in pharmacoresistant epilepsy.

OBJECTIVE: We aimed to use a novel magnetic resonance fingerprinting (MRF) technique to examine in vivo tissue property characteristics of periventricular nodular heterotopia (PVNH). These characteristics were further correlated with stereotactic-electroencephalographic (SEEG) ictal onset findings. METHODS: We included five patients with PVNH who had SEEG-guided surgery and at least 1 year of seizure freedom or substantial seizure reduction. High-resolution MRF scans were acquired at 3 T, generating three-dimensional quantitative T1 and T2  maps. We assessed the differences between T1 and T2  values from the voxels in the nodules located in the SEEG-defined seizure onset zone (SOZ) and non-SOZ, on -individual and group levels. Receiver operating characteristic analyses were performed to obtain the optimal classification performance. Quantification of SEEG ictal onset signals from the nodules was performed by calculating power spectrum density (PSD). The association between PSD and T1 /T2  values was further assessed at different frequency bands. RESULTS: Individual-level analysis showed T1 was significantly higher in SOZ voxels than non-SOZ voxels (p < .05), with an average 73% classification accuracy. Group-level analysis also showed higher T1 was significantly associated with SOZ voxels (p < .001). At the optimal cutoff (normalized T1 of 1.1), a 76% accuracy for classifying SOZ nodules from non-SOZ nodules was achieved. T1  values were significantly associated with ictal onset PSD at the ultraslow, θ, ß, γ, and ripple bands (p < .05). T2  values were significantly associated with PSD only at the ultraslow band (p < .05). SIGNIFICANCE: Quantitative MRF measures, especially T1 , can provide additional noninvasive information to separate nodules in SOZ and non-SOZ. The T1 and T2 tissue property changes carry electrophysiological underpinnings relevant to the epilepsy, as shown by their significant positive associations with power changes during the SEEG seizure onset. The use of MRF as a supplementary noninvasive tool may improve presurgical evaluation for patients with PVNH and pharmacoresistant epilepsy.

Individual localization value of resting-state fMRI in epilepsy presurgical evaluation: A combined study with stereo-EEG.

OBJECTIVE: To examine the individual-patient-level localization value of resting-state functional MRI (rsfMRI) metrics for the seizure onset zone (SOZ) defined by stereo-electroencephalography (SEEG) in patients with medically intractable focal epilepsies. METHODS: We retrospectively included 19 patients who underwent SEEG implantation for epilepsy presurgical evaluation. Voxel-wise whole-brain analysis was performed on 3.0 T rsfMRI to generate clusters for amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo) and degree centrality (DC), which were co-registered with the SEEG-defined SOZ to evaluate their spatial overlap. Subgroup and correlation analyses were conducted for various clinical characteristics. RESULTS: ALFF demonstrated concordant clusters with SEEG-defined SOZ in 73.7% of patients, with 93.3% sensitivity and 77.8% PPV. The concordance rate showed no significant difference when subgrouped by lesional/non-lesional MRI, SOZ location, interictal epileptiform discharges on scalp EEG, pathology or seizure outcomes. No significant correlation was seen between ALFF concordance rate and epilepsy duration, seizure-onset age, seizure frequency or number of antiseizure medications. ReHo and DC did not achieve favorable concordance results (10.5% and 15.8%, respectively). All concordant clusters showed regional activation, representing increased neural activities. CONCLUSION: ALFF had high concordance rate with SEEG-defined SOZ at individual-patient level. SIGNIFICANCE: ALFF activation on rsfMRI can add localizing information for the noninvasive presurgical workup of intractable focal epilepsies.

Multimodal Image Integration for Epilepsy Presurgical Evaluation: A Clinical Workflow.

Multimodal image integration (MMII) is a promising tool to help delineate the epileptogenic zone (EZ) in patients with medically intractable focal epilepsies undergoing presurgical evaluation. We report here the detailed methodology of MMII and an overview of the utility of MMII at the Cleveland Clinic Epilepsy Center from 2014 to 2018, exemplified by illustrative cases. The image integration was performed using the Curry platform (Compumedics Neuroscan™, Charlotte, NC, USA), including all available diagnostic modalities such as Magnetic resonance imaging (MRI), Positron Emission Tomography (PET), single-photon emission computed tomography (SPECT) and Magnetoencephalography (MEG), with additional capability of trajectory planning for intracranial EEG (ICEEG), particularly stereo-EEG (SEEG), as well as surgical resection planning. In the 5-year time span, 467 patients underwent MMII; of them, 98 patients (21%) had a history of prior neurosurgery and recurring seizures. Of the 467 patients, 425 patients underwent ICEEG implantation with further CT co-registration to identify the electrode locations. A total of 351 patients eventually underwent surgery after MMII, including 197 patients (56%) with non-lesional MRI and 223 patients (64%) with extra-temporal lobe epilepsy. Among 269 patients with 1-year post-operative follow up, 134 patients (50%) had remained completely seizure-free. The most common histopathological finding is focal cortical dysplasia. Our study illustrates the usefulness of MMII to enhance SEEG electrode trajectory planning, assist non-invasive/invasive data interpretation, plan resection strategy, and re-evaluate surgical failures. Information presented by MMII is essential to the understanding of the anatomo-functional-electro-clinical correlations in individual cases, which leads to the ultimate success of presurgical evaluation of patients with medically intractable focal epilepsies.

