Deciphering Authentic Nociceptive Thalamic Responses in Rats.

The thalamus and its cortical connections play a pivotal role in pain information processing, yet the exploration of its electrophysiological responses to nociceptive stimuli has been limited. Here, in 2 experiments we recorded neural responses to nociceptive laser stimuli in the thalamic (ventral posterior lateral nucleus and medial dorsal nucleus) and cortical regions (primary somatosensory cortex [S1] and anterior cingulate cortex) within the lateral and medial pain pathways. We found remarkable similarities in laser-evoked brain responses that encoded pain intensity within thalamic and cortical regions. Contrary to the expected temporal sequence of ascending information flow, the recorded thalamic response (N1) was temporally later than its cortical counterparts, suggesting that it may not be a genuine thalamus-generated response. Importantly, we also identified a distinctive component in the thalamus, i.e., the early negativity (EN) occurring around 100 ms after the onset of nociceptive stimuli. This EN component represents an authentic nociceptive thalamic response and closely synchronizes with the directional information flow from the thalamus to the cortex. These findings underscore the importance of isolating genuine thalamic neural responses, thereby contributing to a more comprehensive understanding of the thalamic function in pain processing. Additionally, these findings hold potential clinical implications, particularly in the advancement of closed-loop neuromodulation treatments for neurological diseases targeting this vital brain region.

Dynamic Changes of the Infralimbic Cortex and Its Regulation of the Prelimbic Cortex in Rats with Chronic Inflammatory Pain.

The prelimbic cortex (PL) is actively engaged in pain modulation. The infralimbic cortex (IL) has been reported to regulate the PL. However, how this regulation affects pain remains unclear. In the present study, we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli, but a temporary hypo-function of the IL by in vivo electrophysiological recording in rats with peripheral inflammation. Manipulation of the PL or IL had opposite effects on thermal hyperalgesia. Furthermore, the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL. Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia, whereas its inhibition exacerbated chronic pain. Overall, our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain: hypo-function of the IL leads to hyperactivity of the PL, which regulates thermal hyperalgesia, and thus contributes to the chronicity of pain.

Ventral Hippocampal CA1 Pyramidal Neurons Encode Nociceptive Information.

As a main structure of the limbic system, the hippocampus plays a critical role in pain perception and chronicity. The ventral hippocampal CA1 (vCA1) is closely associated with negative emotions such as anxiety, stress, and fear, yet how vCA1 neurons encode nociceptive information remains unclear. Using in vivo electrophysiological recording, we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats. Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions: the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli, whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties. Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors. Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats, whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain. These results provide direct evidence for the representations of nociceptive information in vCA1.

Pain-preferential thalamocortical neural dynamics across species.

Searching for pain-preferential neural activity is essential for understanding and managing pain. Here, we investigated the preferential role of thalamocortical neural dynamics in encoding pain using human neuroimaging and rat electrophysiology across three studies. In study 1, we found that painful stimuli preferentially activated the medial-dorsal (MD) thalamic nucleus and its functional connectivity with the dorsal anterior cingulate cortex (dACC) and insula in two human functional magnetic resonance imaging (fMRI) datasets (n = 399 and n = 25). In study 2, human fMRI and electroencephalography fusion analyses (n = 220) revealed that pain-preferential MD responses were identified 89-295 ms after painful stimuli. In study 3, rat electrophysiology further showed that painful stimuli preferentially activated MD neurons and MD-ACC connectivity. These converging cross-species findings provided evidence for pain-preferential thalamocortical neural dynamics, which could guide future pain evaluation and management strategies.

Deep brain stimulation in the lateral habenula reverses local neuronal hyperactivity and ameliorates depression-like behaviors in rats.

Deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression, while mechanisms underlying its therapeutic effects remain poorly defined. Increasing evidence has revealed an intimate association between the lateral habenula (LHb) and major depression, and suggests that the LHb might be an effective target of DBS therapy for depression. Here, we found that DBS in the LHb effectively decreased depression-like behaviors in rats experienced with chronic unpredictable mild stress (CUMS), a well-accepted paradigm for modeling depression in rodents. In vivo electrophysiological recording unveiled that CUMS increased neuronal burst firing, as well as the proportion of neurons showing hyperactivity to aversive stimuli in the LHb. Nevertheless, DBS downregulated local field potential power, reversed the CUMS-induced increase of LHb burst firing and neuronal hyperactivity to aversive stimuli, and decreased the coherence between LHb and ventral tegmental area (VTA). Our results demonstrate that DBS in the LHb exerts antidepressant-like effects and reverses local neural hyperactivity, supporting the LHb as a target of DBS therapy for depression.

