Stuttering: A Disorder of Energy Supply to Neurons?

Stuttering is a disorder characterized by intermittent loss of volitional control of speech movements. This hypothesis and theory article focuses on the proposal that stuttering may be related to an impairment of the energy supply to neurons. Findings from electroencephalography (EEG), brain imaging, genetics, and biochemistry are reviewed: (1) Analyses of the EEG spectra at rest have repeatedly reported reduced power in the beta band, which is compatible with indications of reduced metabolism. (2) Studies of the absolute level of regional cerebral blood flow (rCBF) show conflicting findings, with two studies reporting reduced rCBF in the frontal lobe, and two studies, based on a different method, reporting no group differences. This contradiction has not yet been resolved. (3) The pattern of reduction in the studies reporting reduced rCBF corresponds to the regional pattern of the glycolytic index (GI; Vaishnavi et al., 2010). High regional GI indicates high reliance on non-oxidative metabolism, i.e., glycolysis. (4) Variants of the gene ARNT2 have been associated with stuttering. This gene is primarily expressed in the brain, with a pattern roughly corresponding to the pattern of regional GI. A central function of the ARNT2 protein is to act as one part of a sensor system indicating low levels of oxygen in brain tissue and to activate appropriate responses, including activation of glycolysis. (5) It has been established that genes related to the functions of the lysosomes are implicated in some cases of stuttering. It is possible that these gene variants result in a reduced peak rate of energy supply to neurons. (6) Lastly, there are indications of interactions between the metabolic system and the dopamine system: for example, it is known that acute hypoxia results in an elevated tonic level of dopamine in the synapses. Will mild chronic limitations of energy supply also result in elevated levels of dopamine? The indications of such interaction effects suggest that the metabolic theory of stuttering should be explored in parallel with the exploration of the dopaminergic theory.

On the relationship of behavioral distraction and pupil dilation caused by emotional novel sounds

Effects of attentional distraction by unexpected and task-irrelevant sounds on task performance are discussed to comprise costs due to orienting of attention toward a distracting event and benefits due to enhanced level of arousal evoked by the processing of such events. Highly arousing distractor sounds may facilitate information and task processing resulting in reduced distraction effects compared to moderately arousing distractor sounds. By measuring pupil dilation responses as a marker of arousal and task performance as a marker of distraction, we disentangled orienting costs and arousal level changes through variations of the emotional content of distractor sounds. While participants (N=60) performed a visual categorization task, an auditory oddball sequence including standard sounds, highly arousing emotional and moderately arousing neutral novel sounds was presented. Multilevel analyses revealed prolonged reaction times to novel sounds compared to standard sounds. Distraction effects decreased when emotional novel sounds were presented compared to neutral novel sounds. Pupil dilation responses were increased in response to novel sounds compared to standard sounds. This increase was larger for emotional than for neutral novel sounds. None of the considered models supported a correlation at trial level between reduced distraction effects and arousal increase reflected by the pupil in response to emotional novel sounds, indicating at least partly independent underlying mechanisms. An exploratory analysis revealed an impact of the baseline pupil size, that indicates tonic level of arousal, on performance and distraction effects. Moreover, a positive correlation between the negative affect scale in the Adult Temperament Questionnaire and RTs was observed.

Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes

Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26–28 days gestation. No differences were observed in mean arterial pressure, glomerular filtration rate. or electrolyte excretion rates between the Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex-treated fetuses was significantly lower (12.9 ± 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 ± 1.0 nl/min). This resetting of TGF sensitivity persisted after birth ( P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TGF sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TGF response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.

Hypothesis: Hughlings Jackson and presynaptic inhibition: is there a big picture?

Presynaptic inhibition is a very powerful inhibitory mechanism and, despite many detailed studies, its purpose is still only partially understood. One accepted function is that, by reducing afferent inflow to the spinal cord and brainstem, the tonic level of presynaptic inhibition prevents sensory systems from being overloaded. A corollary of this function is that much of the incoming sensory data from peripheral receptors must be redundant, and this conclusion is reinforced by observations on patients with sensory neuropathies or congenital obstetric palsy in whom normal sensation may be preserved despite loss of sensory fibers. The modulation of incoming signals by presynaptic inhibition has a further function in operating a “gate” in the dorsal horn, thereby determining whether peripheral stimuli are likely to be perceived as painful. On the motor side, the finding that even minimal voluntary movement of a single toe is associated with widespread inhibition in the lumbosacral cord points to another function for presynaptic inhibition: to prevent reflex perturbations from interfering with motor commands. This last function, together with the normal suppression of muscle and cutaneous reflex activity at rest, is consistent with Hughlings Jackson's concept of evolving neural hierarchies, with each level inhibiting the one below it.

