Simon S. Keller

Voxel-based morphometry of temporal lobe epilepsy : An introduction and review of the literature

We review the applications and results of voxel‐based morphometry (VBM) studies that have reported brain changes associated with temporal lobe epilepsy (TLE). A PubMed search yielded 18 applications of VBM to study brain abnormalities in patients with TLE up to May 2007. Across studies, 26 brain regions were found to be significantly reduced in volume relative to healthy controls. There was a strong asymmetrical distribution of temporal lobe abnormalities preferentially observed ipsilateral to the seizure focus, particularly of the hippocampus (82.35% of all studies), parahippocampal gyrus (47.06%), and entorhinal (23.52%) cortex. The contralateral hippocampus was reported as abnormal in 17.65% of studies. There was a much more bilateral distribution of extratemporal lobe atrophy, preferentially affecting the thalamus (ipsilateral = 61.11%, contralateral = 50%) and parietal lobe (ipsilateral = 47.06%, contralateral = 52.94%). VBM generally reveals a distribution of brain abnormalities in patients with TLE consistent with the region‐of‐interest neuroimaging and postmortem literature. It is unlikely that VBM has any clinical utility given the lack of robustness for individual comparisons. However, VBM may help elucidate some unresolved important research questions such as how recurrent temporal lobe seizures affect hippocampal and extrahippocampal morphology using serial imaging acquisitions.

Voxel-based morphometric comparison of hippocampal and extrahippocampal abnormalities in patients with left and right hippocampal atrophy.

We used voxel-based morphometry (VBM), an automatic whole-brain MR image analysis technique, to investigate gray matter abnormalities in patients with temporal lobe epilepsy (TLE), in whom hippocampal atrophy (HA) was demonstrated by application of the Cavalieri method of modern design stereology. VBM results (P < 0.05, corrected) indicated preferential gray matter concentration (GMC) reduction in anterior hippocampus in patients with left HA and posterior hippocampus in patients with right HA. GMC reduction was also found in right dorsal prefrontal cortex in left and right HA patients. Prefrontal atrophy may be due to epileptiform excitotoxic discharges from the reciprocally connected pathological hippocampus, and may be the underlying biological cause for executive dysfunction in patients with TLE. GMC excess in ipsilateral parahippocampal, cerebellar, and pericallosal regions was common to both left and right HA groups relative to controls, and is hypothesized to reflect diminished gray-white matter demarcation, underlying white matter atrophy, or structural displacement due to cerebrospinal fluid expansion. However, bilateral temporal lobe GMC excess was observed in left HA patients, while ipsilateral temporal lobe GMC excess was observed in right HA patients. This work demonstrates methodological consistency between automated VBM and manual stereological analysis of the hippocampus in group comparisons, indicates widespread extrahippocampal gray matter abnormalities in unilateral HA, and suggests that there may be inherent differences in the effect of TLE on temporal lobe structures depending on the side of HA.

Voxel based morphometry of grey matter abnormalities in patients with medically intractable temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration

Objectives: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine the relation between side, duration, and age of onset of temporal lobe epilepsy, history of childhood febrile convulsions, and grey matter structure. Methods: Three dimensional magnetic resonance images were obtained from 58 patients with left sided seizure onset (LSSO) and 58 patients with right sided seizure onset (RSSO), defined using EEG and foramen ovale recordings in the course of presurgical evaluation for temporal lobectomy. Fifty eight normal controls formed a comparison group. VBM was used to characterise whole brain grey matter concentration, while the Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal and amygdala volume. Age and sex were used as confounding covariates in analyses. Results: LSSO and RSSO patients showed significant reductions in volume (using stereology) and grey matter concentration (using VBM) of the hippocampus, but not of the amygdala, in the presumed epileptogenic zone when compared with controls, but hippocampal (and amygdala) volume and grey matter concentration were not related to duration or age of onset of epilepsy. LSSO and RSSO patients with a history of childhood febrile convulsions had reduced hippocampal volumes in the presumed epileptogenic zone compared with patients without such a history. Left amygdala volume was also reduced in LSSO patients with a history of childhood convulsions. VBM results indicated bilateral thalamic, prefrontal, and cerebellar GMC reduction in patients, which correlated with duration and age of onset of epilepsy. Conclusions: Hippocampal sclerosis is not necessarily the consequence of recurrent temporal lobe seizures. A major cause of hippocampal sclerosis appears to be an early aberrant neurological insult, such as childhood febrile seizures. Secondary brain abnormalities exist in regions outside the presumed epileptogenic zone and may result from recurrent seizures.