Exogenous melatonin alleviates neuropathic pain-induced affective disorders by suppressing NF-κB/ NLRP3 pathway and apoptosis.

In this study, we aimed to evaluate the anti-inflammatory and anti-apoptotic effects of melatonin (MLT) on neuropathic pain (NP)-induced anxiety and depression in a rat model. Adult male rats were separated into four groups, i.e., Sham-VEH: healthy animals received a vehicle, Sham-MLT (10 mg/kg), and chronic constrictive injury (CCI)-VEH: nerve ligation received the vehicle, and CCI-MLT. Next, we used behavioral tests to evaluate pain severity, anxiety, and depression. Finally, rats were sacrificed for molecular and histopathological studies. Behavioral tests showed that NP could induce depressive- and anxiety-like behaviors. NP activated NF-κB/NLRP3 inflammasome pathways by upregulating NF-κB, NLRP3, ASC, active Caspase-1, also enhancing the concentrations of cytokines (IL-1ß and IL-18) in the prefrontal cortex (PFC) and hippocampus (HC). NP upregulated Bax, downregulated Bcl2, and increased cell apoptosis in the HC and PFC. The rats treated with MLT eliminated the effects of NP, as the reduced pain severity, improved anxiety- and depressive-like behaviors, ameliorated NF-κB/NLRP3 inflammasome pathways, and modulated levels of cytokines in the HC and PFC. MLT could promote cell survival from apoptosis by modulating Bax and Bcl2. Therefore, it might be inferred that its anti-inflammatory and anti-apoptotic properties mediate the beneficial effects of MLT in NP-induced affective disorders.

Cortical complexity and connectivity during isoflurane-induced general anesthesia: a rat study.

Objective.The investigation of neurophysiologic mechanisms of anesthetic drug-induced loss of consciousness (LOC) by using the entropy, complexity, and information integration theories at the mesoscopic level has been a hot topic in recent years. However, systematic research is still lacking.Approach.We analyzed electrocorticography (ECoG) data recorded from nine rats during isoflurane-induced unconsciousness. To characterize the complexity and connectivity changes, we investigated ECoG power, symbolic dynamic-based entropy (i.e. permutation entropy (PE)), complexity (i.e. permutation Lempel-Ziv complexity (PLZC)), information integration (i.e. permutation cross mutual information (PCMI)), and PCMI-based cortical brain networks in the frontal, parietal, and occipital cortical regions.Main results.Firstly, LOC was accompanied by a raised power in the ECoG beta (12-30 Hz) but a decreased power in the high gamma (55-95 Hz) frequency band in all three brain regions. Secondly, PE and PLZC showed similar change trends in the lower frequency band (0.1-45 Hz), declining after LOC (p< 0.05) and increasing after recovery of consciousness (p< 0.001). Thirdly, intra-frontal and inter-frontal-parietal PCMI declined after LOC, in both lower (0.1-45 Hz) and higher frequency bands (55-95 Hz) (p< 0.001). Finally, the local network parameters of the nodal clustering coefficient and nodal efficiency in the frontal region decreased after LOC, in both the lower and higher frequency bands (p< 0.05). Moreover, global network parameters of the normalized average clustering coefficient and small world index increased slightly after LOC in the lower frequency band. However, this increase was not statistically significant.Significance. The PE, PLZC, PCMI and PCMI-based brain networks are effective metrics for qualifying the effects of isoflurane.

Side Effects of Opioids Are Ameliorated by Regulating TRPV1 Receptors.

