Canadian epilepsy priority-setting partnership: Toward a new national research agenda.

BACKGROUND: Health research agendas are often set by researchers or by industry and may not reflect the needs and priorities of end users. This priority-setting partnership (PSP) for epilepsy was undertaken to identify the most pressing unanswered questions about epilepsy and seizures from the perspective of people with epilepsy (PWE) and their care providers. METHODS: Using the methodology developed by the James Lind Alliance (JLA), evidence uncertainties were gathered via online surveys from stakeholders across Canada. Submissions were formed into summary questions and checked against existing evidence to determine if they were true uncertainties. Verified uncertainties were then ranked by patients, caregivers, and healthcare providers and a final workshop was held to reach a consensus on the top 10 priorities. RESULTS: The final top 10 list reflects the priority areas of focus for research as identified by the Canadian epilepsy community, including genetic markers for diagnosis and treatment, concerns about living with the long-term effects of epilepsy, and addressing knowledge gaps in etiology and treatment approaches. CONCLUSION: This project represents the first systematic evidence of patient- and clinician-centered research priorities for epilepsy. The results of this priority-setting exercise provide an opportunity for researchers and funding agencies to align their agendas with the values and needs of the epilepsy community in order to improve clinical outcomes and quality of life (QOL) for PWE.

Teneurins, TCAP, and latrophilins: roles in the etiology of mood disorders.

Mood disorders, including anxiety and depression, are thought to be characterized by disrupted neuronal synapses and altered brain plasticity. The etiology is complex, involving numerous regions of the brain, comprising a multitude of neurotransmitter and neuromodulator systems. Recently, new studies on the teneurins, an evolutionary ancient family of type II transmembrane proteins have been shown to interact with latrophilins (LPHN), a similarly phylogenetically old family of adhesion G protein-coupled receptors (GPCR) forming a transsynaptic adhesion and ligand-receptor pair. Each of the four teneurin proteins contains bioactive sequences termed the teneurin C-terminal associated peptides (TCAP-1-4), which possess a number of neuromodulatory effects. The primary structures of the TCAP are most closely similar to the corticotropin-releasing factor (CRF) family of peptides. CRF has been implicated in a number of diverse mood disorders. Via an association with dystroglycans, synthetic TCAP-1 administration to both embryonic and primary hippocampal cultures induces long-term changes in neuronal structure, specifically increased neurite outgrowth, dendritic branching, and axon growth. Rodent models treated with TCAP-1 show reduced anxiety responses in the elevated plus-maze, openfield test, and acoustic startle test and inhibited CRF-mediated cocaine-seeking behaviour. Thus the teneurin/TCAP-latrophilin interaction may play a major role in the origin, development and treatment of mood disorders.

Ancient interaction between the teneurin C-terminal associated peptides (TCAP) and latrophilin ligand-receptor coupling: a role in behavior.

Teneurins are multifunctional transmembrane proteins that are found in all multicellular animals and exist as four paralogous forms in vertebrates. They are highly expressed in the central nervous system, where they exert their effects, in part, by high-affinity binding to latrophilin (LPHN), a G-protein coupled receptor (GPCR) related to the adhesion and secretin GPCR families. The teneurin C-terminal associated peptides (TCAPs) are encoded by the terminal exon of all four teneurins, where TCAPs 1 and 3 are independently transcribed as soluble peptides, and TCAPs 2 and 4 remain tethered to their teneurin proprotein. Synthetic TCAP-1 interacts with LPHN, with an association with ß-dystroglycan, to induce a tissue-dependent signal cascade to modulate cytoskeletal dynamics. TCAP-1 reduces stress-induced behaviors associated with anxiety, addiction and depression in a variety of models, in part, by regulating synaptic plasticity. Therefore, the TCAP-1-teneurin-LPHN interaction represents a novel receptor-ligand model and may represent a key mechanism underlying the association of behavior and neurological conditions.

Auditory and visual interhemispheric communication in musicians and non-musicians.

The corpus callosum (CC) is a brain structure composed of axon fibres linking the right and left hemispheres. Musical training is associated with larger midsagittal cross-sectional area of the CC, suggesting that interhemispheric communication may be faster in musicians. Here we compared interhemispheric transmission times (ITTs) for musicians and non-musicians. ITT was measured by comparing simple reaction times to stimuli presented to the same hemisphere that controlled a button-press response (uncrossed reaction time), or to the contralateral hemisphere (crossed reaction time). Both visual and auditory stimuli were tested. We predicted that the crossed-uncrossed difference (CUD) for musicians would be smaller than for non-musicians as a result of faster interhemispheric transfer times. We did not expect a difference in CUDs between the visual and auditory modalities for either musicians or non-musicians, as previous work indicates that interhemispheric transfer may happen through the genu of the CC, which contains motor fibres rather than sensory fibres. There were no significant differences in CUDs between musicians and non-musicians. However, auditory CUDs were significantly smaller than visual CUDs. Although this auditory-visual difference was larger in musicians than non-musicians, the interaction between modality and musical training was not significant. Therefore, although musical training does not significantly affect ITT, the crossing of auditory information between hemispheres appears to be faster than visual information, perhaps because subcortical pathways play a greater role for auditory interhemispheric transfer.