Broca's area : Nomenclature, anatomy, typology and asymmetry

In this review, we (i) describe the nomenclature of Brocas area and show how the circumscribed definition of Brocas area is disassociated from Brocas aphasia, (ii) describe in detail how the gross anatomy of Brocas area varies between people, and how the definitions vary between studies, (iii) attempt to reconcile the findings of structural asymmetry of Brocas area with the differences in methodological approaches, (iv) consider the functional significance of cytoarchitectonic definitions of Brocas area, and (v) critically elucidate the significance of circumscribed regions of cortex for language lateralisation and language development. Contrary to what has previously been reported in the literature, asymmetry of Brocas area has not been reproducibly demonstrated, particularly on a gross morphological level. This may be due to major inconsistencies in methodology (including different anatomical boundaries, measurement techniques and samples studied) or that the sulcal contours defining Brocas area are so naturally variable between people making a standard definition difficult. Cytoarchitectonic analyses more often than not report leftward asymmetry of some component of area 44 and/or area 45. If a structural asymmetry of Brocas area does exist, it is variable, which differs from that of the functional asymmetry of language, which is more consistent. One reason for this might be that the link between cellular architecture, connectivity and language function still remains to be elucidated. There is currently no convincing explanation to associate asymmetry of Brocas area with the lateralisation of language.

Comparison of standard and optimized voxel-based morphometry for analysis of brain changes associated with temporal lobe epilepsy

We compared statistical parametric maps (SPMs) of group-wise regional gray matter differences between temporal lobe epilepsy (TLE) patients with unilateral hippocampal atrophy (HA) determined by manual volumetric analysis relative to a healthy control population using standard and optimized voxel-based morphometry (VBM). We also investigated the impact of customized neuroanatomical templates on SPMs. Standard and optimized VBM analyses of gray matter concentration (GMC) and gray matter volume (GMV) correctly identified HA, regardless of the template used for normalization. The distribution of hippocampal and extrahippocampal abnormalities differed according to the technique (standard v optimized; GMC v GMV), but was not dependent on template type (default v customized) within each technique. In particular, hippocampal GMC reduction was confined to subregions of hippocampus, whereas GMV reduction was observed in the hippocampal head, body, and tail. Unlike standard and optimized GMC reduction, symmetrical GMV reduction was observed in bilateral thalamus, lenticular nuclei, cerebellum, and ipsilateral entorhinal cortex, perirhinal cortex, and fusiform gyrus in both left and right HA patients. These results show that group-wise SPMs of GMC (i.e., regional distribution of gray matter) and GMV (i.e., volume per se) reduction can identify focal atrophy that has been quantified with manual region of interest techniques, although effects are attenuated in analyses of GMC. Unlike SPMs of GMC, analyses of GMV revealed similar extrahippocampal abnormalities as previous region-of-interest volumetric and histopathological studies of intractable TLE. We suggest that in studies of neurological disorders, optimized VBM analyses of GMV may reveal subtle neuroanatomical changes that are not identified in analyses of GMC.

