David N. Vaughan

Connectivity-based fixel enhancement: Whole-brain statistical analysis of diffusion MRI measures in the presence of crossing fibres.

In brain regions containing crossing fibre bundles, voxel-average diffusion MRI measures such as fractional anisotropy (FA) are difficult to interpret, and lack within-voxel single fibre population specificity. Recent work has focused on the development of more interpretable quantitative measures that can be associated with a specific fibre population within a voxel containing crossing fibres (herein we use fixel to refer to a specific fibre population within a single voxel). Unfortunately, traditional 3D methods for smoothing and cluster-based statistical inference cannot be used for voxel-based analysis of these measures, since the local neighbourhood for smoothing and cluster formation can be ambiguous when adjacent voxels may have different numbers of fixels, or ill-defined when they belong to different tracts. Here we introduce a novel statistical method to perform whole-brain fixel-based analysis called connectivity-based fixel enhancement (CFE). CFE uses probabilistic tractography to identify structurally connected fixels that are likely to share underlying anatomy and pathology. Probabilistic connectivity information is then used for tract-specific smoothing (prior to the statistical analysis) and enhancement of the statistical map (using a threshold-free cluster enhancement-like approach). To investigate the characteristics of the CFE method, we assessed sensitivity and specificity using a large number of combinations of CFE enhancement parameters and smoothing extents, using simulated pathology generated with a range of test-statistic signal-to-noise ratios in five different white matter regions (chosen to cover a broad range of fibre bundle features). The results suggest that CFE input parameters are relatively insensitive to the characteristics of the simulated pathology. We therefore recommend a single set of CFE parameters that should give near optimal results in future studies where the group effect is unknown. We then demonstrate the proposed method by comparing apparent fibre density between motor neurone disease (MND) patients with control subjects. The MND results illustrate the benefit of fixel-specific statistical inference in white matter regions that contain crossing fibres.

Investigating white matter fibre density and morphology using fixel-based analysis.

ABSTRACT Voxel‐based analysis of diffusion MRI data is increasingly popular. However, most white matter voxels contain contributions from multiple fibre populations (often referred to as crossing fibres), and therefore voxel‐averaged quantitative measures (e.g. fractional anisotropy) are not fibre‐specific and have poor interpretability. Using higher‐order diffusion models, parameters related to fibre density can be extracted for individual fibre populations within each voxel (‘fixels’), and recent advances in statistics enable the multi‐subject analysis of such data. However, investigating within‐voxel microscopic fibre density alone does not account for macroscopic differences in the white matter morphology (e.g. the calibre of a fibre bundle). In this work, we introduce a novel method to investigate the latter, which we call fixel‐based morphometry (FBM). To obtain a more complete measure related to the total number of white matter axons, information from both within‐voxel microscopic fibre density and macroscopic morphology must be combined. We therefore present the FBM method as an integral piece within a comprehensive fixel‐based analysis framework to investigate measures of fibre density, fibre‐bundle morphology (cross‐section), and a combined measure of fibre density and cross‐section. We performed simulations to demonstrate the proposed measures using various transformations of a numerical fibre bundle phantom. Finally, we provide an example of such an analysis by comparing a clinical patient group to a healthy control group, which demonstrates that all three measures provide distinct and complementary information. By capturing information from both sources, the combined fibre density and cross‐section measure is likely to be more sensitive to certain pathologies and more directly interpretable. HIGHLIGHTSA fixel is defined as a specific fibre population within a voxel.We describe a comprehensive approach to fixel‐based analysis (FBA) of white matter.A novel method to investigate fibre bundle morphology (cross‐section) is presented.We compare fibre density, cross‐section and a combined measure in a clinical cohort.The three different analyses give unique yet complementary information.

The piriform cortex and human focal epilepsy.

It is surprising that the piriform cortex, when compared to the hippocampus, has been given relatively little significance in human epilepsy. Like the hippocampus, it has a phylogenetically preserved three-layered cortex that is vulnerable to excitotoxic injury, has broad connections to both limbic and cortical areas, and is highly epileptogenic – being critical to the kindling process. The well-known phenomenon of early olfactory auras in temporal lobe epilepsy highlights its clinical relevance in human beings. Perhaps because it is anatomically indistinct and difficult to approach surgically, as it clasps the middle cerebral artery, it has, until now, been understandably neglected. In this review, we emphasize how its unique anatomical and functional properties, as primary olfactory cortex, predispose it to involvement in focal epilepsy. From recent convergent findings in human neuroimaging, clinical epileptology, and experimental animal models, we make the case that the piriform cortex is likely to play a facilitating and amplifying role in human focal epileptogenesis, and may influence progression to epileptic intractability.

