NMDA receptor binding in focal epilepsies.

OBJECTIVE: To demonstrate altered N-methyl-d-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [(18)F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy. METHODS: Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [(18)F]GE-179 PET scan, in a cross-sectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [(18)F]GE-179 volume-of-distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping. RESULTS: Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [(18)F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [(18)F]GE-179 VT (-29%; p<0.002). There were no focal abnormalities common to the epilepsy group. CONCLUSIONS: In patients with focal epilepsies, we detected primarily global increases of [(18)F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [(18)F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy.

Defining Meyer's loop-temporal lobe resections, visual field deficits and diffusion tensor tractography.

Anterior temporal lobe resection is often complicated by superior quadrantic visual field deficits (VFDs). In some cases this can be severe enough to prohibit driving, even if a patient is free of seizures. These deficits are caused by damage to Meyer's loop of the optic radiation, which shows considerable heterogeneity in its anterior extent. This structure cannot be distinguished using clinical magnetic resonance imaging sequences. Diffusion tensor tractography is an advanced magnetic resonance imaging technique that enables the parcellation of white matter. Using seed voxels antero-lateral to the lateral geniculate nucleus, we applied this technique to 20 control subjects, and 21 postoperative patients. All patients had visual fields assessed with Goldmann perimetry at least three months after surgery. We measured the distance from the tip of Meyer's loop to the temporal pole and horn in all subjects. In addition, we measured the size of temporal lobe resection using postoperative T(1)-weighted images, and quantified VFDs. Nine patients suffered VFDs ranging from 22% to 87% of the contralateral superior quadrant. In patients, the range of distance from the tip of Meyer's loop to the temporal pole was 24-43 mm (mean 34 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -15 to +9 mm (mean 0 mm). In controls the range of distance from the tip of Meyer's loop to the temporal pole was 24-47 mm (mean 35 mm), and the range of distance from the tip of Meyer's loop to the temporal horn was -11 to +9 mm (mean 0 mm). Both quantitative and qualitative results were in accord with recent dissections of cadaveric brains, and analysis of postoperative VFDs and resection volumes. By applying a linear regression analysis we showed that both distance from the tip of Meyer's loop to the temporal pole and the size of resection were significant predictors of the postoperative VFDs. We conclude that there is considerable variation in the anterior extent of Meyer's loop. In view of this, diffusion tensor tractography of the optic radiation is a potentially useful method to assess an individual patient's risk of postoperative VFDs following anterior temporal lobe resection.

Imaging language pathways predicts postoperative naming deficits.

Naming difficulties are a well recognised, but difficult to predict, complication of anterior temporal lobe resection (ATLR) for refractory epilepsy. We used MR tractography preoperatively to demonstrate the structural connectivity of language areas in patients undergoing dominant hemisphere ATLR. Greater lateralisation of tracts to the dominant hemisphere was associated with greater decline in naming function. We suggest that this method has the potential to predict language deficits in patients undergoing ATLR.

Preoperative fMRI predicts memory decline following anterior temporal lobe resection.

BACKGROUND: Anterior temporal lobe resection (ATLR) benefits many patients with refractory temporal lobe epilepsy (TLE) but may be complicated by material specific memory impairments, typically of verbal memory following left ATLR, and non-verbal memory following right ATLR. Preoperative memory functional MRI (fMRI) may help in the prediction of these deficits. OBJECTIVE: To assess the value of preoperative fMRI in the prediction of material specific memory deficits following both left- and right-sided ATLR. METHODS: We report 15 patients with unilateral TLE undergoing ATLR; eight underwent dominant hemisphere ATLR and seven non-dominant ATLR. Patients performed an fMRI memory paradigm which examined the encoding of words, pictures and faces. RESULTS: Individual patients with relatively greater ipsilateral compared with contralateral medial temporal lobe activation had greater memory decline following ATLR. This was the case for both verbal memory decline following dominant ATLR and for non-verbal memory decline following non-dominant ATLR. For verbal memory decline, activation within the dominant hippocampus was predictive of postoperative memory change whereas activation in the non-dominant hippocampus was not. CONCLUSION: These findings suggest that preoperative memory fMRI may be a useful non-invasive predictor of postoperative memory change following ATLR and provide support for the functional adequacy theory of hippocampal function. They also suggest that fMRI may provide additional information, over that provided by neuropsychology, for use in the prediction of postoperative memory decline.

