LTP-like Plasticity Research Articles

Molecular signaling predicts corticospinal axon growth state and muscle response plasticity induced by neuromodulation

Electrical motor cortex stimulation can produce corticospinal system plasticity and enhance motor function after injury. We investigate molecular mechanisms of structural and physiological plasticity following electrical neuromodulation, focusing on identifying molecular predictors, or biomarkers, for durable plasticity. We used two neuromodulation protocols, repetitive multipulse stimulation (rMPS) and patterned intermittent theta burst stimulation (iTBS), incorporating different stimulation durations and follow-up periods. We compared neuromodulation efficacy in promoting corticospinal tract (CST) sprouting, motor cortex muscle evoked potential (MEP) LTP-like plasticity, and their associated molecular underpinnings. Only iTBS produced CST sprouting after short-term neuromodulation (1 d of stimulation; 9-d survival for sprouting expression); both iTBS and rMPS produced sprouting with long-term (10-d) neuromodulation. Significant mTOR signaling activation and phosphatase and tensin homolog (PTEN) protein deactivation predicted axon growth across all neuromodulation conditions that produced significant sprouting. Both neuromodulation protocols, regardless of duration, were effective in producing MEP enhancement. However, persistent LTP-like enhancement of MEPs at 30 d was only produced by long-term iTBS. Statistical modeling suggests that Stat3 signaling is the key mediator of MEP enhancement. Cervical spinal cord injury (SCI) alone did not affect baseline molecular signaling. Whereas iTBS and rMPS after SCI produced strong mTOR activation and PTEN deactivation, only iTBS produced Stat3 activation. Our findings support differential molecular biomarkers for neuromodulation-dependent structural and physiological plasticity and show that motor cortex epidural neuromodulation produces molecular changes in neurons that support axonal growth after SCI. iTBS may be more suitable for repair after SCI because it promotes molecular signaling for both CST growth and MEP plasticity.

Lasting effects of transcranial direct current stimulation on the inducibility of synaptic plasticity by paired-associative stimulation in humans

BackgroundTranscranial direct current stimulation (tDCS) is capable of eliciting changes in cortical neuroplasticity. Increasing duration or repetition of tDCS during the after-effects of a first stimulation has been hypothesized to enhance efficacy. Computational models suggest sequential stimulation patterns with changing polarities to further enhance effects. Lasting tDCS effects on neural plasticity are of great importance for clinical applications.ObjectiveThe study systematically examined the influence of different tDCS paradigms on long term potentiation (LTP)-like plasticity in humans, focusing on stimulation duration, repetition frequency and sequential combinations of changing polarities as the underlying characteristics.MethodsAmplitude changes of motor evoked potentials (MEP) were measured in response to paired associative stimulation (PAS) 6 h after application of different tDCS protocols. In total, 36 healthy participants completed the study, randomised into three groups with different stimulation protocols (N = 12 each).ResultstDCS was able to display lasting modulatory effects on the inducibility of LTP-like plasticity in the human motor cortex 6 h after stimulation. TDCS with the anode on primary motor cortex significantly increased MEP amplitudes following PAS induction. Further analyses highlighted single stimulation block duration to be of higher importance than repetitive protocols for efficacy of effects.ConclusionstDCS is capable of inducing lasting changes in the brain’s capability to interact with future stimuli. Especially, effects on the inducibility of LTP-like plasticity might only be detectable with specific tests such as PAS and might otherwise be overlooked. Refined tDCS protocols should focus on higher current and duration of single stimulations instead of implementing complex repetitive schedules.

Effects of auricular vagus nerve stimulation and electrical earlobe stimulation on motor-evoked potential changes induced by paired associative stimulation.

Paired associative stimulation (PAS) is a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS). PAS can induce long-term potentiation (LTP)-like plasticity in humans, manifested as motor-evoked potential (MEP) enhancement. We have developed a variant of PAS ("high-PAS"), which consists of high-frequency PNS and high-intensity TMS and targets spinal plasticity and promotes rehabilitation after spinal cord injury (SCI). Vagus nerve stimulation (VNS) promotes LTP-like plasticity and enhances recovery in SCI and stroke in humans and animals when combined with repetitive motor training. We combined high-PAS with simultaneous noninvasive transcutaneous auricular VNS (aVNS) to determine if aVNS enhances the extent of PAS-induced MEP amplitude increase. Sixteen healthy participants were stimulated for 20 min in four different sessions (PAS, PAS + aVNS, PAS + shamVNS, and aVNS) in a randomized single-blind setup. MEPs were measured before, immediately after, and at 30, 60, and 90 min post-stimulation. Stimulation protocols with PAS significantly potentiated MEPs (p= 0.005) when compared with aVNS (p= 0.642). Although not significant, MEP enhancement observed after PAS (43.5%) is further increased by aVNS (49.7%) and electrical earlobe stimulation (63.9%). Our aVNS setup failed to significantly enhance the effect of PAS, but sham VNS revealed a trend towards enhanced plasticity. Optimization of auricular VNS stimulation setup is required for possible tests of patients with SCI.

