High-frequency Stimulation Research Articles

Utility of desflurane as an anesthetic in motor-evoked potentials in spine surgery and the facilitating effect in tetanic stimulation of bilateral median nerves.

Although desflurane is a safe and controllable inhalation anesthetic used in spinal surgery, to our knowledge, there have been no reports of successful motor-evoked potential (MEP) recordings under general anesthesia with desflurane alone. A high desflurane concentration may reduce the risk of intraoperative awareness but can also reduce the success of MEP recording. Therefore, we aimed to evaluate the reliability of MEP monitoring and investigate whether tetanic stimulation can augment MEP amplitude under general anesthesia with high-concentration desflurane during spinal surgery. We prospectively evaluated 46 patients who were scheduled to undergo lumbar surgery at a single center between 2018 and 2020. Anesthesia was maintained with an end-tidal concentration of 4% desflurane and remifentanil. Compound muscle action potentials were recorded bilaterally from the abductor pollicis brevis, abductor hallucis, tibialis anterior, gastrocnemius, and quadriceps. For post-tetanic MEPs (p-MEPs), tetanic stimulation was applied to the median nerves (p-MEPm) and tibial nerves (p-MEPt) separately before transcranial stimulation. The average success rates for conventional MEP (c-MEP), p-MEPm, and p-MEPt were 77.9%, 80%, and 79.3%, respectively. The p-MEPm amplitudes were significantly higher than the c-MEP amplitudes in all muscles (P < 0.05), whereas the p-MEPt amplitudes were not significantly different from the c-MEP amplitudes. The MEP recording success rates for the gastrocnemius and quadriceps were inadequate. However, bilateral median nerve tetanic stimulation can effectively augment MEPs safely under general anesthesia with high-concentration desflurane in patients who undergo spinal surgery.

Reliability of quantitative sensory testing in the assessment of somatosensory function after high-frequency stimulation-induced sensitisation of central nociceptive pathways.

The high frequency stimulation (HFS) model can be used alongside quantitative sensory testing (QST) to assess the sensitisation of central nociceptive pathways. However, the validity and between-session reliability of using QST z -score profiles to measure changes in mechanical and thermal afferent pathways in the HFS model are poorly understood. In this study, 32 healthy participants underwent QST before and after HFS (5× 100 Hz trains; 10× electrical detection threshold) in the same heterotopic skin area across 2 repeated sessions. The only mechanical QST z -score profiles that demonstrated a consistent gain of function across repeated test sessions were mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS), which were associated with moderate and good reliability, respectively. There was no relationship between HFS intensity and MPT and MPS z -score profiles. There was no change in low intensity, but a consistent facilitation of high-intensity pin prick stimuli in the mechanical stimulus response function across repeated test sessions. There was no change in cold pain threshold (CPT) and heat pain threshold (HPT) z -score profiles across session 1 and 2, which were associated with moderate and good reliability, respectively. There were inconsistent changes in the sensitivity to innocuous thermal QST parameters, with cool detection threshold (CDT), warm detection threshold (WDT), and thermal sensory limen (TSL) all producing poor reliability. These data suggest that HFS-induced changes in MPS z -score profiles is a reliable way to assess experimentally induced central sensitisation and associated secondary mechanical hyperalgesia in healthy participants.

Habits and Persistent Food Restriction in Patients with Anorexia Nervosa: A Scoping Review.

The aetiology of anorexia nervosa (AN) presents a puzzle for researchers. Recent research has sought to understand the behavioural and neural mechanisms of these patients' persistent choice of calorie restriction. This scoping review aims to map the literature on the contribution of habit-based learning to food restriction in AN. PRISMA-ScR guidelines were adopted. The search strategy was applied to seven databases and to grey literature. A total of 35 studies were included in this review. The results indicate that the habit-based learning model has gained substantial attention in current research, employing neuroimaging methods, scales, and behavioural techniques. Food choices were strongly associated with dorsal striatum activity, and habitual food restriction based on the self-report restriction index was associated with clinical impairment in people chronically ill with restricting AN. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and Regulating Emotions and Changing Habits (REaCH) have emerged as potential treatments. Future research should employ longitudinal studies to investigate the time required for habit-based learning and analyse how developmental status, such as adolescence, influences the role of habits in the progression and severity of diet-related illnesses. Ultimately, seeking effective strategies to modify persistent dietary restrictions controlled by habits remains essential.

Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses.

A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl- importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl- concentration ([Cl- ]i ) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl- ]i with NKCC1, and this gradient promotes Cl- efflux via the astrocytic GABAA receptor (GABAA R). This Cl- efflux buffers the synaptic cleft Cl- concentration to maintain the postsynaptic Cl- gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models. We used the astrocyte-specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABAA R-mediated depolarization was evaluated by applying the GABAA R antagonist bicuculline. The pilocarpine-induced seizure invivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild-type (WT) mice were compared. The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAA R-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both invitro and invivo. Astrocytic NKCC1 inhibits GABA-mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.

Synergistic photoactivation of VTA-catecholaminergic and BLA-glutamatergic projections induces long-term potentiation in the insular cortex

The presentation of novel stimuli induces a reliable dopamine release in the insular cortex (IC) from the ventral tegmental area (VTA). The novel stimuli could be associated with motivational and emotional signals induced by cortical glutamate release from the basolateral amygdala (BLA). Dopamine and glutamate are essential for acquiring and maintaining behavioral tasks, including visual and taste recognition memories. In this study, we hypothesize that the simultaneous activation of dopaminergic and glutamatergic projections to the neocortex can underlie synaptic plasticity. High-frequency stimulation of the BLA-IC circuit has demonstrated a reliable long-term potentiation (LTP), a widely acknowledged synaptic plasticity that underlies memory consolidation. Therefore, the concurrent optogenetic stimulation of the insula’s glutamatergic and dopaminergic terminal fibers would induce reliable LTP. Our results confirmed that combined photostimulation of the VTA and BLA projections to the IC induces a slow-onset LTP. We also found that optogenetically-induced LTP in the IC relies on both glutamatergic NMDA receptors and dopaminergic D1/D5 receptors, suggesting that the combined effects of these neurotransmitters can trigger synaptic plasticity in the neocortex. Overall, our findings provide compelling evidence supporting the essential role of both dopaminergic and glutamatergic projections in modulating synaptic plasticity within the IC. Furthermore, our results suggest that the synergistic actions of these projections have a pivotal influence on the formation of motivational memories.

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30–45 with vehicle or THC (escalating doses, 3–20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3–4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3β (GSK3β), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3β signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

Maximal Fusion Capacity and Efficient Replenishment of the Dense Core Vesicle Pool in Hippocampal Neurons.

Neuropeptides and neurotrophins, stored in dense core vesicles (DCVs), are together the largest currently known group of chemical signals in the brain. Exocytosis of DCVs requires high-frequency or patterned stimulation, but the determinants to reach maximal fusion capacity and for efficient replenishment of released DCVs are unknown. Here, we systematically studied fusion of DCV with single vesicle resolution on different stimulation patterns in mammalian CNS neurons. We show that tetanic stimulation trains of 50-Hz action potential (AP) bursts maximized DCV fusion, with significantly fewer fusion event during later bursts of the train. This difference was omitted by introduction of interburst intervals but did not increase total DCV fusion. Interburst intervals as short as 5 s were sufficient to restore the fusion capacity. Theta burst stimulation (TBS) triggered less DCV fusion than tetanic stimulation, but a similar fusion efficiency per AP. Prepulse stimulation did not alter this. However, low-frequency stimulation (4 Hz) intermitted with fast ripple stimulation (200 APs at 200 Hz) produced substantial DCV fusion, albeit not as much as tetanic stimulation. Finally, individual fusion events had longer durations with more intense stimulation. These data indicate that trains of 50-Hz AP stimulation patterns triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.SIGNIFICANCE STATEMENT Neuropeptides and neurotrophins modulate multiple regulatory functions of human body like reproduction, food intake or mood. They are packed into dense core vesicles (DCVs) that undergo calcium and action potential (AP) fusion with the plasma membrane. In order to study the fusion of DCVs in vitro, techniques like perfusion with buffer containing high concentration of potassium or electric field stimulation are needed to trigger the exocytosis of DCVs. Here, we studied the relationship between DCVs fusion properties and different electric field stimulation patterns. We used six different stimulation patterns and showed that trains of 50-Hz action potential bursts triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.

