Direct Brain Stimulation Research Articles

Common fronto-temporal effective connectivity in humans and monkeys

SummaryHuman brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus.Video

Region-Level Functional and Effective Network Analysis of Human Brain During Cognitive Task Engagement.

Mental disorders are a major source of disability, with few effective treatments. It has recently been argued that these diseases might be effectively treated by focusing on decision-making, and specifically remediating decision-making deficits that act as “ingredients” in these disorders. Prior work showed that direct electrical brain stimulation can enhance human cognitive control, and consequently decision-making. This raises a challenge of detecting cognitive control lapses directly from electrical brain activity. Here, we demonstrate approaches to overcome that challenge. We propose a novel method, referred to as maximal variance node merging (MVNM), that merges nodes within a brain region to construct informative inter-region brain networks. We employ this method to estimate functional (correlational) and effective (causal) networks using local field potentials (LFP) during a cognitive behavioral task. The effective networks computed using convergent cross mapping differentiate task engagement from background neural activity with 85% median classification accuracy. We also derive task engagement networks (TENs): networks that constitute the most discriminative inter-region connections. Subsequent graph analysis illustrates the crucial role of the dorsolateral prefrontal cortex (dlPFC) in task engagement, consistent with a widely accepted model for cognition. We also show that task engagement is linked to prefrontal cortex theta (4-8 Hz) oscillations. We, therefore, identify objective biomarkers associated with task engagement. These approaches may generalize to other cognitive functions, forming the basis of a network-based approach to detecting and rectifying decision deficits.

Frequency-domain identification of stereoelectroencephalographic transfer functions for brain tissue classification

Abstract In drug-resistant epileptic patients, direct electrical brain stimulation sessions may be needed to identify epileptic regions on the brain before surgery. In this context, the classification of the brain tissue in which the electrodes are implanted in is very important for the interpretation of observed responses. This paper presents a new method for tissue classification based on the study of the baseline data with signal processing methods and features estimated from non parametric frequency identification of transfer functions. The method is tested on actual data and compared to visual classification of contacts co-registered on magnetic resonance imaging. The results show that good separability between matters, with up to 80% accuracy, can be achieved when considering the pairing of two consecutive electrodes.

Potential employment of transcranial magnetic stimulation as a beneficial intervention in children with amblyopia: a brief overview

Amblyopia is an early functional imbalance between each eye and the brain that may result in visual cortex inhibition. Current conservative treatments involve altering the input from the ‘good eye’, for example, using patching or biochemical penalization. Direct brain stimulation to the amblyopic cortex might improve the condition. This paper aimed to systematically review the published scientific literature regarding the use of transcranial magnetic stimulation (TMS) as a potential method for treatment in the amblyopic visual cortex. This study was a systematic review of the published scientific literature related to theTMS for the treatment of amblyopia that was performed using “TMS, amblyopia” as keywords. However, only three research papers were found and included in the literature review. A study showed that repetitive TMS of the visual cortex can temporarily improve contrast sensitivity in the amblyopic visual cortex. Another study used continuous thetaburst stimulation (cTBS) delivered to the visual cortex while patients viewed a high contrast stimulus with their non-amblyopic eye. It was found that daily theta burst TMS stimulation improved amblyopic eye contrast sensitivity in five adult volunteers. The TMS also increased median visual acuity in the patient with amblyopia after stimulation with no significant changes in the placebo group.Protocol employing repetitive administration of TMS might result in beneficial effects in amblyopia treatment. TMS works in brain dynamics and experience-dependent plasticity, all of which could be important in investigating and treating amblyopia.

Band power modulation through intracranial EEG stimulation and its cross-session consistency

Objective. Direct electrical stimulation of the brain through intracranial electrodes is currently used to probe the epileptic brain as part of pre-surgical evaluation, and it is also being considered for therapeutic treatments through neuromodulation. In order to effectively modulate neural activity, a given neuromodulation design must elicit similar responses throughout the course of treatment. However, it is unknown whether intracranial electrical stimulation responses are consistent across sessions. The objective of this study was to investigate the within-subject, cross-session consistency of the electrophysiological effect of electrical stimulation delivered through intracranial electroencephalography (iEEG). Approach. We analysed data from 79 epilepsy patients implanted with iEEG who underwent brain stimulation as part of a memory experiment. We quantified the effect of stimulation in terms of band power modulation and compared this effect from session to session. As a reference, we made the same measurements during baseline periods. Main results. In most sessions, the effect of stimulation on band power could not be distinguished from baseline fluctuations of band power. Stimulation effect was consistent in a third of the session pairs, while the rest had a consistency measure not exceeding the baseline standards. Cross-session consistency was highly correlated with the degree of band power increase, and it also tended to be higher when the baseline conditions were more similar between sessions. Significance. These findings can inform our practices for designing neuromodulation with greater efficacy when using direct electrical brain stimulation as a therapeutic treatment.

