Mechanisms of synaptic transmission.
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Action Potentials↗
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Persistence of PAD and presynaptic inhibition of muscle spindle afferents after peripheral nerve crush.
Two to twelve weeks after crushing a muscle nerve, still before the damaged afferents reinnervate the muscle receptors, conditioning stimulation of group I fibers from flexor muscles depolarizes the damaged afferents [M. Enriquez, I. Jimenez, P. Rudomin, Changes in PAD patterns of group I muscle afferents after a peripheral nerve crush. Exp. Brain Res., 107 (1996), 405-420]. It is not known, however, if this primary afferent depolarization (PAD) is indeed related to presynaptic inhibition. We now show in the cat that 2-12 weeks after crushing the medial gastrocnemius nerve (MG), conditioning stimulation of group I fibers from flexors increases the excitability of the intraspinal terminals of both the intact lateral gastrocnemius plus soleus (LGS) and of the previously damaged MG fibers ending in the motor pool, because of PAD. The PAD is associated with the depression of the pre- and postsynaptic components of the extracellular field potentials (EFPs) evoked in the motor pool by stimulation of either the intact LGS or of the previously damaged MG nerves. These observations indicate, in contrast to what has been reported for crushed cutaneous afferents [K.W. Horch, J.W. Lisney, Changes in primary afferent depolarization of sensory neurones during peripheral nerve regeneration in the cat, J. Physiol., 313 (1981), 287-299], that shortly after damaging their peripheral axons, the synaptic efficacy of group I spindle afferents remains under central control. Presynaptic inhibitory mechanisms could be utilized to adjust the central actions of muscle afferents not fully recovered from peripheral lesions.
Animals↗
Reticulospinal neurons inactivated by warming of the preoptic area and anterior hypothalamus of rabbits.
To identify the premotor neurons for vasoconstrictors of the skin, activities of reticulospinal neurons in the rostroventral medulla, the ear sympathetic nerve (ESNA) and the renal sympathetic nerve (RSNA) were recorded in anesthetized and immobilized Japanese White or New Zealand White rabbits. Two groups of neurons were identified according to their responses to thermal stimulation of the preoptic area and the anterior hypothalamus (POAH) and to electrical stimulation of baroreceptor afferents, the aortic nerve (AN). Neurons (Type I neurons, n = 21) whose activity was inhibited by warm stimulation of the POAH but not inhibited by the AN stimulation were located in sites medial to the rostral ventrolateral medulla (RVLM). The other neurons (Type II neurons, n = 20) whose activity was not inhibited by warm stimulation of the POAH but inhibited by the AN stimulation were located in the RVLM. Because the time course of the inhibitory response of Type I neurons to warm stimulation of the POAH was very similar to that of the inhibitory response of the ESNA and activities of these neurons and the ESNA were not inhibited by the stimulation of the AN, it was suggested the Type I neurons might participate in regulation of activity of the vasoconstrictors of the ear skin. The Type II neurons are considered to be the barosensitive RVLM neurons that regulate systemic arterial pressure by controlling the activity of visceral or muscular sympathetic vasoconstrictors or cardiac sympathetic fibers.
Action Potentials↗
Auditory semantic networks for words and natural sounds.
