RESUMEN

The closed-loop control of pathological brain activity is a challenging task. In this study, we investigated the sensitivity of continuous epileptiform short discharge generation to electrical stimulation applied at different phases between the discharges using an in vitro 4-AP-based model of epilepsy in rat hippocampal slices. As a measure of stimulation effectiveness, we introduced a sensitivity function, which we then measured in experiments and analyzed with different biophysical and abstract mathematical models, namely, (i) the two-order subsystem of our previous Epileptor-2 model, describing short discharge generation governed by synaptic resource dynamics; (ii) a similar model governed by shunting conductance dynamics (Epileptor-2B); (iii) the stochastic leaky integrate-and-fire (LIF)-like model applied for the network; (iv) the LIF model with potassium M-channels (LIF+KM), belonging to Class II of excitability; and (v) the Epileptor-2B model with after-spike depolarization. A semi-analytic method was proposed for calculating the interspike interval (ISI) distribution and the sensitivity function in LIF and LIF+KM models, which provided parametric analysis. Sensitivity was found to increase with phase for all models except the last one. The Epileptor-2B model is favored over other models for subthreshold oscillations in the presence of large noise, based on the comparison of ISI statistics and sensitivity functions with experimental data. This study also emphasizes the stochastic nature of epileptiform discharge generation and the greater effectiveness of closed-loop stimulation in later phases of ISIs.

Asunto(s)

Estimulación Eléctrica , Epilepsia , Animales , Ratas , Epilepsia/fisiopatología , Epilepsia/terapia , Estimulación Eléctrica/métodos , Hipocampo/fisiopatología , Modelos Neurológicos , Potenciales de Acción/fisiología , Ratas Wistar , Red Nerviosa/fisiopatología , Masculino

RESUMEN

Brain-responsive neurostimulation is firmly ensconced among treatment options for drug-resistant focal epilepsy, but over a quarter of patients treated with the RNS System do not experience meaningful seizure reduction. Initial titration of RNS therapy is typically similar for all patients, raising the possibility that treatment response might be enhanced by consideration of patient-specific variables. Indeed, small, single-center studies have yielded preliminary evidence that RNS System effectiveness depends on the brain state during which stimulation is applied. The generalizability of these findings remains unclear, however, and it is unknown whether state-dependent effects of responsive neurostimulation are also stratified by location of the seizure onset zone where stimulation is delivered. We aimed to determine whether state-dependent effects of the RNS System are evident in the large, diverse, multi-center cohort of RNS System clinical trial participants and to test whether these effects differ between mesiotemporal and neocortical epilepsies. Eighty-one of 256 patients who were treated with the RNS System across 31 centers during clinical trials met criteria for inclusion in this retrospective study. Risk states were defined in relation to phases of daily and multi-day cycles of interictal epileptiform activity that are thought to determine seizure likelihood. We found that the probabilities of risk state transitions depended on the stimulation parameter being changed, the starting seizure risk state, and the stimulated brain region. Changes in two commonly adjusted stimulation parameters, charge density and stimulation frequency, produced opposite effects on risk state transitions depending on seizure localization. Greater variance in acute risk state transitions was explained by state-dependent responsive neurostimulation for bipolar stimulation for neocortical epilepsies and for monopolar stimulation for mesiotemporal epilepsies. Variability in effectiveness of RNS System therapy across individuals may relate, at least partly, to the fact that current treatment paradigms do not account fully for fluctuations in brain states or locations of simulation sites. State-dependence of electrical brain stimulation may inform development of next-generation closed-loop devices that can detect changes in brain state and deliver adaptive, localization-specific patterns of stimulation to maximize therapeutic effects.

