Integration of multimodal MRI data via PCA to explain language performance.

OBJECTIVE/METHODS: Neuroimaging research has predominantly focused on exploring how cortical or subcortical brain abnormalities are related to language dysfunction in patients with neurological disease through the use of single modality imaging. Still, limited knowledge exists on how various MRI measures relate to each other and to patients' language performance. In this study, we explored the relationship between measures of regional cortical thickness, gray-white matter contrast (GWMC), white matter diffusivity [mean diffusivity (MD) and fractional anisotropy (FA)] and the relative contributions of these MRI measures to predicting language function across patients with temporal lobe epilepsy (TLE) and healthy controls. T1- and diffusion-weighted MRI data were collected from 56 healthy controls and 52 patients with TLE. By focusing on frontotemporal regions implicated in language function, we reduced each domain of MRI data to its principal component (PC) and quantified the correlations among these PCs and the ability of these PCs to explain the variation in vocabulary, naming and fluency. We followed up our significant findings by assessing the predictive power of the implicated PCs with respect to language impairment in our sample. RESULTS: We found significant positive associations between PCs representing cortical thickness, GWMC and FA that appeared to be partially mediated by changes in total brain volume. We also found a significant association between reduced FA and increased MD after controlling for confounding factors (e.g., age, field strength, total brain volume). Reduced FA was significantly associated with reductions in visual naming while increased MD was associated with reductions in auditory naming scores, even after controlling for the variability explained by reductions in hippocampal volumes. Inclusion of FA and MD PCs in predictive models of language impairment resulted in significant improvements in sensitivity and specificity of the predictions. CONCLUSIONS: Quantitative MRI measures from T1 and diffusion-weighted scans are unlikely to represent perfectly orthogonal vectors of disease in individuals with epilepsy. On the contrary, they exhibit highly intercorrelated PCs in their factor structures, which is consistent with an underlying pathological process that affects both the cortical and the subcortical structures simultaneously. In addition to hippocampal volume, the PCs of diffusion weighted measures (FA and MD) increase the sensitivity and specificity for determining naming impairment in patients with TLE. These findings underline the importance of combining multimodal imaging measures to better predict language performance in TLE that could extend to other patients with prominent language impairments.

Role of frontotemporal fiber tract integrity in task-switching performance of healthy controls and patients with temporal lobe epilepsy.

The objective of this study is to investigate the relationships among frontotemporal fiber tract compromise and task-switching performance in healthy controls and patients with temporal lobe epilepsy (TLE). We performed diffusion tensor imaging (DTI) on 30 controls and 32 patients with TLE (15 left TLE). Fractional anisotropy (FA) was calculated for four fiber tracts [uncinate fasciculus (UncF), arcuate fasciculus (ArcF), dorsal cingulum (CING), and inferior fronto-occipital fasciculus (IFOF)]. Participants completed the Trail Making Test-B (TMT-B) and Verbal Fluency Category Switching (VFCS) test. Multivariate analyses of variances (MANOVAs) were performed to investigate group differences in fiber FA and set-shifting performances. Canonical correlations were used to examine the overall patterns of structural-cognitive relationships and were followed by within-group bivariate correlations. We found a significant canonical correlation between fiber FA and task-switching performance. In controls, TMT-B correlated with left IFOF, whereas VFCS correlated with FA of left ArcF and left UncF. These correlations were not significant in patients with TLE. We report significant correlations between frontotemporal fiber tract integrity and set-shifting performance in healthy controls that appear to be absent or attenuated in patients with TLE. These findings suggest a breakdown of typical structure-function relationships in TLE that may reflect aberrant developmental or degenerative processes.

Changes in fiber tract integrity and visual fields after anterior temporal lobectomy.

