Non-periodic Stimulation Research Articles

Non-periodic acoustic stimulation: preliminar reports of an alternative therapeutic for epilepsy

Being refractory is a significant challenge for one third of patients with epilepsy, and there is a need for new treatments. Non-periodic Stimulation (NPS) has shown promise in animal models, but it involves invasive technology. Consequently, non-invasive non-periodic Acoustic Non-periodic Stimulation (ANPS) has been developed based on NPS, with the hope that it could offer anticonvulsant effects. However, it is essential to ensure the safety of ANPS, particularly in individuals with refractory epilepsy, before it can be used in a specific application. To this end, this study aimed to assess the safety of ANPS in patients with refractory epilepsy (n=14; 8 women; 18-49 years old) using Electroencephalographic (EEG) recording and side effect evaluations over a period of five days. A questionnaire was administered immediately following the ANPS exposure and 30 days later. The study also aimed to investigate whether ANPS could trigger electrographic seizure events by counting epileptiform interictal spikes and sharp waves before and after ANPS. Additionally, the effects of ANPS on overall EEG signal properties and synchronicity were studied by calculating entropy and Phase Lock Value (PLV). Results indicate that ANPS did not trigger seizures or side effects after acute exposure or 30 days later. Rather, an improvement in quality of life and a reduction of interictal peaks and sharp waves in the EEG were observed, indicating possible anticonvulsant effects of ANPS. ANPS also increased EEG signal entropy and induced changes in brain synchrony, as evidenced by increased PLV values in some neural networks and decreased PLV values in others. Overall, these findings suggest that ANPS is well-tolerated and safe in patients with refractory epilepsy and may have anticonvulsant properties. Further investigation of its effects on neurophysiology and refractory epilepsy is warranted.

On temporal scale-free non-periodic stimulation and its mechanisms as an infinite improbability drive of the brain's functional connectogram.

Rationalized development of electrical stimulation (ES) therapy is of paramount importance. Not only it will foster new techniques and technologies with increased levels of safety, efficacy, and efficiency, but it will also facilitate the translation from basic research to clinical practice. For such endeavor, design of new technologies must dialogue with state-of-the-art neuroscientific knowledge. By its turn, neuroscience is transitioning-a movement started a couple of decades earlier-into adopting a new conceptual framework for brain architecture, in which time and thus temporal patterns plays a central role in the neuronal representation of sampled data from the world. This article discusses how neuroscience has evolved to understand the importance of brain rhythms in the overall functional architecture of the nervous system and, consequently, that neuromodulation research should embrace this new conceptual framework. Based on such support, we revisit the literature on standard (fixed-frequency pulsatile stimuli) and mostly non-standard patterns of ES to put forward our own rationale on how temporally complex stimulation schemes may impact neuromodulation strategies. We then proceed to present a low frequency, on average (thus low energy), scale-free temporally randomized ES pattern for the treatment of experimental epilepsy, devised by our group and termed NPS (Non-periodic Stimulation). The approach has been shown to have robust anticonvulsant effects in different animal models of acute and chronic seizures (displaying dysfunctional hyperexcitable tissue), while also preserving neural function. In our understanding, accumulated mechanistic evidence suggests such a beneficial mechanism of action may be due to the natural-like characteristic of a scale-free temporal pattern that may robustly compete with aberrant epileptiform activity for the recruitment of neural circuits. Delivering temporally patterned or random stimuli within specific phases of the underlying oscillations (i.e., those involved in the communication within and across brain regions) could both potentiate and disrupt the formation of neuronal assemblies with random probability. The usage of infinite improbability drive here is obviously a reference to the "The Hitchhiker's Guide to the Galaxy" comedy science fiction classic, written by Douglas Adams. The parallel is that dynamically driving brain functional connectogram, through neuromodulation, in a manner that would not favor any specific neuronal assembly and/or circuit, could re-stabilize a system that is transitioning to fall under the control of a single attractor. We conclude by discussing future avenues of investigation and their potentially disruptive impact on neurotechnology, with a particular interest in NPS implications in neural plasticity, motor rehabilitation, and its potential for clinical translation.

