This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies.
Publication date: July 2016
Source:Journal of Phonetics, Volume 57
Author(s): Natalia Kartushina, Alexis Hervais-Adelman, Ulrich Hans Frauenfelder, Narly Golestani
We studied mutual influences between native and non-native vowel production during learning, i.e., before and after short-term visual articulatory feedback training with non-native sounds. Monolingual French speakers were trained to produce two non-native vowels: the Danish /ɔ/, which is similar to the French /o/, and the Russian /ɨ/, which is dissimilar from French vowels. We examined relationships between the production of French and non-native vowels before training, and the effects of training with non-native vowels on the production of French ones. We assessed for each participant the acoustic position and compactness of the trained vowels, and of the French /o/, /ø/, /y/ and /i/ vowels, which are acoustically closest to the trained vowels. Before training, the compactness of the French vowels was positively related to the accuracy and compactness in the production of non-native vowels. After training, French speakers' accuracy and stability in the production of the two trained vowels improved on average by 19% and 37.5%, respectively. Interestingly, the production of native vowels was also affected by this learning process, with a drift towards non-native vowels. The amount of phonetic drift appears to depend on the degree of similarity between the native and non-native sounds.
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Publication date: July 2016
Source:Journal of Phonetics, Volume 57
Author(s): Natalia Kartushina, Alexis Hervais-Adelman, Ulrich Hans Frauenfelder, Narly Golestani
We studied mutual influences between native and non-native vowel production during learning, i.e., before and after short-term visual articulatory feedback training with non-native sounds. Monolingual French speakers were trained to produce two non-native vowels: the Danish /ɔ/, which is similar to the French /o/, and the Russian /ɨ/, which is dissimilar from French vowels. We examined relationships between the production of French and non-native vowels before training, and the effects of training with non-native vowels on the production of French ones. We assessed for each participant the acoustic position and compactness of the trained vowels, and of the French /o/, /ø/, /y/ and /i/ vowels, which are acoustically closest to the trained vowels. Before training, the compactness of the French vowels was positively related to the accuracy and compactness in the production of non-native vowels. After training, French speakers' accuracy and stability in the production of the two trained vowels improved on average by 19% and 37.5%, respectively. Interestingly, the production of native vowels was also affected by this learning process, with a drift towards non-native vowels. The amount of phonetic drift appears to depend on the degree of similarity between the native and non-native sounds.
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Publication date: July 2016
Source:Journal of Phonetics, Volume 57
Author(s): Natalia Kartushina, Alexis Hervais-Adelman, Ulrich Hans Frauenfelder, Narly Golestani
We studied mutual influences between native and non-native vowel production during learning, i.e., before and after short-term visual articulatory feedback training with non-native sounds. Monolingual French speakers were trained to produce two non-native vowels: the Danish /ɔ/, which is similar to the French /o/, and the Russian /ɨ/, which is dissimilar from French vowels. We examined relationships between the production of French and non-native vowels before training, and the effects of training with non-native vowels on the production of French ones. We assessed for each participant the acoustic position and compactness of the trained vowels, and of the French /o/, /ø/, /y/ and /i/ vowels, which are acoustically closest to the trained vowels. Before training, the compactness of the French vowels was positively related to the accuracy and compactness in the production of non-native vowels. After training, French speakers' accuracy and stability in the production of the two trained vowels improved on average by 19% and 37.5%, respectively. Interestingly, the production of native vowels was also affected by this learning process, with a drift towards non-native vowels. The amount of phonetic drift appears to depend on the degree of similarity between the native and non-native sounds.
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Decision making is an adaptive behavior that takes into account several internal and external input variables and leads to the choice of a course of action over other available and often competing alternatives. While it has been studied in diverse fields ranging from mathematics, economics, ecology and ethology, to psychology and neuroscience, recent cross-talk among perspectives from different fields have yielded novel descriptions of decision processes. Reinforcement guided decision making models are based on economic and reinforcement learning theories and their focus is on the maximization of acquired benefit over a defined period of time. Studies based on reinforcement guided decision making have implicated a large network of neural circuits across brain. This network includes a wide range of cortical (e.g. orbitofrontal cortex and anterior cingulate cortex) and subcortical (e.g. nucleus accumbens and subthalamic nucleus) brain areas and use several neurotransmitter systems (e.g. dopaminergic and serotonergic systems) to communicate and process decision related information. This review discusses distinct as well as overlapping contributions of these networks and neurotransmitter systems to the processing of decision making. We end the review by touching neural circuitry and neuromodulatory regulation of the exploratory decision making.