Combined EEG-fMRI and tractography to visualise propagation of epileptic activity.

In a patient with refractory temporal lobe epilepsy, EEG-fMRI showed activation in association with left anterior temporal interictal discharges, in the left temporal, parietal and occipital lobes. Dynamic causal modelling suggested propagation of neural activity from the temporal focus to the area of occipital activation. Tractography showed connections from the site of temporal lobe activation to the site of occipital activation. This demonstrates the principle of combining EEG-fMRI and tractography to delineate the pathways of propagation of epileptic activity.

T2 relaxometry of the hippocampus at 3T.

BACKGROUND AND PURPOSE: T2 mapping is useful for identifying and quantifying abnormalities of the hippocampus and amygdala. It is particularly useful in the presurgical evaluation of patients with temporal lobe epilepsy and for the identification of bilateral hippocampal sclerosis (HS). The purpose of this study was to implement and validate a dual-echo method for producing coronal T2 maps with complete coverage of the hippocampus and the rest of the brain on a 3T MR imaging scanner. MATERIALS AND METHODS: T2 relaxation times were estimated on 10 occasions on 3 quality assessment Eurospin II (Diagnostic Sonar, Livingstone, Scotland) test objects with the use of conventional spin-echo (CSE), fast spin-echo, and fast recovery fast spin-echo (FRFSE) sequences on a 3T Excite MR imaging scanner (GE Healthcare, Milwaukee, Wis). Hippocampal T2 relaxation times were then measured in 15 healthy subjects and 20 subjects with clear-cut HS who were scanned at 1.5 T with a previously validated dual-echo CSE sequence and 3T with an FRFSE sequence. RESULTS: 3T FRFSE data were as reliable as CSE data at 1.5 T. Reliability of hippocampal T2 measures was good on healthy volunteers and subjects with HS. FRFSE images were suitable for qualitative radiologic reporting and with complete brain coverage, so no additional T2-weighted sequences were required. There was good correlation between the 3T hippocampal T2 measurements and values obtained with the previously validated technique at 1.5 T, with reliable identification of all of the subjects with HS. CONCLUSIONS: T2 mapping with an FRFSE 30/80 sequence may be readily applied at 3T and can produce reliable T2 values in vivo with contiguous 5-mm sections and in a much reduced scan time of 3 minutes 1 second compared with 10 minutes 30 seconds for the CSE sequence at 1.5 T.

Magnetization transfer ratio in Alzheimer disease: comparison with volumetric measurements.

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is accompanied by macroscopic atrophy on volumetric MR imaging. A few studies have also demonstrated reduction in magnetization transfer ratio (MTR), suggesting microstructural changes in remaining brain tissue. This study assessed the value of measuring MTR in addition to volumetric MR in differentiating patients with AD from control subjects. MATERIALS AND METHODS: Volumetric T1-weighted images and 3D MTR maps were obtained from 18 patients with AD and 18 age-matched control subjects. Whole-brain (WB) and total hippocampal (Hc) volumes were measured using semiautomated techniques and adjusted for total intracranial volume. Mean MTR was obtained for WB and in the Hc region. Histogram analysis was performed for WB MTR. Among patients, associations between volumetric and MTR parameters and the Mini-Mental State Examination (MMSE) were explored. RESULTS: Patients with AD had significantly reduced WB volume (P<.0001) and mean WB MTR (P=.002) and Hc volume (P<.0001) and Hc mean MTR (P<.0001) compared with control subjects. Histogram analysis of WB MTR revealed significant reduction in the 25th percentile point in patients with AD (P=.03). Both WB volume and mean MTR were independently associated with case-control status after adjusting for the other using linear regression models. However, measuring Hc mean MTR added no statistically significant discriminatory value over and above Hc volume measurement alone. Of all MR imaging parameters, only WB volume was significantly correlated with MMSE (r=0.47, P=.048). CONCLUSIONS: This study demonstrates the independent reduction of WB volume and mean MTR in AD. This suggests that the 2 parameters reflect complementary aspects of the AD pathologic lesion at macrostructural and microstructural levels.

