Brain-derived neurotrophic factor signaling modifies hippocampal gene expression during epileptogenesis in transgenic mice

Brain-derived neurotrophic factor (BDNF) regulates neuronal survival, differentiation and plasticity. It has been shown to promote epileptogenesis and transgenic mice with decreased and increased BDNF signaling show opposite alterations in epileptogenesis. However, the mechanisms of BDNF action are largely unknown. We studied the gene expression changes 12 days after kainic acid-induced status epilepticus in transgenic mice overexpressing either the functional BDNF receptor trkB or a dominant-negative truncated trkB. Epileptogenesis produced marked changes in expression of 27 of 1090 genes. Cluster analysis revealed BDNF signalling-mediated regulation of functional gene classes involved in cellular transport, DNA repair and cell death, including kinesin motor kinesin family member 3A involved in cellular transport. Furthermore, the expression of cytoskeletal and extracellular matrix components, such as tissue inhibitor of metalloproteinase 2 was altered, emphasizing the importance of intracellular transport and interplay between neurons and glia during epileptogenesis. Finally, mice overexpressing the dominant-negative trkB, which were previously shown to have reduced epileptogenesis, showed a decrease in mRNAs of several growth-associated genes, including growth-associated protein 43. Our data suggest that BDNF signaling may partly mediate the development of epilepsy and propose that regrowth or repair processes initiated by status epilepticus and promoted by BDNF signaling may not be as advantageous as previously thought.     

Magnetic Resonance Imaging in Animal Models of Epilepsy—Noninvasive Detection of Structural Alterations

Summary:  Small animal magnetic resonance imaging (MRI) has opened a window through which brain abnormalities can be observed over time in rodents noninvasively. We review MRI studies done during epileptogenesis triggered by status epilepticus in rat. Most of these studies have used quantitative T2, diffusion, and/or volumetric MRI. The goal has been to identify the distribution and severity of structural lesions during the epileptogenic process, that is, soon after status epilepticus, during epileptogenesis, and after the appearance of spontaneous seizures. Data obtained demonstrate that MRI can be used to associate the development of brain pathology with the evolution of clinical phenotype. MRI can also be used to select animals to preclinical studies based on the severity and/or distribution of brain damage, thus making the study population more homogeneous, for example, for assessment of novel antiepileptogenic or neuroprotective treatments. Importantly, follow-up data collected emphasize interindividual differences in the dynamics of development of abnormalities that could have remained undetected in a typical histologic analysis providing a snapshot to brain pathology. A great future challenge is to take advantage of interanimal variability in MRI in the development of surrogate markers for epilepsy or its comorbidities such as memory impairment. Understanding of molecular and cellular mechanisms underlying changes in various MRI techniques will help to better understand complex progressive pathological processes associated with epileptogenesis and epilepsy.     

From traumatic brain injury to posttraumatic epilepsy: What animal models tell us about the process and treatment options

A large number of animal models of traumatic brain injury (TBI) are already available for studies on mechanisms and experimental treatments of TBI. Immediate and early seizures have been described in many of these models with focal or mixed type (both gray and white matter damage) injury. Recent long-term video-electroencephalography (EEG) monitoring studies have demonstrated that TBI produced by lateral fluid-percussion injury in rats results in the development of late seizures, that is, epilepsy. These animals develop hippocampal alterations that are well described in status epilepticus–induced spontaneous seizure models and human posttraumatic epilepsy (PTE). In addition, these rats have damage ipsilaterally in the cortical injury site and thalamus. Although studies in the trauma field provide a large amount of information about the molecular and cellular alterations corresponding to the immediate and early phases of PTE, chronic studies relevant to the epileptogenesis phase are sparse. Moreover, despite the multiple preclinical pharmacologic and cell therapy trials, there is no information available describing whether these therapeutic approaches aimed at improving posttraumatic recovery would also affect the development of lowered seizure threshold and epilepsy. To make progress, there is an obvious need for information exchange between the trauma and epilepsy fields. In addition, the inclusion of epilepsy as an outcome measure in preclinical trials aiming at improving somatomotor and cognitive recovery after TBI would provide valuable information about possible new avenues for antiepileptogenic interventions and disease modification after TBI.     