Persistence of neural function in animals submitted to seizure-suppressing scale-free nonperiodic electrical stimulation applied to the amygdala

Based on the rationale that neural hypersynchronization underlies epileptic phenomena, nonperiodic stimulation (NPS) was designed and successfully tested as an electrical stimulus with robust anticonvulsant action. Considering the scale-free temporal structure of NPS mimics natural-like activity, here we hypothesized its application to the amygdala would induce minor to none impairment of neural function in treated animals. Wistar rats underwent gold-standard behavioral tests such as open field (OF), elevated plus-maze (EPM), novel object recognition, and social interaction test in order to evaluate the functions of base-level anxiety, motor function, episodic memory, and sociability. We also performed daily (8 days, 6 h per day) electrophysiological recordings (local field potential/LFP and electromyography) to assess global forebrain dynamics and the sleep-wake cycle architecture and integrity. All animals displayed an increased proportion of time exploring new objects, spent more time in the closed arms of the EPM and in the periphery of the OF arena, with similar numbers of crossing between quadrants and no significant changes of social behaviors. In the sleep-wake cycle electrophysiology experiments, we found no differences regarding duration and proportion of sleep stages and the number of transitions between stages. Finally, the power spectrum of LFP recordings and neurodynamics were also unaltered. We concluded that NPS did not impair neural functions evaluated and thus, it may be safe for clinical studies. Additionally, results corroborate the notion that NPS may exert an on-demand only desynchronization effect by efficiently competing with epileptiform activity for the physiological and healthy recruitment of neural circuitry. Considering the very dynamical nature of circuit activation and functional activity underlying neural function in general (including cognition, processing of emotion, memory acquisition, and sensorimotor integration) and its corruption leading to disorder, such mechanism of action may have important implications in the investigation of neuropsychological phenomena and also in the development of rehabilitation neurotechnology.

Survival analysis of nonperiodic stimulation (NPS) performance

Electrical Stimulation (ES) of the nervous system is a promising alternative to treat refractory epilepsy. Recent developments in the area have led to a novel method involving a non-standard form of electrical stimulation with randomized inter-pulse intervals called non-periodic stimulation (NPS). Although it is an interesting approach, there is limited statistical proof to confirm its effectiveness. Therefore this brief communication presents a survival analysis of a pre-clinical trial to assess the significance of NPS therapy. The experiment comprised four groups of rats that have been compared: two with and two without NPS treatment. ES was applied bilaterally to the amygdala in animals subjected to the pentylenetetrazole continuous infusion (10 mg/ml/min) model, myoclonic or tonic-clonic generalized seizures were triggered. The Kaplan-Meier estimator was used to develop survival functions and the Logrank test was carried out to check the differences among groups. The first comparison was made between two groups of rats that developed generalized tonic-clonic seizures (GTC groups), those who received NPS treatment took longer to develop epileptic seizures. The logrank test proved statistical difference due to reaching a p-value of 7%. The second comparison was performed between two groups of rats that developed myoclonic seizures (MYO groups), and once again better survival probabilities were observed for the NPS group. The Logrank test revealed a p-value of 0.5% thereof. Thus, a survival analysis of NPS treatment proved effectiveness against seizures by promoting an anticonvulsant effect. By comparing the groups selected for this study, it was found that the NPS treatment yielded better results, mainly against myoclonic seizures.

Seizure suppression by asynchronous non-periodic electrical stimulation of the amygdala is partially mediated by indirect desynchronization from nucleus accumbens

Electrical stimulation (ES) of the nervous system is a promising alternative for the treatment of refractory epilepsy. Based on the understanding that seizures are the expression of neural hypersynchronism, our group developed and tested a non-standard form of low-energy temporally unstructured ES termed NPS (Non-periodic stimulation), with pseudo-randomized inter-pulse intervals. Previous investigation demonstrated that NPS applied to the amygdala has a robust anticonvulsant effect against both acute and chronic seizures, and suggested that its therapeutic effect is based on direct desynchronization of ictogenic neural circuits. Further mechanistic investigation using functional magnetic resonance imaging has shown that NPS also activates nucleus accumbens (NAc) in seizure-free rats, raising the hypothesis of an alternative therapeutic mechanism: NPS-enhanced indirect inhibition / desynchronization of ictogenic circuits by NAc. In order to investigate this idea, here we evaluated behavior and cortical electrographic activity from animals submitted to pentylenetetrazole (PTZ) induced seizures, treated with NPS and with or without bilateral electrolytic lesion of NAc. NPS-treated animals with bilateral lesion of NAc expressed unexpected straub tail in addition to other stereotypical convulsive behavior, displayed increased susceptibility to PTZ (lower drug threshold), and had a much longer electrographic seizure, with a greater number of spikes, firing at a higher rate. Moreover, analysis of spike morphology showed an increase in amplitude and slope in these animals, suggesting that ablation of NAc results in disinhibition and/or increase of neural synchronism within ictogenic circuits. NPS had no therapeutic effect whatsoever in lesioned animals, while it displayed a mild anticonvulsant effect in those with intact brains. Results corroborate the notion that NAc has a key role in controlling aberrant epileptiform activity in ictogenic circuits through indirect polysynaptic connections that may enroll the ventral pallidum and ventral tegmental area. They also point to the possibility that NPS may enhance this effect, putatively by benefiting from the structure’s property of detecting saliences.