The relationship between the apparent diffusion coefficient measured by magnetic resonance imaging, anoxic depolarization, and glutamate efflux during experimental cerebral ischemia.

A reduction in the apparent diffusion coefficient (ADC) of water measured by magnetic resonance imaging (MRI) has been shown to occur early after cerebrovascular occlusion. This change may be a useful indicator of brain tissue adversely affected by inadequate blood supply. The objective of this study was to test the hypothesis that loss of membrane ion homeostasis and depolarization can occur simultaneously with the drop in ADC. Also investigated was whether elevation of extracellular glutamate ([GLU]e) would occur before ADC changes. High-speed MRI of the trace of the diffusion tensor (15-second time resolution) was combined with simultaneous recording of the extracellular direct current (DC) potential and on-line [GLU]e from the striatum of the anesthetized rat. After a control period, data were acquired during remote middle cerebral artery occlusion for 60 minutes, followed by 30 minutes of reperfusion, and cardiac arrest-induced global ischemia. After either focal or global ischemia, the ADC was reduced by 10 to 25% before anoxic depolarization occurred. After either insult, the time for half the maximum change in ADC was significantly shorter than the corresponding DC potential parameter (P < 0.05). The [GLU]e remained at low levels during the entire period of varying ADC and DC potential and did not peak until much later after either ischemic insult. This study demonstrates that ADC changes can occur before membrane depolarization and that high [GLU]e has no involvement in the early rapid ADC decrease.

Serial magnetization transfer imaging to characterize the early evolution of new MS lesions.

OBJECTIVE: To explore the temporal relation of demyelination and blood-brain barrier breakdown during new lesion formation. BACKGROUND: Conventional MRI appears sensitive for detecting changes due to MS, but may be limited by poor pathologic specificity. By indirectly assessing protons bound to rigid macromolecules, magnetization transfer (MT) imaging may provide information relating to tissue structure and, by inference, myelin integrity. METHODS: Gadolinium contrast-enhanced MRI and MT imaging were performed at weekly intervals for 3 months in three patients with MS. For each enhancing lesion, the largest corresponding area of proton density hyperintensity seen during the study was outlined and magnetization transfer ratio (MTR) calculated at each time point from coregistered calculated MTR images. Lesions greater than 20 mm2, not affected by partial volume effects, and first enhancing after the baseline study were analyzed. Two-dimensional registration software allowed accurate evaluation of MTR in regions both before and after the initial appearance of MS lesions. RESULTS: Mean lesion MTR decreased significantly during the first week of enhancement (29.6 percent units [pu] immediately pre-enhancement versus 28.2 pu at first documented stage of enhancement). No significant MTR reduction was noted before this. CONCLUSION: The lack of observable change in MTR before the first detectable gadolinium enhancement within MS lesions suggests that blood-brain barrier disruption is closely related to, but not preceded by, demyelination.

Investigating regional white matter in schizophrenia using diffusion tensor imaging.

Diffusion tensor imaging (DTI) was used to investigate regional white matter in vivo in patients with schizophrenia. DTI is capable of providing information about the organization of white matter tracts and has only recently been used to study schizophrenia. In this study, a voxel based analysis of DTI maps in 14 patients and 19 controls did not reveal any areas of significant differences in DTI measures in white matter. The findings suggest that the structural integrity of white matter in these patients was not disrupted. These results are discussed in relation to previous studies reporting positive findings. It is concluded that further studies using DTI in larger samples, improved and standardised methods of data acquisition and analysis are needed.