The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as central respiratory chemoreceptors, i.e the mechanism by which brain PCO2 regulates breathing. The molecular and cellular basis of central respiratory chemoreception is based on the detection of CO2 via intrinsic proton receptors (TASK-2, GPR4) as well as synaptic input from peripheral chemoreceptors and other brain regions. Murine models of Congenital Central Hypoventilation Syndrome designed with PHOX2B mutations have suggested RTN neuron agenesis. In this review, we examine through human and experimental animal models, how a restricted number of neurons that express the transcription factor PHOX2B play a crucial role in the control of breathing and autonomic regulation.
Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) enables non-invasive neurophysiological investigation of the human cortex. A TMS paradigm of short-latency afferent inhibition (SAI) is characterised by attenuation of the motor evoked potential (MEP) and modulation of N100 of the TMS-evoked potential (TEP) when TMS is delivered to motor cortex (M1) following median nerve stimulation. SAI is a marker of cholinergic activity in the motor cortex, however, the SAI has not been tested from the prefrontal cortex. We aimed to explore the effect of SAI in dorsolateral prefrontal cortex (DLPFC). SAI was examined in 12 healthy subjects with median nerve stimulation and TMS delivered to M1 and DLPFC at inter-stimulus intervals (ISI) relative to the individual N20 latency. SAI in M1 was tested at the optimal ISI of N20+2ms. SAI in DLPFC was investigated at a range of ISI from N20+2 to N20+20ms to explore its temporal profile. For SAI in M1, the attenuation of MEP amplitude was correlated with increase of TEP N100 from the left central area. A similar spatiotemporal neural signature of SAI in DLPFC was observed with marked increase of N100 amplitude. SAI in DLPFC was maximal at ISI N20+4ms at the left frontal area. These findings establish the neural signature of SAI in DLPFC. Future studies could explore whether DLPFC-SAI is neurophysiological marker of cholinergic dysfunction in cognitive disorders.
Short-latency afferent inhibition (SAI) is characterized by the suppression of the Transcranial magnetic stimulation (TMS) motor evoked potential (MEP) by the cortical arrival of a somatosensory afferent volley. It remains unknown whether the magnitude of SAI reflects changes in the sensory afferent volley, similar to that observed for somatosensory evoked potentials (SEPs). The present study investigated stimulus-response relationships between sensory nerve action potentials (SNAPs), SAI and SEPs, and their interrelatedness. Experiment 1 (n=23, aged 23 ± 1.5) investigated the stimulus-response profile for SEPs and SAI in the flexor carpi radialis (FCR) muscle following stimulation of the mixed, median nerve at the wrist using ~25%, 50%, 75% and 100% of the maximum SNAP and at 1.2x and 2.4x motor threshold (the latter equated to 100% of the maximum SNAP). Experiment 2 (n=20, aged 23.1 ± 2) probed SEPs and SAI stimulus-response relationships following stimulation of the cutaneous digital nerve at ~25%, 50%, 75% and 100% of the maximum SNAP recorded at the elbow. Results indicate that, for both nerve types, SAI magnitude is dependent on the volume of the sensory afferent volley and ceases to increase once all afferent fibers within the nerve are recruited. Further, for both nerve types, the magnitude of SAI and SEPs are related such that an increase in excitation within somatosensory cortex is associated with an increase in the magnitude of afferent-induced MEP inhibition.