OBJECTIVE: To investigate postoperative changes in fiber tract integrity in patients with temporal lobe epilepsy (TLE) following anterior temporal lobectomy (ATL) and to determine whether postoperative changes are 1) stable vs progressive and 2) related to visual field defects. METHODS: Diffusion tensor imaging (DTI) was obtained in 7 patients with TLE before, 2 months after, and 1 year after ATL. Changes in fractional anisotropy (FA) were evaluated in a whole-brain voxel-wise analysis, as well within specific fiber tracts. Repeated-measures analysis of variance was performed to examine the time course of FA changes within ipsilateral and contralateral fiber tracts. Quantitative visual field analysis was performed to determine whether decreases in regional FA were related to the extent or location of visual field defects. RESULTS: Patients showed decreased FA 2 months post-ATL in ipsilateral fiber tracts transected during surgery (parahippocampal cingulum, uncinate fasciculus, inferior longitudinal fasciculus, and fornix), as well as in fiber tracts not directly transected (inferior fronto-occipital fasciculus and corpus callosum). Additional decreases in FA were not observed from 2 months to 1 year post-ATL. Visual field defects in most patients were characterized by incomplete quadrantanopsias. However, FA reductions in one patient extended into temporo-occipital cortex and the splenium of the corpus callosum and were associated with a complete hemianopia. CONCLUSIONS: Wallerian degeneration is apparent 2 months following unilateral ATLs in ipsilateral fibers directly and indirectly affected during surgery. These changes do not appear to progress over the course of a year, but may correlate with the nature and extent of postoperative visual field defects.

Side matters: diffusion tensor imaging tractography in left and right temporal lobe epilepsy.

BACKGROUND AND PURPOSE: Noninvasive imaging plays a pivotal role in lateralization of the seizure focus in presurgical patients with temporal lobe epilepsy (TLE). Our goal was to evaluate the utility of diffusion tensor imaging (DTI) tractography in TLE. MATERIALS AND METHODS: Twenty-one patients with TLE (11 right, 10 left TLE) and 21 controls were enrolled. A 1.5T MR imaging scanner was used to obtain 51 diffusion-gradient-direction images per subject. Eight pairs of white matter fiber tracts were traced, and fiber tract fractional anisotropy (FA) was calculated and compared with controls. Fiber tract FA asymmetry and discriminant function analysis were evaluated in all subjects and fiber tracts respectively. RESULTS: Compared with controls, patients with TLE demonstrated decreased FA in 5 ipsilateral fiber tracts. Patients with left TLE had 6 ipsilateral and 4 contralateral fiber tracts with decreased FA. Patients with right TLE had 4 ipsilateral but no contralateral tracts with decreased FA compared with controls. Right-sided FA asymmetry was demonstrated in patients with right TLE for 5 fiber tracts, and left-sided asymmetry, for patients with left TLE for 1 fiber tract. Discriminant function analysis correctly categorized patients into left-versus-right TLE in 90% of all cases (100% correct in all patients without hippocampal sclerosis) by using uncinate fasciculus and parahippocampal fiber tracts. CONCLUSIONS: We found widespread reductions in fiber tract FA in patients with TLE, which were most pronounced ipsilateral to the seizure focus. Patients with left TLE had greater, more diffuse changes, whereas patients with right TLE showed changes that were primarily ipsilateral. Disease was lateralized to a high degree independent of identifiable hippocampal pathology noted on conventional MR imaging.

Diffusion tensor imaging correlates of memory and language impairments in temporal lobe epilepsy.