MRI-negative temporal lobe epilepsy A network disorder of neocortical connectivity

Objective: To define the functional network changes that characterize MRI-negative temporal lobe epilepsy (TLE) and TLE with hippocampal sclerosis (HS-TLE). Methods: We studied 36 patients with medically refractory unilateral TLE, having either a normal clinical MRI (n = 18) or unilateral hippocampal sclerosis (n = 18). Patients were compared to healthy controls of equivalent age and sex (n = 27). Functional connectivity in 10 minutes of task-free functional MRI was assessed using a voxel-resolution graph theoretic analysis, using the metrics of degree, clustering coefficient, eigenvector, and betweenness centrality. Significant clusters were further explored with a seed-based analysis. Results: MRI-negative TLE showed decreased connectivity at the ipsilateral superior and middle temporal gyri compared to controls (decreased eigenvector centrality). No functional abnormality was detected within mesial temporal structures. In contrast, HS-TLE showed increased connectivity within the affected hippocampus and anterior thalamus (increased clustering coefficient) and decreased connectivity of the ventromesial prefrontal cortex (decreased betweenness centrality). Using the detected clusters as seed regions revealed decreased connectivity from the sclerotic hippocampus to both the contralateral temporal lobe and regions of the default mode network. Conclusion: MRI-negative TLE is associated with impaired interictal connectivity of the temporal neocortex, lateralized to the epileptic side. HS-TLE shows a different pattern, with functional segregation of the sclerotic hippocampus and impairment of its long-range connectivity. This suggests that MRI-negative TLE is not merely a subtle version of hippocampal sclerosis, but is rather a separate condition that involves distinct brain networks.

Abnormal cognitive network interactions in Lennox-Gastaut syndrome: A potential mechanism of epileptic encephalopathy

In patients with Lennox‐Gastaut syndrome (LGS), recurrent epileptic activity is thought to contribute to impaired cognition (epileptic encephalopathy). Using concurrent electroencephalography‐functional magnetic resonance imaging (EEG‐fMRI), we recently showed that epileptiform discharges in LGS recruit large‐scale networks that normally support key cognitive processes. In LGS, given that epileptic activity engages cognitive networks, and cognition is pervasively impaired, we hypothesized that cognitive network interactions in LGS are persistently abnormal.

Dynamic regional phase synchrony (DRePS): an instantaneous measure of local fMRI connectivity within spatially clustered brain areas

Dynamic functional brain connectivity analysis is a fast expanding field in computational neuroscience research with the promise of elucidating brain network interactions. Sliding temporal window based approaches are commonly used in order to explore dynamic behavior of brain networks in task‐free functional magnetic resonance imaging (fMRI) data. However, the low effective temporal resolution of sliding window methods fail to capture the full dynamics of brain activity at each time point. These also require subjective decisions regarding window size and window overlap. In this study, we introduce dynamic regional phase synchrony (DRePS), a novel analysis approach that measures mean local instantaneous phase coherence within adjacent fMRI voxels. We evaluate the DRePS framework on simulated data showing that the proposed measure is able to estimate synchrony at higher temporal resolution than sliding windows of local connectivity. We applied DRePS analysis to task‐free fMRI data of 20 control subjects, revealing ultra‐slow dynamics of local connectivity in different brain areas. Spatial clustering based on the DRePS feature time series reveals biologically congruent local phase synchrony networks (LPSNs). Taken together, our results demonstrate three main findings. Firstly, DRePS has increased temporal sensitivity compared to sliding window correlation analysis in capturing locally synchronous events. Secondly, DRePS of task‐free fMRI reveals ultra‐slow fluctuations of ∼0.002–0.02 Hz. Lastly, LPSNs provide plausible spatial information about time‐varying brain local phase synchrony. With the DRePS method, we introduce a framework for interrogating brain local connectivity, which can potentially provide biomarkers of human brain function in health and disease. Hum Brain Mapp 37:1970–1985, 2016.