Arc expression regulates long-term potentiation magnitude and metaplasticity in area CA1 of the hippocampus in ArcKR mice.

Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that the disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD). Here, we have investigated if ArcKR expression changes long-term potentiation (LTP) in CA1 area of the hippocampus. As previously reported, there was no change in basal synaptic transmission at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus wild-type (WT) mice. There was, however, a significant increase in the amplitude of synaptically induced (with low frequency paired-pulse stimulation) LTD in ArcKR mice. Theta burst stimulation (TBS)-evoked LTP at SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 h). Group 1 mGluR priming of LTP was abolished in ArcKR mice, which could also potentially contribute to a depression of LTP. Although high frequency stimulation (HFS)-induced LTP was not significantly different in ArcKR compared with WT mice (after 1h), there was a phenotype in environmentally enriched mice, with the ratio of LTP to short-term potentiation (STP) significantly reduced in ArcKR mice. These findings support the hypothesis that Arc ubiquitination supports the induction and expression of LTP, likely via limiting Arc-dependent removal of AMPA receptors at synapses.

Intraoperative motor-evoked potential with tetanic stimulation changes pre- and post-hemispherotomy.

Careful examination of motor-evoked potential (MEP) findings is critical to the safety of intraoperative neuromonitoring during neurosurgery. We reviewed the intraoperative MEP findings in a pediatric patient who had undergone hemispherotomy for refractory epilepsy. The patient was a 4-year-and-2-month-old boy with extensive right cerebral hemisphere, drug-resistant epilepsy, left upper and lower extremity paralysis, and cognitive impairment. We examined intraoperative MEP results both before and after hemispherotomy. Post-hemispherotomy and MEPs were successfully elicited through transcranial electrical stimulation (TES) but not via direct cortical stimulation on the right side. Furthermore, TES on the right side, following hemispherotomy, led to a reduction in the MEP amplification effect resulting from tetanic stimulation of the left unilateral median and tibial nerves. Conversely, we observed the effects of MEP amplification during TES on the left side after tetanic stimulation of these nerves. Postoperatively, the patient underwent magnetic resonance imaging and electroencephalogram examinations, confirming the anatomical and electrophysiological completeness of the dissection. Notably, the seizures disappeared, and no apparent complications were observed. Collectively, our findings suggest that TES can still activate deep structures and elicit MEPs, even in cases where the corticospinal connections to the posterior limb of the internal capsule are entirely severed. Thalamo-cortical interactions may affect the MEP amplification, observed during tetanic stimulation. Injury to the corticospinal tracts of the white matter may be obscured on conventional MEP findings; however, it may be identified by MEP changes in tetanic stimulation.

Interactions between cathodic- and anodic-pulses during high-frequency stimulations with the monophasic-pulses alternating in polarity at axons—experiment and simulation studies

