Cortical Stimulation Research Articles

A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI

BackgroundEmerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI). Accelerated intermittent theta burst stimulation (iTBS) rTMS protocols are promising as they substantially reduce...

Microscopic deconstruction of cortical circuit stimulation by transcranial ultrasound.

Transcranial Ultrasound Stimulation (TUS) can noninvasively and reversibly perturb neuronal activity, but the mechanisms by which ultrasound engages brain circuits to induce functional effects remain unclear. To elucidate these interactions, we applied TUS to the cortex of awake mice and concurrently monitored local neural activity at the acoustic focus with two-photon calcium imaging. We show that TUS evokes highly focal responses in three canonical neuronal populations, with cell-type-specific dose dependencies. Through independent parametric variations, we demonstrate that evoked responses collectively scale with the time-average intensity of the stimulus. Finally, using computational unmixing we propose a physiologically realistic cortical circuit model that predicts TUS-evoked responses as a result of both direct effects and local network interactions. Our results provide a first direct evidence of TUS's focal effects on cortical activity and shed light on the complex circuit mechanisms underlying these effects, paving the way for TUS's deployment in clinical settings.

Mapping the basal temporal language network: a SEEG functional connectivity study

The Basal Temporal Language Area (BTLA) is recognized in epilepsy surgery setting when cortical electrical stimulation (CES) of the ventral temporal cortex (VTC) trigger anomia or paraphasia during naming tasks. Despite acknowledging a ventral language stream, current cognitive language models fail to properly integrate this entity. In this SEEG study we used cortico-cortical evoked potentials in nine epileptic patients to assess and compare the effective connectivity of 73 sites in the left VTC of which 26 were deemed eloquent for naming after CES (BTLA). Eloquent sites connectivity supports the existence of a basal temporal language network (BTLN) structured around posterior projectors while the fusiform gyrus behaved as an integrator. BTLN was strongly connected to the amygdala and hippocampus unlike the non-eloquent sites, except for the anterior fusiform gyrus (FG). These observations support the FG as a multimodal functional hub and add to our understanding of ventral temporal language processing.

Cortical sites critical to language function act as connectors between language subnetworks

Historically, eloquent functions have been viewed as localized to focal areas of human cerebral cortex, while more recent studies suggest they are encoded by distributed networks. We examined the network properties of cortical sites defined by stimulation to be critical for speech and language, using electrocorticography from sixteen participants during word-reading. We discovered distinct network signatures for sites where stimulation caused speech arrest and language errors. Both demonstrated lower local and global connectivity, whereas sites causing language errors exhibited higher inter-community connectivity, identifying them as connectors between modules in the language network. We used machine learning to classify these site types with reasonably high accuracy, even across participants, suggesting that a site’s pattern of connections within the task-activated language network helps determine its importance to function. These findings help to bridge the gap in our understanding of how focal cortical stimulation interacts with complex brain networks to elicit language deficits.

The effect of common parameters of bipolar stimulation on brain evoked potentials

ObjectiveTo identify optimal bipolar stimulation parameters for robust generation of brain evoked potentials (BEPs), namely the interelectrode distance (IED) and the intensity of stimulation (IS), in cortical and axonal stimulation. MethodsIn 15 patients who underwent awake surgery for brain tumor removal, BEPs were elicited at different values of IED and IS, respectively: 5 mm-5 mA, 5 mm-10 mA, and 10 mm-10 mA. The number of BEPs elicited by stimulation, as well as the delays and amplitudes of the N1 waves were compared between the different groups of stimulation parameters and according to the stimulated brain structure (cortical vs. axonal). ResultsThe amplitudes of N1 increased with the intensity of bipolar stimulation, either in cortical or axonal stimulation, while N1 peak delays were not affected by the stimulation parameters. Furthermore, axonal stimulation produced more N1s than cortical stimulation, with lower latencies. ConclusionsUnderstanding the relationship between stimulation parameters and BEP is of utmost importance to determine whether the generated N1 waves accurately reflect the underlying structural anatomy. Other factors, such as stimulation frequency or pulse width and shape, may also play a role and warrant further investigation. SignificanceThis study represents the first step in describing the influence of common bipolar stimulation parameters on robustness of BEPs by examining the impact of IED and IS on the N1 wave.

Epilepsy Research in the Institute of Physiology of the Czech Academy of Sciences in Prague.