RESUMEN

AIMS: Subclinical atrial fibrillation (AF) is associated with increased risk of progression to clinical AF, stroke, and cardiovascular death. We hypothesized that in pacemaker patients requiring dual-chamber rate-adaptive (DDDR) pacing, closed loop stimulation (CLS) integrated into the circulatory control system through intra-cardiac impedance monitoring would reduce the occurrence of atrial high-rate episodes (AHREs) compared with conventional DDDR pacing. METHODS AND RESULTS: Patients with sinus node dysfunctions (SNDs) and an implanted pacemaker or defibrillator were randomly allocated to dual-chamber CLS (n = 612) or accelerometer-based DDDR pacing (n = 598) and followed for 3 years. The primary endpoint was time to the composite endpoint of the first AHRE lasting ≥6 min, stroke, or transient ischaemic attack (TIA). All AHREs were independently adjudicated using intra-cardiac electrograms. The incidence of the primary endpoint was lower in the CLS arm (50.6%) than in the DDDR arm (55.7%), primarily due to the reduction in AHREs lasting between 6 h and 7 days. Unadjusted site-stratified hazard ratio (HR) for CLS vs. DDDR was 0.84 [95% confidence interval (CI), 0.72-0.99; P = 0.035]. After adjusting for CHA2DS2-VASc score, the HR remained 0.84 (95% CI, 0.71-0.99; P = 0.033). In subgroup analyses of AHRE incidence, the incremental benefit of CLS was greatest in patients without atrioventricular block (HR, 0.77; P = 0.008) and in patients without AF history (HR, 0.73; P = 0.009). The contribution of stroke/TIA to the primary endpoint (1.3%) was low and not statistically different between study arms. CONCLUSION: Dual-chamber CLS in patients with SND is associated with a significantly lower AHRE incidence than conventional DDDR pacing.

Asunto(s)

Fibrilación Atrial , Estimulación Cardíaca Artificial , Frecuencia Cardíaca , Ataque Isquémico Transitorio , Marcapaso Artificial , Síndrome del Seno Enfermo , Accidente Cerebrovascular , Humanos , Femenino , Masculino , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/terapia , Fibrilación Atrial/epidemiología , Anciano , Síndrome del Seno Enfermo/terapia , Síndrome del Seno Enfermo/fisiopatología , Estimulación Cardíaca Artificial/métodos , Ataque Isquémico Transitorio/prevención & control , Ataque Isquémico Transitorio/epidemiología , Persona de Mediana Edad , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/epidemiología , Incidencia , Resultado del Tratamiento , Factores de Tiempo , Factores de Riesgo , Desfibriladores Implantables , Técnicas Electrofisiológicas Cardíacas , Acelerometría , Anciano de 80 o más Años

RESUMEN

INTRODUCTION: Closed Loop Stimulation (CLS) is a rate-responsive algorithm that adjusts heart rate (HR) based on changes in intracardiac impedance measured from the right ventricle lead. However, the use of CLS in conduction system pacing has not been investigated. In this retrospective study, we aimed to assess whether CLS with left bundle branch area pacing (LBBAP) can generate an appropriate distribution of HR in daily life. METHODS AND RESULTS: Our study included 24 patients with CLS pacing and chronotropic incompetence, comparing them with 19 patients receiving DDD pacing, all with LBBAP. Cumulative HR distribution charts were generated using data from a single device interrogation with a minimum follow-up period of 30 days. In DDD-CLS mode, there was a higher percentage of atrial pacing compared to DDD mode (median 58% [interquartile range 29%-83%] vs. 13% [10%-26%], p = .001), and CLS-paced beats were present across all frequency bins. The distribution of beats between the groups was similar (p = .643), resulting in comparable mean HR (72 bpm [70-77] vs. 73 bpm [65-75], p = .615). CONCLUSIONS: In the context of LBBAP, CLS effectively modulates pacing rates over a wide frequency range. This lead position does not adversely affect the rate-responsive performance of the algorithm.

RESUMEN

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories.1,2 Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD.3,4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory.5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.

Asunto(s)

Extinción Psicológica , Miedo , Sueño REM , Animales , Miedo/fisiología , Sueño REM/fisiología , Ratones , Extinción Psicológica/fisiología , Masculino , Ratones Endogámicos C57BL , Memoria/fisiología , Consolidación de la Memoria/fisiología , Condicionamiento Clásico/fisiología , Células Piramidales/fisiología