Does lexical processing rely on a specialized semantic network in the brain, or does it draw on more general semantic resources? The primary goal of this study was to compare behavioral and electrophysiological responses evoked during the processing of words, environmental sounds, and non-meaningful sounds in semantically matching or mismatching visual contexts. A secondary goal was to characterize the dynamic relationship between the behavioral and neural activities related to semantic integration using a novel analysis technique, ERP imaging. In matching trials, meaningful-sound ERPs were characterized by an extended positivity (200-600 ms) that in mismatching trials partly overlapped with centro-parietal N400 and frontal N600 negativities. The mismatch word-N400 peaked later than the environmental sound-N400 and was only slightly more posterior in scalp distribution. Single-trial ERP imaging revealed that for meaningful stimuli, the match-positivity consisted of a sensory P2 (200 ms), a semantic positivity (PS, 300 ms), and a parietal response-related positivity (PR, 500-800 ms). The magnitudes (but not the timing) of the N400 and PS activities correlated with subjects' reaction times, whereas both the latency and magnitude of the PR was correlated with subjects' reaction times. These results suggest that largely overlapping neural networks process verbal and non-verbal semantic information. In addition, it appears that semantic integration operates across different time scales: earlier processes (indexed by the PS and N400) utilize the established meaningful, but not necessarily lexical, semantic representations, whereas later processes (indexed by the PR and N600) are involved in the explicit interpretation of stimulus semantics and possibly of the required response.
Acoustic Stimulation↗
The physiological basis of transcranial motor cortex stimulation in conscious humans.
Transcranial stimulation of the human motor cortex can evoke several different kinds of descending activity depending on the type of stimulation, the intensity of stimulation and the area of the cortex being stimulated. Thus, transcranial magnetic stimulation preferentially activates different structures than transcranial electrical stimulation. In addition, the response to magnetic stimulation depends on the direction of the induced current in the brain, the waveform of the stimulating current, and the shape of the coil. Stimulation of the lower limb area of motor cortex recruits different elements than stimulation of the upper limb area. These differences occur because different structures in the motor cortex have a differential threshold to the different techniques of stimulation. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by the different techniques of transcranial stimulation from the epidural space of conscious patients with chronically implanted spinal electrodes. These recordings provide insights about the physiological basis of the excitatory and inhibitory phenomena produced by transcranial stimulation.
Efferent Pathways↗
Excitability of facial nucleus and related brain-stem reflexes in hemifacial spasm, post-facial palsy synkinesis and facial myokymia.
OBJECTIVE: To compare the electrophysiological excitability characteristics of the facial nucleus and related structures in hemifacial spasm (HFS), post-facial palsy synkinesis (PFPS) and facial myokymia (FM). METHODS: Facial F-waves, blink reflex recoveries and magnetically elicited silent periods (SP) were prospectively studied in 17 HFS, 17 PFPS, 8 FM cases and in 13 controls. Earlier unpublished observations on abnormal impulse transmission in 36 HFS and 29 PFPS cases were also included. RESULTS: Enhanced F-waves were recorded on the symptomatic side in PFPS and HFS cases with a tendency to be more pronounced in PFPS. HFS and PFPS groups both showed an earlier blink reflex recovery, more prominent in PFPS patients, when stimulated and/or recorded on the symptomatic side. Unelicitable SPs were encountered after 24/39 stimulations in 5 patients with PFPS and rarely in HFS cases. Duration of elicitable SPs did not change remarkably. FM group had similar characteristics as normal controls in the 3 electrophysiological tests. Latencies of the lateral and synkinetic spread responses were significantly prolonged in the earlier PFPS group as compared to HFS. In two-point stimulation, both groups showed a greater latency shift in late responses, again more pronounced in PFPS. CONCLUSIONS: PFPS and HFS cases had similar enhanced excitability patterns at the facial nucleus and related brain-stem structures, more marked on the symptomatic side and more obvious in the PFPS group. Findings elicited in the FM group were thought to be caused by asynchronous hyperactivity of facial motoneurons. SIGNIFICANCE: In this comparative electrophysiological study, similar excitability patterns were found in HFS and PFPS groups, albeit with different intensities.
Adolescent↗
Motor cortex excitability after thalamic infarction.
