Assessment of excitability in brainstem circuits mediating the blink reflex and the startle reaction

Excitability is probably the concept that fits better with the definition of the role of neurophysiology in the study of brainstem functions and circuits. Neurophysiological techniques are likely the best suited of all paraclinical tests for documenting the eventual excitability changes that may occur in certain physiological states and in many neurological disorders. The best known test of brainstem excitability is the blink reflex. While a single stimulus can already indicate the readiness of the interneuronal path and the facial motoneurons to fire, pairs of stimuli (conditioning and test) are suited to analyze the degree of excitability recovery after a single discharge. Another brainstem reflex circuit, which excitability testing can be of interest for physiological and clinical exams is the one involved in the startle reaction. The size of the responses and their habituation are the typical measures of excitability of the startle reflex circuit. Prepulse inhibition is a method to modulate both, the blink reflex and the startle reaction. It is defined as the inhibitory effect caused by a stimulus of an intensity low enough not to induce a response by itself on the response elicited by a subsequent stimulus. The circuits of the blink reflex, startle reaction and prepulse inhibition share some commonalities but they are different enough for the three techniques to provide unique, clinically relevant, information in certain conditions. The role of neurophysiology is not limited to testing those functions. It is important also for the assessment of many other circuits, such as those implicated in eye movements, vestibular reflexes, arousal, sleep, breathing, or autonomic reactions, which are not considered in this review.     

Alterations in excitatory and inhibitory brainstem interneuronal circuits in fibromyalgia: Evidence of brainstem dysfunction

ObjectivePatients with fibromyalgia syndrome (FMS) perceive stimuli differently and show altered cortical sensory representation maps following peripheral stimulation. Altered sensory gating may play a causal role.MethodsBlink reflex, blink reflex excitability recovery, and prepulse inhibition of the blink reflex – representing brainstem excitability – were assessed in 10 female patients with FMS and 26 female healthy controls.ResultsUnconditioned blink reflex characteristics (R1 latency and amplitude, R2 and R2c latency and area-under-the-curve) did not differ significantly between patients and controls. Blink reflex excitability recovery was enhanced in patients versus controls at all intervals tested. Prepulses significantly suppressed R2 area and increased R2 latency in patients and controls. However, R2 area suppression was significantly less in patients than in controls (patients: to 80.0 ± 28.9%, controls: to 47.8 ± 21.7%). The general pattern of corresponding changes in R2c was similar.ConclusionsBlink reflex is normal, whereas blink reflex excitability recovery is enhanced and blink reflex prepulse inhibition is reduced in patients with FMS, suggesting functional changes at the brainstem level in FMS.SignificanceReduced blink reflex prepulse inhibition concurs with altered sensory gating in patients with FMS.     

Reflexes elicited from cutaneous and mucosal trigeminal afferents in normal human subjects

It has been shown that in patients in whom the central stump of the hypoglossal nerve has been anastomosed to the peripheral stump of a lesioned facial nerve, supraorbital nerve stimulation can elicit a short-latency reflex (12.5±0.6 ms; mean±S.D.) in facial muscles similar to the R1 disynaptic blink reflex response, but not followed by an R2 blink reflex component⁴⁶. Thus in addition to replacing the facial neurons at peripheral synapses, these hypoglossal nerves contribute to a trigemino-hypoglossal reflex. The aim of this work was to study the type of reflex activities which can be elicited in both facial and tongue muscles by electrical stimulation of cutaneous (supraorbital nerve) or mucosal (lingual nerve) trigeminal (V) afferents in normal subjects. The results show that although stimulation of cutaneous V1 afferents elicits the well-known double component (R1–R2) blink reflex response in the orbicularis oculi muscles, it does not produce any detectable reflex response in the genioglossus muscle, even during experimental paradigms designed to facilitate the reflex activity. Conversely, stimulation of mucosal V3 afferents can elicit a single reflex response of the R1 type in the genioglossus muscle but not in the orbicularis oculi muscles, even during experimental paradigms designed to facilitate the reflex activity. These data are discussed in terms of two similar but separate circuits for the R1 responses of cutaneous (blink reflex) and mucosal (tongue reflex) origins. They suggest that in patients with hypoglossal-facial (XII–VII) nerve anastomosis, the short-latency trigemino-‘hypoglossal-facial' reflex of the R1 blink reflex type observed in facial muscles following supraorbital nerve stimulation could be due to changes in synaptic effectiveness of the central connectivity within the principal trigeminal nucleus where both cutaneous and mucosal trigeminal afferents project.     