Background. Electrical neuromodulation therapies commonly utilize high-frequency stimulations (HFS) of biphasic-pulses to treat neurological disorders. The biphasic pulse consists of a leading cathodic-phase to activate neurons and a lagging anodic-phase to balance electrical charges. Because both monophasic cathodic- and anodic-pulses can depolarize neuronal membranes, splitting biphasic-pulses into alternate cathodic- and anodic-pulses could be a feasible strategy to improve stimulation efficiency. Objective. We speculated that neurons in the volume initially activated by both polarity pulses could change to be activated only by anodic-pulses during sustained HFS of alternate monophasic-pulses. To verify the hypothesis, we investigated the interactions of the monophasic pulses during HFS and revealed possible underlying mechanisms. Approach. Different types of pulse stimulations were applied at the alvear fibers (i.e. the axons of CA1 pyramidal neurons) to antidromically activate the neuronal cell bodies in the hippocampal CA1 region of anesthetized rats in-vivo. Sequences of antidromic HFS (A-HFS) were applied with alternate monophasic-pulses or biphasic-pulses. The pulse frequency in the A-HFS sequences was 50 or 100 Hz. The A-HFS duration was 120 s. The amplitude of antidromically-evoked population spike was measured to evaluate the neuronal firing induced by each pulse. A computational model of axon was used to explore the possible mechanisms of neuronal modulations. The changes of model variables during sustained A-HFS were analyzed. Main results. In rat experiments, with a same pulse intensity, the activation volume of a cathodic-pulse was greater than that of an anodic-pulse. In paired-pulse tests, a preceding cathodic-pulse was able to prevent a following anodic-pulse from activating neurons due to refractory period. This indicated that the activation volume of a cathodic-pulse covered that of an anodic-pulse. However, during sustained A-HFS of alternate monophasic-pulses, the anodic-pulses were able to prevail over the cathodic-pulses in activating neurons in the overlapped activation volume. Model simulation results show the mechanisms of the activation failures of cathodic-pulses. They include the excessive membrane depolarization caused by an accumulation of potassium ions, the obstacle of hyperpolarization in the conduction pathway and the interactions from anodic-pulses. Significance. The study firstly showed the domination of anodic-pulses over cathodic-pulses in their competitions to activate neurons during sustained HFS. The finding provides new clues for designing HFS paradigms to improve the efficiency of neuromodulation therapies.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on global cognitive function of elderly in mild to moderate Alzheimer's disease: a systematic review and meta-analysis.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a non-invasive brain stimulation technique used to improve cognitive deficits in patients with Alzheimer's disease (AD). This systematic review and meta-analysis aimed to evaluate the efficacy of HF-rTMS in improving global cognitive function rehabilitation in elderly patients with mild to moderate AD. A detailed literature search of publications using ten databases (Chinese: Wanfang, VIP Periodical, SinoMed, the Chinese National Knowledge Infrastructure; English: PubMed, Embase, OVID, Web of Science, Cochrane Library, and EBSCOhost) was performed to identify English and Chinese language articles published up to December 2022. We only included randomized controlled trials (RCTs) that evaluate the effect of HF-rTMS on elderly patients with mild to moderate AD. The retrieved studies were carefully reviewed, extracted data, and assessed quality. Seventeen studies, including 1161 elderly patients with mild to moderate AD, were included in this meta-analysis. Compared to the control group, HF-rTMS could increase MMSE (mean difference [MD] = 3.64; 95%CI 1.86-5.42; P < 0.0001), MoCA (MD = 3.69; 95%CI 1.84-5.54; P < 0.0001), P300 amplitude (MD = 1.09; 95%CI 0.45-1.72; P = 0.0008), and total effective rate scores (MD = 3.64; 95% CI 2.14-6.18; P < 0.00001) while decreasing ADAS-Cog (MD = - 3.53; 95%CI - 4.91- - 2.15; P < 0.00001) and P300 latency scores (MD = - 38.32; 95%CI - 72.40- - 4.24; P = 0.03). Our study showed that HF-rTMS could improve the global cognitive function of elderly patients with mild to moderate AD. HF-rTMS can improve global cognitive function in elderly patients with mild to moderate AD, which is an effective and safe rehabilitation treatment tool for AD patients.

Effects of carbonic anhydrase activity on the excitability of hippocampal axons during high-frequency firing

Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such signaling is unclear, but likely involves an altered function of several types of ligand- and voltage-gated channels in postsynaptic membranes caused by increasing cytosolic and extracellular [H+]. In addition, axonal conduction properties may be altered by endogenous pH signals, but this has not been investigated. In the present study, we have recorded the axonal compound action potential (fiber volley) in hippocampal slices in the presence of glutamatergic and GABAergic antagonists. During high-frequency stimulation (HFS) of the Schaffer collaterals, the fiber volley was depressed and its latency from stimulus to peak increased. In the CA1 stratum radiatum these changes were enhanced when the carbonic anhydrase inhibitor acetazolamide (1 mM) was co-perfused. The enhancing effect of acetazolamide was absent after lowering of [Ca2+] in the perfusion medium. Acetazolamide had no detectable effect on HFS-evoked fiber volleys recorded from a more proximal site along the Schaffer collaterals (at the CA2-CA3 border) or from axons in the alveus of CA1. Intracellular acidification imposed by washout of NH4Cl (5 mM) had qualitatively similar effects on fiber volleys evoked at low frequency as those observed with acetazolamide during HFS in CA1 stratum radiatum. The results suggest that carbonic anhydrase-dependent pH regulation counteracts activity-induced reduction of the excitability of Schaffer collateral axons in CA1. A possible influence from local synaptic terminals on this effect is discussed.

