Extensive Cortical Convergence to Primate Reticulospinal Pathways.

Early evolution of the motor cortex included development of connections to brainstem reticulospinal neurons; these projections persist in primates. In this study, we examined the organization of corticoreticular connections in five macaque monkeys (one male) using both intracellular and extracellular recordings from reticular formation neurons, including identified reticulospinal cells. Synaptic responses to stimulation of different parts of primary motor cortex (M1) and supplementary motor area (SMA) bilaterally were assessed. Widespread short latency excitation, compatible with monosynaptic transmission over fast-conducting pathways, was observed, as well as longer latency responses likely reflecting a mixture of slower monosynaptic and oligosynaptic pathways. There was a high degree of convergence: 56% of reticulospinal cells with input from M1 received projections from M1 in both hemispheres; for SMA, the equivalent figure was even higher (70%). Of reticulospinal neurons with input from the cortex, 78% received projections from both M1 and SMA (regardless of hemisphere); 83% of reticulospinal cells with input from M1 received projections from more than one of the tested M1 sites. This convergence at the single cell level allows reticulospinal neurons to integrate information from across the motor areas of the cortex, taking account of the bilateral motor context. Reticulospinal connections are known to strengthen following damage to the corticospinal tract, such as after stroke, partially contributing to functional recovery. Extensive corticoreticular convergence provides redundancy of control, which may allow the cortex to continue to exploit this descending pathway even after damage to one area.SIGNIFICANCE STATEMENT The reticulospinal tract (RST) provides a parallel pathway for motor control in primates, alongside the more sophisticated corticospinal system. We found extensive convergent inputs to primate reticulospinal cells from primary and supplementary motor cortex bilaterally. These redundant connections could maintain transmission of voluntary commands to the spinal cord after damage (e.g., after stroke or spinal cord injury), possibly assisting recovery of function.

Classification of Neurons in the Primate Reticular Formation and Changes after Recovery from Pyramidal Tract Lesion.

The reticular formation is important in primate motor control, both in health and during recovery after brain damage. Little is known about the different neurons present in the reticular nuclei. Here we recorded extracellular spikes from the reticular formation in five healthy female awake behaving monkeys (193 cells), and in two female monkeys 1 year after recovery from a unilateral pyramidal tract lesion (125 cells). Analysis of spike shape and four measures derived from the interspike interval distribution identified four clusters of neurons in control animals. Cluster 1 cells had a slow firing rate. Cluster 2 cells had narrow spikes and irregular firing, which often included high-frequency bursts. Cluster 3 cells were highly rhythmic and fast firing. Cluster 4 cells showed negative spikes. A separate population of 42 cells was antidromically identified as reticulospinal neurons in five anesthetized female monkeys. The distribution of spike width in these cells closely overlaid the distribution for cluster 2, leading us tentatively to suggest that cluster 2 included neurons with reticulospinal projections. In animals after corticospinal lesion, cells could be identified in all four clusters. The firing rate of cells in clusters 1 and 2 was increased in lesioned animals relative to control animals (by 52% and 60%, respectively); cells in cluster 2 were also more regular and more bursting in the lesioned animals. We suggest that changes in both membrane properties and local circuits within the reticular formation occur following lesioning, potentially increasing reticulospinal output to help compensate for lost corticospinal descending drive.SIGNIFICANCE STATEMENT This work is the first to subclassify neurons in the reticular formation, providing insights into the local circuitry of this important but little understood structure. The approach developed can be applied to any extracellular recording from this region, allowing future studies to place their data within our current framework of four neural types. Changes in reticular neurons may be important to subserve functional recovery after damage in human patients, such as after stroke or spinal cord injury.

Different contributions of primary motor cortex, reticular formation, and spinal cord to fractionated muscle activation.