OBJECTIVE: To investigate the relationship between white matter tract integrity and language and memory performances in patients with temporal lobe epilepsy (TLE). METHODS: Diffusion tensor imaging (DTI) was performed in 17 patients with TLE and 17 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated for six fiber tracts (uncinate fasciculus [UF], arcuate fasciculus [AF], fornix [FORX], parahippocampal cingulum [PHC], inferior fronto-occipital fasciculus [IFOF], and corticospinal tract [CST]). Neuropsychological measures of memory and language were obtained and correlations were performed to evaluate the relationship between DTI and neuropsychological measures. Hierarchical regression was performed to determine unique contributions of each fiber tract to cognitive performances after controlling for age and hippocampal volume (HV). RESULTS: Increases in MD of the left UF, PHC, and IFOF were associated with poorer verbal memory in TLE, as were bilateral increases in MD of the AF, and decreases in FA of the right AF. Increased MD of the AF and UF, and decreased FA of the AF, UF, and left IFOF were related to naming performances. No correlations were found between DTI measures and nonverbal memory or fluency in TLE. Regression analyses revealed that several fibers, including the AF, UF, and IFOF, independently predicted cognitive performances after controlling for HV. CONCLUSIONS: The results suggest that structural compromise to multiple fiber tracts is associated with memory and language impairments in patients with temporal lobe epilepsy. Furthermore, we provide initial evidence that diffusion tensor imaging tractography may provide clinically unique information for predicting neuropsychological status in patients with epilepsy.

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures.

PURPOSE: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.

Oxcarbazepine.

The success of carbamazepine (CBZ) as a broad-spectrum antiepileptic drug (AED) has led to its use as first-line therapy in children and adults for partial and generalized tonic-clonic seizures. The limitations of CBZ include toxicity in sensitive individuals, autoinduction, which requires dose adjustment when therapy is initiated, and chronic hepatic induction, producing drug interactions when CBZ is used with AEDs and other drugs that undergo hepatic metabolism. One of two main products of CBZ microsomal metabolism, CBZ-10,11-epoxide (formed by oxidation of the double bond between C-10 and C-11), appears to provide antiepileptic efficacy but contributes significantly to clinical toxicity. The most common adverse effects of CBZ are central nervous system (CNS) symptoms, followed by gastrointestinal, hepatic, endocrine disturbances, and teratogenic effects. Oxcarbazepine (OXC) was developed to provide a compound chemically similar enough to CBZ to mimic its efficacy and overall safety while improving its side-effect profile. Biotransformation of OXC does not involve formation of an epoxide metabolite. Compared with the parent compound, hepatic microsomal enzyme induction and autoinduction are greatly reduced. The clinical efficacy of OXC compares favorably with CBZ in clinical trials. Clinical development of OXC began in Europe. Results of Phase I trials started to appear in the early 1980s. Controlled clinical trials, reported in the mid- to late 1980s, led to approval of OXC in many European countries, and now in over 50 nations around the world. United States multicenter clinical trials have recently been completed, and at this writing the drug is awaiting approval by the FDA. This article reviews the pharmacology, animal data, outcomes of published controlled clinical trials, postmarketing data, adverse experiences, and current recommendations for clinical use of OXC.

Vagus nerve stimulation for medication-resistant generalized epilepsy. E04 VNS Study Group.

We treated 24 generalized epilepsy patients with vagus nerve stimulation (VNS), comparing seizure rates during a 1-month baseline with 3 months of VNS. Median seizure rate reduction was -46%. Sixteen of the 24 patients had better than a -30% reduction and 11 of the 24 patients had better than a -50% reduction in seizure rate. A mild cough during stimulation occurred in six patients. Patients with higher baseline seizure rates and later ages at epilepsy onset had the best responses to VNS. Our findings suggest VNS is an effective treatment for medication-resistant generalized epilepsy even in patients as young as 4 years.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Magnetic source imaging of abnormal low-frequency magnetic activity in presurgical evaluations of epilepsy.

PURPOSE: Regional cortical dysfunction associated with epileptogenic activity was predicted from interictal localized abnormal low frequency neuromagnetic activity (ALFMA) using Magnetic Source Imaging (MSI). ALFMA can be detected in patients who show no interictal spikes. METHODS: A large array biomagnetometer was used in a blinded, rapid screening protocol. The MSI procedure required no alteration in epileptic medications. MSI results were compared with the presumed epileptogenic region as determined by a consensus of standard techniques, which included MR and electroclinical monitoring. RESULTS: One or more sites of localized abnormality were detected by MSI ALFMA in 29 of the 33 epileptic patients. ALFMA mapped with MSI showed a 48.5% specificity with respect to the presumed epileptogenic region. MSI ALFMA was in agreement with the final consensus as often as was ictal noninvasive video EEG monitoring, and was exceeded in specificity overall only by invasive ictal video EEG monitoring, which was required for conventional localization in 21 of the 33 patients tested with MSI. CONCLUSIONS: ALFMA measurements with MSI may augment the array of noninvasive methods used for reaching a consensus for epilepsy surgery.

