Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury

Background: Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus results in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. Methods: The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC pyramidal neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling.Results: Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC pyramidal neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. Conclusions: The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain.

Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex

Inhibitory neurons innervating the perisomatic region of cortical excitatory principal cells are known to control the emergence of several physiological and pathological synchronous events, including epileptic interictal spikes. In humans, little is known about their role in synchrony generation, although their changes in epilepsy have been thoroughly investigated. This paper demonstraits how parvalbumin (PV)- and type 1 cannabinoid receptor (CB1R)-positive perisomatic interneurons innervate pyramidal cell bodies, and their role in synchronous population events spontaneously emerging in the human epileptic and non-epileptic neocortex, in vitro. Quantitative electron microscopy showed that the overall, PV+ and CB1R+ somatic inhibitory inputs remained unchanged in focal cortical epilepsy. On the contrary, the size of PV-stained synapses increased, and their number decreased in epileptic samples, in synchrony generating regions. Pharmacology demonstrated—in conjunction with the electron microscopy—that although both perisomatic cell types participate, PV+ cells have stronger influence on the generation of population activity in epileptic samples. The somatic inhibitory input of neocortical pyramidal cells remained almost intact in epilepsy, but the larger and consequently more efficient somatic synapses might account for a higher synchrony in this neuron population. This, together with epileptic hyperexcitability, might make a cortical region predisposed to generate or participate in hypersynchronous events.

Attention enhances category representations across the brain with strengthened residual correlations to ventral temporal cortex

How does attention enhance neural representations of goal-relevant stimuli while suppressing representations of ignored stimuli across regions of the brain? While prior studies have shown that attention enhances visual responses, we lack a cohesive understanding of how selective attention modulates visual representations across the brain. Here, we used functional magnetic resonance imaging (fMRI) while participants performed a selective attention task on superimposed stimuli from multiple categories and used a data-driven approach to test how attention affects both decodability of category information and residual correlations (after regressing out stimulus-driven variance) with category-selective regions of ventral temporal cortex (VTC). Our data reveal three main findings. First, when two objects are simultaneously viewed, the category of the attended object can be decoded more readily than the category of the ignored object, with the greatest attentional enhancements observed in occipital and temporal lobes. Second, after accounting for the response to the stimulus, the correlation in the residual brain activity between a cortical region and a category-selective region of VTC was elevated when that region's preferred category was attended vs. ignored, and more so in the right occipital, parietal, and frontal cortices. Third, we found that the stronger the residual correlations between a given region of cortex and VTC, the better visual category information could be decoded from that region. These findings suggest that heightened residual correlations by selective attention may reflect the sharing of information between sensory regions and higher-order cortical regions to provide attentional enhancement of goal-relevant information.

Neurochemical profiles of the anterior temporal lobe predict response of repetitive transcranial magnetic stimulation on semantic processing

The effect of repetitive transcranial magnetic stimulation can vary considerably across individuals, but the reasons for this still remain unclear. Here, we investigated whether the response to continuous theta-burst stimulation (cTBS) – an effective protocol for decreasing cortical excitability – related to individual differences in glutamate and GABA neurotransmission. We applied cTBS over the anterior temporal lobe (ATL), a hub for semantic representation, to explore the relationship between the baseline neurochemical profiles in this region and the response to this stimulation. Our experiments revealed that non-responders (subjects who did not show an inhibitory effect of cTBS on subsequent semantic performance) had higher excitatory-inhibitory balance (glutamate + glutamine/GABA ratio) in the ATL, which led to up-regulated task-induced regional activity as well as increased ATL-connectivity with other semantic regions compared to responders. These results disclose that the baseline neurochemical state of a cortical region can be a significant factor in predicting responses to cTBS.