Probing Network Mechanisms of Brain Stimulation in the Mood Circuit

Direct brain stimulation has diverse effects on network activity. In this issue of Neuron, Qiao etal. (2020) demonstrate a novel approach for using stimulation to characterize and modulate interactions between areas of the mood processing network.

Amygdala Stimulation Leads to Functional Network Connectivity State Transitions in the Hippocampus.

Several studies have shown that direct brain stimulation can enhance memory in humans and animal models. Investigating the neurophysiological changes induced by brain stimulation is an important step towards understanding the neural processes underlying memory function. Furthermore, it paves the way for developing more efficient neuromodulation approaches for memory enhancement. In this study, we utilized a combination of unsupervised and supervised machine learning approaches to investigate how amygdala stimulation modulated hippocampal network activities during the encoding phase. Using a sliding window in time, we estimated the hippocampal dynamic functional network connectivity (dFNC) after stimulation and during sham trials, based on the covariance of local field potential recordings in 4 subregions of the hippocampus. We extracted different network states by combining the dFNC samples from 5 subjects and applying k-means clustering. Next, we used the between-state transition numbers as the latent features to classify between amygdala stimulation and sham trials across all subjects. By training a logistic regression model, we could differentiate stimulated from sham trials with 67% accuracy across all subjects. Using elastic net regularization as a feature selection method, we identified specific patterns of hippocampal network state transition in response to amygdala stimulation. These results offer a new approach to better understanding of the causal relationship between hippocampal network dynamics and memory-enhancing amygdala stimulation.

The Preoperative Evaluation of Drug-Resistant Epilepsy

Antiepileptic drugs afford good seizure control for approximately 70% of individuals with epilepsy. Epilepsy surgery is extremely helpful for appropriate individuals with drug resistance. Since antiquity, trephination was a crude and invasive technique to manage epilepsy. The late 1800s saw the advent of a more evidence-based approach with attempts to define seizure foci and determine areas of function. Seizure localization initially required direct brain stimulation during surgery before resection. Fortunately, improved knowledge of seizure semiology and advancements in preoperative investigations have enabled epilepsy specialists to better analyze the benefit of seizure reduction versus risk of functional harm. This preoperative phase and the investigative techniques used to analyze surgical candidacy will be discussed in this article.

Estimation of phase in EEG rhythms for real-time applications

Objective. Estimating the ongoing phase of oscillations in electroencephalography (EEG) recordings is an important aspect of understanding brain function, as well as for the development of phase-dependent closed-loop real-time systems that deliver stimuli. Such stimuli may take the form of direct brain stimulation (for example transcranial magnetic stimulation), or sensory stimuli (for example presentation of an auditory stimulus). We identify two linked problems related to estimating the phase of EEG rhythms with a specific focus on the alpha-band: 1) when the signal after a specific stimulus is unknown (real-time case), or 2) when it is corrupted by the presence of the stimulus itself (offline analysis). We propose methods to estimate the phase at the presentation time of these stimuli. Approach. Machine learning methods are used to learn the causal mapping from an unprocessed EEG recording to a phase estimate generated with a non-causal signal processing chain. This mapping is then used to predict the phase causally where non-causal methods are inappropriate. Main results. We demonstrate the ability of these machine learning methods to estimate instantaneous phase from an EEG signal subjected to very minor pre-processing with higher accuracy than commonly used signal-processing methods. Significance. Neural oscillations have been implicated in a wide variety of sensory, cognitive and motor functions. The instantaneous phase of these rhythms may reflect specific processes of computation which can be acted upon if they can be estimated with sufficient accuracy. Such brain-state dependent paradigms are of increasing medical and scientific interest.