Frequency and characteristics of visual field deficits after surgery for mesial temporal sclerosis.

In a series of 33 patients undergoing tailored temporal lobe resection for mesial temporal sclerosis, the frequency of postoperative visual field deficit (VFD) was 52%. The size and configuration were similar after operation in the right and left hemispheres. We observed partial upper quadrantanopias in 16 of 28 patients who became seizure-free and in only one of five patients with residual seizures. VFDs may provide an independent measure of the functional extent of resection.

Traumatic neuronal injury in vitro is attenuated by NMDA antagonists.

Pure traumatic neuronal injury was modeled in dispersed neocortical cell cultures derived from fetal mice. A plastic stylet was used to tear the neuronal and glial cell layer; medium oxygen content, pH, and glucose remained unchanged. Adjacent to this local disruption, many neurons developed acute swelling and went on to degenerate over the next day, but glia were relatively spared. If the same mechanical insult was delivered in the presence of the N-methyl-D-aspartate (NMDA) antagonists dextrorphan or D-2-amino-5-phosphonovalerate, resultant neuronal degeneration was markedly reduced. The protective effect of these NMDA antagonists was concentration-dependent between 1 and 100 microM, with EC50 near 10 microM for both compounds. Present findings suggest that endogenous excitatory amino acids may participate significantly in the propagation of central neuronal cell loss in response to a purely mechanical insult.

GABAergic neocortical neurons are resistant to NMDA receptor-mediated injury.

N-methyl-D-aspartate (NMDA) receptors are thought to mediate much of the central neuronal loss produced by certain neurologic insults, including hypoxia-ischemia, hypoglycemia, and trauma. Therefore, the specific vulnerability of GABAergic inhibitory neurons to NMDA receptor-mediated toxicity might be an important determinant of the potential for epileptogenesis following these insults. We have examined the fate of GABAergic cortical neurons in mouse cell cultured neuronal population) were identified either by immunoreactivity with antisera to GABA or by autoradiography following high-affinity uptake of 3H-GABA. Cultures exposed for 5 min to 20 to 750 microM NMDA showed NMDA concentration-dependent, widespread neuronal loss. However, GABAergic neurons were relatively spared, and thus represented an enhanced fraction of neuronal survivors. These observations suggest that GABAergic cortical neurons may possess some intrinsic resistance to NMDA receptor-mediated neurotoxicity, a property which might convey an anticonvulsant "inhibitory safety factor" to neocortex against certain forms of injury.

Transient catecholamine modulation of neutrophil activation: kinetic and intracellular aspects of isoproterenol action.

Modulation of neutrophil activation by catecholamines may reflect regulatory mechanisms that couple beta-adrenergic and N-formyl peptide receptors to antagonistic biochemical pathways. We examined kinetic and mechanistic aspects of the inhibition by catecholamines of neutrophil activation by formyl peptides. Inhibition of oxidant production by isoproterenol (ISO) was detected as low as 3 nM, had an ID50 of 10(-7) M, and could be blocked and reversed by propranolol. Recovery of cell function occurred over a period of minutes when the concentration of ISO was less than 10(-6) M. These observations are discussed in terms of the interaction of ISO with the adrenergic receptors. The site of catecholamine action is addressed. ISO neither influences formyl peptide-receptor interaction nor does it inhibit oxidant production by phorbol ester. These results suggest an impairment of intracellular signalling processes that couple the formyl peptide-receptor binding to cell activation. We observed inhibition of intracellular Ca++ elevation by ISO only at low formyl peptide concentrations. This inhibition is consistent with a partial inhibition of phosphoinositide metabolism, which was observed. Several other cell responses, including actin polymerization and right angle light scatter, are minimally inhibited by 10(-6) M ISO indicating that the cell activation process is not entirely obliterated. The presence of catecholamine and formyl peptide results in a synergistic elevation of cAMP. The intracellular targets of ISO action may be regulated by cAMP dependent kinases and could follow a branchpoint in the activation sequence that leads distinctly to oxidase activation and cytoskeletal activation.