Humans have used opioids to suppress moderate to severe pain for thousands of years. However, the long-term use of opioids has several adverse effects, such as opioid tolerance, opioid-induced hyperalgesia, and addiction. In addition, the low efficiency of opioids in controlling neuropathic pain limits their clinical applications. Combining nonopioid analgesics with opioids to target multiple sites along the nociceptive pathway may alleviate the side effects of opioids. This study reviews the feasibility of reducing opioid side effects by regulating the transient receptor potential vanilloid 1 (TRPV1) receptors and summarizes the possible underlying mechanisms. Blocking and activating TRPV1 receptors can improve the therapeutic profile of opioids in different manners. TRPV1 and µ-opioid receptors are bidirectionally regulated by ß-arrestin2. Thus, drug combinations or developing dual-acting drugs simultaneously targeting µ-opioid and TRPV1 receptors may mitigate opioid tolerance and opioid-induced hyperalgesia. In addition, TRPV1 receptors, especially expressed in the dorsal striatum and nucleus accumbens, participate in mediating opioid reward, and its regulation can reduce the risk of opioid-induced addiction. Finally, co-administration of TRPV1 antagonists and opioids in the primary action sites of the periphery can significantly relieve neuropathic pain. In general, the regulation of TRPV1 may potentially ameliorate the side effects of opioids and enhance their analgesic efficacy in neuropathic pain.

Quantitative Electrophysiological Evaluation of the Analgesic Efficacy of Two Lappaconitine Derivatives: A Window into Antinociceptive Drug Mechanisms.

Quantitative evaluation of analgesic efficacy improves understanding of the antinociceptive mechanisms of new analgesics and provides important guidance for their development. Lappaconitine (LA), a potent analgesic drug extracted from the root of natural Aconitum species, has been clinically used for years because of its effective analgesic and non-addictive properties. However, being limited to ethological experiments, previous studies have mainly investigated the analgesic effect of LA at the behavioral level, and the associated antinociceptive mechanisms are still unclear. In this study, electrocorticogram (ECoG) technology was used to investigate the analgesic effects of two homologous derivatives of LA, Lappaconitine hydrobromide (LAH) and Lappaconitine trifluoroacetate (LAF), on Sprague-Dawley rats subjected to nociceptive laser stimuli, and to further explore their antinociceptive mechanisms. We found that both LAH and LAF were effective in reducing pain, as manifested in the remarkable reduction of nocifensive behaviors and laser-evoked potentials (LEPs) amplitudes (N2 and P2 waves, and gamma-band oscillations), and significantly prolonged latencies of the LEP-N2/P2. These changes in LEPs reflect the similar antinociceptive mechanism of LAF and LAH, i.e., inhibition of the fast signaling pathways. In addition, there were no changes in the auditory-evoked potential (AEP-N1 component) before and after LAF or LAH treatment, suggesting that neither drug had a central anesthetic effect. Importantly, compared with LAH, LAF was superior in its effects on the magnitudes of gamma-band oscillations and the resting-state spectra, which may be associated with their differences in the octanol/water partition coefficient, degree of dissociation, toxicity, and glycine receptor regulation. Altogether, jointly applying nociceptive laser stimuli and ECoG recordings in rats, we provide solid neural evidence for the analgesic efficacy and antinociceptive mechanisms of derivatives of LA.

The Prediction of Acute Postoperative Pain Based on Neural Oscillations Measured before the Surgery.

Even with an improved understanding of pain mechanisms and advances in perioperative pain management, inadequately controlled postoperative pain remains. Predicting acute postoperative pain based on presurgery physiological measures could provide valuable insights into individualized, effective analgesic strategies, thus helping improve the analgesic efficacy. Considering the strong correlation between pain perception and neural oscillations, we hypothesize that acute postoperative pain could be predicted by neural oscillations measured shortly before the surgery. Here, we explored the relationship between neural oscillations 2 hours before the thoracoscopic surgery and the subjective intensity of acute postoperative pain. The spectral power density of resting-state beta and gamma band oscillations at the frontocentral region was significantly different between patients with different levels of acute postoperative pain (i.e., low pain vs. moderate/high pain). A positive correlation was also observed between the spectral power density of resting-state beta and gamma band oscillations and subjective reports of postoperative pain. Then, we predicted the level of acute postoperative pain based on features of neural oscillations using machine learning techniques, which achieved a prediction accuracy of 92.54% and a correlation coefficient between the real pain intensities and the predicted pain intensities of 0.84. Altogether, the prediction of acute postoperative pain based on neural oscillations measured before the surgery is feasible and could meet the clinical needs in the future for better control of postoperative pain and other unwanted negative effects. The study was registered on the Clinical Trial Registry (https://clinicaltrials.gov/ct2/show/NCT03761576?term=NCT03761576&draw=2&rank=1) with the registration number NCT03761576.