RESUMEN

INTRODUCTION: For patients with drug-resistant epilepsy (DRE) who are not suitable for surgical resection, neuromodulation with vagus nerve stimulation (VNS) is an established approach. However, there is limited evidence of seizure reduction when replacing traditional VNS (tVNS) device with a cardiac-based one (cbVNS). This meta-analysis compares the seizure reduction achieved by replacing tVNS with cbVNS in a population with DRE. METHODS: We systematically searched PubMed, Embase, and Cochrane Central following PRISMA guidelines. The main outcomes were number of patients experiencing a ≥ 50 % and ≥80 % reduction in seizures, as defined by the McHugh scale. Additionally, we assessed the number of patients achieving freedom from seizures. RESULTS: We included 178 patients with DRE from 7 studies who were initially treated with tVNS and subsequently had it replaced by cbVNS. The follow-up for cbVNS ranged from 6 to 37.5 months. There was a statistically significant reduction in seizure frequency with the replacement of tVNS by cbVNS, using a ≥ 50 % (OR 1.79; 95 % CI 1.07 to 2.97; I²=0 %; p = 0.03) and a ≥ 80 % (OR 2.06; 95 % CI 1.17 to 3.62; I²=0 %; p = 0.01) reduction threshold. Nineteen (13 %) participants achieved freedom from seizures after switching to cbVNS. There was no difference in the rate of freedom from seizures between groups (OR 1.85; 95 % CI 0.81 to 4.21; I²=0 %; p = 0.14). CONCLUSION: In patients with DRE undergoing battery replacement, cbVNS might be associated with seizure reduction (≥50 % and ≥80 % threshold) after switching from tVNS. Randomised controlled trials are necessary to validate these findings.

Asunto(s)

Convulsiones , Estimulación del Nervio Vago , Humanos , Estimulación del Nervio Vago/métodos , Estimulación del Nervio Vago/instrumentación , Convulsiones/terapia , Epilepsia Refractaria/terapia

RESUMEN

Closed-loop auditory stimulation (CLAS) is a brain modulation technique in which sounds are timed to enhance or disrupt endogenous neurophysiological events. CLAS of slow oscillation up-states in sleep is becoming a popular tool to study and enhance sleep's functions, as it increases slow oscillations, evokes sleep spindles and enhances memory consolidation of certain tasks. However, few studies have examined the specific neurophysiological mechanisms involved in CLAS, in part because of practical limitations to available tools. To evaluate evidence for possible models of how sound stimulation during brain up-states alters brain activity, we simultaneously recorded electro- and magnetoencephalography in human participants who received auditory stimulation across sleep stages. We conducted a series of analyses that test different models of pathways through which CLAS of slow oscillations may affect widespread neural activity that have been suggested in literature, using spatial information, timing and phase relationships in the source-localized magnetoencephalography data. The results suggest that auditory information reaches ventral frontal lobe areas via non-lemniscal pathways. From there, a slow oscillation is created and propagated. We demonstrate that while the state of excitability of tissue in auditory cortex and frontal ventral regions shows some synchrony with the electroencephalography (EEG)-recorded up-states that are commonly used for CLAS, it is the state of ventral frontal regions that is most critical for slow oscillation generation. Our findings advance models of how CLAS leads to enhancement of slow oscillations, sleep spindles and associated cognitive benefits and offer insight into how the effectiveness of brain stimulation techniques can be improved.

Asunto(s)

Magnetoencefalografía , Sueño , Humanos , Estimulación Acústica , Sueño/fisiología , Electroencefalografía/métodos , Encéfalo/fisiología

RESUMEN

In the same way that beauty lies in the eye of the beholder, what a stimulus does to the brain is determined not simply by the nature of the stimulus but by the nature of the brain that is receiving the stimulus at that instant in time. Over the past decades, therapeutic brain stimulation has typically applied open-loop fixed protocols and has largely ignored this principle. Only recent neurotechnological advancements have enabled us to predict the nature of the brain (i.e., the electrophysiological brain state in the next instance in time) with sufficient temporal precision in the range of milliseconds using feedforward algorithms applied to electroencephalography time-series data. This allows stimulation exclusively whenever the targeted brain area is in a prespecified excitability or connectivity state. Preclinical studies have shown that repetitive stimulation during a particular brain state (e.g., high-excitability state), but not during other states, results in lasting modification (e.g., long-term potentiation) of the stimulated circuits. Here, we survey the evidence that this is also possible at the systems level of the human cortex using electroencephalography-informed transcranial magnetic stimulation. We critically discuss opportunities and difficulties in developing brain state-dependent stimulation for more effective long-term modification of pathological brain networks (e.g., in major depressive disorder) than is achievable with conventional fixed protocols. The same real-time electroencephalography-informed transcranial magnetic stimulation technology will allow closing of the loop by recording the effects of stimulation. This information may enable stimulation protocol adaptation that maximizes treatment response. This way, brain states control brain stimulation, thereby introducing a paradigm shift from open-loop to closed-loop stimulation.