OBJECTIVE: We examined 8 patients with hemihypesthesia due to an ischemic thalamic lesion to explore the effects of a central sensory dysfunction on motor cortex excitability. METHODS: Motor excitability was assessed using transcranial magnetic stimulation techniques and electrical peripheral nerve stimulation. Motor function was evaluated by the Nine-Hole-Peg Test and measurement of hand grip strength. The affected side was compared with the non-lesioned side and with an age-matched control group. RESULTS: Patients had a loss of inhibition and an increase of facilitation in the motor cortex of the affected side. The silent period was prolonged and motor function was impaired on the affected side. CONCLUSIONS: A thalamic lesion can modulate motor cortical excitability. SIGNIFICANCE: This study suggests that, under normal conditions, somatosensory afferents influence inhibitory and excitatory properties in the motor cortex.
Adult↗
Half sine, monophasic and biphasic transcranial magnetic stimulation of the human motor cortex.
OBJECTIVE: To compare half sine transcranial magnetic stimuli (TMS) with conventional monophasic and biphasic stimuli, measuring resting and active motor threshold, motor evoked potential (MEP) input/output curve, MEP latency, and silent period duration. METHODS: We stimulated the dominant hand representation of the motor cortex in 12 healthy subjects utilising two different MagPro stimulators to generate TMS pulses of distinct monophasic, half sine and biphasic shape with anteriorly or posteriorly directed current flow. RESULTS: The markedly asymmetric monophasic pulse with a posterior current flow in the brain yielded a higher motor threshold, a less steep MEP input/output curve and a longer latency than all other TMS types. Similar but less pronounced results were obtained with a less asymmetric half sine pulses. The biphasic stimuli yielded the lowest motor threshold and a short latency, particularly with the posterior current direction. CONCLUSIONS: The more asymmetric the monophasic pulse, the stronger the difference to biphasic pulses. The 3rd and 4th quarter cycle of the biphasic waveform make it longer than any other waveform studied here and likely contribute to lowering motor threshold, shortening MEP latency and reversing the influence of current direction. SIGNIFICANCE: This systematic comparison of 3 waveforms and two current directions allows a better understanding of the mechanisms of TMS.
Adult↗
Transcallosal inhibition in amyotrophic lateral sclerosis.
OBJECTIVE: Assessment of upper motor neuron (UMN) involvement is essential for the diagnosis of amyotrophic lateral sclerosis (ALS). In a number of ALS cases, mirror movements (MM) suggest an involvement of transcallosal fibre tracts in conjunction with UMN involvement. The present study analysed whether deficient transcallosal inhibition (TI) tested by TMS enables detection of cortical affection in ALS, even at early stages of the disease. METHODS: In three patients with definite ALS and 12 patients with early ALS (aged 64.1+/-7.8 years) TMS investigation included analysis of contralateral (cMEP) and ipsilateral (iMEP) motor evoked potentials as well as measurement of TI (latency, duration) with recording from both first dorsal interosseus muscles. RESULTS: Clinical UMN signs were present in four patients. 83.3% of patients showed a pathological TI (prolongation or loss of TI). Five out of eight ALS patients showing a pathological TI had no clinical UMN signs. Two of these patients showed MM. One patient displayed also pathological findings in TI investigation. CONCLUSIONS: Our findings suggest a functional deficit of transcallosal fibre tracts even at early stages of the disease still lacking clinical UMN signs. SIGNIFICANCE: Measurement of TI tested by TMS can detect an involvement of the cortical output system in ALS and may be helpful in an early assessment of the diagnosis.
Aged↗
Immature developmental pattern of the monosynaptic reflex in isolated spinal cord of glial mutant taiep rats.
There is increasing evidence suggesting that glial cells play a crucial role in the formation and maturation of neural circuits. However, little is known about the effects of glial alterations on the establishment of functional circuitry in vivo during the development. The taiep rat, a long-lived neurological mutant characterized by early astrogliosis and demyelination affecting selectively the CNS, provides an interesting model to study the glia-neuron interaction in situ. In the present study, we evaluated the functional development of segmental neural circuits recording the monosynaptic reflex responses (MSR) in the isolated spinal cord of neonatal taiep rats. To evaluate the developmental changes during the first two postnatal weeks, we measured the latency of MSR, the magnitude of depression to paired pulses and the time course of post-tetanic recovery. During the early postnatal period, the MSR of control rats reduced their latency and decreased their sensitivity to depression, as a function of age. By contrast, the MSR of taiep rats failed to develop further from neonatal stage. Near the end of the second postnatal week, the MSR latencies were still prolonged, and the MSR showed a significantly stronger paired pulse depression, and higher post-tetanic recovery times than the age-matched controls. The lack of MSR maturation in taiep rats suggests an early alteration of functional mechanisms underlying the maturation of the spinal reflexes, probably due to the characteristic glial dysfunction(s) of this mutant.