Psychic distress and the immune response.

This minireview surveys recent progress in the field of immunoregulation by the central nervous system. Representative findings from human and animal studies show evidence for significant immunosuppression in states of psychic distress. Mechanisms of immunomodulation are discussed in light of data implicating neuroendocrine, genetic, neuroanatomical, and learning factors. Evidence for reciprocal modulation of immune and nervous systems is considered. A simple hierarchical model proposes traits that are acted on by environment and experience to produce chronic states of mental health vs. psychic distress; these states determine baseline immunocompetence and response to afferent signals during acute immune challenge. Multidisciplinary interest in psychoneuroimmunology has accelerated the rate of inquiry into the mechanistic details of immunoregulation and has generated new appreciation for the pervasive effects of mental status on physiologic homeostasis.

Membrane deenergization by colicin K affects fluorescence of exogenously added but not biosynthetically esterified parinaric acid probes in Escherichia coli.

Fluorescence of the conjugated polyene fatty acid, parinaric acid (PnA), was studied in membranes of Escherichia coli during deenergization by colicin K. The free fatty acid and biosynthetically esterified forms of cis-PnA (9,11,13,15-cis,trans,trans,cis-octadecatetraenoic acid), both of which are sensitive to E. coli lipid-phase transitions, were compared. When free cis-PnA was added exogenously to respiring bacteria, dissipation of the energized state of the membrane resulted in a dramatic increase in cis-PnA fluorescence; all-trans-PnA was much less sensitive. Neither spectral shifts nor a change in cis-PnA fluorescence polarization were observed. Analysis of the PnA content of extracellular fractions of deenergized and control cells revealed a difference in probe distribution: the membranes of energy-poisoned E. coli bound about 77% of exogenously added cis-PnA, whereas membranes of actively respiring controls bound only about 44%. No fluorescence enhancement was observed in cells centrifuged to remove unbound cis-PnA before colicin treatment. When cis-PnA was biosynthetically esterified to phospholipids of an unsaturated fatty acid auxotroph of E. coli, the fluorescence did not change during membrane deenergization. In double-probe experiments, membrane deenergization resulted in fluorescence enhancement of exogenously added N-phenyl-1-naphthylamine, without change in esterified PnA fluorescence. We conclude that deenergization of E. coli membranes leads to increased binding and fluorescence of exogenously added PnA and cannot be detected from within the inner and outer membranes by PnA esterified in vivo.

Conjugated polyene fatty acids as fluorescent probes: biosynthetic incorporation of parinaric acid by Escherichia coli and studies of phase transitions.

The use of the fluorescent fatty acid, parinaric acid (9, 11, 13, 15-octadecatetraenoic acid) (PnA), was studied in cells of an unsaturated fatty acid auxotroph of Escherichia coli. Growth conditions were found that permitted biosynthetic incorporation of PnA (up to 3%) into membrane phospholipids during growth on oleic or elaidic acid. Fluorescence measurements of incorporated PnA revealed phase transitions in cells, membranes, and phospholipids at temperatures that reflected the fatty acid composition of the sample. Transitions had a well-defined onset from high temperature, while the lower and end point was less well defined. cis- and trans-PnA (cis, trnas, trans, cis, and all trans, respectively) gave comparable results. Similar phase transitions were detected with PnA, which was not biosynthetically incorporated. Fluorescence of tryptophan was measured in E. coli membranes as a function of concentration of PnA. Significant quenching of tryptophan fluorescence by PnA was observed.