Redirection of the hypoglossal nerve to facial muscles alters central connectivity in human brainstem

Functional motor control requires perfect matching of central connectivity of motoneurones with their peripheral connections. However, it is not known to what extent central circuitry is influenced by target muscles, either during development or following a lesion. Surgical interventions aimed at restoring function following peripheral nerve lesions provide an opportunity for studying this interaction in the mature human nervous system. We have followed 8 patients in whom the hypoglossal nerve was anastomosed into a lesioned facial nerve, allowing voluntary contractions of the previously paralyzed muscles. We show that, in addition to replacing the facial neurons at peripheral synapses, a new short-latency trigemino-hypoglossal reflex, of the R1 blink reflex type, can be demonstrated in patients showing recovery, implying a sprouting of trigeminal neurons towards hypoglossal motoneurones, over a distance of at least 0.5 cm. These surprising results show an unexpected influence of the periphery in remodelling central connectivity in man.     

Neurophysiological assessment of trigeminal nerve reflexes in disorders of central and peripheral nervous system.

The trigeminal nerve and nuclei (the trigeminal complex) are unique in the human body with regard to their anatomical and physiological characteristics. They are also special regarding the lesions in which they are involved, both at the peripheral level because of the susceptibility of some terminal branches, and at the nuclei because of their large size and the large amount of connections with other centers. Conventional magnetic resonance imaging studies are often not sufficiently informative to demonstrate very tiny lesions that could be responsible for an important damage in the brainstem. Therefore, clinical neurophysiology and specifically, the techniques used in the study of the trigeminal functions, remain as convenient diagnostic and research tools to document clinically evident lesions or uncover subclinical abnormalities. This review is focussed on the clinical applicability of the study of trigeminal reflexes, including methods employed in the documentation of focal lesions of peripheral branches, trigeminal involvement of peripheral neuropathies, specific lesions of the trigeminal ganglia, central nervous dysfunctions causing abnormalities in the excitability of trigeminal neurons, and the possible use of trigeminal nerve reflexes in the study of facial pain syndromes and headache.     

The role of pedunculopontine nucleus in isolated REM sleep behavior disorder and REM sleep without atonia

IntroductionThe aim of this study was to analyze the functions of pedunculopontine nucleus (PPN) in isolated REM sleep behavior disorder (iRBD) and REM sleep without atonia (RSWA) to investigate the role of PPN in dream-enacting motor behaviors in RBD. We evaluated the activity of PPN through the prepulse modulation (PPM) together with other brainstem reflexes to investigate the differences in changes at brainstem.MethodsWe included nine patients with isolated RSWA and 10 patients with iRBD. For diagnosis, all patients underwent polysomnography. None of the patients had parkinsonism or dementia. We also included 17 healthy participants with similar age and sex. Blink reflex (BR), PPM of BR, recovery excitability of BR, and auditory startle reflex (ASR) were recorded in all participants.ResultsThere was a prepulse inhibition deficit in iRBD and RSWA groups compared to healthy subjects. The BR-R2 recovery at 200 ms interval was also higher in patients with iRBD and RSWA. In ASR recordings, the response probabilities were higher in the RBD group compared to RSWA and control groups.ConclusionThe PPM was abnormal in both iRBD and RSWA whereas ASR was enhanced in iRBD. We suggest that there are certain similarities and differences in the pathophysiologies of iRBD and RSWA.     

Central motor conduction to upper and lower limbs after magnetic stimulation of the brain and peripheral nerve abnormalities in 20 patients with Friedreich''s ataxia

Central motor conduction time (CMCT) to thenar and soleus muscles was measured after magnetic stimulation of the cortex in 20 cases of Friedreich's ataxia (FA) and was abnormal in all. CMCT values were related to disease duration and disability. The amplitude of CMAP after cortex stimulation was severely reduced in the most disabled patients. Reduction in amplitude of the nerve evoked potentials was related neither to disease duration nor grade of disability. These results suggest that clinical worsening in FA is mainly due to progressive central motor pathway involvement. CMCT study is a better index of disease progression than peripheral nerve examination. Abnormalities in CMCT may be the third electrophysiological diagnostic criterion in FA, after reduced amplitude of nerve action potentials and absent H reflex.     