Asunto(s)

Trastorno Depresivo Mayor , Humanos , Encéfalo/fisiología , Estimulación Magnética Transcraneal/métodos , Electroencefalografía , Potenciación a Largo Plazo

RESUMEN

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states-that is, stimulation during periods with a lower or higher risk of generating epileptiform activity-in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states and out of rhythmic high-risk states predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super-responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction.

Asunto(s)

Estimulación Encefálica Profunda , Epilepsia Refractaria , Epilepsia , Humanos , Estimulación Encefálica Profunda/métodos , Epilepsia/terapia , Convulsiones/terapia , Encéfalo , Epilepsia Refractaria/terapia

RESUMEN

AIMS: This study aimed to investigate the effectiveness of closed-loop stimulation (CLS) pacing compared with the traditional DDD mode in patients with chronotropic incompetence (CI) using bicycle-based cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: This single-centre, randomized crossover trial involved 40 patients with CI. Patients were randomized to receive either DDD-CLS or DDD mode pacing for 2 months, followed by a crossover to the alternative mode for an additional 2 months. Bicycling-based CPET was conducted at the 3- and 5-month follow-up visits to assess exercise capacity. Other cardiopulmonary exercise outcome measures and health-related quality of life (QoL) were also assessed. DDD-CLS mode pacing significantly improved exercise capacity, resulting in a peak oxygen uptake (14.8 ± 4.0 vs. 12.0 ± 3.6 mL/kg/min, P < 0.001) and oxygen uptake at the ventilatory threshold (10.0 ± 2.2 vs. 8.7 ± 1.8 mL/kg/min, P < 0.001) higher than those of the DDD mode. However, there were no significant differences in other cardiopulmonary exercise outcome measures such as ventilatory efficiency of carbon dioxide production slope, oxygen uptake efficiency slope, and end-tidal carbon dioxide between the two modes. Patients in the DDD-CLS group reported a better QoL, and 97.5% expressed a preference for the DDD-CLS mode. CONCLUSION: DDD-CLS mode pacing demonstrated improved exercise capacity and QoL in patients with CI, highlighting its potential as an effective pacing strategy for this patient population.

Asunto(s)

Estimulación Cardíaca Artificial , Calidad de Vida , Humanos , Estimulación Cardíaca Artificial/métodos , Dióxido de Carbono , Ciclismo , Tolerancia al Ejercicio , Estudios Cruzados , Prueba de Esfuerzo , Oxígeno , Frecuencia Cardíaca/fisiología

RESUMEN

Objective.Healthy sleep plays a critical role in general well-being. Enhancement of slow-wave sleep by targeting acoustic stimuli to particular phases of delta (0.5-2 Hz) waves has shown promise as a non-invasive approach to improve sleep quality. Closed-loop stimulation during other sleep phases targeting oscillations at higher frequencies such as theta (4-7 Hz) or alpha (8-12 Hz) could be another approach to realize additional health benefits. However, systems to track and deliver stimulation relative to the instantaneous phase of electroencephalogram (EEG) signals at these higher frequencies have yet to be demonstrated outside of controlled laboratory settings.Approach.Here we examine the feasibility of using an endpoint-corrected version of the Hilbert transform (ecHT) algorithm implemented on a headband wearable device to measure alpha phase and deliver phase-locked auditory stimulation during the transition from wakefulness to sleep, during which alpha power is greatest. First, the ecHT algorithm is implementedin silicoto evaluate the performance characteristics of this algorithm across a range of sleep-related oscillatory frequencies. Secondly, a pilot sleep study tests feasibility to use the wearable device by users in the home setting for measurement of EEG activity during sleep and delivery of real-time phase-locked stimulation.Main results.The ecHT is capable of computing the instantaneous phase of oscillating signals with high precision, allowing auditory stimulation to be delivered at the intended phases of neural oscillations with low phase error. The wearable system was capable of measuring sleep-related neural activity with sufficient fidelity for sleep stage scoring during the at-home study, and phase-tracking performance matched simulated results. Users were able to successfully operate the system independently using the companion smartphone app to collect data and administer stimulation, and presentation of auditory stimuli during sleep initiation did not negatively impact sleep onset.Significance.This study demonstrates the feasibility of closed-loop real-time tracking and neuromodulation of a range of sleep-related oscillations using a wearable EEG device. Preliminary results suggest that this approach could be used to deliver non-invasive neuromodulation across all phases of sleep.