Electrophysiological Activity and Brain Network During Recovery of Propofol Anesthesia: A Stereoelectroencephalography-Based Analysis in Patients With Intractable Epilepsy—An Exploratory Research

Background: The oscillations and interactions between different brain areas during recovery of consciousness (ROC) from anesthesia in humans are poorly understood. Reliable stereoelectroencephalography (SEEG) signatures for transitions between unconsciousness and consciousness under anesthesia have not yet been fully identified.Objective: This study was designed to observe the change of electrophysiological activity during ROC and construct a ROC network based on SEEG data to describe the network property of cortical and deep areas during ROC from propofol-induced anesthetic epileptic patients.Methods: We analyzed SEEG data recorded from sixteen right-handed epileptic patients during ROC from propofol anesthesia from March 1, 2019, to December 31, 2019. Power spectrum density (PSD), correlation, and coherence were used to describe different brain areas' electrophysiological activity. The clustering coefficient, characteristic path length, modularity, network efficiency, degrees, and betweenness centrality were used to describe the network changes during ROC from propofol anesthesia. Statistical analysis was performed using MATLAB 2016b. The power spectral data from different contacts were analyzed using a one-way analysis of variance (ANOVA) test with Tukey's post-hoc correction. One sample t-test was used for the analysis of network property. Kolmogorov-Smirnov test was used to judge data distribution. Non-normal distribution was analyzed using the signed rank-sum test.Result: From the data of these 16 patients, 10 cortical, and 22 deep positions were observed. In this network, we observed that bilateral occipital areas are essential parts that have strong links with many regions. The recovery process is different in the bilateral cerebral cortex. Stage B (propofol 3.0-2.5 μg/ml) and E (propofol 1.5 μg/ml-ROC) play important roles during ROC exhibiting significant changes. The clustering coefficient gradually decreases with the recovery from anesthesia, and the changes mainly come from the cortical region. The characteristic path length and network efficiency do not change significantly during the recovery from anesthesia, and the changes of network modularity and clustering coefficient are similar. Deep areas tend to form functional modules. The left occipital lobe, the left temporal lobe, bilateral amygdala are essential nodes in the network. Some specific cortical regions (i.e., left angular gyrus, right angular gyrus, right temporal lobe, left temporal lobe, and right angular gyrus) and deep regions (i.e., right amygdala, left cingulate gyrus, right insular lobe, right amygdala) have more significant constraints on other regions.Conclusion: We verified that the bilateral cortex's recovery process is the opposite, which is not found in the deep regions. Significant PSD changes were observed in many areas at the beginning of stop infusion and near recovery. Our study found that during the ROC process, the modularity and clustering coefficient of the deep area network is significantly improved. However, the changes of the bilateral cerebral cortex were different. Power spectrum analysis shows that low-frequency EEG in anesthesia recovery accounts for a large proportion. The changes of the bilateral brain in the process of anesthesia recovery are different. The clustering coefficient gradually decreased with the recovery from anesthesia, and the changes mainly came from the cortical region. The characteristic path length and network efficiency do not change significantly during the recovery from anesthesia, and the changes of network modularity and clustering coefficient were similar. During ROC, the left occipital lobe, the left temporal lobe, bilateral amygdala were essential nodes in the network. The findings of the current study suggest SEEG as an effective tool for providing direct evidence of the anesthesia recovery mechanism.

Closed-loop Controller Based on Reference Signal Tracking for Absence Seizures

Deep brain stimulation (DBS) targeting thalamus reticular nucleus (TRN) brain regions has been proven to play an irreplaceable role in the treatment of absence seizures. Compared with open-loop DBS, closed-loop DBS has been recognized by researchers for its advantages of significantly inhibiting seizures and having fewer side effects. However, due to the complexity of the nervous system, the mechanism of DBS control epilepsy is still unclear, which hinders the study of closed-loop DBS. In our study, based on the biophysical model jointly constituted by cortical, thalamic, and basal ganglia, we selected the 2-4 Hz spike and wave discharges (SWDs) of the cortical region as a biomarker for response to absence epilepsy, and the mean firing rate (MFR) of substantia nigra pars reticulata (SNr) was used as a reference signal for modulation of closed-loop DBS. Moreover, to obtain the linear relationship between the stimulus and the response, we adopted an algorithm that combines controlled auto-regressive (CAR) and recursive least squares (RLS), and we built a proportional integral (PI) controller to make the DBS stimulus parameters self-update to control the seizures. The numerical simulation results show that the closed-loop DBS controllers based on frequency modulation and amplitude modulation respectively not only successfully track the firing rate (FR) of SNr, but also significantly destroy the SWDs of cerebral cortex and restore it to the other two normal discharge modes.