Modality-related scalp responses after electrical stimulation of cutaneous and muscular upper limb afferents in humans

To elucidate whether the selective electrical stimulation of muscle as well as cutaneous afferents evokes modality-specific responses in somatosensory evoked potentials (SEPs) recorded on the scalp of humans, we compared scalp SEPs to electrical stimuli applied to the median nerve and to the abductor pollicis brevis (APB) motor point. In three subjects, we also recorded SEPs after stimulation of the distal phalanx of the thumb, which selectively involved cutaneous afferents. Motor point and median nerve SEPs showed the same scalp distribution; moreover, very similar dipole models, showing the same dipolar time courses, explained well the SEPs after both types of stimulation. Since the non-natural stimulation of muscle afferents evokes responses also in areas specifically devoted to cutaneous input processing, it is conceivable that, in physiological conditions, muscle afferents are differentially gated in somatosensory cortex. The frontocentral N30 response was absent after purely cutaneous stimulation; by contrast, it was relatively more represented in motor point rather than in mixed nerve SEPs. These data suggest that the N30 response is specifically evoked by proprioceptive inputs.     

F-waves and facilitated late responses of the mentalis muscle in patients with a cerebrovascular accident

Abstract

F-waves in the extremities result from the backfiring of antidromically activated anterior horn cells and F-waves of the mentalis muscle can be also elicited after stimulation of the marginal mandibular branch of the facial nerve. In order to investigate the influence of the descending pathway of the excitability of the facial motonucleus, the F-wave of the mentalis muscle and the facilitated late response, which follows F-waves and which seems to be the snout reflex due to their similar latency and habituation, were studied in 11 conscious patients with a hemispheric cerebrovascular accident (CVA) presenting with hemiparesis, and in 10 unconscious patients with CVA or head injury. The duration and the persistence of the F-waves increased significantly statistically on the normal side in the CVA patients compared with those of the palsy side and the normal subjects. In comatose patients the F-waves and the facilitated late response were not elicited. The latency (46.1 ± 13.3 msec) of the facilitated late responses in the unconscious patients tended to increase compared with the latency (36.6 ±4.3 msec) in the conscious patients. These findings suggest that the hyperexcitability of the facial motoneuron is ipsilateral to any hemispheric lesion; the hemispheric lesion exerts a bilateral excitatory influence on the interneuron of the facilitated late response: and that the reticular formation may influence the facial motoneuron and any interneurons concerned in the facilitated late response. F-waves and facilitated late responses should be further examined as neurophysiologically useful diagnostic methods [Neurol Res 2000; 22: 576-582]     

The digastric reflex evoked by tooth-pulp stimulation in the cat and its modulation by stimuli applied to the limbs

The digastric reflex evoked by electrical stimulation of tooth pulp in anaesthetized cats was studied together with the effects on this reflex of stimulating other parts of the body.The threshold for the digastric reflex generally lay in the range of stimulus intensities which would excite a large proportion of the pulpal afferent fibres which suggested that a large amount of central summation was required to evoke the reflex. During the course of 2527 experiments, the threshold for the reflex increased. It was also found that repeated application of suprathreshold stimuli produced first an increase and then a decrease in the reflex response.The application of noxious but not of non-noxious mechanical conditioning stimuli to the limbs produced strong, long-lasting depressions of the digastric reflex. Electrical conditioning stimuli applied to the limbs also depressed the reflex; this depression had a latency of onset of 20–50 ms and lasted for up to 500 ms. When conditioning stimuli were applied to the saphenous nerve, the depression of the reflex occurred only when the stimuli were of an intensity sufficient to excite fibres conducting at less than 40 m·s⁻¹; it may be assumed that some of these fibres would have been high threshold mechanoreceptors or nociceptors. These results show that noxious stimulation of anatomically remote structures can depress the activity of a population of trigeminal brainstem neurones.The opiate antagonist, naloxone, had no detectable effect on either the digastric reflex or the depression of the reflex produced by stimulating other parts of the body. The serotonin antagonists, methysergide and cinanserin, strongly depressed the digastric reflex but it was not clear whether these drugs also affected the depression of the reflex by the conditioning stimuli.     

Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated with amisulpride or olanzapine.

BACKGROUND: Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia. METHODS: The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise. RESULTS: Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect. CONCLUSIONS: Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.     