Tract-specific atrophy in focal epilepsy: Disease, genetics, or seizures?

To investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts.

Amygdala enlargement: Temporal lobe epilepsy subtype or nonspecific finding?

OBJECTIVE Amygdala enlargement (AE) is observed in patients with temporal lobe epilepsy (TLE), which has led to the suggestion that it represents a distinct TLE subtype; however, it is unclear whether AE is found at similar rates in other epilepsy syndromes or in healthy controls, which would limit its value as a marker for focal epileptogenicity. METHODS We compared rates of AE, defined quantitatively from high-resolution T1-weighted MRI, in a large multi-site sample of 136 patients with nonlesional localization related epilepsy (LRE), including TLE and extratemporal (exTLE) focal epilepsy, 34 patients with idiopathic generalized epilepsy (IGE), and 233 healthy controls (HCs). RESULTS AE was found in all groups including HCs; however, the rate of AE was higher in LRE (18.4%) than in IGE (5.9%) and HCs (6.4%). Patients with unilateral LRE were further evaluated to compare rates of concordant ipsilateral AE in TLE and exTLE, with the hypothesis that rates of ipsilateral AE would be higher in TLE. Although ipsilateral AE was higher in TLE (19.4%) than exTLE (10.5%), this difference was not significant. Furthermore, among the 25 patients with unilateral LRE and AE, 13 (52%) had either bilateral AE or AE contralateral to seizure onset. CONCLUSION Results suggest that AE, as defined with MRI volumetry, may represent an associated feature of nonlesional localization related epilepsy with limited seizure onset localization value.

Dynamic coupling between fMRI local connectivity and interictal EEG in focal epilepsy: A wavelet analysis approach

Simultaneous scalp EEG‐fMRI recording is a noninvasive neuroimaging technique for combining electrophysiological and hemodynamic aspects of brain function. Despite the time‐varying nature of both measurements, their relationship is usually considered as time‐invariant. The aim of this study was to detect direct associations between scalp‐recorded EEG and regional changes of hemodynamic brain connectivity in focal epilepsy through a time‐frequency paradigm. To do so, we developed a voxel‐wise framework that analyses wavelet coherence between dynamic regional phase synchrony (DRePS, calculated from fMRI) and band amplitude fluctuation (BAF) of a target EEG electrode with dominant interictal epileptiform discharges (IEDs). As a proof of concept, we applied this framework to seven patients with focal epilepsy. The analysis produced patient‐specific spatial maps of DRePS‐BAF coupling, which highlight regions with a strong link between EEG power and local fMRI connectivity. Although we observed DRePS‐BAF coupling proximate to the suspected seizure onset zone in some patients, our results suggest that DRePS‐BAF is more likely to identify wider ‘epileptic networks’. We also compared DRePS‐BAF with standard EEG‐fMRI analysis based on general linear modelling (GLM). There was, in general, little overlap between the DRePS‐BAF maps and GLM maps. However, in some subjects the spatial clusters revealed by these two analyses appeared to be adjacent, particularly in medial posterior cortices. Our findings suggest that (1) there is a strong time‐varying relationship between local fMRI connectivity and interictal EEG power in focal epilepsy, and (2) that DRePS‐BAF reflect different aspects of epileptic network activity than standard EEG‐fMRI analysis. These two techniques, therefore, appear to be complementary. Hum Brain Mapp 38:5356–5374, 2017.

Electrical stimulation of the piriform cortex for the treatment of epilepsy: A review of the supporting evidence

In this review, we consider how the piriform cortex is engaged in both focal and generalized epilepsy networks and postulate the various neural pathways that can be effectively neuromodulated by stimulation at this site. This highlights the common involvement of the piriform cortex in epilepsy. We address both current and future preclinical studies of deep brain stimulation (DBS) of the piriform cortex, with attention to the critical features of these trials that will enable them to be of greatest utility in informing clinical translation. Although recent DBS trials have utilized thalamic targets, electrical stimulation of the piriform cortex may also be a useful intervention for people with epilepsy. However, more work is required to develop a solid foundation for this approach before considering human trials.