Interneuron-based cell transplantation is a powerful method to modify network function in a variety of neurological disorders, including epilepsy. Whether new interneurons integrate into native neural networks in a subtype-specific manner is not well understood and the therapeutic mechanisms underlying interneuron-based cell therapy, including the role of synaptic inhibition, are debated. Here, we tested subtype-specific integration of transplanted interneurons using acute cortical brain slices and visualized patch clamp recordings to measure excitatory synaptic inputs, intrinsic properties, and inhibitory synaptic outputs. Fluorescently labeled progenitor cells from the embryonic medial ganglionic eminence (MGE) were used for transplantation. At five weeks after transplantation, MGE-derived parvalbumin-positive (PV+) interneurons received excitatory synaptic inputs, exhibited mature interneuron firing properties, and made functional synaptic inhibitory connections to native pyramidal cells that were comparable to native PV+ interneurons. These findings demonstrate that MGE-derived PV+ interneurons functionally integrate into subtype-appropriate physiological niches within host networks following transplantation.
The visual line bisection task (LBT) is sensitive to perceptual biases of visuospatial attention, showing slight leftward (for horizontal lines) and upward (for vertical lines) errors in healthy subjects. It may be solved in an egocentric or allocentric reference frame and there is no obvious need for graviceptive input. However, for other visual line adjustments, such as the subjective visual vertical, otolith input is integrated. We hypothesized that graviceptive input is incorporated when performing the LBT and predicted reduced accuracy and precision when roll-tilted. Twenty healthy right-handed subjects repetitively bisected earth-horizontal and body-horizontal lines in darkness. Recordings were obtained before, during and after roll-tilt (+/-45deg, +/-90deg) for 5min each. Additionally, bisections of earth-vertical and oblique lines were obtained in 17 subjects. When roll-tilted +/-90deg ear-down, bisections of earth-horizontal (i.e., body-vertical) lines were shifted towards the direction of the head (p<0.001). However, after correcting for vertical line-bisection errors when upright, shifts disappeared. Bisecting body-horizontal lines while roll-tilted did not cause any shifts. The precision of earth-horizontal line bisections decreased (p<=0.006) when roll-tilted, while no such changes were observed for body-horizontal lines. Regardless of the trial condition and paradigm, the scanning direction of the bisecting cursor (leftward vs. rightward) significantly (p<=0.021) affected line bisections. Our findings reject our hypothesis, and suggest that gravity does not modulate the LBT. Roll-tilt dependent shifts are rather explained by the headward bias when bisecting lines oriented along a body-vertical axis. Increased variability when roll-tilted likely reflects larger variability when bisecting body-vertical than body-horizontal lines.
Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl- gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl- export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated ECl, endocannabinoid-mediated depression was prevented by blocking Cl- import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and was only weakly affected by disruption of Cl- import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of TRPV channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses, and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl- gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.
Pain is associated with changes in the neural drive to muscles. For the upper trapezius muscle, surface EMG recordings have indicated that acute noxious stimulation in either the cranial or the caudal region of the muscle leads to a relative decrease in muscle activity in the cranial region. It is however not known if this adaption reflects different recruitment thresholds of the upper trapezius motor units in the cranial and caudal region or a non-uniform nociceptive input to the motor units of both regions. This study investigated these potential mechanisms by direct motor unit identification. Motor unit activity was investigated with high-density surface EMG signals recorded from the upper trapezius muscle of 12 healthy volunteers at baseline, control (intramuscular injection of isotonic saline), and painful condition (hypertonic saline). The EMG was decomposed into individual motor unit spike trains. Motor unit discharge rates decreased significantly from control to pain conditions by 4.0 ± 3.6 pps in the cranial region but not in the caudal region (1.4 ± 2.8 pps; not significant). These changes were compatible with variations in the synaptic input to the motor neurons of the two regions. These adjustments were observed irrespective of the location of noxious stimulation. These results strongly indicate that the nociceptive synaptic input is distributed in a non-uniform way across regions of the upper trapezius muscle.
In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole-cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse), and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (T0.25°C pulse -1). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each IR heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with a Q102. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise , and an inward conduction current driven by T. An iberiotoxin-sensitive (ibTX) inhibitory conduction current (BK) was also evoked by T, rising in <3ms and decaying with a time constant of ~24ms. The inhibitory component dominated whole cell currents in 50% of hair cells at -68mV, and in 67% of hair cells at -60mV. Responses were quantified and described based on first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs, and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability.