Focus on the pedunculopontine nucleus. Consensus review from the May 2018 brainstem society meeting in Washington,DC, USA

The pedunculopontine nucleus (PPN) is located in the mesopontine tegmentum and is best delimited by a group of large cholinergic neurons adjacent to the decussation of the superior cerebellar peduncle. This part of the brain, populated by many other neuronal groups, is a crossroads for many important functions. Good evidence relates the PPN to control of reflex reactions, sleep-wake cycles, posture and gait. However, the precise role of the PPN in all these functions has been controversial and there still are uncertainties in the functional anatomy and physiology of the nucleus. It is difficult to grasp the extent of the influence of the PPN, not only because of its varied functions and projections, but also because of the controversies arising from them. One controversy is its relationship to the mesencephalic locomotor region (MLR). In this regard, the PPN has become a new target for deep brain stimulation (DBS) for the treatment of parkinsonian gait disorders, including freezing of gait. This review is intended to indicate what is currently known, shed some light on the controversies that have arisen, and to provide a framework for future research.     

Use of a physiological reflex to standardize vagal nerve stimulation intensity improves data reproducibility in a memory extinction assay

BackgroundModulating brainstem activity, via electrical vagus nerve stimulation (VNS), influences cognitive functions, including memory. However, controlling for changes in stimulus efficacy during chronic studies, and response variability between subjects, is problematic.Objective/Hypothesis: We hypothesized that recruitment of an autonomic reflex, the Hering-Breuer reflex, would provide robust confirmation of VNS efficacy. We compared this to measurement of electrode resistance over time. We also examined whether VNS modulates contextual memory extinction.MethodsElectrodes for VNS and diaphragm electromyography recording were implanted into anesthetized Sprague Dawley rats. When conscious, we measured the electrode resistance as well as the minimum VNS current required to evoke the Hering-Breuer reflex, before, and after, an inhibitory avoidance assay - a two chamber, dark/light model, where the dark compartment was paired with an aversive foot shock. The extinction of this contextual memory was assessed in sham and VNS treated rats, with VNS administered for 30 s at 1.5 times the Hering-Breuer reflex threshold during extinction memory formation.ResultsAssessment of VNS-evoked Hering-Breuer reflex successfully identified defective electrodes. VNS accelerated extinction memory and decreased multiple physiological metrics of fear expression. We observed an inverse relationship between memory extinction and respiratory rate during the behavioural assay. Additionally, no current - response relationship between VNS and extinction memory formation was established.ConclusionThese data demonstrate that reliable, experimental VNS studies can be produced by verifying reflex initiation as a consequence of stimulation. Further, studies could be standardised by indexing stimulator efficacy to initiation of autonomic reflexes.     

Retractor bulbi muscle responses to oculomotor nerve and nucleus stimulation in the cat

This study demonstratesthe presence of retractor bulbi motoneurons within the oculomotor nucleus which activate muscle units within all 4 slips of the cat retractor bulbi muscle. These muscle units are mechanically different and physiologically separate from retractor bulbi muscle units innervated by the abducens nerve. The retractor bulbi muscle, then, is innervated by two separate pools of motoneurons whose axons are carried in two different cranial nerves. These observations of mechanical properties of retractor bulbi muscle suggest that the oculomotor retractor bulbi motor units may be activated during patterned eye movements.     

Expression and conditioned inhibition of fear-potentiated startle after stimulation and blockade of AMPA/Kainate and GABAA receptors in the dorsal periaqueductal gray

Previous work showed that the dorsal periaqueductal gray is involved in the inhibition of fear-potentiated startle. The present study investigated the effects of blockade and stimulation of Kainate/AMPA and GABA_A receptors within the dorsal periaqueductal gray on expression and conditioned inhibition of fear-potentiated startle. Blockade of the Kainate/AMPA receptors enhanced whereas stimulation of the Kainate/AMPA receptors decreased expression of fear-potentiated startle. These effects do not reflect conditioned inhibition since this modulation was not changed by injections of Kainate/AMPA receptor agonists or antagonists into the dorsal periaqueductal gray. Stimulation and blockade of GABA_A receptors within the dorsal periaqueductal gray neither affected expression of fear-potentiated startle nor its conditioned inhibition. The present results together with findings from the literature indicate that glutamate in the dorsal periaqueductal gray is a critical substrate for the expression and modulation of fear-related behaviours.     