Starting from simple clinical statistics, the spectrum of methods used in epilepsy research in the Institute of Physiology of the Czechoslovak (now Czech) Academy of Sciences progressively increased. Professor Servít used electrophysiological methods for study of brain activity in lower vertebrates, neuropathology was focused on electronmicroscopic study of cortical epileptic focus and ion-sensitive microelectrodes were used for studies of cortical direct current potentials. Developmental studies used electrophysiological methods (activity and projection of cortical epileptic foci, EEG under the influence of convulsant drugs, hippocampal, thalamic and cortical electrical stimulation for induction of epileptic afterdischarges and postictal period). Extensive pharmacological studies used seizures elicited by convulsant drugs (at first pentylenetetrazol but also other GABA antagonists as well as agonists of glutamate receptors). Motor performance and behavior were also studied during brain maturation. The last but not least molecular biology was included into the spectrum of methods. Many original data were published making a background of position of our laboratory in the first line of laboratories interested in brain development.

Machine learning allows expert level classification of intraoperative motor evoked potentials during neurosurgical procedures

ObjectiveTo develop and evaluate machine learning (ML) approaches for muscle identification using intraoperative motor evoked potentials (MEPs), and to compare their performance to human experts. BackgroundThere is an unseized opportunity to apply ML analytic techniques to the world of intraoperative neuromonitoring (IOM). MEPs are the ideal candidates given the importance of their correct interpretation during a surgical operation to the brain or the spine. In this work, we develop and test a set of different ML models for muscle identification using intraoperative MEPs and compare their performance to human experts. In addition, we provide a review of the available literature on current ML applications to IOM data in neurosurgery. MethodsWe trained and tested five different ML classifiers on a MEP database developed from six different muscles in patients who underwent brain or spinal cord surgery. MEPs were obtained by both transcranial (TES) and direct cortical stimulation (DCS) protocols. The models were evaluated within a single patient and on previously unseen patients, considering signals from TES and DCS both independently and mixed. Ten expert neurophysiologists classified a set of 50 randomly selected MEPs, and their performance was compared to the best performing model. ResultsA total of 25.423 MEPs were included in the study. Random Forest proved to be the best performing model with 99 % accuracy in the single patient dataset task and a 78 %–94 % accuracy range on previously unseen patients. The model performance was maximized by representing MEPs as a set of features typically employed in signal processing compared to traditional neurophysiological parameters. The classification ability of the Random Forest model between six different muscles and across different MEP acquisition modalities (79 %) significantly exceeded that of human experts (mean 48 %). ConclusionsCarefully selected ML models proved to have reliable capacity of extracting meaningful information to classify intraoperative MEPs using a limited number of features, proving robustness across patients and signal acquisition modalities, outperforming human experts, and with the potential to act as decision support systems to the IOM team. Such encouraging results lay the path to further explore the underlying nature of clinically important signals, with the aim to continue to produce useful applications to make surgeries safer and more efficient.

Central and peripheral neuromuscular fatigue following ramp and rapid maximal voluntary isometric contractions.

Maximal voluntary isometric contractions (MVICs) as a fatiguing modality have been widely studied, but little attention has been given to the influence of the rate of torque development. Given the established differences in motor command and neuromuscular activation between ramp and rapid MIVCs, it is likely performance fatigue differs as well as the underlying physiological mechanisms. To compare responses for rapid and maximal torque following ramp and rapid MVICs, and the corresponding neuromuscular and corticospinal alterations. On separate visits, twelve healthy males (22.8 ± 2.5years) performed fatiguing intermittent MVICs of the knee extensors with either 2s (RAMP) or explosive (RAPID) ramp-ups until a 50% reduction in peak torque was achieved. Before and after each condition, maximal and rapid torque measures were determined from an MVIC. Additionally, peripheral (twitch parameters) and central (voluntary activation) fatigue, as well as rapid muscle activation, and cortical-evoked twitch and electromyographic responses were recorded. Maximal and late-phase rapid torque measures (p ≤ 0.001; = 0.635-0.904) were reduced similarly, but early rapid torque capacity (0-50ms) (p = 0.003; d = 1.11 vs. p = 0.054; d = 0.62) and rapid muscle activation (p = 0.008; d = 1.07 vs. p = 0.875; d = 0.06) decreased more after RAMP. Changes in peripheral fatigue, as indicated by singlet and doublet contractile parameters (p < 0.001 for all; = 0.752-0.859), and nerve-evoked voluntary activation (p < 0.001; 0.660) were similar between conditions. Corticospinal inhibition (via silent period) was only increased after RAPID (p = 0.007; d = 0.94 vs. p = 0.753; d = 0.09), whereas corticospinal voluntary activation and excitability were unchanged. Ramp, fatiguing MVICs impaired early rapid torque capacity more than rapid MVICs, and this was accompanied by decrements in rapid muscle activation. Responses for peripheral and central fatigue (nerve and cortical stimulation) were largely similar between conditions, except that rapid MVICs increased corticospinal inhibition.