Consequences of adolescent social isolation on behavior and synaptic plasticity in the dorsal and ventral hippocampus in male Wistar rats

ABSTRACT Objective Social interaction at a young age plays a critical role in the normal maturation of the brain and neuroendocrine system. Deprivation of social contacts has been associated with numerous cognitive and emotional abnormalities. However, neurobiological mechanisms that may underlie these effects remain poorly understood. In the present study, we examined the effect of 4–6-week social isolation during the adolescent period on rat spatial memory and emotional responses and investigated synaptic plasticity in the dorsal (DH) and ventral hippocampus (VH), which are known to be differently involved in these behaviors. Methods Male Wistar rats were housed individually or in groups of four for 4–6 weeks immediately after weaning. At the end of the isolation period, rats were subjected to behavioral testing or electrophysiological studies. Behavioral tests included behavioral excitability, sucrose preference, open field (OF), elevated plus maze (EPM), Morris water maze (MWM), and Y-maze test. For plasticity experiments, long-term potentiation (LTP) in Schaffer collateral/СA1 synapses was induced using high-frequency stimulation (HFS) on transverse hippocampal slices. Results Social isolation induced hyperexcitability, increased anxiety- and anhedonia-like behaviors, while no significant changes were observed in cognitive tasks. Electrophysiological recordings revealed enhanced short-term potentiation (STP) in the VH and suppressed LTP in the DH of isolated animals compared to group-housed controls. Conclusions Our findings suggest that adolescent social isolation has distinct effects on synaptic plasticity in the VH and DH and leads to emotional dysregulation rather than impairments in cognitive performance.

From Tetranitromethane to Gem-Dinitro-Bridged Nitrogen-Rich Heterocyclic Compound: Achieving High Heat of Detonation.

Improving the detonation performance of tetranitromethane (TNM) by introducing energetic moieties is an intriguing area in the field of energetic materials. Incorporation of a mono nitrogen-rich skeleton into TNM usually results in unsatisfactory detonation performance. Now, we reported the design and synthesis of an advanced TNM-like molecule (3) containing nitrogen-rich triazole and nitro-triazinane moieties. In addition, two of its analogues (4 and 5) were also obtained. Taking advantage of the positive heat of formation brought by triazole and triazinane rings and high-density properties donated by many nitro groups, 3 shows promising heat of detonation (Q = 5859 kJ kg-1), which is 2.8 times of TNM and higher than most of its mono ring-modified derivatives (Q: 2076 to 5594 kJ kg-1). The detonation velocity and detonation pressure of 3 (Dv = 8964 m s-1 and P = 35.7 GPa) are competitive with those of RDX (Q = 5763 kJ kg-1, Dv = 8782 m s-1, and P = 34.7 GPa). Structural modification by using triazole and nitro-triazinane rings may be helpful in exploring more TNM derivatives and other types of high-performance explosives.

Unlocking potential: low frequency subthalamic nucleus stimulation enhances executive function in Parkinson's disease patients with postural instability/gait disturbance.