The Distinct Functions of Dopaminergic Receptors on Pain Modulation: A Narrative Review.

Chronic pain is considered an economic burden on society as it often results in disability, job loss, and early retirement. Opioids are the most common analgesics prescribed for the management of moderate to severe pain. However, chronic exposure to these drugs can result in opioid tolerance and opioid-induced hyperalgesia. On pain modulation strategies, exploiting the multitarget drugs with the ability of the superadditive or synergistic interactions attracts more attention. In the present report, we have reviewed the analgesic effects of different dopamine receptors, particularly D1 and D2 receptors, in different regions of the central nervous system, including the spinal cord, striatum, nucleus accumbens (NAc), and periaqueductal gray (PAG). According to the evidence, these regions are not only involved in pain modulation but also express a high density of DA receptors. The findings can be categorized as follows: (1) D2-like receptors may exert a higher analgesic potency, but D1-like receptors act in different manners across several mechanisms in the mentioned regions; (2) in the spinal cord and striatum, antinociception of DA is mainly mediated by D2-like receptors, while in the NAc and PAG, both D1- and D2-like receptors are involved as analgesic targets; and (3) D2-like receptor agonists can act as adjuvants of µ-opioid receptor agonists to potentiate analgesic effects and provide a better approach to pain relief.

A novel method to simultaneously record spinal cord electrophysiology and electroencephalography signals.

The brain and the spinal cord together make up the central nervous system (CNS). The functions of the human brain have been the focus of neuroscience research for a long time. However, the spinal cord is largely ignored, and the functional interaction of these two parts of the CNS is only partly understood. This study developed a novel method to simultaneously record spinal cord electrophysiology (SCE) and electroencephalography (EEG) signals and validated its performance using a classical resting-state study design with two experimental conditions: eyes-closed (EC) and eyes-open (EO). We recruited nine postherpetic neuralgia patients implanted with a spinal cord stimulator, which was modified to record SCE signals simultaneously with EEG signals. For both EEG and SCE, similar differences were found in delta- and alpha-band oscillations between the EC and EO conditions, and the spectral power of these frequency bands was able to predict EC/EO behaviors. Moreover, causal connectivity analysis suggested a top-down regulation in delta-band oscillations from the brain to the spinal cord. Altogether, this study demonstrates the validity of simultaneous SCE-EEG recording and shows that the novel method is a valuable tool to investigate the brain-spinal interaction. With this method, we can better unite knowledge about the brain and the spinal cord for a deeper understanding of the functions of the whole CNS.

The Neural Origin of Nociceptive-Induced Gamma-Band Oscillations.

Gamma-band oscillations (GBOs) elicited by transient nociceptive stimuli are one of the most promising biomarkers of pain across species. Still, whether these GBOs reflect stimulus encoding in the primary somatosensory cortex (S1) or nocifensive behavior in the primary motor cortex (M1) is debated. Here we recorded neural activity simultaneously from the brain surface as well as at different depths of the bilateral S1/M1 in freely-moving male rats receiving nociceptive stimulation. GBOs measured from superficial layers of S1 contralateral to the stimulated paw not only had the largest magnitude, but also showed the strongest temporal and phase coupling with epidural GBOs. Also, spiking of superficial S1 interneurons had the strongest phase coherence with epidural GBOs. These results provide the first direct demonstration that scalp GBOs, one of the most promising pain biomarkers, reflect neural activity strongly coupled with the fast spiking of interneurons in the superficial layers of the S1 contralateral to the stimulated side.SIGNIFICANCE STATEMENT Nociceptive-induced gamma-band oscillations (GBOs) measured at population level are one of the most promising biomarkers of pain perception. Our results provide the direct demonstration that these GBOs reflect neural activity coupled with the spike firing of interneurons in the superficial layers of the primary somatosensory cortex (S1) contralateral to the side of nociceptive stimulation. These results address the ongoing debate about whether nociceptive-induced GBOs recorded with scalp EEG or epidurally reflect stimulus encoding in the S1 or nocifensive behavior in the primary motor cortex (M1), and will therefore influence how experiments in pain neuroscience will be designed and interpreted.