Intrinsic connections of the rat amygdaloid complex: Projections originating in the lateral nucleus

The amygdaloid complex receives sensory information from a variety of sources. A widely held view is that the amygdaloid complex utilizes this information to orchestrate appropriate species-specific behaviors to ongoing experiences. Relatively little is known, however, about the circuitry through which information is processed within the amygdaloid complex. The lateral nucleus is the major recipient of extrinsic sensory information and is the origin of many intra-amygdaloid projections. In this study, we reinvestigated the organization of intraamygdaloid projections originating from the lateral nucleus using the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L). The lateral nucleus has highly organized intranuclear connections. Dense projections interconnect rostral and caudal levels of the lateral and the medial divisions of the nucleus, and the lateral and medial divisions of the lateral nucleus are also interconnected. The major extranuclear projections of the lateral nucleus are (in descending order of magnitude) to the accessory basal nucleus, the basal nucleus, the periamygdaloid cortex, the dorsal portion of the central division of the medial nucleus, the posterior cortical nucleus, the capsular division of the central nucleus, and the lateral division of the amygdalohippocampal area. The pattern of extranuclear projections varied depending on the rostrocaudal or mediolateral location of the injection site within the lateral nucleus. These findings indicate that intra-amygdaloid projections originating in the lateral nucleus are both more widespread and more topographically organized than was previously appreciated. © 1995 Wiley-Liss, Inc.     

MR volumetric analysis of the piriform cortex and cortical amygdala in drug-refractory temporal lobe epilepsy

BACKGROUND AND PURPOSE: The assessment of patients with temporal lobe epilepsy (TLE) traditionally focuses on the hippocampal formation. These patients, however, may present structural abnormalities in other brain areas. Our purpose was to develop a method to measure the combined volume of the human piriform cortex and cortical amygdala (PCA) by using MR imaging and to investigate PCA atrophy. METHODS: The definition of anatomic landmarks on MR images was based on histologic analysis of 23 autopsy control subjects. Thirty-nine adults with chronic TLE and 23 age-matched control subjects were studied. All underwent high-spatial-resolution MR imaging at 1.5T, including a tilted T1-weighted 3D dataset. The PCA volumes were compared with the control values and further correlated with hippocampal, amygdala, and entorhinal cortex volumes. RESULTS: The normal volume was 530 +/- 59 mm(3) (422-644) [mean +/- 1 SD (range)] on the right and 512 +/- 60 mm(3) (406-610) on the left PCA (no asymmetry, and no age or sex effect). The intraobserver and interobserver variability were 6% and 8%, respectively. In right TLE patients, the mean right PCA volume was 18% smaller than in control subjects (P < .001) and 15% smaller than in left TLE (P < .001). In left TLE, the mean left PCA volume was 16% smaller than in control subjects (P < .001) and 19% smaller than in right TLE (P < .001). Overall, 46% (18/39) of the patients had a greater than 20% volume reduction in the ipsilateral PCA. There was bilateral atrophy in 18% (7/39). Patients with hippocampal volumes of at least 2 SDs below the control mean had an 18% reduction in the mean PCA volume compared with patients without hippocampal atrophy (P < .001). Ipsilaterally, hippocampal (r = 0.756, P < .01), amygdaloid (r = 0.548, P < .01), and entorhinal (r = 0.500, P < .01) volumes correlated with the PCA volumes. CONCLUSION: The quantification of PCA volume with MR imaging showed that the PCA is extensively damaged in chronic TLE patients, particularly in those with hippocampal atrophy.     

Posterior tibial tendon insufficiency: which ligaments are involved?

