The concept of temporal 'plus' epilepsy.

The concept of temporal 'plus' epilepsy (T+E) is not new, and a number of observations made by means of intracerebral electrodes have illustrated the complexity of neuronal circuits that involve the temporal lobe. The term T+E was used to unify and better individualize these specific forms of multilobar epilepsies, which are characterized by electroclinical features primarily suggestive of temporal lobe epilepsy, MRI findings that are either unremarkable or show signs of hippocampal sclerosis, and intracranial recordings which demonstrate that seizures arise from a complex epileptogenic network including a combination of brain regions located within the temporal lobe and over closed neighbouring structures such as the orbitofrontal cortex, the insulo-opercular region, and the temporo-parieto-occipital junction. We will review here how the term of T+E has emerged, what it means, and which practical consideration it raises.

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.

Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.

Toxic neurofilamentous axonopathies accumulation of neurofilaments and axonal degeneration

A number of neurotoxic chemicals induce accumulation of neurofilaments in axonal swellings that appear at varying distances from the cell body. This pathology is associated with axonal degeneration of different degrees. The clinical manifestation is most commonly that of a mixed motor-sensory peripheral axonopathy with a disto-proximal pattern of progression, as in cases of chronic exposure to n-hexane and carbon disulphide. It has been demonstrated that protein adduct formation is a primary molecular mechanism of toxicity in these axonopathies, but how this mechanism leads to neurofilament accumulation and axonal degeneration remains unclear. Furthermore, little is known regarding the mechanisms of neurofilamentous axonopathy caused by 3,3′-iminodipropionitrile, an experimental toxin that induces proximal axon swelling that is strikingly similar to that found in early amyotrophic lateral sclerosis. Here, we review the available data and main hypotheses regarding the toxic axonopathies and compare them with the current knowledge of the biological basis of neurofilament transport. We also review recent studies addressing the question of how these axonopathies may cause axonal degeneration. Understanding the mechanisms underlying the toxic axonopathies may provide insight into the relationship between neurofilament behaviour and axonal degeneration, hopefully enabling the identification of new targets for therapeutic intervention. Because neurofilament abnormalities are a common feature of many neurodegenerative diseases, advances in this area may have a wider impact beyond toxicological significance

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event.

Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets.

During different forms of neurodegenerative diseases, including the retinal degeneration, several cell cycle proteins are expressed in the dying neurons from Drosophila to human revealing that these proteins are a hallmark of neuronal degeneration. This is true for animal models of Alzheimer's, and Parkinson's diseases, Amyotrophic Lateral Sclerosis and for Retinitis Pigmentosa as well as for acute injuries such as stroke and light damage. Longitudinal investigation and loss-of-function studies attest that cell cycle proteins participate to the process of cell death although with different impacts, depending on the disease. In the retina, inhibition of cell cycle protein action can result to massive protection. Nonetheless, the dissection of the molecular mechanisms of neuronal cell death is necessary to develop adapted therapeutic tools to efficiently protect photoreceptors as well as other neuron types.

Programming Hippocampal Neural Stem/Progenitor Cells into Oligodendrocytes Enhances Remyelination in the Adult Brain after Injury.

Demyelinating diseases are characterized by a loss of oligodendrocytes leading to axonal degeneration and impaired brain function. Current strategies used for the treatment of demyelinating disease such as multiple sclerosis largely rely on modulation of the immune system. Only limited treatment options are available for treating the later stages of the disease, and these treatments require regenerative therapies to ameliorate the consequences of oligodendrocyte loss and axonal impairment. Directed differentiation of adult hippocampal neural stem/progenitor cells (NSPCs) into oligodendrocytes may represent an endogenous source of glial cells for cell-replacement strategies aiming to treat demyelinating disease. Here, we show that Ascl1-mediated conversion of hippocampal NSPCs into mature oligodendrocytes enhances remyelination in a diphtheria-toxin (DT)-inducible, genetic model for demyelination. These findings highlight the potential of targeting hippocampal NSPCs for the treatment of demyelinated lesions in the adult brain.

B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.

Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling.

The occurrence of cognitive disturbances upon CNS inflammation or infection has been correlated with increased levels of the cytokine tumor necrosis factor-α (TNFα). To date, however, no specific mechanism via which this cytokine could alter cognitive circuits has been demonstrated. Here, we show that local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses. Astrocytic TNFR1 signaling is necessary for the hippocampal synaptic alteration and contextual learning-memory impairment observed in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS). This process may contribute to the pathogenesis of cognitive disturbances in MS, as well as in other CNS conditions accompanied by inflammatory states or infections.

The Increasing Spectrum of Indications of Whole-Body MRI Beyond Oncology: Imaging Answers to Clinical Needs.

Whole-body coverage using MRI was developed almost 2 decades ago. The first applications focused on the investigation of the skeleton to detect neoplastic disease, mainly metastases from solid cancers, and involvement by multiple myeloma and lymphoma. But the extensive coverage of the whole musculoskeletal system, combined with the exquisite sensitivity of MRI to tissue alteration in relation to different pathologic conditions, mainly inflammation, has led to the identification of a growing number of indications outside oncology. Seronegative rheumatisms, systemic sclerosis, inflammatory diseases involving muscles or fascias, and multifocal osseous, vascular, or neurologic diseases represent currently validated or emerging indications of whole-body MRI (WB-MRI). We first illustrate the most valuable indications of WB-MRI in seronegative rheumatisms that include providing significant diagnostic information in patients with negative or ambiguous MRI of the sacroiliac joints and the lumbar spine, assessing disease activity in advanced (ankylosed) central disease, and evaluating the peripherally dominant forms of spondyloarthropathy. Then we review the increasing indications of WB-MRI in other rheumatologic and nonneoplastic disorders, underline the clinical needs, and illustrate the role of WB-MRI in the positive diagnosis and evaluation of disease burden, therapeutic decisions, and treatment monitoring.

Continuing Medical Education Self-Assessment Questions Vol. 50, No. 2 - April 2014. Focal vibration in neurorehabilitation.

During the last decade, many studies have been carried out to understand the effects of focal vibratory stimuli at various levels of the central nervous system and to study pathophysiological mechanisms of neurological disorders as well as the therapeutic effects of focal vibration in neurorehabilitation. This review aimed to describe the effects of focal vibratory stimuli in neurorehabilitation including the neurological diseases or disorders like stroke, spinal cord injury, multiple sclerosis, Parkinson's' disease and dystonia. In conclusion, focal vibration stimulation is well tolerated, effective and easy to use, and it could be used to reduce spasticity, to promote motor activity and motor learning within a functional activity, even in gait training, independent from etiology of neurological pathology. Further studies are needed in the future well- designed trials with bigger sample size to determine the most effective frequency, amplitude and duration of vibration application in the neurorehabilitation.