Interneuron Accumulation of Phosphorylated tau Impairs Adult Hippocampal Neurogenesis by Suppressing GABAergic Transmission.

Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer's disease (AD), but whether and how tau dysregulates AHN in AD remain poorly understood. Here, we found a prominent accumulation of phosphorylated tau in GABAergic interneurons in the dentate gyrus (DG) of AD patients and mice. Specific overexpression of human tau (hTau) in mice DG interneurons induced AHN deficits but increased neural stem cell-derived astrogliosis, associating with a downregulation of GABA and hyperactivation of neighboring excitatory neurons. Chemogenetic inhibition of excitatory neurons or pharmacologically strengthening GABAergic tempos rescued the tau-induced AHN deficits and improved contextual cognition. These findings evidenced that intracellular accumulation of tau in GABAergic interneurons impairs AHN by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche, suggesting a potential of GABAergic potentiators for pro-neurogenic or cell therapies of AD.

Spontaneous Pain Disrupts Ventral Hippocampal CA1-Infralimbic Cortex Connectivity and Modulates Pain Progression in Rats with Peripheral Inflammation.

Pain involves an intrinsically dynamic connectome characterized by fluctuating spontaneous brain activity and continuous neuroplastic changes of relevant circuits. Activity in the hippocampus-medial prefrontal cortex (mPFC) pathway has been suggested to correlate with spontaneous pain and pain chronicity, but causal evidence is lacking. Here we combine longitudinal in vivo electrophysiological recording with behavioral testing and show that persistent spontaneous pain disrupts ventral hippocampal CA1-infralimbic cortex (vCA1-IL) connectivity and hippocampal modulation of IL neuronal activity in rats with peripheral inflammation. Chemo- and optogenetic rescue of vCA1-IL dysfunction relieves spontaneous pain. Circuit-specific overexpression of brain-derived neurotrophic factor (BDNF) in vCA1-IL reverses electrophysiological changes, relieves spontaneous pain, and accelerates overall recovery from inflammatory pain. Our work identifies a neural pathway that specifically correlates with spontaneous pain and supports the significance of using a circuit dynamics-based strategy for more comprehensive understanding of circuitry mechanisms underlying chronic pain.

Anterior cingulate cortex modulates the affective-motivative dimension of hyperosmolality-induced thirst.

Neuroimaging studies have shown that the anterior cingulate cortex (ACC) is consistently activated by thirst and may underlie the affective motivation of drinking behaviour demanded by thirst. But direct evidence for this hypothesis is lacking. The present study evaluated potential correlations between ACC neuronal activity and drinking behaviour in rats injected with different concentrations of saline. We observed an increased number of c-Fos-positive neurons in the ACC after injection of hypertonic saline, indicating strong ACC neuronal activation under hyperosmotic thirst. Increased firing rates of putative ACC pyramidal neurons preceded drinking behaviour and positively correlated with both the total duration of drinking and the total amount of water consumed. Chemogenetic inhibition of ACC pyramidal neurons changed drinking behaviour from an explosive and short-lasting pattern to a gradual but more persistent pattern, without affecting either the total duration of drinking or the total amount of water consumed. Together, these findings support a role of the ACC in modulating the affective-motivative dimension of hyperosmolality-induced thirst.

Cross-Species Investigation on Resting State Electroencephalogram.