Effect of Blockage of the Ducts of the Vomeronasal Organ on LH Plasma Levels during the “Whitten Effect” in Does

Eighteen mature, nonpregnant, and indigenous South African does were randomly divided into two groups to test if their vomeronasal organs exert an influence on LH plasma levels during a Whitten effect experimental trial. Does in the treatment (VNO ablated) group had their vomeronasal organs rendered nonfunctional by cauterization of the nasoincisive duct under surgical anesthesia. Does in the control group had their nasal civities irrigated with physiological saline under surgical anesthesia. All does were synchronized into oestrus and introduced to bucks one day prior to their expected second oestrus cycle. Successful matings were recorded. Timely blood samples were collected during each of the five days before and five days after buck introduction. Blood plasma concentrations of estradiol and LH were determined by radioimmunoassay. Analysis of variance between groups demonstrated that the does in the VNO ablated group did not demonstrate any interest in mating, did not become pregnant, and did not demonstrate the primary increase in tonic plasma levels of LH that is necessary for ovulation to occur. By contrast, all of the does in the control group demonstrated successful matings, became pregnant, and demonstrated typical primary tonic level increases and preovulation surges in LH. Thus, it was concluded that the vomeronasal organ modulates the primary increase in tonic levels of LH and thus influences ovulation that occurs during the Whitten effect in South African indigenous does.

Differential regulation of the central neural cardiorespiratory system by metabotropic neurotransmitters

Central neurons in the brainstem and spinal cord are essential for the maintenance of sympathetic tone, the integration of responses to the activation of reflexes and central commands, and the generation of an appropriate respiratory motor output. Here, we will discuss work that aims to understand the role that metabotropic neurotransmitter systems play in central cardiorespiratory mechanisms. It is well known that blockade of glutamatergic, gamma-aminobutyric acidergic and glycinergic pathways causes major or even complete disruption of cardiorespiratory systems, whereas antagonism of other neurotransmitter systems barely affects circulation or ventilation. Despite the lack of an ‘all-or-none’ role for metabotropic neurotransmitters, they are nevertheless significant in modulating the effects of central command and peripheral adaptive reflexes. Finally, we propose that a likely explanation for the plethora of neurotransmitters and their receptors on cardiorespiratory neurons is to enable differential regulation of outputs in response to reflex inputs, while at the same time maintaining a tonic level of sympathetic activity that supports those organs that significantly autoregulate their blood supply, such as the heart, brain, retina and kidney. Such an explanation of the data now available enables the generation of many new testable hypotheses.

The Physiological Activation Effect on Performance in Shooting

The present study was devised to analyze the relationship between sporting performance and physiological activation. Fourteen subjects participated in a modern pentathlon shooting competition. Six autonomic nervous system (ANS) parameters were simultaneously recorded in real time: Skin Potential, Skin resistance, Instantaneous Heart Rate and Respiratory Frequency, Skin Temperature, and Skin Blood Flow. The duration of concentration was considered the time lapse between the “start” order and the shot. Subjects tried to keep their arm and pistol stable during this phase. Results showed a complex relationship between activation, relaxation, and performance. ANS activity indicated an increase in physiological activation and at the same time, relaxation: activation was observed through electrodermal activity, while thermovascular indices indicated relaxation. Tonic level variations were, thus, a reliable indicator of the contrasting requirements of this sporting activity. Finally, the results challenge theories that have suggested that autonomic activity is undifferentiated.