Animals↗
Facilitation and inhibition of withdrawal reflexes following repetitive stimulation: electro- and psychophysiological evidence for activation of noxious inhibitory controls in humans.
A systematic evaluation of nociceptive withdrawal reflexes and pain rating was undertaken in order to explore the mechanisms underlying temporal summation of repetitive electrocutaneous stimulation in healthy individuals (n=12; age=27.5+/-1.5 years). Five-second subreflex threshold (RT) electrocutaneous stimulation at different frequencies (single stimulus, 5, 10, and 20 Hz) and intensities (0.6RT and 0.8RT) was applied on the dorsum of the foot, and the withdrawal reflex from the ipsilateral biceps femoris muscle was measured. The subjects scored the pain intensity on a visual analogue scale (0-100 mm) for the beginning, the middle and the end phase of the 5 s series of stimulation, and the respective averaged reflex size was calculated. The reflex size increased at stimulus frequencies 10 Hzx0.8RT and 20 Hzx0.8RT as compared with 5 Hzx0.8RT (SNK, P<0.05), and by an increase in current intensity from 0.6RT to 0.8RT (SNK, P<0.05). Pain intensity increased with the increase in the current intensity from 0.6RT to 0.8RT (SNK, P<0.05). Profound activation of inhibition following electrocutaneous pain stimuli was demonstrated by reduction in pain intensity and reflex size during the last second as compared with the first second at 0.6RT current intensity (SNK, P<0.05). The pain intensity peaked between 5 and 10 Hz (P<0.05) and was reduced at 20 Hz for current intensities at 0.8RT (P<0.05). This study provides evidence for both frequency dependent central integration of the repetitive electrocutaneous stimuli and activation of a pain inhibitory system by psychophysical and electrophysiological means, demonstrating the delicate balance between neuronal facilitation and inhibition in the human pain system.
Adult↗
Lateral asymmetry in the ABR of neonates: evidence and mechanisms.
Lateralized processing of auditory stimuli occurs at the level of the auditory cortex but differences in function between the left and right sides are not clear at lower levels of the auditory system. The current study is designed to (1) investigate asymmetric auditory function at the ear and brainstem in human infants and (2) investigate possible mechanisms for asymmetry at these levels. Study 1 evaluated auditory brainstem responses (ABRs) in response to high and low-level clicks presented to the right and left ears of neonates. Wave V was significantly larger in amplitude and waves III and V were shorter in latency when the ABR was generated in the right ear. Study 2 investigated two possible mechanisms of such asymmetry by (a) using contralateral white noise masking to activate the medial olivocochlear system and (b) increasing stimulus rate to reveal neural conduction and synaptic mechanisms. ABR wave V, evoked by clicks to the left ear, showed a greater reduction in amplitude with contralateral noise than the response evoked from the right ear. No systematic asymmetries in ABR latencies or amplitudes were found with increased stimulus rate. We conclude that (1) the click-evoked ABR in neonates demonstrates asymmetric auditory function with a small but significant right ear advantage and (2) asymmetric activation of the medial olivocochlear system, specifically greater contralateral suppression of ABR produced by the left ear, is a possible mechanism for asymmetry.
Acoustic Stimulation↗
A computer model of field potential responses for the study of short-term plasticity in hippocampus.