Reproducible localization of interictal epileptiform discharges using EEG-triggered fMRI.

We report preliminary experiences using fMRI triggered by EEG to localize the site of interictal epileptiform activity. EEG was recorded in the scanner and monitored on-line; the recording quality was good enough to allow the clear identification of spikes in the EEG. Snap-shot EPI was performed 2-4 s after an epileptiform discharge ('spike') or after at least 10 s of background activity ('rest') was observed. A pixel-by-pixel t-test was performed between the 'rest' and the 'spike' images to determine areas of significant activation. Significant activation was obtained in a patient with epilepsy. To assess the reliability and reproducibility of the technique, the patient was scanned on four separate occasions with similar areas being activated in all the studies, confirming the validity of the result.

Water diffusion in the human hippocampus in epilepsy.

The hippocampus plays a central role in the generation and propagation of seizures in patients with complex partial seizures. Hippocampal sclerosis (HS) is a common structural abnormality in patients with refractory epilepsy. The aim of this study was to quantify diffusion in the hippocampus in patients with epilepsy to evaluate the diffusion changes associated with HS. We scanned 20 subjects (14 patients and 6 controls) with a 1.5T magnetic resonance (MR) system using a cardiac-gated, navigated spin-echo diffusion-weighted sequence. Hippocampal ADC measurements were performed on maps of the ADC measured in three orthogonal directions labeled x, y, and z. The mean ADC (ADCav) and an anisotropy index (AI) were calculated. Hippocampi which fulfilled the MR criteria for HS had a higher ADCav (p < 0.001) and a lower AI (p=0.04) than normal appearing hippocampi in patients and hippocampi in controls. These results imply a loss of structural organization in sclerotic hippocampi and an expansion of the extracellular space. Quantitative measurements of diffusion can be used as an independent parameter for the identification and characterization of abnormal hippocampi in epilepsy.

Reduced anisotropy of water diffusion in structural cerebral abnormalities demonstrated with diffusion tensor imaging.

We used diffusion tensor imaging (DTI) to investigate the behavior of water diffusion in cerebral structural abnormalities. The fractional anisotropy, a measure of directionality of the molecular motion of water, and the mean diffusivity, a measure of the magnitude of the molecular motion of water, were measured in 18 patients with longstanding partial epilepsy and structural abnormalities on standard magnetic resonance imaging and the results compared with measurements in the white matter of 10 control subjects. Structural abnormalities were brain damage (postsurgical brain damage, nonspecific brain damage, perinatal brain damage, perinatal infarct, ischemic infarct, perinatal hypoxia, traumatic brain damage (n = 3), mitochondrial cytopathy and mesiotemporal sclerosis), dysgenesis (cortical dysplasia (n = 2) and heterotopia) and tumors (meningioma (n = 2), hypothalamic hamartoma and glioma). Anisotropy was reduced in all structural abnormalities. In the majority of abnormalities this was associated with an increased mean diffusivity; however, 30% of all structural abnormalities (some patients with brain damage and dysgenesis) had a normal mean diffusivity in combination with a reduced anisotropy. There was no correlation between fractional anisotropy and mean diffusivity measurements in structural abnormalities (r = -0.1). Our findings suggest that DTI is sensitive for the detection of a variety of structural abnormalities, that a reduced anisotropy is the common denominator in structural cerebral abnormalities of different etiologies and that mean diffusivity and fractional anisotropy may be, in part, independent. Combined measurements of mean diffusivity and fractional anisotropy are likely to increase the specificity of DTI.

Spatio-temporal imaging of focal interictal epileptiform activity using EEG-triggered functional MRI.