Coordinated movement requires patterned activation of muscles. In this study, we examined differences in selective activation of primate upper limb muscles by cortical and subcortical regions. Five macaque monkeys were trained to perform a reach and grasp task, and electromyogram (EMG) was recorded from 10 to 24 muscles while weak single-pulse stimuli were delivered through microelectrodes inserted in the motor cortex (M1), reticular formation (RF), or cervical spinal cord (SC). Stimulus intensity was adjusted to a level just above threshold. Stimulus-evoked effects were assessed from averages of rectified EMG. M1, RF, and SC activated 1.5 ± 0.9, 1.9 ± 0.8, and 2.5 ± 1.6 muscles per site (means ± SD); only M1 and SC differed significantly. In between recording sessions, natural muscle activity in the home cage was recorded using a miniature data logger. A novel analysis assessed how well natural activity could be reconstructed by stimulus-evoked responses. This provided two measures: normalized vector length L, reflecting how closely aligned natural and stimulus-evoked activity were, and normalized residual R, measuring the fraction of natural activity not reachable using stimulus-evoked patterns. Average values for M1, RF, and SC were L = 119.1 ± 9.6, 105.9 ± 6.2, and 109.3 ± 8.4% and R = 50.3 ± 4.9, 56.4 ± 3.5, and 51.5 ± 4.8%, respectively. RF was significantly different from M1 and SC on both measurements. RF is thus able to generate an approximation to the motor output with less activation than required by M1 and SC, but M1 and SC are more precise in reaching the exact activation pattern required. Cortical, brainstem, and spinal centers likely play distinct roles, as they cooperate to generate voluntary movements. NEW & NOTEWORTHY Brainstem reticular formation, primary motor cortex, and cervical spinal cord intermediate zone can all activate primate upper limb muscles. However, brainstem output is more efficient but less precise in producing natural patterns of motor output than motor cortex or spinal cord. We suggest that gross muscle synergies from the reticular formation are sculpted and refined by motor cortex and spinal circuits to reach the finely fractionated output characteristic of dexterous primate upper limb movements.

Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits.

Injury to the mature motor system drives significant spontaneous axonal sprouting instead of axon regeneration. Knowing the circuit-level determinants of axonal sprouting is important for repairing motor circuits after injury to achieve functional rehabilitation. Competitive interactions are known to shape corticospinal tract axon outgrowth and withdrawal during development. Whether and how competition contributes to reorganization of mature spinal motor circuits is unclear. To study this question, we examined plastic changes in corticospinal axons in response to two complementary proprioceptive afferent manipulations: (1) enhancing proprioceptive afferents activity by electrical stimulation; or (2) diminishing their input by dorsal rootlet rhizotomy. Experiments were conducted in adult rats. Electrical stimulation produced proprioceptive afferent sprouting that was accompanied by significant corticospinal axon withdrawal and a decrease in corticospinal connections on cholinergic interneurons in the medial intermediate zone and C boutons on motoneurons. In contrast, dorsal rootlet rhizotomy led to a significant increase in corticospinal connections, including those on cholinergic interneurons; C bouton density increased correspondingly. Motor cortex-evoked muscle potentials showed parallel changes to those of corticospinal axons, suggesting that reciprocal corticospinal axon changes are functional. Using the two complementary models, we showed that competitive interactions between proprioceptive and corticospinal axons are an important determinant in the organization of mature corticospinal axons and spinal motor circuits. The activity- and synaptic space-dependent properties of the competition enables prediction of the remodeling of spared corticospinal connection and spinal motor circuits after injury and informs the target-specific control of corticospinal connections to promote functional recovery. SIGNIFICANCE STATEMENT: Neuroplasticity is limited in maturity, but it is promoted after injury. Axons of the major descending motor pathway for motor skills, the corticospinal tract (CST), sprout after brain or spinal cord injury. This contributes to spontaneous spinal motor circuit repair and partial motor recovery. Knowing the determinants that enhance this plasticity is critical for functional rehabilitation. Here we examine the remodeling of CST axons directed by sensory fibers. We found that the CST projection is regulated dynamically in maturity by the competitive, activity-dependent actions of sensory fibers. Knowledge of the properties of this competition enables prediction of the remodeling of CST connections and spinal circuits after injury and informs ways to engineer target-specific control of CST connections to promote recovery.

Changes in descending motor pathway connectivity after corticospinal tract lesion in macaque monkey.