Repeated spaced cortical paired associative stimulation promotes additive plasticity in the human parietal-motor circuit

ObjectiveRepeated spaced sessions of repetitive transcranial magnetic stimulation (TMS) to the human primary motor cortex can lead to dose-dependent increases in motor cortical excitability. However, this has yet to be demonstrated in a defined cortical circuit. We aimed to examine the effects of repeated spaced cortical paired associative stimulation (cPAS) on excitability in the motor cortex. MethodscPAS was delivered to the primary motor cortex (M1) and posterior parietal cortex (PPC) with two coils. In the multi-dose condition, three sessions of cPAS were delivered 50-min apart. The single-dose condition had one session of cPAS, followed by two sessions of a control cPAS protocol. Motor-evoked potentials were evaluated before and up to 40 min after each cPAS session as a measure of cortical excitability. ResultsCompared to a single dose of cPAS, motor cortical excitability significantly increased after multi-dose cPAS. Increasing the number of cPAS sessions resulted in a cumulative, dose-dependent effect on excitability in the motor cortex, with each successive cPAS session leading to notable increases in potentiation. ConclusionRepeated spaced cPAS sessions summate to increase motor cortical excitability induced by single cPAS. SignificanceRepeated spaced cPAS could potentially restore abilities lost due to disorders like stroke.

Pilot Study of Personalized Transcranial Magnetic Stimulation with Spectral Electroencephalogram Analyses for Assessing and Treating Persons with Autism.

Autism spectrum condition (ASC) is a neurodevelopmental condition that is only partly responsive to prevailing interventions. ASC manifests core challenges in social skills, communication, and sensory function and by repetitive stereotyped behaviors, along with imbalances in the brain's excitatory (E) and inhibitory (I) signaling. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in ASC and may be a useful addition to applied behavioral analysis (ABA), a gold-standard psychotherapeutic intervention. We report an open-label clinical pilot (initial) study in which ABA-treated ASC persons (n = 123) received our personalized rTMS protocol (PrTMS). PrTMS uses low TMS pulse intensities and continuously updates multiple cortical stimulation locales and stimulation frequencies based on the spectral EEG and psychometrics. No adverse effects developed, and 44% of subjects had ASC scale scores reduced to below diagnostic cutoffs. Importantly, in PrTMS responders, the spectral EEG regression flattened, implying a more balanced E/I ratio. Moreover, with older participants, alpha peak frequency increased, a positive correlate of non-verbal cognition. PrTMS may be an effective ASC intervention, offering improved cognitive function and overall symptomatology. This warrants further research into PrTMS mechanisms and specific types of subjects who may benefit, along with validation of the present results and exploration of broader clinical applicability.

Intraoperative Neuromonitoring for the Lower-Extremity Region Using Motor-Evoked Potential With Direct Cortical Stimulation in Brain Tumor Surgeries.

To evaluate the motor function of the lower extremity (LE), we used direct cortical stimulation motor-evoked potential (D-MEP) monitoring with a single six-contact subdural strip electrode placed in the interhemispheric fissure. Intraoperative neuromonitoring using D-MEPs in the LE was performed in 18 cases (16 patients) for brain tumor surgery from December 2018 to April 2023 with a follow-up period of at least 3 months. After dural opening, a single six-contact subdural strip electrode was placed inside the interhemispheric fissure. To identify the central sulcus, phase reversal was recorded using somatosensory evoked potentials. Next, direct cortical stimulation was applied to the primary motor cortex. The baseline waveform was defined as a reproducible waveform of 30 µV or higher, and a significant decrease of ≥50% in the amplitude resulted in a warning during surgery. The success rate of central sulcus identification in the LE was 66.7% (12/18 cases). Direct cortical stimulation motor-evoked potential monitoring could record stable contralateral motor-evoked potentials of the tibialis anterior, gastrocnemius, and abductor hallucis in 16 of 18 cases (88.9%). The mean intensity of stimulation for D-MEPs was 20.5 ± 9.9 mA, and the 16 cases showed no significant reduction in amplitude. Seventeen cases showed no deterioration of motor function of the LE at 1 and 3 months postoperatively. In the remaining case with unsuccessful D-MEP, paralysis of the LE worsened at 1 and 3 months postoperatively. The placement of electrodes in the interhemispheric fissure on the primary motor cortex of the LE enabled motor-function monitoring in the LE with D-MEPs, suggesting that D-MEP-based monitoring may be a reliable approach.