BACKGROUND: The pathology manifested in posterior tibial tendon insufficiency (PTTI) is not limited to the posterior tibial tendon. The association of ligament failure with deformity has been discussed in numerous publications, but extensive documentation of the structures involved has not been performed. The purpose of this observational study was to identify the pattern of ligament involvement using standardized, high-resolution magnetic resonance imaging (MRI) in a series of 31 consecutive patients diagnosed with PTTI compared to an age matched control group without PTTI. METHOD: The structures evaluated by MRI were the posterior tibial tendon, superomedial and inferomedial components of the spring ligament complex, talocalcaneal interosseous ligament, long and short plantar ligaments, plantar fascia, deltoid ligament, plantar naviculocuneiform ligament, and tarsometatarsal ligaments. Structural derangement was graded on a five-part scale (0 to IV) with level 0 being normal and level IV indicating a tear of more than 50% of the cross-sectional area of the ligament. Standard flatfoot measurements taken from preoperative plain standing radiographs were correlated with the MRI grading system. RESULTS: Statistically significant differences in frequency of pathology in the PTTI group and controls were found for the superomedial calcaneonavicular ligament (p < 0.0001), inferomedial calcaneonavicular ligament (p < 0.0001), interosseous ligament (p = 0.0009), anterior component of the superficial deltoid (p < 0.0001), plantar metatarsal ligaments (p = 0.0002) and plantar naviculocuneiform ligament (p = 0.0006). The ligaments with the most severe involvement were the spring ligament complex (superomedial and inferomedial calcaneonavicular ligaments) and the talocalcaneal interosseous ligament. CONCLUSION: Ligament involvement is extensive in PTTI, and the spring ligament complex is the most frequently affected. Because ligament pathology in PTTI is nearly as common as posterior tibial tendinopathy, treatment should seek to protect or prevent progressive failure of these ligaments.     

Simultaneous fMRI and local field potential measurements during epileptic seizures in medetomidine‐sedated rats using raser pulse sequence

Simultaneous electrophysiological and functional magnetic resonance imaging measurements of animal models of epilepsy are methodologically challenging, but essential to better understand abnormal brain activity and hemodynamics during seizures. In this study, functional magnetic resonance imaging of medetomidine‐sedated rats was performed using novel rapid acquisition by sequential excitation and refocusing (RASER) fast imaging pulse sequence and simultaneous local field potential measurements during kainic acid‐induced seizures. The image distortion caused by the hippocampal‐measuring electrode was clearly seen in echo planar imaging images, whereas no artifact was seen in RASER images. Robust blood oxygenation level–dependent responses were observed in the hippocampus during kainic acid‐induced seizures. The recurrent epileptic seizures were detected in the local field potential signal after kainic acid injection. The presented combination of deep electrode local field potential measurements and functional magnetic resonance imaging under medetomidine anesthesia, which does not significantly suppress kainic acid‐induced seizures, provides a unique tool for studying abnormal brain activity in rats. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

WONOEP appraisal: Imaging biomarkers in epilepsy

Neuroimaging offers a wide range of opportunities to obtain information about neuronal activity, brain inflammation, blood–brain barrier alterations, and various molecular alterations during epileptogenesis or for the prediction of pharmacoresponsiveness as well as postoperative outcome. Imaging biomarkers were examined during the XIII Workshop on Neurobiology of Epilepsy (XIII WONOEP) organized in 2015 by the Neurobiology Commission of the International League Against Epilepsy (ILAE). Here we present an extended summary of the discussed issues and provide an overview of the current state of knowledge regarding the biomarker potential of different neuroimaging approaches for epilepsy.     

Function of anterior talofibular and calcaneofibular ligaments during in-vivo motion of the ankle joint complex

Background  

Despite the numerous in-vitro studies on the mechanical properties and simulated injury mechanisms of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL), the in-vivo biomechanical behavior of these two ligaments has not yet been described.