EEG-triggered, blood oxygen level-dependent functional MRI (BOLD-fMRI) was used in 24 patients with localization-related epilepsy and frequent interictal epileptiform discharges (spikes) to identify those brain areas involved in generating the spikes, and to study the evolution of the BOLD signal change over time. The location of the fMRI activation was compared with the scalp EEG spike focus and the structural MR abnormality. Twelve patients (50%) had an fMRI activation concordant with the EEG focus and structural brain abnormalities where present (n = 7). In 2 other patients, the fMRI activation was non-concordant with electroclinical findings. The remaining 10 patients (41.7%) showed no significant fMRI activation. These patients had significantly lower mean spike amplitudes compared to those with positive fMRI results (p = 0.03). The time course of the BOLD response was studied in 3 patients and this revealed a maximum signal change 1.5 to 7.5 sec after the spike. In conclusion, EEG-triggered fMRI can directly identify the generators of interictal epileptiform activity, with high spatial resolution, in selected patients with frequent spikes. The superior spatial resolution obtainable through EEG-triggered fMRI may provide an additional non-invasive tool in the presurgical evaluation of patients with intractable focal seizures.

Structural changes in the temporal lobe and piriform cortex in frontal lobe epilepsy.

BACKGROUND: Neuronal networks involved in seizure generation, maintenance and spread of epileptic activity comprise cortico-subcortical circuits. Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common structures in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity. In this study, we aimed to identify common areas of structural abnormalities in patients with frontal lobe epilepsy (FLE). METHODS: T1-weighted MRI scans of 43 FLE patients and 25 healthy controls were analysed using voxel based morphometry. Differences in regional grey matter volume were examined across the whole brain, and correlated with age at epilepsy onset, duration and frequency of seizures. RESULTS: We detected areas of increased grey matter volume in the piriform cortex, amygdala and parahippocampal gyrus bilaterally, as well as left mid temporal gyrus of patients relative to controls, which did not correlate with any of the clinical variables tested. No common areas of atrophy were detected across the FLE group. CONCLUSIONS: Structural abnormalities within the piriform cortex and adjacent structures of patients with FLE provide further evidence for the involvement of this area in the epileptogenic network of focal epilepsies. Lack of correlation with duration or age of onset of epilepsy suggests that this area of abnormality is not a consequence of seizure activity.

Development of a high-resolution fat and CSF-suppressed optic nerve DTI protocol at 3T: application in multiple sclerosis.

Clinical trials of neuroprotective interventions in multiple sclerosis require outcome measures that reflect the disease pathology. Measures of neuroaxonal integrity in the anterior visual pathways are of particular interest in this context, however imaging of the optic nerve is technically challenging. We therefore developed a 3T optic nerve diffusion tensor imaging protocol incorporating fat and cerebrospinal fluid suppression and without parallel imaging. The sequence used a scheme with six diffusion-weighted directions, b = 600 smm(-2) plus one b ≈ 0 (b(0)) and 40 repetitions, averaged offline, giving an overall scan time of 30 minutes. A coronal oblique orientation was used with voxel size 1.17 mm x 1.17 mm x 4 mm, We validated the sequence in 10 MS patients with a history of optic neuritis and 11 healthy controls: mean fractional anisotropy was reduced in the patients: 0.346(±0.159) versus 0.528(±0.123), p<0.001; radial diffusivity was increased: 0.940(±0.370)x10(-6) mm(2) s(-1) compared to 0.670(± 0.221)x10(-6) mm(2) s(-1) (p<0.01). No significant differences were seen for mean diffusivity or mean axial diffusivity.

Disrupted segregation of working memory networks in temporal lobe epilepsy.