Asunto(s)

Electroencefalografía , Sueño de Onda Lenta , Electroencefalografía/métodos , Sueño/fisiología , Sueño de Onda Lenta/fisiología , Fases del Sueño/fisiología , Estimulación Acústica/métodos

RESUMEN

Objective. The compromise of the hippocampal loop is a hallmark of mesial temporal lobe epilepsy (MTLE), the most frequent epileptic syndrome in the adult population and the most often refractory to medical therapy. Hippocampal sclerosis is found in >50% of drug-refractory MTLE patients and primarily involves the CA1, consequently disrupting the hippocampal output to the entorhinal cortex (EC). Closed-loop deep brain stimulation is the latest frontier to improve drug-refractory MTLE; however, current approaches do not restore the functional connectivity of the hippocampal loop, they are designed by trial-and-error and heavily rely on seizure detection or prediction algorithms. The objective of this study is to evaluate the anti-ictogenic efficacy and robustness of an artificial bridge restoring the dialog between hippocampus and EC.Approach. In mouse hippocampus-EC slices treated with 4-aminopyridine and in which the Schaffer Collaterals are severed, we established an artificial bridge between hippocampus and EC wherein interictal discharges originating in the CA3 triggered stimulation of the subiculum so to entrain EC networks. Combining quantification of ictal activity with tools from information theory, we addressed the efficacy of the bridge in controlling ictogenesis and in restoring the functional connectivity of the hippocampal loop.Main results. The bridge significantly decreased or even prevented ictal activity and proved robust to failure; when operating at 100% of its efficiency (i.e., delivering a pulse upon each interictal event), it recovered the functional connectivity of the hippocampal loop to a degree similar to what measured in the intact circuitry. The efficacy and robustness of the bridge stem in mirroring the adaptive properties of the CA3, which acts as biological neuromodulator.Significance. This work is the first stepping stone toward a paradigm shift in the conceptual design of stimulation devices for epilepsy treatment, from function control to functional restoration of the salient brain circuits.

Asunto(s)

Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Ratones , Animales , Sistema Límbico , Hipocampo/fisiología , Convulsiones/terapia , Corteza Entorrinal , Epilepsia del Lóbulo Temporal/terapia

RESUMEN

Closed-loop acoustic stimulation (CLAS) during sleep has shown to boost slow wave (SW) amplitude and spindle power. Moreover, sleep SW have been classified based on different processes of neuronal synchronization. Thus, different types of SW events may have distinct functional roles and be differentially affected by external stimuli. However, the SW synchronization processes affected by CLAS are not well understood. Here, we studied the effect of CLAS on the dissociation of SW events based on two features of neuronal synchronization in the electroencephalogram (topological spread and wave slope). We evaluated and classified individual SW events of 14 healthy subjects during a CLAS stimulated (STM) and a control night (CNT). Three main categories of SW events were found denoting (C1) steep slope SW with global spread, (C2) flat-slope waves with localized spread and homeostatic decline, and (C3) multipeaked flat-slope events with global spread. Comparing between conditions, we found a consistent increase of event proportion and trough amplitudes for C1 events during the time of stimulation. Furthermore, we found similar increases in post-stimulus spectral power in θ, ß, and σ frequencies for CNT vs STIM condition independently of sleep stage or SW categories. However, topological analysis showed differentiated spatial dynamics in N2 and N3 for SW categories and the co-occurrence with spindle events. Our findings support the existence of multiple types of SW with differential response to external stimuli and possible distinct neuronal mechanisms.