Postural instability/gait disturbance (PIGD) is very common in advanced Parkinson's disease, and associated with cognitive dysfunction. Research suggests that low frequency (5-12 Hz) subthalamic nucleus-deep brain stimulation (STN-DBS) could improve cognition in patients with Parkinson's disease (PD). However, the clinical effectiveness of low frequency stimulation in PIGD patients has not been explored. This study was designed in a double-blinded randomized cross-over manner, aimed to verify the effect of low frequency STN-DBS on cognition of PIGD patients. Twenty-nine PIGD patients with STN-DBS were tested for cognitive at off (no stimulation), low frequency (5 Hz), and high frequency (130 Hz) stimulation. Neuropsychological tests included the Stroop Color-Word Test (SCWT), Verbal fluency test, Symbol Digital Switch Test, Digital Span Test, and Benton Judgment of Line Orientation test. For conflict resolution of executive function, low frequency stimulation significantly decreased the completion time of SCWT-C (p = 0.001) and Stroop interference effect (p < 0.001) compared to high frequency stimulation. However, no significant differences among stimulation states were found for other cognitive tests. Here we show, low frequency STN-DBS improved conflict resolution of executive function compared to high frequency. Our results demonstrated the possibility of expanding the treatment coverage of DBS to cognitive function in PIGD, which will facilitate integration of low frequency stimulation into future DBS programming.

The Induction of Long-Term Potentiation by Medial Septum Activation under Urethane Anesthesia Can Alter Gene Expression in the Hippocampus.

We studied changes in the expression of early genes in hippocampal cells in response to stimulation of the dorsal medial septal area (dMSA), leading to long-term potentiation in the hippocampus. Rats under urethane anesthesia were implanted with stimulating electrodes in the ventral hippocampal commissure and dMSA and a recording electrode in the CA1 area of the hippocampus. We found that high-frequency stimulation (HFS) of the dMSA led to the induction of long-term potentiation in the synapses formed by the ventral hippocampal commissure on the hippocampal CA1 neurons. One hour after dMSA HFS, we collected the dorsal and ventral hippocampi on both the ipsilateral (damaged by the implanted electrode) and contralateral (intact) sides and analyzed the expression of genes by qPCR. The dMSA HFS led to an increase in the expression of bdnf and cyr61 in the ipsilateral hippocampi and egr1 in the ventral contralateral hippocampus. Thus, dMSA HFS under the conditions of degeneration of the cholinergic neurons in the medial septal area prevented the described increase in gene expression. The changes in cyr61 expression appeared to be dependent on the muscarinic M1 receptors. Our data suggest that the induction of long-term potentiation by dMSA activation enhances the expression of select early genes in the hippocampus.

Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse

Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively. Muscimol microinjections into the LPB significantly attenuated eVNS-evoked respiratory rate responses. Notably, muscimol injections reaching the caudal LPB, previously unrecognised for respiratory modulation, potently modulated eVNS-evoked apnoea, whilst muscimol injections reaching the intermediate LPB selectively modulated the eVNS-evoked tachypnoea. The effects of muscimol on eVNS-evoked breathing rate changes occurred without altering basal eupneic breathing. These results highlight novel roles for the LPB in regulating vagally-evoked respiratory reflexes.

Feasibility of the pupillary pain index as a guide for depth of analgesia during opioid-sparing anesthesia with continuous infusion of dexmedetomidine

BackgroundThe pupillary dilation reflex (PDR) is an objective indicator of analgesic levels in anesthetized patients. Through measurement of the PDR during increasing tetanic stimulation (10–60 mA), it is possible to obtain the pupillary pain index (PPI), a score that assesses the level of analgesia.ObjectivesThe depth of analgesia during opioid-sparing anesthesia (OSA) with continuous infusion of dexmedetomidine in addition to general anesthesia was assessed.DesignObservational prospective feasibility pilot studySettingThis study was performed in the operating rooms of the Spedali Civili University-affiliated hospital of Brescia, Italy.PatientsForty-five adults who underwent elective open (5-cm incision) surgery under general anesthesia (78% inhalation anesthesia), from Feb. 18th to Aug. 1st, 2019, were enrolled. Exclusion criteria were as follows: implanted pacemaker or ICD, ophthalmological comorbidities, chronic opioid use, peripheral neuropathy, other adjuvant drugs, epidural analgesia, or locoregional block.Main outcome measuresThe first aim was to verify the feasibility of applying a study protocol to evaluate the depth of analgesia during intraoperative dexmedetomidine administration using an instrumental pupillary evaluation. The secondary outcome was to evaluate appropriate analgesia, drug dosage, anesthesia depth, heart rate, blood pressure, transient side effects, postoperative nausea and vomiting (PONV), and pain numerical rating scale (NRS) score.ResultsThirty out of 50 patients (60%) treated with dexmedetomidine during the study period were included in the DEX group (8 males, age 42 ± 13 years, BMI 45 ± 8), and 15 other patients were included in the N-DEX group (8 males, age 62 ± 13 years, BMI 26 ± 6). Patients who underwent bariatric, abdominal, or plastic surgery were enrolled. At least 3 pupillary evaluations were taken for each patient. PPI ≤ 3 was observed in 97% of patients in the DEX group and 53% in the N-DEX group. Additionally, the DEX group received less than half the remifentanil dose than the N-DEX group (0.13 ± 0.07 vs 0.3 ± 0.11 mcg kg−1 min−1). The average dose of dexmedetomidine administered was 0.17 ± 0.08 mcg kg−1 h−1.ConclusionThe feasibility of applying the protocol was verified. An OSA strategy involving dexmedetomidine may be associated with improved analgesic stability: a randomized controlled trial is necessary to verify this hypothesis.Trial registrationTrial.gov registration number: NCT05785273