Working memory is a critical building block for almost all cognitive tasks, and impairment can cause significant disruption to daily life routines. We investigated the functional connectivity (FC) of the visuo-spatial working memory network in temporal lobe epilepsy and its relationship to the underlying white matter tracts emanating from the hippocampus. Fifty-two patients with unilateral hippocampal sclerosis (HS) (30 left) and 30 healthy controls underwent working memory functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). Six seed regions were identified for FC analysis; 4 within a task-positive network (left and right middle frontal gyri and superior parietal lobes), and 2 within a task-negative network (left and right hippocampi). FC maps were created by extracting the time-series of the fMRI signal in each region in each subject and were used as regressors of interest for additional GLM fMRI analyses. Structural connectivity (SC) corresponding to areas to which the left and right hippocampi were connected was determined using tractography, and a mean FA for each hippocampal SC map was calculated. Both left and right HS groups showed atypical FC between task-positive and task-negative networks compared to controls. This was characterised by co-activation of the task-positive superior parietal lobe ipsilateral to the typically task-negative sclerosed hippocampus. Correlational analysis revealed stronger FC between superior parietal lobe and ipsilateral hippocampus, was associated with worse performance in each patient group. The SC of the hippocampus was associated with the intra-hemispheric FC of the superior parietal lobe, in that greater SC was associated with weaker parieto-frontal FC. The findings suggest that the segregation of the task-positive and task-negative FC networks supporting working memory in TLE is disrupted, and is associated with abnormal structural connectivity of the sclerosed hippocampus. Co-activation of parieto-temporal regions was associated with poorer working memory and this may be associated with working memory dysfunction in TLE.

Altered microstructural connectivity in juvenile myoclonic epilepsy: the missing link.

OBJECTIVES: Juvenile myoclonic epilepsy (JME) is characterized by myoclonic jerks of the upper limbs, often triggered by cognitive stressors. Here we aim to reconcile this particular seizure phenotype with the known frontal lobe type neuropsychological profile, photosensitivity, hyperexcitable motor cortex, and recent advanced imaging studies that identified abnormal functional connectivity of the motor cortex and supplementary motor area (SMA). METHODS: We acquired fMRI and diffusion tensor imaging (DTI) in a cohort of 29 patients with JME and 28 healthy control subjects. We used fMRI to determine functional connectivity and DTI-based region parcellation and voxel-wise comparison of probabilistic tractography data to assess the structural connectivity profiles of the mesial frontal lobe. RESULTS: Patients with JME showed alterations of mesial frontal connectivity with increased structural connectivity between the prefrontal cognitive cortex and motor cortex. We found a positive correlation between DTI and fMRI-based measures of structural and functional connectivity: the greater the structural connectivity between these 2 regions, the greater the observed functional connectivity of corresponding areas. Furthermore, connectivity was reduced between prefrontal and frontopolar regions and increased between the occipital cortex and the SMA. CONCLUSION: The observed alterations in microstructural connectivity of the mesial frontal region may represent the anatomic basis for cognitive triggering of motor seizures in JME. Changes in the mesial frontal connectivity profile provide an explanatory framework for several other clinical observations in JME and may be the link between seizure semiology, neurophysiology, neuropsychology, and imaging findings in JME.

Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy.

OBJECTIVE: The aim of this study was to determine if there were focal cortical abnormalities in juvenile myoclonic epilepsy (JME) using neuropsychological investigations and MRI. METHODS: Twenty-eight patients with JME and a large sample of healthy controls were assessed using a series of neuropsychological tests as well as structural and diffusion tensor MRI (DTI). DTI measures assessed fractional anisotropy (FA) within a white matter skeleton. RESULTS: Neuropsychological testing indicated subtle dysfunctions in verbal fluency, comprehension, and expression, as well as nonverbal memory and mental flexibility. Utilizing whole-brain voxel-based morphometry for gray matter MRI data and tract-based spatial statistics for white matter diffusion MRI data, we found reductions in gray matter volume (GMV) in the supplementary motor area and posterior cingulate cortex and reductions in FA in underlying white matter of the corpus callosum. Supplementary motor area FA predicted scores in word naming tasks and expression scores. Posterior cingulate cortex GMV and FA predicted cognitive inhibition scores on the mental flexibility task. CONCLUSIONS: The neuropsychological, structural, and tractography results implicate mesial frontal cortex, especially the supplementary motor area, and posterior cingulate cortex in JME.