Simulation-Informed Power Budget Estimate of a Fully-Implantable Brain-Computer Interface.

This study aims to estimate the maximum power consumption that guarantees a thermally safe operation for a titanium-enclosed chest wall unit (CWU) subcutaneously implanted in the pre-pectoral area. This unit is a central piece of an envisioned fully-implantable bi-directional brain-computer interface (BD-BCI). To this end, we created a thermal simulation model using the finite element method implemented in COMSOL. We also performed a sensitivity analysis to ensure that our predictions were robust against the natural variation of physiological and environmental parameters. Based on this analysis, we predict that the CWU can consume between 378 and 538mW of power without raising the surrounding tissue's temperature above the thermal safety threshold of 2 C. This power budget should be sufficient to power all of the CWU's basic functionalities, which include training the decoder, online decoding, wireless data transmission, and cortical stimulation. This power budget assessment provides an important specification for the design of a CWU-an integral part of a fully-implantable BD-BCI system.

More widespread functionality of posterior language area in patients with brain tumors.

Damage to the posterior language area (PLA), or Wernicke's area causes cortical reorganization in the corresponding regions of the contralateral hemisphere. However, the details of reorganization within the ipsilateral hemisphere are not fully understood. In this context, direct electrical stimulation during awake surgery can provide valuable opportunities to investigate neuromodulation of the human brain in vivo, which is difficult through the non-invasive approaches. Thus, in this study, we aimed to investigate the characteristics of the cortical reorganization of the PLA within the ipsilateral hemisphere. Sixty-two patients with left hemispheric gliomas were divided into groups depending on whether the lesion extended to the PLA. All patients underwent direct cortical stimulation with a picture-naming task. We further performed functional connectivity analyses using resting-state functional magnetic resonance imaging (MRI) in a subset of patients and calculated betweenness centrality, an index of the network importance of brain areas. During direct cortical stimulation, the regions showing positive (impaired) responses in the non-PLA group were localized mainly in the posterior superior temporal gyrus (pSTG), whereas those in the PLA group were widely distributed from the pSTG to the posterior supramarginal gyrus (pSMG). Notably, the percentage of positive responses in the pSMG was significantly higher in the PLA group (47%) than in the non-PLA group (8%). In network analyses of functional connectivity, the pSMG was identified as a hub region with high betweenness centrality in both the groups. These findings suggest that the language area can spread beyond the PLA to the pSMG, a hub region, in patients with lesion progression to the pSTG. The change in the pattern of the language area may be a compensatory mechanism to maintain efficient brain networks.

A virtual patient simulation modeling the neural and perceptual effects of human visual cortical stimulation, from pulse trains to percepts

The field of cortical sight restoration prostheses is making rapid progress with three clinical trials of visual cortical prostheses underway. However, as yet, we have only limited insight into the perceptual experiences produced by these implants. Here we describe a computational model or ‘virtual patient’, based on the neurophysiological architecture of V1, which successfully predicts the perceptual experience of participants across a wide range of previously published human cortical stimulation studies describing the location, size, brightness and spatiotemporal shape of electrically induced percepts in humans. Our simulations suggest that, in the foreseeable future the perceptual quality of cortical prosthetic devices is likely to be limited by the neurophysiological organization of visual cortex, rather than engineering constraints.