Asynchronous, bilateral, and biphasic temporally unstructured electrical stimulation of amygdalae enhances the suppression of pentylenetetrazole-induced seizures in rats

A promising alternative for the treatment of refractory epilepsy is electrical stimulation (ES) of the central nervous system. Based on the premise that epilepsy is a result of neural hypersynchronization, we have previously demonstrated that a novel non-standard form of electrical stimulation with randomized inter-pulse intervals, termed non-periodic stimulation (NPS), applied to the amygdala is robustly anticonvulsant. This investigation also suggested that NPS attains its therapeutic effect by desynchronization of epileptiform activity. Here, we further explored the desynchronization hypothesis by testing how the efficacy of NPS in the suppression of convulsive behaviors depends on morphological, spatial, and temporal parameters of stimulus. For this purpose, we varied the number of pulse phases (monopolar versus bipolar square pulses), side of stimulation (right versus left), number of application hemispheres (unilateral versus bilateral), and interhemispheric temporal synchronicity (synchronous versus asynchronous), while measuring the impact on the anticonvulsant action of NPS. Wistar rats received a controlled infusion of the convulsant agent pentylenetetrazole (PTZ, 10 mg/min), together with one of six variations of NPS applied to the amygdala. A stimulated PTZ-free group of animals was also performed as a positive control. Latency to convulsive behavior was used to measure seizure threshold. Animals receiving NPS displayed significant higher threshold for forelimb clonus and generalized tonic-clonic seizures for all patterns. Thresholds seemed to increase gradually from mono to biphasic, unilateral to bilateral, and synchronous to asynchronous stimuli. Thus, combined biphasic, bilateral, and asynchronous stimulation resulted in the greatest seizure threshold. PTZ free animals did not develop any observable convulsive behavior or other uncommon motor activity. These results confirm that NPS has anticonvulsant properties and that biphasic, bilateral, and asynchronous stimulation enhances its efficacy. The fact that lack of synchronism between stimuli of each hemisphere maximizes NPS anticonvulsant power is evidence to desynchronization as tool for suppression of seizures.

Periodic Visuotactile Stimulation Slowly Enhances the Rubber Hand Illusion in Individuals with High Autistic Traits.

In a rubber hand illusion (RHI) task, synchronous brush stroking of a rubber hand and a participant's hidden hand induces body ownership of the rubber hand. The effects of spatial distances and temporal lags on the RHI have been extensively examined; however, the effect of periodicity of the stimuli on illusory body ownership has not been examined. Meanwhile, the occurrence of RHI tends to be weak in individuals with autism-spectrum disorders (ASD) and high autistic traits. Preference for stimulus having regularity of tempo is generally observed in individuals with ASD, and thus, periodic stimulation might be more effective to elicit the body ownership illusion in individuals with high autistic traits. Hence, we investigated whether stimulus periodicity influenced RHI as well as its association with participant's autistic traits. Brush strokes were applied to a participant's own hand and the rubber hand periodically (2 s) or non-periodically (1–3 s), either synchronously or asynchronously. Two blocks were performed in each condition. We found that periodic stimulation enhanced the spatial updating of tactile sensation induced by RHI in the subsequent block in participants with high autistic traits, whereas both periodic and non-periodic stimulation strongly elicited RHI in blocks 1 and 2. These results indicate that the periodicity of stimulation has different effects based on an individual's autistic traits. Since individuals with ASD are known to sustain their focus on interoceptive sensations (heartbeats), a periodic stimulation that is potentially correlated with heartbeats might be effective to enhance the visuotactile integration during RHI in individuals with high autistic traits.

The epileptic amygdala: Toward the development of a neural prosthesis by temporally coded electrical stimulation.

Many patients with epilepsy do not obtain proper control of their seizures through conventional treatment. We review aspects of the pathophysiology underlying epileptic phenomena, with a special interest in the role of the amygdala, stressing the importance of hypersynchronism in both ictogenesis and epileptogenesis. We then review experimental studies on electrical stimulation of mesiotemporal epileptogenic areas, the amygdala included, as a means to treat medically refractory epilepsy. Regular high-frequency stimulation (HFS) commonly has anticonvulsant effects and sparse antiepileptogenic properties. On the other hand, HFS is related to acute and long-term increases in excitability related to direct neuronal activation, long-term potentiation, and kindling, raising concerns regarding its safety and jeopardizing in-depth understanding of its mechanisms. In turn, the safer regular low-frequency stimulation (LFS) has a robust antiepileptogenic effect, but its pro- or anticonvulsant effect seems to vary at random among studies. As an alternative, studies by our group on the development and investigation of temporally unstructured electrical stimulation applied to the amygdala have shown that nonperiodic stimulation (NPS), which is a nonstandard form of LFS, is capable of suppressing both acute and chronic spontaneous seizures. We hypothesize two noncompetitive mechanisms for the therapeutic role of amygdala in NPS, 1) a direct desynchronization of epileptic circuitry in the forebrain and brainstem and 2) an indirect desynchronization/inhibition through nucleus accumbens activation. We conclude by reintroducing the idea that hypersynchronism, rather than hyperexcitability, may be the key for epileptic phenomena and epilepsy treatment.