The effects of direct brain stimulation in humans depend on frequency, amplitude, and white-matter proximity

BackgroundResearchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. ObjectiveThe goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain. MethodsTo examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. ResultsOverall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. ConclusionBy characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

Combined and Isolated Effects of Acute Exercise and Brain Stimulation on Executive Function in Healthy Young Adults.

Acute cognitive enhancement has been sought by healthy young individuals to improve academic and professional performance. Among several methods, physical exercise interventions and transcranial direct current brain stimulation (tDCS) have shown promise in impacting executive functions. Here, we observed a set of new findings about the causal effect of acute aerobic exercise and tDCS across three facets of executive function: Inhibition (as measured by a flanker task) was selectively impacted by acute aerobic exercise but not tDCS, whereas working memory (as measured by an n-back task) was impacted by both acute aerobic exercise and tDCS, with effects emerging on distinct processing components for each manipulation. Sustained attention (as measured by the Mackworth clock task), on the other hand, was not impacted by acute aerobic exercise or tDCS. Interestingly, no effects of combining acute aerobic exercise and tDCS emerged. We argue that understanding the unique and combined contributions of these cognitive enhancement techniques can not only contribute to a deeper mechanistic explanation in healthy individuals but also inform future research with clinical and aging populations.

Low-Intensity Ultrasonic Neuromodulation Enhances Cell-Type-Specific Functional Encoding in Rat Anteroventral Cochlear Nucleus

Low-intensity ultrasound (LIUS) has proven to be an effective tool for direct neuro-modulation or potential non-invasive deep brain stimulation technology for treating various neurological disorders. However, the cell-type-specific modulation by LIUS has remained less well understood. In this study, we demonstrate that LIUS medicates cell-type-specific firing pattern in two major neurons of the anteroventral cochlear nucleus (AVCN), the bushy (BCs) and stellate cells (SCs), using whole-cell patch-clamp recordings in vitro. The results show that BCs are well maintaining phase-locking firing by LIUS to provide precise temporal processing, whereas LIUS significant increase the rate of tonic firing in SCs to promote the processing of sounds envelope. Both cell types are received similar modulation of their intrinsic membrane properties by LIUS but engage different ion channels modulatory mechanisms. Therefore, our results promote mechanisms understanding for the development of ultrasonic neuro-modulation technology and may offer an alternative therapy for central auditory processing disorders.

Modelling acute and lasting effects of tDCS on epileptic activity.

Transcranial Direct brain stimulation (tDCS) is commonly used in order to modulate cortical networks activity during physiological processes through the application of weak electrical fields with scalp electrodes. Cathodal stimulation has been shown to decrease brain excitability in the context of epilepsy, with variable success. However, the cellular mechanisms responsible for the acute and the long-lasting effect of tDCS remain elusive. Using a novel approach of computational modeling that combines detailed but functionally integrated neurons we built a physiologically-based thalamocortical column. This model comprises 10,000 individual neurons made of pyramidal cells, and 3 types of gamma-aminobutyric acid (GABA) -ergic cells (VIP, PV, and SST) respecting the anatomy, layers, projection, connectivity and neurites orientation. Simulating realistic electric fields in term of intensity, main results showed that 1) tDCS effects are best explained by modulation of the presynaptic probability of release 2) tDCS affects the dynamic of cortical network only if a sufficient number of neurons are modulated 3)VIP GABAergic interneurons of the superficial layer of the cortex are especially affected by tDCS 4) Long lasting effect depends on glutamatergic synaptic plasticity.

Comparison of fiber tract low frequency stimulation to focal and ANT stimulation in an acute rat model of focal cortical seizures

BackgroundCurrent implementations of direct brain stimulation for epilepsy in patients involve high-frequency (HFS) electrical current and targeting of grey matter. Studies have shown that low-frequency (LFS) fiber-tract stimulation may also prove effective. To compare the efficacy of high-frequency grey matter stimulation to the low-frequency fiber tract stimulation technique a well-controlled set of experiments using a single animal model of epilepsy is needed. ObjectiveThe goal of this study was to determine the relative efficacy of different direct brain stimulation techniques for suppressing seizures using an acute rat model of focal cortical seizures. Methods4-AP was injected into the S1 region of cortex in rodents over 3 h. LFPs were recorded from the seizure focus and mirror focus to monitor seizure frequency during the experiments. CC-LFS, HFS-ANT, Focal-HFS, or a transection of the CC was applied. ResultsStimulation of the CC yielded a 65% ±14% (p = 0.0014) reduction of seizures in the focus and a 97% ±15% (p = 0.0026) reduction in the mirror focus (n = 7). By comparison transection of the CC produced a 65% ±18% reduction in the focus and a non-statistically significant reduction of 57% ±18% (p = 0.1381) in the mirror focus (n = 5). All other methods of stimulation failed to have a statistically significant effect on seizure suppression. ConclusionsLFS of the CC is the only method of stimulation to significantly reduce seizure frequency in this model of focal cortical seizures. These results support the hypothesis that LFSof fiber tracts has significant potential for seizure control.