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.

Alternating zones selective to faces and written words in the human ventral occipitotemporal cortex.

Recognition of faces and written words is associated with category-specific brain activation in the ventral occipitotemporal cortex (vOT). However, topological and functional relationships between face-selective and word-selective vOT regions remain unclear. In this study, we collected data from patients with intractable epilepsy who underwent high-density recording of surface field potentials in the vOT. "Faces" and "letterstrings" induced outstanding category-selective responses among the 24 visual categories tested, particularly in high-γ band powers. Strikingly, within-hemispheric analysis revealed alternation of face-selective and letterstring-selective zones within the vOT. Two distinct face-selective zones located anterior and posterior portions of the mid-fusiform sulcus whereas letterstring-selective zones alternated between and outside of these 2 face-selective zones. Further, a classification analysis indicated that activity patterns of these zones mostly represent dedicated categories. Functional connectivity analysis using Granger causality indicated asymmetrically directed causal influences from face-selective to letterstring-selective regions. These results challenge the prevailing view that different categories are represented in distinct contiguous regions in the vOT.

Altered activity of the primary visual area during gaze processing in individuals with high-functioning autistic spectrum disorder: a magnetoencephalography study.

BACKGROUND: Individuals with autistic spectrum disorder (ASD) demonstrate an impaired ability to infer the mental states of others from their gaze. Thus, investigating the relationship between ASD and eye gaze processing is crucial for understanding the neural basis of social impairments seen in individuals with ASD. In addition, characteristics of ASD are observed in more comprehensive visual perception tasks. These visual characteristics of ASD have been well-explained in terms of the atypical relationship between high- and low-level gaze processing in ASD. METHOD: We studied neural activity during gaze processing in individuals with ASD using magnetoencephalography, with a focus on the relationship between high- and low-level gaze processing both temporally and spatially. Minimum Current Estimate analysis was applied to perform source analysis of magnetic responses to gaze stimuli. RESULTS: The source analysis showed that later activity in the primary visual area (V1) was affected by gaze direction only in the ASD group. Conversely, the right posterior superior temporal sulcus, which is a brain region that processes gaze as a social signal, in the typically developed group showed a tendency toward greater activation during direct compared with averted gaze processing. CONCLUSION: These results suggest that later activity in V1 relating to gaze processing is altered or possibly enhanced in high-functioning individuals with ASD, which may underpin the social cognitive impairments in these individuals.

Effect of the number of pins and inter-pin distance on somatosensory evoked magnetic fields following mechanical tactile stimulation.

Magnetoencephalography (MEG) recordings were collected to investigate the effect of the number of mechanical pins and inter-pin distance on somatosensory evoked magnetic fields (SEFs) following mechanical stimulation (MS). We used a 306-ch whole-head MEG system. SEFs were elicited through tactile stimuli with 1-, 2-, 3-, 4- and 8-pins using healthy participants. Tactile stimuli were applied to the tip of the right index finger. SEF following electrical stimulation of the index finger was recorded in order to compare the activity in the primary somatosensory cortex (S1) following MS. Prominent SEFs were recorded from the contralateral hemisphere approximately 54 ms (P50m) and 125 ms (P100m) after MS regardless of the number of pins. Equivalent current dipoles were located in the S1. The source activities for P50m and P100m significantly increased in tandem with the number of pins for MS. However, the increased ratios for the source activities according to the increase in the number of pins were significantly smaller than that induced by electrical stimulation, and when the number of the pins doubled from 1-pin to 2-pins, from 2-pins to 4-pins, and from 4-pins to 8-pins, S1 activities increased by only 130%. Additionally, source activities significantly increased when the inter-pin distance increased from 2.4 to 7.2 mm. The number of stimulated receptors was considered to have increased with an increase in the inter-pin distance as well as an increase in the number of pins. These findings clarified the effect of the number of pins and inter-pin distance for MS on SEFs.

Activation of the human premotor cortex during motor preparation in visuomotor tasks.

Functional brain mapping studies in humans suggest that both motor and premotor cortices interact during movement execution. The aim of this study was to investigate whether the premotor cortex also participates in motor planning. We measured movement-related cerebral fields (MRCFs) using magnetoencephalography from the left hemisphere of 12 healthy right-handed participants during two simple visuomotor tasks cued by two visual stimuli S1 and S2. Participants performed a unilateral task in which they always extended the right index finger after S2 presentation regardless of the color of S1 and a bilateral task in which they extended either the right or left index finger after S2 presentation according to the color of S1. Significantly higher MRCF activity was observed during the 500 ms S1 to S2 interval in the bilateral task than in the unilateral task. In the bilateral task trials, the latency of the peak MRCF during the S1 to S2 interval was 343.9 ± 73.5 ms after S1 presentation and that of the peak of movement-evoked field 1 was 33.4 ± 3.9 ms after movement onset in the bilateral task. Equivalent current dipoles at the peak MRCF were significantly medial (9.2 ± 12.1 mm) and anterior (19.8 ± 6.9 mm) to the reference location in the somatosensory cortex (area 3b) established by median nerve stimulation. This location corresponds to the dorsal premotor cortex. These findings suggest that activation of the premotor cortex observed during the interstimulus interval may represent a neurophysiological marker of response selection.