Nerve fiber impairment of anterior thalamocortical circuitry in juvenile myoclonic epilepsy

Background: Juvenile myoclonic epilepsy (JME) is a syndrome of idiopathic generalized epilepsy (IGE) without structural brain abnormalities detectable by MRI or CT. Objective: In the present study, we addressed the question of whether diffusion tensor MRI (DTI) can detect disease-specific white matter (WM) abnormalities in patients with JME. Methods: We performed whole head DTI at 3 T in 10 patients with JME, 8 age-matched patients with cryptogenic partial epilepsy (CPE), and 67 age-matched healthy volunteers. Nerve fiber integrity was compared between the groups on the basis of optimized voxel-by-voxel statistics of fractional anisotropy (FA) maps obtained by DTI (analysis of covariance, categorical factor “group,” covariate “age”). Results: FA was reduced in a WM region associated with the anterior thalamus and prefrontal cortex in patients with JME compared to both control subjects and patients with CPE (p < 0.001). The patients with CPE showed normal values in this particular WM region. The FA reductions in the patients with JME correlated with the frequency of generalized tonic-clonic seizures (Spearman R = 0.54, p = 0.05). No significant correlations were found in the JME sample between FA reduction and the duration of antiepileptic medication. Conclusions: The results support the hypothesis that juvenile myoclonic epilepsy is associated with abnormalities of the thalamocortical network that can be detected by diffusion tensor MRI. CPE = cryptogenic partial epilepsy; DTI = diffusion tensor imaging; EPI = echoplanar imaging; FA = fractional anisotropy; GMC = gray matter concentration; GTCS = generalized tonic-clonic seizures; IGE = idiopathic generalized epilepsy; JME = juvenile myoclonic epilepsy; MNI = Montreal Neurological Institute; ROI = region of interest; VBM = voxel based morphometry; WM = white matter.

Voxel-based morphometry and stereology provide convergent evidence of the importance of medial prefrontal cortex for fluid intelligence in healthy adults

We investigated whether a relationship exists between frontal lobe volume and fluid intelligence as measured by both Cattells Culture Fair test and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Performance scale, but not with crystallized intelligence as measured by the WAIS-R Verbal scale, in healthy adults, using two well-established image analysis techniques applied to high-resolution MR brain images. Firstly, using voxel-based morphometry (VBM), we investigated whether a significant relationship exists between gray matter concentration and fluid intelligence on a voxel-by-voxel basis. Secondly, we applied the Cavalieri method of modern design stereology in combination with point counting to investigate possible relationships between macroscopic volumes of relevant brain regions defined as dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex on the basis of neuroanatomical landmarks, and fluid intelligence. We also examined the effect on these relationships of normalizing regional brain volumes to intracranial volume. VBM analysis revealed a positive correlation between gray matter concentration in the medial region of prefrontal cortex and Culture Fair scores (corrected for multiple comparisons), and also WAIS-R Performance Intelligence sum of scaled scores (SSS) (uncorrected for multiple comparisons before controlling for age, and this converges with the stereological finding of the positive correlation between volume of dorsomedial prefrontal cortex normalized to intracranial volume and Culture Fair scores after controlling for age. WAIS-R Verbal Intelligence SSS showed no correlations. We interpret our findings, from independent analyses of both VBM and stereology, as evidence of the importance of medial prefrontal cortex in supporting fluid intelligence.

Sulcal variability, stereological measurement and asymmetry of Broca's area on MR images.