Study of Direct Brain Recording and Stimulation for Memory Enhancement

Study of Direct Brain Recording and Stimulation for Memory Enhancement

The role of the dorsal anterior insula in ecstatic sensation revealed by direct electrical brain stimulation

BackgroundAn ecstatic phenomenon is an altered state of consciousness with a sense of “hyper-reality”, and a complete present-moment awareness with a feeling of union with the Universe. A better understanding of the network mechanisms underlying this fascinating subjective experience may help to unravel some mysteries of human consciousness. Insula has been recently proposed to be a key region to elicit these symptoms. Objective/HypothesisWe studied functional connectivity changes in several brain areas during the induction of ecstatic auras by direct electrical stimulation of the dorsal anterior insular cortex in patients with refractory focal epilepsy implanted with intracerebral electrodes (stereotactic-EEG, SEEG) in the context of their pre-surgical evaluation. MethodsThree patients were selected on the basis of the occurrence of ecstatic symptoms triggered by direct intracerebral electrical stimulation (ES) of the antero-dorsal part of the insula. ES was performed (50 Hz, 1.5–2.1 mA, in a bipolar fashion to each contact in the gray matter during a 3 s period) to map functional cortices and trigger habitual seizures. One stimulation inducing ecstatic changes in each patient was analyzed. Functional connectivity analysis was performed by measuring interdependencies (nonlinear regression analysis based on the h2 coefficient) between SEEG signals before and after stimulations. ResultsIn all patients, only the stimulation of dorsal anterior insula was able to reproduce an ecstatic aura. We observed a significant increase of functional connectivity values between several brain regions in the immediate period following stimulations. The most commonly implicated region was the dorsal anterior insula. Out-degrees (a measure intended to identify leading structures in a network) identified the dorsal anterior insula as the most common leading region in the induced networks. Conclusion(s)Our findings bring additional support in favor of a major role played by the dorsal anterior insula in ecstatic experiences.

No effect of transcranial direct current stimulation of frontal, motor or visual cortex on performance of a self-paced visuomotor skill

ObjectivesTranscranial direct current stimulation (tDCS) is a form of neurostimulation that can modulate neural activity in targeted brain regions through electrical current applied directly to the scalp. Previous findings have shown cognitive enhancement and improved motor learning following tDCS. Consequently, there has been growing interest in direct brain stimulation for enhancing sporting skills. We aimed to assess the effect of tDCS on golf putting performance and control of visual attention. DesignUsing a mixed factorial design, the effect of stimulation (between-participants) was assessed at baseline, following stimulation and in a pressure test (within-participants). Methods73 novice golfers were randomly assigned to transcranial direct current stimulation of frontal, motor or visual cortex, or sham stimulation. Participants first performed a series of golf putts at baseline, then while receiving tDCS and finally under pressurised conditions. Putting performance (distance from the hole) and control of visual attention (quiet eye duration) was assessed. ResultsThere was no effect of real tDCS stimulation compared to sham stimulation on either performance or visual attention (quiet eye durations), for any stimulation site. ConclusionsWhile beneficial effects of tDCS have been found in computerised cognitive tests and simple motor tasks, there is currently little evidence that this will transfer to real-world sporting performance.

Corticomotoneuronal Model for Intraoperative Neurophysiological Monitoring During Direct Brain Stimulation.