DHHC2 regulates fear memory formation, LTP, and AKAP150 signaling in the hippocampus

Palmitoyl acyltransferases (PATs) have been suggested to be involved in learning and memory. However, the underlying mechanisms have not yet been fully elucidated. Here, we found that the activity of DHHC2 was upregulated in the hippocampus after fear conditioning, and DHHC2 knockdown impaired fear induced memory and long-term potentiation (LTP). Additionally, the activity of DHHC2 and its synaptic expression were increased after high frequency stimulation (HFS) or glycine treatment. Importantly, fear learning selectively augmented the palmitoylation level of AKAP150, not PSD-95, and this effect was abolished by DHHC2 knockdown. Furthermore, 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150 and the interaction between AKAP150 and PSD-95 induced by HFS. Lastly, DHHC2 knockdown reduced the phosphorylation level of GluA1 at Ser845, and also induced an impairment of LTP in the hippocampus. Our results suggest that DHHC2 plays a critical role in regulating fear memory via AKAP150 signaling.

Objective evaluation of intracochlear electrocochleography: repeatability, thresholds, and tonotopic patterns.

Intracochlear electrocochleography (ECochG) is increasingly being used to measure residual inner ear function in cochlear implant (CI) recipients. ECochG signals reflect the state of the inner ear and can be measured during implantation and post-operatively. The aim of our study was to apply an objective deep learning (DL)-based algorithm to assess the reproducibility of longitudinally recorded ECochG signals, compare them with audiometric hearing thresholds, and identify signal patterns and tonotopic behavior. We used a previously published objective DL-based algorithm to evaluate post-operative intracochlear ECochG signals collected from 21 ears. The same measurement protocol was repeated three times over 3 months. Additionally, we measured the pure-tone thresholds and subjective loudness estimates for correlation with the objectively detected ECochG signals. Recordings were made on at least four electrodes at three intensity levels. We extracted the electrode positions from computed tomography (CT) scans and used this information to evaluate the tonotopic characteristics of the ECochG responses. The objectively detected ECochG signals exhibited substantial repeatability over a 3-month period (bias-adjusted kappa, 0.68; accuracy 83.8%). Additionally, we observed a moderate-to-strong dependence of the ECochG thresholds on audiometric and subjective hearing levels. Using radiographically determined tonotopic measurement positions, we observed a tendency for tonotopic allocation with a large variance. Furthermore, maximum ECochG amplitudes exhibited a substantial basal shift. Regarding maximal amplitude patterns, most subjects exhibited a flat pattern with amplitudes evenly distributed over the electrode carrier. At higher stimulation frequencies, we observed a shift in the maximum amplitudes toward the basal turn of the cochlea. We successfully implemented an objective DL-based algorithm for evaluating post-operative intracochlear ECochG recordings. We can only evaluate and compare ECochG recordings systematically and independently from experts with an objective analysis. Our results help to identify signal patterns and create a better understanding of the inner ear function with the electrode in place. In the next step, the algorithm can be applied to intra-operative measurements.