Damage to the corticospinal tract is a leading cause of motor disability, for example in stroke or spinal cord injury. Some function usually recovers, but whether plasticity of undamaged ipsilaterally descending corticospinal axons and/or brainstem pathways such as the reticulospinal tract contributes to recovery is unknown. Here, we examined the connectivity in these pathways to motor neurons after recovery from corticospinal lesions. Extensive unilateral lesions of the medullary corticospinal fibres in the pyramidal tract were made in three adult macaque monkeys. After an initial contralateral flaccid paralysis, motor function rapidly recovered, after which all animals were capable of climbing and supporting their weight by gripping the cage bars with the contralesional hand. In one animal where experimental testing was carried out, there was (as expected) no recovery of fine independent finger movements. Around 6 months post-lesion, intracellular recordings were made from 167 motor neurons innervating hand and forearm muscles. Synaptic responses evoked by stimulating the unlesioned ipsilateral pyramidal tract and the medial longitudinal fasciculus were recorded and compared with control responses in 207 motor neurons from six unlesioned animals. Input from the ipsilateral pyramidal tract was rare and weak in both lesioned and control animals, suggesting a limited role for this pathway in functional recovery. In contrast, mono- and disynaptic excitatory post-synaptic potentials elicited from the medial longitudinal fasciculus significantly increased in average size after recovery, but only in motor neurons innervating forearm flexor and intrinsic hand muscles, not in forearm extensor motor neurons. We conclude that reticulospinal systems sub-serve some of the functional recovery after corticospinal lesions. The imbalanced strengthening of connections to flexor, but not extensor, motor neurons mirrors the extensor weakness and flexor spasm which in neurological experience is a common limitation to recovery in stroke survivors.

Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease.

In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15-30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15-30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control subjects, we estimated the likelihood that a given measurement reflects corticospinal tract degeneration. Therefore, intermuscular coherence has potential as a quantitative test of subclinical upper motor neuron involvement in motor neuron disease.

Reticular formation responses to magnetic brain stimulation of primary motor cortex.

Transcranial magnetic stimulation (TMS) of cerebral cortex is a popular technique for the non-invasive investigation of motor function. TMS is often assumed to influence spinal circuits solely via the corticospinal tract. We were interested in possible trans-synaptic effects of cortical TMS on the ponto-medullary reticular formation in the brainstem, which is the source of the reticulospinal tract and could also generate spinal motor output. We recorded from 210 single units in the reticular formation of three anaesthetized macaque monkeys whilst TMS was performed over primary motor cortex. Short latency responses were observed consistent with activation of a cortico-reticular pathway. However, we also demonstrated surprisingly powerful responses at longer latency, which often appeared at lower threshold than the earlier effects. These late responses seemed to be generated partly as a consequence of the sound click made by coil discharge, and changed little with coil location. This novel finding has implications for the design of future studies using TMS, as well as suggesting a means of non-invasively probing an otherwise inaccessible important motor centre.

NIRS-measured oxy- and deoxyhemoglobin changes associated with EEG spike-and-wave discharges in a genetic model of absence epilepsy: the GAERS.

PURPOSE: Absence epilepsy may be severe and is frequently accompanied by cognitive delay, yet its metabolic/hemodynamic aspects have not been established. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an isomorphic, predictive, and homologous model of human absence epilepsy. We studied hemodynamic changes related to generalized spike-and-wave discharges (GSWDs) in GAERS by using a technique with high temporal resolution: near-infrared spectroscopy (NIRS). We hypothesized that conflicting results from other techniques might be due to the averaging of a biphasic response such as the one we described in children. METHODS: NIRS is particularly suitable for monitoring changes in the concentrations of oxy-, deoxy-, and total hemoglobin (HbO2, HHb, and HbT), using the specific absorption properties of living tissues in the near infrared range. We obtained concomitant high quality electroencephalography (EEG)-NIRS recordings in six GAERS (total of 444 seizures), and tested whether the discharges were related to changes in cardiac or respiration rates. RESULTS: The onset of GSWDs was preceded by a deactivation, followed by an activation that was possibly due to seizure-suppression mechanisms. The end was marked by a deactivation. The onset of GSWDs was associated with a decrease and the end with a brief increase in respiratory rate. DISCUSSION: Our results differ partially from those of previous studies on hemodynamic aspects of GSWDs (many of which describe a simple deactivation), probably due to differences in temporal resolution and data processing; however, they are consistent with metabolic studies, functional magnetic resonance imaging (fMRI) studies on WAG/Rij rats, and some results in children with absence epilepsy.