Intraoperative neurophysiological monitoring during brain surgery uses direct cortical stimulation to map the motor cortex by recording muscle activity induced by the excitation of alpha motor neurons (MNs). Computational models have been used to understand local brain stimulation. However, a computational model revealing the stimulation process from the cortex to MNs has not yet been proposed. Thus, the aim of the current study was to develop a corticomotoneuronal (CMN) model to investigate intraoperative stimulation during surgery. The CMN combined the following three processes into one system for the first time: (1) induction of an electric field in the brain based on a volume conductor model; (2) activation of pyramidal neuron (PNs) with a compartment model; and (3) formation of presynaptic connections of the PNs to MNs using a conductance-based synaptic model coupled with a spiking model. The implemented volume conductor model coupled with the axon model agreed with experimental strength-duration curves. Additionally, temporal/spatial and facilitation effects of CMN synapses were implemented and verified. Finally, the integrated CMN model was verified with experimental data. The results demonstrated that our model was necessary to describe the interaction between frequency and pulses to assess the difference between low-frequency and multi-pulse high-frequency stimulation in cortical stimulation. The proposed model can be used to investigate the effect of stimulation parameters on the cortex to optimize intraoperative monitoring.

Does transcranial direct current stimulation to the prefrontal cortex affect social behavior? A meta-analysis.

This meta-analysis (k = 48, N = 2196) examined the effect of transcranial direct current brain stimulation (tDCS) applied to the prefrontal cortex on a variety of social behaviors, including aggression, overeating, impulsivity, bias, honesty, and risk-taking. tDCS showed an overall significant effect on reducing undesirable behaviors, with an average effect size of d = −0.20. tDCS was most effective at reducing risk-taking behavior, bias, and overeating. tDCS did not affect aggression, impulsivity, or dishonesty. We examined moderators such as brain region of interest, online vs offline stimulation, within- vs between-subjects designs, dose, and duration, but none showed significant interactions. We also tested for potential publication bias using two different tools, which indicated signs of publication bias in the literature. After correcting for potential publication bias, the effect of tDCS was still significant, but the size was reduced (d = −0.10). These findings suggest the presence of tDCS studies with null findings outside of the published literature. Taken together, these results suggest that although tDCS can reduce undesirable behaviors, researchers should consider the types of behaviors they measure and use strategies to ensure sufficient power to detect a possible effect of tDCS on social behavior.

T14. Potential electrocorticographic seizure biomarkers

Identifying electrographic features that differentiate patients with the most favorable response to epilepsy treatments will aid in discovering disease biomarkers and treatment endpoints, and could enhance patient selection. The RNS® System provides responsive direct-brain stimulation and is FDA approved for the treatment of medically refractory focal epilepsies in adults. The median percent seizure reduction in clinical trials reaches 72% at 7 years with 30% experiencing a reduction in seizures of ⩾90% based on most recent 3 months of follow-up. The device also provides chronic ambulatory electrocorticographic data. The objective of this study was to assess electrographic and demographic differences between patients treated with the RNS® System (NeuroPace, Inc.) who had the greatest and the least reductions in clinical seizure frequency. 179 adults within clinical trials of the RNS System had ⩾6 months of clinical seizure data at year 7 of treatment and were included in this analysis. Patients in the upper (n = 45: MTL = 16, Neocortical = 27, MTL + neocortical = 2) and lower (n = 45: MTL = 16, Neocortical = 26, MTL + neocortical = 3) clinical seizure response quartiles were determined by ranking mean change in clinical seizure rates in year 7 compared to baseline. Electrographic features (interictal spikes, total spectral power and band spectral power) were extracted from 76,570 scheduled (putatively interictal baseline) ambulatory 4-channel electrocorticographic (ECoG) records (each ∼90 s) collected over 7 years. Differences in electrographic features and clinical seizures over time in the upper and lower response quartile patients were measured. Demographic characteristics (gender, age at enrollment, age of onset, number of onsets, baseline seizure rate, and presence or absence of previous resection, callosotomy, subpial transection and prior intracranial monitoring) were compared. ECoG feature trends over time (6 months to 7 years) closely followed clinical seizure rate trends in both MTL and neocortical groups, with higher feature values significantly (p < 0.05) correlated with higher clinical seizure rates. Ranking features according to their ability to differentiate upper and lower response quartile patients revealed spike rate as the strongest feature in the MTL group. In the neocortical group, high gamma (50–125 Hz) emerged as the strongest feature. There were no significant differences in the demographic characteristics between upper and lower quartile patients when considered as one group or when divided into MTL and neocortical onset groups. Chronic ambulatory ECoG data obtained from a trial of the RNS System revealed electrophysiological differences between patients in the upper and lower quartiles of clinical seizure response. Changes in spike frequency and in high gamma could be potential seizure biomarkers.