Electrical stimulation in special clinical situations

Introduction: Neuromodulation is an approach used to treat diseases that are refractory to clinical treatments by employing electrical and chemical stimulation techniques, especially in cardiac, neurological, and psychiatric disorders. Objective: This study aims to provide an overview of the latest developments in neuromodulation therapies that use electrical stimulation. Methods and results: The present study describes the most common neuromodulation techniques. Neuroplasticity is used to adjust the ions and neural excitability in response to central and peripheral nervous system stimulation. The spinal cord, dorsal root, and gastric stimulations are effective treatments for neuropathies, chronic pain, muscle spasticity, epilepsy, depression, cluster headaches, heart failure, and gastroparesis symptoms. Deep brain stimulation and invasive cortical stimulation are medical procedures used selectively to treat Parkinson’s disease, dystonia, obsessive-compulsive disorder, and chronic pain. Barostimulation therapy is beneficial in controlling refractory hypertension, reducing the risk of cardiovascular events, and improving overall quality of life. Repetitive Transcranial Magnetic Stimulation is a recommended treatment option for fibromyalgia, neuropathic pain, chronic headaches, treatment-resistant depression, generalized anxiety disorders, schizophrenia, and attention deficit disorder. While controlling obesity shows promise in regulating appetite and promoting satiety, more research is needed to understand the safety and efficacy of these therapies in various groups. Conclusion: Neuromodulation devices hold promise for treating diseases that do not respond to clinical treatments. Additional clinical trials and studies are required to understand it fully.

Interventional neurorehabilitation for glioma patients: A systematic review

Abstract Harnessing the neuroplastic potential of the human brain is being increasingly recognized as an important neuro-oncological paradigm to facilitate safe resection of brain tumors while preserving neurological function and quality of life. Interventional neurorehabilitation, employing both invasive and noninvasive neuromodulation techniques, represents an important emerging therapeutic strategy to induce or enhance neural plasticity to promote functional recovery in brain tumor patients. This study aimed to conduct a comprehensive review of interventional neurorehabilitation techniques for glioma patients. Methods: In accordance with PRISMA guidelines, searches of Medline, Embase, Web of Science, APA PsycINFO, and Cochrane were undertaken from database inception to November 28, 2023. Studies reporting on neuromodulation applied to glioma patients were included. Results: Seven studies reporting findings from 118 patients met the inclusion criteria. Three neuromodulation techniques were identified and included transcranial magnetic stimulation (TMS) reported in 5 out of 7 (71.4%) studies; transcranial direct current stimulation (tDCS); and continuous cortical electrical stimulation (cCES) using grid electrodes, reported in one study each. All studies applying noninvasive stimulation to ameliorate postoperative deficits demonstrated an improvement on at least one outcome measure. The 2 studies applying tDCS and cCES to induce plasticity reported evidence of functional reorganization. Conclusions: There is emerging evidence of benefits of neuromodulation to improve postoperative outcome in glioma patients. In the current literature, noninvasive stimulation has shown to have a favorable safety profile. Large-scale, double-blind, sham-controlled trials are warranted to further investigate the effectiveness of these interventions for modulating different cognitive networks in patients undergoing glioma surgery.

The effect of high-definition transcranial direct current stimulation on pain in somatic symptom disorder with predominant pain: A randomized single-blind sham-controlled crossover study

Somatic symptom disorder with predominant pain (SSD-P) is a commonly encountered disorder, yet treatment options often yield unsatisfactory outcomes. Transcranial direct current stimulation (tDCS) has proven useful in chronic pain conditions and may hold potential for treating somatoform pain. High-definition tDCS (HD-tDCS) offers more precise cortical stimulation than conventional tDCS. However, this modality has not been extensively studied in SSD-P. Consequently, this study aims to assess the effects of a novel HD-tDCS protocol on pain and other associated variables in patients with SSD-P. The Institute Ethics Committee approved the study, which was also registered in the Clinical Trials Registry of India. A single-blind, sham-controlled, crossover study design was employed. Thirty right-handed patients with DSM-5 diagnosis of SSD-P, aged 18 &amp;ndash; 60 years and receiving stable treatment, were enrolled through consecutive sampling. After simple randomization, two repeated, short-interval sessions (2 mA, 20 min each) of either active or sham HD-tDCS were administered, followed by a washout period of 7 days and a subsequent crossover. Assessments were conducted at baseline, week 1, and week 2. Participants in active and sham arms were comparable on all baseline parameters. At the end of the 1st week, patients in the active group showed significant improvement in the study variables compared to the sham group. By week 2, all participants, irrespective of being in the active or sham arm, demonstrated a statistically significant difference (Cohen&amp;rsquo;s d &gt; 0.8) in pain and associated parameters such as depression, anxiety, pain-related interference, burden, and disability (P &lt; 0.01). Transient mild local side effects such as burning, pain, and itching were noted, with no cognitive side effects reported. In conclusion, this novel HD-tDCS protocol is effective in reducing pain in patients with SSD-P, with sustained effects up to 1 week.