Early Disruption of Cortical Sleep-Related Oscillations in a Mouse Model of Dementia With Lewy Bodies (DLB) Expressing Human Mutant (A30P) Alpha-Synuclein.

Changes in sleep behavior and sleep-related cortical activity have been reported in conditions associated with abnormal alpha-synuclein (α-syn) expression, in particular Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Notably, changes can occur in patients years before the onset of cognitive decline. Sleep-related network oscillations play a key role in memory function, but how abnormal α-syn impacts the generation of such activity is currently unclear. To determine whether early changes in sleep-related network activity could also be observed, prior to any previously reported cognitive dysfunction, we used mice that over-express human mutant α-syn (A30P). Recordings in vivo were performed under urethane anesthesia in the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus in young male (2.5 - 4 months old) A30P and age-matched wild type (WT) mice. We found that the slow oscillation (SO) < 1 Hz frequency was significantly faster in both the mPFC and hippocampus in A30P mice, and Up-state-associated fast oscillations at beta (20 - 30 Hz) and gamma (30 - 80 Hz) frequencies were delayed relative to the onset of the Up-state. Spindle (8 - 15 Hz) activity in the mPFC was also altered in A30P mice, as spindles were shorter in duration and had reduced density compared to WT. These changes demonstrate that dysregulation of sleep-related oscillations occurs in young A30P mice long before the onset of cognitive dysfunction. Our data suggest that, as seen in patients, changes in sleep-related oscillations are an early consequence of abnormal α-syn aggregation in A30P mice.

Vagus nerve stimulation induces changes in respiratory sinus arrhythmia of epileptic children during sleep.

PURPOSE: This study analyzed the direct short-term effect of vagus nerve stimulation (VNS) on respiratory sinus arrhythmia (RSA) in children with pharmacoresistant epilepsy. METHODS: RSA magnitude is calculated as the ratio between maximum and minimum heart rate for each respiratory cycle-before, during, and after the actual VNS period. In 10 children, changes in RSA magnitude were evaluated on polysomnographic recordings, including electrocardiography (ECG), electroencephalography (EEG), thoracoabdominal distension, nasal airflow, and VNS artifacts. Measurements during stimulation were compared with those at baseline, immediately preceding the VNS periods and individually for each patient. RESULT: During VNS, respiratory frequency increased and respiratory amplitude decreased with a variable effect on cardiac activity. The coupling between heart rate and respiratory rate was disturbed and RSA magnitude decreased significantly in 6 of 10 children during VNS. These changes in RSA magnitude varied from one child to another. The observed changes for respiratory and cardiac activity were concomitant with changes in RSA but were not correlated. CONCLUSION: Together with disorders of respiration, cardiac activity, and oxygen saturation (SaO(2)) described previously. VNS also modifies synchronization between cardiac and respiratory activity, resulting in poor optimization of oxygen delivery to tissues that can be regarded as an additive side effect, which should be considered in patients with already altered brain function. This interaction between the effects of VNS and potential autonomic nervous system (ANS) dysfunction already reported in epileptic patients should be considered to be potentially life-threatening. In addition, evaluation of changes in respiratory parameters can also provide reliable markers for further evaluation of the effectiveness of VNS.

NIRS-measured oxy- and deoxyhemoglobin changes associated with EEG spike-and-wave discharges in children.