Asunto(s)

Fases del Sueño , Sueño , Humanos , Estimulación Acústica , Sueño/fisiología , Fases del Sueño/fisiología , Electroencefalografía , Voluntarios Sanos

RESUMEN

Electroencephalogram (EEG)-guided adaptive neurostimulation is an innovative kind of non-invasive closed-loop brain stimulation technique that uses audio-visual stimulation on-line modulated by rhythmical EEG components of the individual. However, the opportunity to enhance its effectiveness is a challenging task and needs further investigation. The present study aims to experimentally test whether it is possible to increase the efficiency of EEG-guided adaptive neurostimulation by pre- strengthening the modulating factor (subject's EEG) through the procedure of resonance scanning, i.e., LED photostimulation with the frequency gradually increasing in the range of main EEG rhythms (4-20 Hz). Thirty-six university students in a state of exam stress were randomly assigned to two matched groups. One group was presented with the EEG-guided adaptive neurostimulation alone, whereas another matched group was presented with the combination of resonance scanning and EEG-guided adaptive neurostimulation. The changes in psychophysiological indicators after stimulation relative to the initial level were used. Although both types of stimulation led to an increase in the power of EEG rhythms, accompanied by a decrease in the number of errors in the word recognition test and a decrease in the degree of emotional maladjustment, these changes reached the level of significance only in experiments with preliminary resonance scanning. Resonance scanning increases the brain's responsiveness to subsequent EEG-guided adaptive neurostimulation, acting as a tool to enhance its efficiency. The results obtained clearly indicate that the combination of resonance scanning and EEG-guided adaptive neurostimulation is an effective way to reach the signs of cognitive improvement in stressed individuals.

RESUMEN

The control circuits of blood pressure have a strong neural regulatory element important in the pathogenesis of essential drug-resistant hypertension. Targeting lower medullary neural control mechanisms of blood pressure by electrical stimulation could be beneficial, and therefore, a novel device is needed. This paper presents a remotely programmable deep brain stimulator with an invasive continuous blood pressure monitoring system in a non-tethered rat model. The device is designed for lower medullary deep brain stimulation research with minimal interference to a daily animal routine. Electrodes were implanted in the caudal ventrolateral medulla. Animal survivability, catheter patency rates, and device data drift were evaluated. Eight out of ten rats survived the surgery and testing period with no or mild temporary neurological compromise. The study revealed that carotid catheters filled with heparinized glycerol ensure better catheter patency rates and blood pressure transduction. There was no significant drift in the device's pressure sensitivity during the experiment. To our knowledge, this is the first experimental study to show considerable animal survival after lower medullary implantation. Combining the ability to measure and monitor invasive blood pressure with a closed-loop brain pulse generator in a single device could be of potential value in future hemodynamic animal research.

RESUMEN

The corticospinal tract plays a major role in the control of voluntary limb movements, and its damage impedes voluntary limb control. We investigated the feasibility of closed-loop brain-controlled subdural spinal stimulation through a corticospinal interface for the modulation of wrist torque in the paralyzed forearm of monkeys with spinal cord injury at C4/C5. Subdural spinal stimulation of the preserved cervical enlargement activated multiple muscles on the paralyzed forearm and wrist torque in the range from flexion to ulnar-flexion. The magnitude of the evoked torque could be modulated by changing current intensity. We then employed the corticospinal interface designed to detect the firing rate of an arbitrarily selected "linked neuron" in the forearm territory of the primary motor cortex (M1) and convert it in real time to activity-contingent electrical stimulation of a spinal site caudal to the lesion. Linked neurons showed task-related activity that modulated the magnitude of the evoked torque and the activation of multiple muscles depending on the required torque. Unlinked neurons, which were independent of spinal stimulation and located in the vicinity of the linked neurons, exhibited task-related or -unrelated activity. Thus, monkeys were able to modulate the wrist torque of the paralyzed forearm by modulating the firing rate of M1 neurons including unlinked and linked neurons via the corticospinal interface. These results suggest that the corticospinal interface can replace the function of the corticospinal tract after spinal cord injury.