Effects of different types of contingent tactile stimulation on crying, smiling, and sleep in newborns: An observational study

Sleep, the brain and the ability to interact with the environment change a great deal over the first year of life; however, there are no studies on the possible influence of different environmental stimulations on the organization of subsequent sleep-wake cycles in infants. The hypothesis of this study was that greater continuity of contingent tactile stimulation decreases crying behavior, subsequent active sleep (AS) and its fragmentation, and increases smiling behavior and subsequent quiet sleep in newborns. Forty out of the 82 newborns (15- to 30-hr old) of the initial sample satisfied the inclusion criteria and completed the first cycle of sleep during the period between two feedings. The 40 newborns were randomly assigned to four groups after 2' of baseline observation: continuous stimulation (CS, n = 10); discontinuous nonperiodic stimulation (DnPS, n = 10); discontinuous periodic stimulation (DPS, n = 10); absent stimulation (AbS, n = 10). During baseline measurements, there were no significant differences in crying and smiling behaviors between the four groups, while during the subsequent stimulated wake, the CS group compared to the DnPS group showed more smiling (p < .05) and less crying (p < .05), longer poststimulation wake before sleep (p < .01) as well as AS with a lower percentage of grouped-rapid eye movements [grouped REM (GREM); p < .001]. The number of GREM during AS was negatively correlated to the number of smiles (p < .05) and positively to the number of cries (p < .05) of the previous stimulated wake. These findings suggest that, after birth, different continuity levels of contingent tactile stimulations may affect crying and smiling behaviors and the organization of behavioral states. AS could have an important role in processing affective states.

Effects of muscle length on the EMG-force relationship of the cat soleus muscle studied using non-periodic stimulation of ventral root filaments.

The effects of changing the length of the cat soleus muscle on electromyographic (EMG) signals, muscle force and the corresponding EMG-force relationship were assessed using distributed stimulation of ten ventral root filaments and irregular interpulse intervals. EMG-force relationships were first determined for four muscle lengths using a protocol of simultaneous addition and rate modulation of ventral root filaments. In the second test, three submaximal levels of stimulation were applied at eight muscle lengths. EMG signals were obtained using surface and wire electrodes, and force was measured using a strain transducer. For most muscle lengths, the relationships between integrated EMG and mean force obtained using wire and surface electrodes were sigmoid with a linear intermediate region. The effects of muscle length on EMG signals were likely to be associated with movement of the recording electrodes relative to each other and to the active motor units. Mean forces increased with increasing muscle length and with increasing levels of stimulation. Mean force-length relationships obtained using submaximal stimulation were not simply scaled down versions of the force-length relationship obtained using supramaximal stimulation of the soleus nerve, but appeared to be shifted towards longer muscle lengths.

EMG-force relationship of the cat soleus muscle studied with distributed and non-periodic stimulation of ventral root filaments.

Distributed stimulation of ventral root (VR) filaments and pseudo-random interpulse intervals (based on a Gaussian distribution with a coefficient of variation of 12.5%) were used to modulate electromyographic activity (EMG) and force of the cat soleus muscle to assess the EMG-force relationship. A protocol consisting of addition and rate modulation of ten VR filaments that contain alpha motoneurones to the soleus muscle was adopted. EMG was measured using indwelling electrodes and forces were measured at the distal tendon using a strain transducer. EMG records obtained using this approach were similar in the time and frequency domains to those obtained during voluntary contractions. Force records obtained from stimulation of single VR filaments showed summation effects typical of irregular interpulse intervals. The overall relationship between integrated rectified EMG (IEMG) and mean force was found to be non-linear. At low and high stimulation levels, IEMG tended to increase proportionally more than mean force. In the intermediate stimulation region (i.e. producing forces between approximately 5% and 88% of the maximal tetanic force), the IEMG-mean force relationship was virtually linear. Muscles with a homogeneous fibre type composition, such as the cat soleus muscle, have been reported to have a linear EMG-force relationship.