PURPOSE: Absence epilepsy is characterized by 3-Hz generalized spike-and-wave discharges (GSWD) on the electroencephalogram, associated with behavioral arrest. It may be severe, and even in childhood benign absence epilepsy cognitive delay is frequent, yet the metabolic/hemodynamic aspects of this kind of epilepsy have not been established. We aimed to determine if the GSWD were related to hemodynamic changes by using a new technique with high temporal resolution: near infrared spectroscopy (NIRS). METHODS: NIRS is gaining acceptance as a technique particularly suitable for routine follow-up in children, using the specific absorption properties of living tissues in the near infrared range to measure changes in the concentrations of oxy-, deoxy- and total hemoglobin (HbO(2), HHb, and HbT, respectively). We performed simultaneous electroencephalography (EEG) and left frontal NIRS recordings in six children with GSWD. We also tested if the discharges were related to changes in cardiac or respiratory rates. RESULTS: GSWD were associated in the frontal area with an oxygenation (beginning 10 s before the GSWD) followed by strong deoxygenation, then oxygenation again with [HbT] increase, and a return to baseline. We did not identify any relationship between the onset of the GSWD and heart or respiratory rates. DISCUSSION: Our results partially differ from previous studies on GSWD hemodynamic aspects (many of which described a simple deactivation), probably due to differences in temporal resolution and data processing. Simultaneous acquisition of EEG and NIRS can optimize the use of both techniques and help shed light on the mechanisms underlying spike-and-wave discharges.

Cardiorespiratory effects induced by vagus nerve stimulation in epileptic children.

Vagus nerve stimulation (VNS) is used in pharmaco-resistant epilepsy to decrease the number of seizures. Although it is well known that VNS affects respiration, there are only a few reports concerning an effect of VNS on heart rate or heart rate variability (HRV). We investigated the relationship between respiratory frequency and the high frequency (HF) domain of the discrete Fourier transform (DFT) of the RR interval function during night sleep recordings of ten subjects treated with VNS. Our results show that VNS shifts the frequency of maximal power spectrum density (PSD) in the HF-band, decreases the related PSD and induces a partial cardiorespiratory decoupling.

Pathways mediating functional recovery.

Following damage to the motor system (e.g., after stroke or spinal cord injury), recovery of upper limb function exploits the multiple pathways which allow motor commands to be sent to the spinal cord. Corticospinal fibers originate from premotor as well as primary motor cortex. While some corticospinal fibers make direct monosynaptic connections to motoneurons, there are also many connections to interneurons which allow control of motoneurons indirectly. Such interneurons may be placed within the cervical enlargement, or more rostrally (propriospinal interneurons). In addition, connections from cortex to the reticular formation in the brainstem allow motor commands to be sent over the reticulospinal tract to these spinal centers. In this review, we consider the relative roles of these different routes for the control of hand function, both in healthy primates and after recovery from lesion.

Multi-electrode stimulation in somatosensory cortex increases probability of detection.

OBJECTIVE: Brain machine interfaces (BMIs) that decode control signals from motor cortex have developed tremendously in the past decade, but virtually all rely exclusively on vision to provide feedback. There is now increasing interest in developing an afferent interface to replace natural somatosensation, much as the cochlear implant has done for the sense of hearing. Preliminary experiments toward a somatosensory neuroprosthesis have mostly addressed the sense of touch, but proprioception, the sense of limb position and movement, is also critical for the control of movement. However, proprioceptive areas of cortex lack the precise somatotopy of tactile areas. We showed previously that there is only a weak tendency for neighboring neurons in area 2 to signal similar directions of hand movement. Consequently, stimulation with the relatively large currents used in many studies is likely to activate a rather heterogeneous set of neurons. APPROACH: Here, we have compared the effect of single-electrode stimulation at subthreshold levels to the effect of stimulating as many as seven electrodes in combination. MAIN RESULTS: We found a mean enhancement in the sensitivity to the stimulus (d') of 0.17 for pairs compared to individual electrodes (an increase of roughly 30%), and an increase of 2.5 for groups of seven electrodes (260%). SIGNIFICANCE: We propose that a proprioceptive interface made up of several hundred electrodes may yield safer, more effective sensation than a BMI using fewer electrodes and larger currents.

Limb-state information encoded by peripheral and central somatosensory neurons: implications for an afferent interface.