Resting state electroencephalography (EEG) during eyes-closed and eyes-open conditions is widely used to evaluate brain states of healthy populations and brain dysfunctions in clinical conditions. Although several results have been obtained by measuring these brain activities in humans, it remains unclear whether the same results can be replicated in animals, i.e., whether the physiological properties revealed by these findings are phylogenetically conserved across species. In the present study, we describe a paradigm for recording resting state EEG activities during eyes-closed and eyes-open conditions from rats, and investigated the differences between eyes-closed and eyes-open conditions for humans and rats. We found that compared to the eyes-open condition, human EEG spectral amplitude in the eyes-closed condition was significantly higher at 8-12 Hz and 18-22 Hz in the occipital region, but significantly lower at 18-22 Hz and 30-100 Hz in the frontal region. In contrast, rat EEG spectral amplitude was significantly higher in the eyes-closed condition than in the eyes-open condition at 1-4 Hz, 8-12 Hz, and 13-17 Hz in the frontal-central region. In both species, the 1/f-like power spectrum scaling of resting state EEG activities was significantly higher in the eyes-closed condition than in the eyes-open condition at parietal-occipital and frontal regions. These results provided a neurophysiological basis for future translational studies from experimental animal findings to human psychophysiology, since the validity of such translation critically relies on a well-established experimental paradigm and a carefully-examined signal characteristic to bridge the gaps across different species.

Top-down control of the medial orbitofrontal cortex to nucleus accumbens core pathway in decisional impulsivity.

Decisional impulsivity is one of the risk factors for occurrence and development of many mental disorders, and that the dysfunctions of orbitofrontal cortex (OFC) and nucleus accumbens core (NAcC) are at least involved. Although previous studies have shown that the role of OFC as a whole in regulating decision-making impulse behavior is inconsistent, it's still unclear that the roles of the subregions of OFC including their projections to the NAcC in decisional impulsivity. The present study was designed to investigate the roles of OFC subregions, medial OFC (mOFC) and lateral OFC (lOFC) and their projections to the NAcC in decisional impulsivity in free-moving rats. We found that rats with low level of decisional impulsivity (LI) showed higher neuronal activity in both the mOFC and lOFC, and more neurons in mOFC but not lOFC projecting to the NAcC were activated, compared with high level of decisional impulsivity (HI) rats. The mOFC-NAcC projections of LI rats showed stronger information communication in beta and low gamma oscillations in the expected reward choice and delay time windows. Further, specific activation (in HI rats) or inhibition (in LI rats) of the mOFC-NAcC pathway could partly reverse their decisional impulsive behaviors. The findings first demonstrated that the mOFC-NAcC pathway was more important than the lOFC-NAcC pathway to the top-down control in decisional impulsivity, which could be a new neural physiological mechanism for psychiatric disorders associated with decisional impulsivity.

Simultaneous Recordings of Cortical Local Field Potentials and Electrocorticograms in Response to Nociceptive Laser Stimuli from Freely Moving Rats.

Electrocortical responses, elicited by laser heat pulses that selectively activate nociceptive free nerve endings, are widely used in many animal and human studies to investigate the cortical processing of nociceptive information. These laser-evoked brain potentials (LEPs) consist of several transient responses that are time-locked to the onset of laser stimuli. However, the functional properties of the LEP responses are still largely unknown, due to the lack of a sampling technique that can simultaneously record neural activities at the surface of the cortex (i.e., electrocorticogram [ECoG] and scalp electroencephalogram [scalp EEG]) and inside the brain (i.e., local field potential [LFP]). To address this issue, we present here an animal protocol using freely moving rats. This protocol is composed of three main procedures: (1) animal preparation and surgical procedures, (2) a simultaneous recording of ECoG and LFP in response to nociceptive laser stimuli, and (3) data analysis and feature extraction. Specifically, with the help of a 3D-printed protective shell, both ECoG and LFP electrodes implanted on the rat's skull were securely held together. During data collection, laser pulses were delivered on the rat's forepaws through gaps in the bottom of the chamber when the animal was in spontaneous stillness. Ongoing white noise was played to avoid the activation of the auditory system by the laser-generated ultrasounds. As a consequence, only nociceptive responses were selectively recorded. Using the standard analytical procedures (e.g., band-pass filtering, epoch extraction, and baseline correction) to extract stimulus-related brain responses, we obtained results showing that LEPs with a high signal-to-noise ratio were simultaneously recorded from ECoG and LFP electrodes. This methodology makes the simultaneous recording of ECoG and LFP activities possible, which provides a bridge of electrocortical signals at the mesoscopic and macroscopic levels, thereby facilitating the investigation of nociceptive information processing in the brain.