Leftward volume asymmetry of the pars opercularis and pars triangularis may exist in the human brain, frequently referred to as Brocas area, given the functional asymmetries observed in this region with regard to language expression. However, post‐mortem and magnetic resonance imaging (MRI) studies have failed to consistently identify such a volumetric asymmetry. In the present study, an analysis of the asymmetry of sulco‐gyral anatomy and volume of this anterior speech region was performed in combination with an analysis of the morphology and volume asymmetry of the planum temporale, located within the posterior speech region, in 50 healthy subjects using MRI. Variations in sulcal anatomy were documented according to strict classification schemes and volume estimation of the grey matter within the brain structures was performed using the Cavalieri method of stereology. Results indicated great variation in the morphology of and connectivity between the inferior frontal, inferior precentral and diagonal sulci. There were significant inter‐hemispheric differences in the presence of (1) the diagonal sulcus within the pars opercularis, and (2) horizontal termination of the posterior Sylvian fissure (relative to upward oblique termination), both with an increased leftward incidence. Double parallel inferior precentral sulci and absent anterior rami of the Sylvian fissure prevented stereological measurements in five subjects. Therefore volumes were obtained from 45 subjects. There was a significant leftward volume asymmetry of the pars opercularis (P = 0.02), which was significantly related to the asymmetrical presence of the diagonal sulcus (P < 0.01). Group‐wise pars opercularis volume asymmetry did not exist when a diagonal sulcus was present in both or neither hemispheres. There was no significant volume asymmetry of the pars triangularis. There was a significant leftward volume asymmetry of the planum temporale (P < 0.001), which was significantly associated with the shape of the posterior Sylvian fissure as a unilateral right or left upward oblique termination was always associated with leftward or rightward volume asymmetry respectively (P < 0.01). There was no relationship between volume asymmetries of the anterior and posterior speech regions. Our findings illustrate the extent of morphological variability of the anterior speech region and demonstrate the difficulties encountered when determining volumetric asymmetries of the inferior frontal gyrus, particularly when sulci are discontinuous, absent or bifid. When the intrasulcal grey matter of this region is exhaustively sampled according to strict anatomical landmarks, the volume of the pars opercularis is leftward asymmetrical. This manuscript illustrates the importance of simultaneous consideration of brain morphology and morphometry in studies of cerebral asymmetry.

Concomitant fractional anisotropy and volumetric abnormalities in temporal lobe epilepsy: cross-sectional evidence for progressive neurologic injury.

Background In patients with temporal lobe epilepsy and associated hippocampal sclerosis (TLEhs) there are brain abnormalities extending beyond the presumed epileptogenic zone as revealed separately in conventional magnetic resonance imaging (MRI) and MR diffusion tensor imaging (DTI) studies. However, little is known about the relation between macroscopic atrophy (revealed by volumetric MRI) and microstructural degeneration (inferred by DTI). Methodology/Principal Findings For 62 patients with unilateral TLEhs and 68 healthy controls, we determined volumes and mean fractional anisotropy (FA) of ipsilateral and contralateral brain structures from T1-weighted and DTI data, respectively. We report significant volume atrophy and FA alterations of temporal lobe, subcortical and callosal regions, which were more diffuse and bilateral in patients with left TLEhs relative to right TLEhs. We observed significant relationships between volume loss and mean FA, particularly of the thalamus and putamen bilaterally. When corrected for age, duration of epilepsy was significantly correlated with FA loss of an anatomically plausible route - including ipsilateral parahippocampal gyrus and temporal lobe white matter, the thalamus bilaterally, and posterior regions of the corpus callosum that contain temporal lobe fibres - that may be suggestive of progressive brain degeneration in response to recurrent seizures. Conclusions/Significance Chronic TLEhs is associated with interrelated DTI-derived and volume-derived brain degenerative abnormalities that are influenced by the duration of the disorder and the side of seizure onset. This work confirms previously contradictory findings by employing multi-modal imaging techniques in parallel in a large sample of patients.

Microstructural and volumetric abnormalities of the putamen in juvenile myoclonic epilepsy

Purpose:  Patients with juvenile myoclonic epilepsy (JME) show evidence of microstructural white matter (WM) damage of thalamocortical fiber tracts and changes of blood oxygen level dependent (BOLD) signal in a striatothalamocortical network. The objective of the present study was to investigate microstructural and volumetric alterations of the putamen in patients with JME using diffusion tensor imaging (DTI) and conventional magnetic resonance imaging (MRI).