RESUMEN

Objective. Deep brain stimulation is a treatment option for patients with refractory obsessive-compulsive disorder. A new generation of stimulators hold promise for closed loop stimulation, with adaptive stimulation in response to biologic signals. Here we aimed to discover a suitable biomarker in the ventral striatum in patients with obsessive compulsive disorder using local field potentials.Approach.We induced obsessions and compulsions in 11 patients undergoing deep brain stimulation treatment using a symptom provocation task. Then we trained machine learning models to predict symptoms using the recorded intracranial signal from the deep brain stimulation electrodes.Main results.Average areas under the receiver operating characteristics curve were 62.1% for obsessions and 78.2% for compulsions for patient specific models. For obsessions it reached over 85% in one patient, whereas performance was near chance level when the model was trained across patients. Optimal performances for obsessions and compulsions was obtained at different recording sites.Significance. The results from this study suggest that closed loop stimulation may be a viable option for obsessive-compulsive disorder, but that intracranial biomarkers are patient and not disorder specific.Clinical Trial:Netherlands trial registry NL7486.

Asunto(s)

Trastorno Obsesivo Compulsivo , Estriado Ventral , Humanos , Conducta Obsesiva/diagnóstico , Conducta Obsesiva/terapia , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/terapia

RESUMEN

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

Asunto(s)

Sueño de Onda Lenta , Adulto Joven , Humanos , Sueño de Onda Lenta/fisiología , Estudios de Factibilidad , Sueño/fisiología , Polisomnografía , Electroencefalografía/métodos , Estimulación Acústica/métodos

RESUMEN

Most post-stroke patients have long-lasting gait disturbances that reduce their daily activities. They often show impaired hip and knee joint flexion and ankle dorsiflexion of the lower limbs during the swing phase of gait, which is controlled by the corticospinal tract from the primary motor cortex (M1). Recently, we reported that gait-synchronized closed-loop brain stimulation targeting swing phase-related activity in the affected M1 can improve gait function in post-stroke patients. Subsequently, a gait-training robot (Orthobot®) was developed that could assist lower-limb joint movements during the swing phase of gait. Therefore, we investigated whether gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase could enhance the recovery of post-stroke gait disturbance. A 57-year-old female patient with chronic post-stroke hemiparesis underwent closed-loop brain stimulation combined with robot-assisted training for 10 min 2 years after left pons infarction. For closed-loop brain stimulation, we used transcranial oscillatory electrical current stimulation over the lesioned M1 foot area with 1.5 mA of DC offset and 0-3 mA of sine-wave formed currents triggered by the paretic heel contact to set the maximum current just before the swing phase (intervention A; two times repeated, A1 and A2). According to the N-of-1 study design, we also performed sham stimulation (intervention B) and control stimulation not targeting the swing phase (intervention C) combined with robot-assisted training in the order of A1-B-A2-C interventions. As a result, we found larger improvements in gait speed, the Timed Up and Go test result, and muscle strength after the A1 and A2 interventions than after the B and C interventions. After confirming the short-term effects, we performed an additional long-term intervention twice a week for 5 weeks, for a total of 10 sessions. Gait parameters also largely improved after long-term intervention. Gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase of gait may promote the recovery of gait function in post-stroke patients. Further studies with a larger number of patients are necessary.

RESUMEN

Effective rate-adaptive pacing may be difficult in the presence of atrial fibrillation (AF), and is important during high-intensity exercise. This case presents a 74-year-old elite cyclist with AF and a biventricular pacemaker after atrioventricular (AV) node ablation. He reported sudden breathlessness due to heart rate drops, caused by breaching the artefact threshold on the minute-ventilation sensor. He was exchanged to a generator with an impedance-derived contractility sensor (closed-loop stimulation), resulting in resolution of symptoms, and no further rate drops. This is the first description of the utility of closed-loop stimulation in high-intensity exercise.

Asunto(s)

Fibrilación Atrial , Marcapaso Artificial , Masculino , Humanos , Anciano , Impedancia Eléctrica , Frecuencia Cardíaca/fisiología , Fibrilación Atrial/cirugía , Estimulación Cardíaca Artificial/métodos