Population-Based Tract-To-Region Connectome of the Human Brain and Its Hierarchical Topology

Connectome maps region-to-region connectivities but does not inform which white matter pathways form the connections. Here we constructed the first population-based tract-to-region connectome to fill this information gap. The constructed connectome quantifies the population probability of a white matter tract innervating a cortical region. The results show that ~85% of the tract-to-region connectome entries are consistent across individuals, whereas the remaining (~15%) have substantial individual differences requiring individualized mapping. Further hierarchical clustering on cortical regions revealed their parcellations into dorsal, ventral, and limbic networks based on the tract-to-region connective patterns. The clustering results on white matter bundles revealed the connectome-based categorization of fiber bundle systems in the association pathways. This new tract-to-region connectome provides insights into the connective topology between cortical regions and white matter bundles. The derived hierarchical relation further offers a connectome-based categorization of gray matter and white matter structures.

The Effects of a Novel Non-catechol Dopamine Partial Agonist on Working Memory in the Aged Rhesus Monkey

Aged-related declines in cognition, especially working memory and executive function, begin in middle-age and these abilities are known to be mediated by the prefrontal cortex (PFC) and more specifically the dopamine (DA) system within the PFC. In both humans and monkeys, there is significant evidence that the PFC is the first cortical region to change with age and the PFC appears to be particularly vulnerable to age-related loss of dopamine (DA). Therefore, the DA system is a strong candidate for therapeutic intervention to slow or reverse age related declines in cognition. In the present study, we administered a novel selective, potent, non-catechol DA D1 R agonist PF-6294 (Pfizer, Inc.) to aged female rhesus monkeys and assessed their performance on two benchmark tasks of working memory – the Delayed Non-match to Sample Task (DNMS) and Delayed Recognition Span Task (DRST). The DNMS task was administered first with the standard 10 s delay and then with 5 min delays, with and without distractors. The DRST was administered each day with four trials with unique sequences and one trial of a repeated sequence to assess evidence learning and retention. Overall, there was no significant effect of drug on performance on any aspect of the DNMS task. In contrast, we demonstrated that a middle range dose of PF-6294 significantly increased memory span on the DRST on the first and last days of testing and by the last day of testing the increased memory span was driven by the performance on the repeated trials.

Extensive frontal focused ultrasound mediated blood–brain barrier opening for the treatment of Alzheimer’s disease: a proof-of-concept study

Background Focused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies, but this is rarely reported in clinical studies. This study was conducted to evaluate the safety, feasibility and potential benefits of repeated extensive BBB opening. Methods In this open-label, prospective study, six patients with Alzheimer’s disease (AD) were enrolled at Severance Hospital in Korea between August 2020 and September 2020. Five of them completed the study. FUS-mediated BBB opening, targeting the bilateral frontal lobe regions over 20 cm3, was performed twice at three-month intervals. Magnetic resonance imaging, 18F-Florbetaben (FBB) positron emission tomography, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI) and comprehensive neuropsychological tests were performed before and after the procedures. Results FUS targeted a mean volume of 21.1 ± 2.7 cm3 and BBB opening was confirmed at 95.7% ± 9.4% of the targeted volume. The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease, which was statistically significant, compared to the pre-procedure value (− 1.6%, 0.986 vs1.002, P = 0.043). The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline (2.2 ± 3.0 vs 8.6 ± 6.0, P = 0.042), but recovered after 3 months (5.2 ± 5.8 vs 8.6 ± 6.0, P = 0.89). No adverse effects were observed. Conclusions The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. In addition, the BBB opening is potentially beneficial for amyloid removal in AD patients.