Activity-dependent synaptic plasticity has important implications for network function. The previously developed model of the hippocampal CA1 area, which contained pyramidal cells (PC) and two types of interneurons involved in feed-forward and recurrent inhibition, respectively, and received synaptic inputs from CA3 neurons via the Schaffer collaterals, was enhanced by incorporating dynamic synaptic connections capable of changing their weights depending on presynaptic activation history. The model output was presented as field potentials, which were compared with those derived experimentally. The parameters of Schaffer collateral-PC excitatory model synapse were determined, with which the model successfully reproduced the complicated dynamics of train-stimulation sequential potentiation/depression observed in experimentally recorded field responses. It was found that the model better reproduces the time course of experimental field potentials if the inhibitory synapses on PC are also made dynamic, with expressed properties of frequency-dependent depression. This finding supports experimental evidence that these synapses are subject to activity-dependent depression. The model field potentials in response to various randomly generated and real (derived from recorded CA3 unit activity) long stimulating trains were calculated, illustrating that short-term plasticity with the observed characteristics could play specific roles in frequency processing in hippocampus and thus providing a new tool for the theoretical study of activity-dependent synaptic plasticity.
Animals↗
Day-night variations in zinc sensitivity of GABAA receptor-channels in rat suprachiasmatic nucleus.
In the suprachiasmatic nucleus (SCN), electrical activity, secretion, and other cellular functions undergo profound rhythm during day-night cycle due to oscillatory expression of clock gene constituents. Although SCN is enriched with gamma-aminobutyric acid (GABA)-ergic neurons, it is unknown whether there are circadian changes in the GABAA receptor expression and/or function. Here we investigated the possible daily variations in zinc sensitivity of GABAA channels in rat SCN neurons maintained in brain slices. Extracellular zinc inhibited GABA-induced currents in all ventrolateral (VL) and dorsomedial (DM) SCN neurons studied, as well as in neurons of non-SCN regions. In SCN neurons, the currents evoked by 30 microM GABA were inhibited by Zn2+ with an IC50 of 50.3+/-3.2 microM, whereas currents evoked by 100 microM GABA were inhibited with an IC50 of 181.6+/-32.0 microM. The antagonist action of zinc saturated at 97.4+/-0.7% for 30 microM GABA and 91.6+/-2.7% for 100 microM GABA. These observations indicate that Zn2+ inhibits SCN GABAA receptor competitively and in part non-competitively. In SCN neurons, but not in other neurons, the zinc sensitivity varied with daily time. During the day, the calculated IC50 for zinc was significantly lower than during the night (43.9+/-4.7 microM vs. 58.6+/-3.8, respectively). These results indicate that native GABAA receptors in SCN neurons display pharmacological properties of receptors having and not having gamma subunit and that the proportionality of these receptors could change during the day and night.
Animals↗
Spinal and cortical spreading depression enhance spinal cord activity.
Cortical spreading depression (CSD) has been suggested to underlie some neurological disorders such as migraine. Despite the intensity with which many investigators have studied SD in the brain, only a few studies have aimed to identify SD in the spinal cord. Here we described the main characteristic features of SD in the spinal cord induced by different methods including various spinal cord injury models and demonstrated that SD enhances the spinal cord activity following a transient suppressive period. These findings suggest that SD may play a role in the mechanisms of spinal neurogenic shock, spinal cord injury, and pain. Furthermore, we studied the effect of CSD on the neuronal activity of the spinal cord. CSD was induced via cortical pinprick injury or KCl injection in the somatosensory cortex. CSD did not propagate into the cervical spinal cord. However, intracellular recordings of the neurons in the dorsal horn of C2 segment, ipsilateral to the hemisphere in which CSD was evoked, showed a transient suppression of spontaneous burst discharges, followed by a significant enhancement of the neuronal activity. This indicates a link between a putative cause of the neurological symptoms and the subsequent pain of migraine.
Action Potentials↗
Effects of phencyclidines on signal transfer from the entorhinal cortex to the hippocampus in rats.