Functional parcellation of the cingulate gyrus by electrical cortical stimulation: a synthetic literature review and future directions

BackgroundThe cingulate gyrus (CG), a brain structure above the corpus callosum, is recognised as part of the limbic system and plays numerous vital roles. However, its full functional capacity is...

Neuroprotection of Transcranial Cortical and Peripheral Somatosensory Electrical Stimulation by Modulating a Common Neuronal Death Pathway in Mice with Ischemic Stroke.

Therapeutic electrical stimulation, such as transcranial cortical stimulation and peripheral somatosensory stimulation, is used to improve motor function in patients with stroke. We hypothesized that these stimulations exert neuroprotective effects during the subacute phase of ischemic stroke by regulating novel common signaling pathways. Male C57BL/6J mouse models of ischemic stroke were treated with high-definition (HD)-transcranial alternating current stimulation (tACS; 20 Hz, 89.1 A/mm2), HD-transcranial direct current stimulation (tDCS; intensity, 55 A/mm2; charge density, 66,000 C/m2), or electroacupuncture (EA, 2 Hz, 1 mA) in the early stages of stroke. The therapeutic effects were assessed using behavioral motor function tests. The underlying mechanisms were determined using transcriptomic and other biomedical analyses. All therapeutic electrical tools alleviated the motor dysfunction caused by ischemic stroke insults. We focused on electrically stimulating common genes involved in apoptosis and cell death using transcriptome analysis and chose 11 of the most potent targets (Trem2, S100a9, Lgals3, Tlr4, Myd88, NF-kB, STAT1, IL-6, IL-1β, TNF-α, and Iba1). Subsequent investigations revealed that electrical stimulation modulated inflammatory cytokines, including IL-1β and TNF-α, by regulating STAT1 and NF-kB activation, especially in amoeboid microglia; moreover, electrical stimulation enhanced neuronal survival by activating neurotrophic factors, including BDNF and FGF9. Therapeutic electrical stimulation applied to the transcranial cortical- or periphery-nerve level to promote functional recovery may improve neuroprotection by modulating a common neuronal death pathway and upregulating neurotrophic factors. Therefore, combining transcranial cortical and peripheral somatosensory stimulation may exert a synergistic neuroprotective effect, further enhancing the beneficial effects on motor deficits in patients with ischemic stroke.

The Integration of Top-down and Bottom-up Inputs to the Striatal Cholinergic Interneurons.

Cholinergic interneurons (ChIs) are important for learning and memory. They exhibit a multiphasic excitation-pause-rebound response to reward or sensory cues indicating a reward, believed to gate dopamine-dependent learning. Although ChIs receive extensive top-down inputs from the cortex and bottom-up inputs from the thalamus and midbrain, it is unclear which inputs are involved in the development of ChI multiphasic activity. We used a single-unit recording of putative ChIs (pChIs) in response to cortical and visual stimulation to investigate how top-down and bottom-up inputs regulate the firing pattern of ChIs. We demonstrated that cortical stimulation strongly regulates pChIs, with the maximum firing rate occurring at the peak of the inverted local field potential (iLFP), reflecting maximum cortical stimulation. Pauses in pChIs occurred during the descending phase of iLFP, indicating withdrawal of excitatory cortical input. Visual stimulation induced long pauses in pChIs, but it is unlikely that bottom- up inputs alone induce pauses in behaving animals. Also, the firing pattern of ChIs triggered by visual stimulation did not correlate with the iLFP as it did after cortical stimulation. Top-down and bottom-up inputs independently regulate the firing pattern of ChIs with similar efficacy but notably produce a well-defined pause in ChI firing. This study provides in vivo evidence that the multiphasic ChI response may require both top-down and bottom-up inputs. The findings suggest that the firing pattern of ChIs correlated to the iLFP might be a useful tool for estimating the degree of contribution of top-down and bottom-up inputs in regulating the firing activity of ChIs.