Responses from dorsal column nuclei (DCN) in the monkey to stimulation of upper and lower limbs and spinal cord

Responses from the dorsal surface of the exposed dorsal column nuclei (DCN) in baboons and a monkey (Macaca fascicularis) were recorded in response to electrical stimulation of the posterior tibial nerve at the ankle, the common peroneal nerve at the knee, the sciatic nerve, the spinal cord at T10, and the median nerve at the wrist. Recordings of far-field potentials from the vertex with a non-cephalic reference were made before exposing the DCN and simultaneously with recordings from the DCN. The response recorded from the DCN using a monopolar electrode to median nerve stimulation was a negative deflection (N wave) followed by a large and slow positive wave (P wave). The N wave was often preceded by a small positive deflection. The response from the median nerve to electrical stimulation of the DCN had the same latency as the initial positive peak and the initial portion of the N wave in the response from the DCN to stimulation of the median nerve, indicating that the initial positive peak was generated by presynaptic events in the DCN. The response recorded from the surface of the DCN to stimulation of the lower limbs consisted of many irregular waves followed by a large, positive deflection. Sometimes these irregular waves were superimposed on a small negative peak, and they were preceded by a positive deflection. The response from the tibial nerve to stimulation of the DCN consisted of a series of waves that had the same latency as the waves of the response from the DCN to stimulation of the tibial nerve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transient and steady-state responses to mechanical stimulation of different fingers reveal interactions based on lateral inhibition

Objective

Simultaneous tactile finger stimulation evokes transient ERP responses that are smaller than the linear summation of ERP responses to individual stimulation. Occlusion and lateral inhibition are two possible mechanisms responsible for this effect. The present study disentangles these two effects using steady-state somatosensory evoked potentials (SSSEP). Simultaneous stimulation on adjacent and distant finger pairs with the same and different stimulation frequencies are compared.

Methods

The index finger (IF), middle finger (MF) and little finger (LF) were mechanically stimulated with a frequency of 18, 22 or 26 Hz, respectively. Stimulation was applied for each finger separately, and for the IF (18 Hz) in combination with either the MF or LF for 22 and 26 Hz, respectively. A measure for interaction (IR) was calculated for the P60 component and the SSSEP amplitude.

Results

Significant interactions were found in both the P60 response and in the SSSEP response. Stimulation of adjacent finger combinations caused more interaction than distant finger combinations. No difference was found between stimulation of two fingers with the same or a different frequency.

Conclusions

Our results indicate that lateral inhibition is mainly responsible for the interaction effect.

Significance

These observations provide further insight in the mechanisms behind interaction between somatosensory inputs.     

Oligosynaptic inhibition of group Ia afferents from brachioradialis to triceps brachii motor neurons in humans

Introduction: This study examines effects of low‐threshold afferents from the brachioradialis (BR) on excitability of triceps brachii (TB) motor neurons in humans. Methods: We evaluated the effects using a post stimulus time histogram (PSTH) and electromyogram averaging (EMG‐A) methods in 13 healthy human participants. Electrical conditioning stimulation to the radial nerve branch innervating BR with the intensity below the motor threshold was delivered. Results: In the PSTH study, the stimulation produced a trough (inhibition) in 36/69 TB motor units for all the participants. A cutaneous stimulation never provoked such inhibition. The central latency of the inhibition was 1.5 ± 0.5 ms longer than that of the homonymous facilitation. In the EMG‐A study, the stimulation produced inhibition in EMG‐A of TB in all participants. The inhibition diminished with a tonic vibration stimulation to BR. Discussion: These findings suggest that oligosynaptic inhibition mediated by group Ia afferents from BR to TB exists in humans. Muscle Nerve 57 : 122–128, 2018     

Effects of electrical and chemical stimulation of nucleus raphe magnus on responses to renal nerve stimulation

Electrical stimulation of the nucleus raphe magnus (NRM) inhibits some somatic and visceral input at the spinal level. This study was designed to examine the effects of electrical and chemical stimulation of NRM on neuronal responses to afferent renal nerve (ARN) stimulation. In chloralose-anesthetized rats, electrical stimulation of ARN elicited predominantly excitatory responses in spinal gray neurons. In 10 neurons studied, electrical stimulation of the NRM elicited an inhibition of spontaneous activity of 8 neurons and inhibited evoked responses to ARN stimulation in 6 neurons. Microinjection of glutamate (5-10 nmol in 0.5-1 microliter) into the NRM elicited an inhibition of spontaneous activity in 9 neurons, a facilitation in 6 neurons and no response in 8 neurons receiving ARN input. Responses evoked by ARN stimulation were inhibited in 12 neurons, facilitated in 4 neurons and not affected in 8 neurons. We conclude that renal input can be modulated at the spinal level by activation of the NRM and adjacent tissue. Furthermore, the inhibition of spinal gray neuronal responses elicited by stimulation of the NRM appears to be due, at least in part, to activation of fibers of passage since non-selective electrical stimulation is more efficacious than selective chemical stimulation of neuronal soma and dendrites.