A major issue to be addressed in the development of neural interfaces for prosthetic control is the need for somatosensory feedback. Here, we investigate two possible strategies: electrical stimulation of either dorsal root ganglia (DRG) or primary somatosensory cortex (S1). In each approach, we must determine a model that reflects the representation of limb state in terms of neural discharge. This model can then be used to design stimuli that artificially activate the nervous system to convey information about limb state to the subject. Electrically activating DRG neurons using naturalistic stimulus patterns, modeled on recordings made during passive limb movement, evoked activity in S1 that was similar to that of the original movement. We also found that S1 neural populations could accurately discriminate different patterns of DRG stimulation across a wide range of stimulus pulse-rates. In studying the neural coding in S1, we also decoded the kinematics of active limb movement using multi-electrode recordings in the monkey. Neurons having both proprioceptive and cutaneous receptive fields contributed equally to this decoding. Some neurons were most informative of limb state in the recent past, but many others appeared to signal upcoming movements suggesting that they also were modulated by an efference copy signal. Finally, we show that a monkey was able to detect stimulation through a large percentage of electrodes implanted in area 2. We discuss the design of appropriate stimulus paradigms for conveying time-varying limb state information, and the relative merits and limitations of central and peripheral approaches.

Animal model of the short-term cardiorespiratory effects of intermittent vagus nerve stimulation.

PURPOSE: To develop an animal model of the effects of vagus nerve stimulation (VNS) on heart rate and respiration in studies of seizure treatment. METHODS: Nine rats implanted with ECG, EMG, and VNS electrodes and pulse generator were stimulated with 81 different sets of parameters while they slept in a plethysmographic box. RESULT: From cardiorespiratory effects of VNS, an index (alpha) was found to distinguish between weak and strong VNS doses. Weak VNS dose induced an increase in respiratory frequency and no significant change in heart rate. The effect of VNS on respiration, similar to that observed in children, can be divided into 3 phases. Strong VNS dose induced a decrease in respiratory frequency concomitant with a decrease in heart rate. Increasing the intensity of the VNS induced a proportional increase in the maximal inspiratory strength. CONCLUSION: Various VNS parameter settings induce different and concomitant cardiorespiratory variations in conscious sleeping rats. These effects correlate with the intensity of the VNS parameters. Understanding the effects of the intensity of VNS parameters may allow for further optimization of VNS parameters in patients receiving VNS.

Vagus nerve stimulation therapy induces changes in heart rate of children during sleep.

PURPOSE: This study analyzed changes in the heart rates of children receiving vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy. METHODS: Changes in the heart rates of ten children receiving VNS therapy for pharmacoresistant epilepsy were evaluated with polysomnographic recordings, including electrocardiogram (ECG), EEG, thoraco-abdominal distension, nasal airflow, and VNS artifacts. Measurements during stimulation were compared with those at baseline for each patient. RESULT: While the VNS therapy pulse generator was delivering stimulation, the heart rates of four children increased significantly (p < 0.01), decreased for one child, and increased at the end of the stimulation for one child. The heart rates of four children did not change. Changes in heart rate varied during VNS, within stimulation cycles for individual children and from one child to another. Changes in heart rate differed between rapid eye movement (REM) and non-REM (NREM) sleep states. Respiratory changes (increases in frequency and decreases in amplitude) were concomitant with the changes in heart rate. CONCLUSION: In this case series of children with pharmacoresistant epilepsy, cardiorespiratory variations occurred while the VNS therapy pulse generator was delivering stimulation. Understanding these variations may allow further optimization of VNS parameters.

Vagus nerve stimulation induces concomitant respiratory alterations and a decrease in SaO2 in children.

PURPOSE: To analyze respiratory alterations and effects on SaO(2) caused by vagus nerve stimulation (VNS) in children with epilepsy. METHODS: Polysomnographic recordings, including electroencephalography, thoracoabdominal distention, nasal airflow, SaO(2), and VNS artifact were evaluated in 10 children with pharmacoresistant epilepsy treated with VNS. RESULTS: Each VNS caused a significant increase in respiratory frequency (p < 0.05) throughout the stimulation period and a decrease in thoracoabdominal-distention amplitude (p < 0.05), especially at the beginning of the stimulation. These respiratory alterations induced a decrease in SaO(2) from 1 to 5%. The effects of VNS on respiration differed significantly between rapid-eye-movement (REM) and non-REM (NREM) sleep states. CONCLUSIONS: VNS caused a pronounced change in respiration in children with epilepsy, and this induced a decrease in SaO(2). It is possible that VNS has a neuroprotective effect, and this possibility calls for further investigation.