Involvement of adenosine in vascular contractile preconditioning

Measurements of isometric tensions of rat aortic rings revealed the fact that when aortic rings with intact endothelium were precontracted (preconditioned) for 20 min by the α1-adrenergic agonist phenylephrine (10 μM), the tonic level of subsequent contraction by the same agonist was depressed and/or declined regardless of the presence or absence of endothelium during the second contraction. The removal of endothelium before preconditioning showed no such phenomenon. With the use of specific blockers, involvements of adenosine or of ATP-sensitive K+(KATP) channels during preconditioning or second contraction, respectively, were evaluated. Actions of nitric oxide synthase, cyclooxygenase, P2 ATP purinoceptors, or KATP channels during preconditioning appear not to be involved. Exogenous adenosine (up to 100 μM) without endothelium could mimic the preconditioning; however, contractile preconditioning by phenylephrine, mechanical stretching, or activation of protein kinase C needed to be done. The release of adenosine and adenine nucleotides from aortic rings was augmented by phenylephrine or by mechanical stretching of the rings with intact endothelium. Our results suggest that during vasocontraction, endothelium-derived adenosine acquires an ability to protect vascular tone against subsequent repeated contractions by mediating a delayed, possibly indirect, opening of KATP channels.

Differential Effects of GABAA Receptor Antagonists in the Control of Respiratory Neuronal Discharge Patterns

Dogas, Z., M. Krolo, E. A. Stuth, M. Tonkovic-Capin, F. A. Hopp, D. R. McCrimmon, and E. J. Zuperku. Differential effects of GABAA receptor antagonists in the control of respiratory neuronal discharge patterns. J. Neurophysiol. 80: 2368–2377, 1998. To ascertain the role of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in shaping and controlling the phasic discharge patterns of medullary respiratory premotor neurons, localized pressure applications of the competitive GABAA receptor antagonist bicuculline (BIC) and the noncompetitive GABAA receptor antagonist picrotoxin (PIC) were studied. Multibarrel micropipettes were used in halothane anesthetized, paralyzed, ventilated, vagotomized dogs to record single unit activity from inspiratory and expiratory neurons in the caudal ventral respiratory group and to picoeject GABAA receptor antagonists. The moving time average of phrenic nerve activity was used to determine respiratory phase durations and to synchronize cycle-triggered histograms of discharge patterns. Picoejection of BIC and PIC had qualitatively different effects on the discharge patterns of respiratory neurons. BIC caused an increase in the discharge rate during the neuron's active phase without inducing activity during the neuron's normally silent phase. The resulting discharge patterns were amplified replicas (×2–3) of the underlying preejection phasic patterns. In contrast, picoejection of PIC did not increase the peak discharge rate during the neuron's active phase but induced a tonic level of activity during the neuron's normally silent phase. The maximum effective BIC dose (15 ± 1.8 pmol/min) was considerably smaller than that for PIC (280 ± 53 pmol/min). These findings suggest that GABAA receptors with differential pharmacology mediate distinct functions within the same neuron, 1) gain modulation that is BIC sensitive but PIC insensitive and 2) silent-phase inhibition blocked by PIC. These studies also suggest that the choice of an antagonist is an important consideration in the determination of GABA receptor function within the respiratory motor control system.

Contribution of Cerebrovascular Parasympathetic and Sensory Innervation to the Short-Term Control of Blood Flow in Rat Cerebral Cortex

In two groups of normotensive rats anaesthetised with halothane, either the nasociliary nerve (NCN) or the NCN and parasympathetic (PS) fibres together (NCN-PS) were functionally blocked at the right ethmoidal foramen. Blocking was achieved reversibly and repeatedly using a cooling probe. Cortical regional CBF (rCBF) was measured bilaterally using laser–Doppler probes. In Group 1, bilateral common carotid occlusion (CCO) was applied for 1 min both with and without block. In Group 2, CCO was applied permanently followed by stages of controlled haemorrhagic hypotension to deepen the ischaemia and the block applied at each stage. In Group 1, during CCO, rCBF was unaffected by blocking NCN-PS. However, during the transient postocclusive hyperaemia, blocking NCN-PS, but not NCN alone, significantly increased right side rCBF. In Group 2 and in Group 1 in the absence of CCO (normotension), rCBF was unaffected by blocking either set of fibres. We conclude that neither NCN nor PS fibres contribute to the tonic level of rCBF or to its autoregulatory control, but PS fibres conduct impulses tending to resolve postischaemic hyperaemia. We suggest that a subpopulation of PS fibres containing neuropeptide Y is activated under conditions of supernormal rCBF.