The information transfer from the superficial layers of the entorhinal cortex (EC) to the hippocampus is regulated in a frequency dependent manner. Phencyclidine and related compounds such as MK-801 produce psychotic symptoms that closely resemble schizophrenia. We studied the effects of systemic administration of MK-801 on the signal transfer from the EC layer III to the hippocampal area CA1. High frequency (above 10 Hz) activation of the bi-synaptic entorhinal input in control animals results in a strong suppression of the field potentials in the stratum lacunosum-moleculare of the area CA1. In contrast, in MK-801 pretreated rats the field response was less reduced. The field potential responses evoked in these two groups of animals by high-frequency activation of the monosynaptic input were similar suggesting selective alterations in layer III of the medial EC. We suggest, that MK-801 causes disinhibition of layer III projection cells and, therefore, may cause strong, pathological activation of direct layer III-CA1 pathway.
Action Potentials↗
Short-term high-frequency transcutaneous electrical nerve stimulation decreases human motor cortex excitability.
Several previous studies have shown that periods of changed sensory input can have after effects on the excitability of the corticospinal system. Here we test whether the parameters of peripheral stimulation conventionally used to treat pain with transcutaneous electrical nerve stimulation (TENS: 90 Hz) also have modulatory effects on the motor system. We measured the amplitude of motor evoked potentials (MEPs) elicited by the focal transcranial magnetic stimulation in the right abductor pollicis brevis and first dorsal interosseous muscles before and after 30 min TENS over the right thenar eminence. In addition, we evaluated tactile and 2-point discrimination thresholds at the same site. TENS transiently reduced MEPs and increased sensory thresholds. This suggests that short-term TENS might have an inhibitory effect on both the sensory and motor systems.
Adult↗
Seeking a mechanism of action for the novel anticonvulsant lacosamide.
Lacosamide (LCM) is anticonvulsant in animal models and is in phase 3 assessment for epilepsy and neuropathic pain. Here we seek to identify cellular actions for the new drug and effects on recognised target sites for anticonvulsant drugs. Radioligand binding and electrophysiology were used to study the effects of LCM at well-established mammalian targets for clinical anticonvulsants. 10 microM LCM did not bind with high affinity to a plethora of rodent, guinea pig or human receptor sites including: AMPA; Kainate; NMDA (glycine/PCP/MK801); GABA(A) (muscimol/benzodiazepine); GABA(B); adenosine A1,2,3; alpha1, alpha2; beta1, beta2; M1,2,3,4,5; H1,2,3; CB1,2; D1,2,3,4,5; 5HT1A,1B,2A,2C,3,5A,6,7 and KATP. Weak displacement (25%) was evident at batrachotoxin site 2 on voltage gated Na+ channels. LCM did not inhibit neurotransmitter transport mechanisms for norepinephrine, dopamine, 5-HT or GABA, nor did it inhibit GABA transaminase. LCM at 100 microM produced a significant reduction in the incidence of excitatory postsynaptic currents (EPSC's) and inhibitory postsynaptic currents (IPSC's) in cultured cortical cells and blocked spontaneous action potentials (EC50 61 microM). LCM did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. The voltage-gated sodium channel (VGSC) blocker phenytoin potently blocked sustained repetitive firing (SRF) but, in contrast, 100 microM LCM failed to block SRF. No effect was observed on voltage-clamped Ca2+ channels (T-, L-, N- or P-type). Delayed-rectifier or A-type potassium currents were not modulated by LCM (100 microM). LCM did not mimic the effects of diazepam as an allosteric modulator of GABA(A) receptor currents, nor did it significantly modulate evoked excitatory neurotransmission mediated by NMDA or AMPA receptors (n > or = 5). Evidently LCM perturbs excitability in primary cortical cultures but does not appear to do so via a high-affinity interaction with an acknowledged recognition site on a target for existing antiepileptic drugs.
Acetamides↗