Multi-scale modelling of location- and frequency-dependent synaptic plasticity induced by transcranial magnetic stimulation in the dendrites of pyramidal neurons.

Repetitive transcranial magnetic stimulation (rTMS) induces long-term changes of synapses, but the mechanisms behind these modifications are not fully understood. Although there has been progress in the development of multi-scale modeling tools, no comprehensive module for simulating rTMS-induced synaptic plasticity in biophysically realistic neurons exists.. We developed a modelling framework that allows the replication and detailed prediction of long-term changes of excitatory synapses in neurons stimulated by rTMS. We implemented a voltage-dependent plasticity model that has been previously established for simulating frequency-, time-, and compartment-dependent spatio-temporal changes of excitatory synapses in neuronal dendrites. The plasticity model can be incorporated into biophysical neuronal models and coupled to electrical field simulations. We show that the plasticity modelling framework replicates long-term potentiation (LTP)-like plasticity in hippocampal CA1 pyramidal cells evoked by 10-Hz repetitive magnetic stimulation (rMS). This plasticity was strongly distance dependent and concentrated at the proximal synapses of the neuron. We predicted a decrease in the plasticity amplitude for 5 Hz and 1 Hz protocols with decreasing frequency. Finally, we successfully modelled plasticity in distal synapses upon local electrical theta-burst stimulation (TBS) and predicted proximal and distal plasticity for rMS TBS. Notably, the rMS TBS-evoked synaptic plasticity exhibited robust facilitation by dendritic spikes and low sensitivity to inhibitory suppression. The plasticity modelling framework enables precise simulations of LTP-like cellular effects with high spatio-temporal resolution, enhancing the efficiency of parameter screening and the development of plasticity-inducing rTMS protocols.

Neurochemical mechanisms underlying serotonergic modulation of neuroplasticity in humans

BackgroundStudies in animals and humans have shown that cortical neuroplasticity can be modulated by increasing serotonin levels by administering selective serotonin reuptake inhibitors (SSRI). However, little is known about the mechanistic background, especially the contribution of intracortical inhibition and facilitation, which depend on gamma-aminobutyric acid (GABA) and glutamate. ObjectiveWe aimed to explore the relevance of drivers of plasticity (glutamate- and GABA-dependent processes) for the effects of serotonin enhancement on tDCS-induced plasticity in healthy humans. MethodsA crossover, partially double-blinded, randomized, and sham-controlled study was conducted in 21 healthy right-handed individuals. In each of the 7 sessions, plasticity was induced via transcranial direct current stimulation (tDCS). Anodal, cathodal, and sham tDCS were applied to the left motor cortex under SSRI (20 mg/40 mg citalopram) or placebo. Short-interval cortical inhibition (SICI) and intracortical facilitation (ICF) were monitored by paired-pulse transcranial magnetic stimulation for 5–6 h after intervention. ResultsUnder placebo, anodal tDCS-induced LTP-like plasticity decreased SICI and increased ICF. In contrast, cathodal tDCS-elicited LTD-like plasticity induced the opposite effect. Under 20 mg and 40 mg citalopram, anodal tDCS did not affect SICI largely, while ICF was enhanced and prolonged. For cathodal tDCS, citalopram converted the increase of SICI and decrease of ICF into antagonistic effects, and this effect was dosage-dependent since it lasted longer under 40 mg when compared to 20 mg. ConclusionWe speculate that the main effects of acute serotonergic enhancement on tDCS-induced plasticity, the increase and prolongation of LTP-like plasticity effects, involves mainly the glutamatergic system.

Age-related differences in long-term potentiation-like plasticity and short-latency afferent inhibition and their association with cognitive function

BackgroundThe neurophysiological differences in cortical plasticity and cholinergic system function due to ageing and their correlation with cognitive function remain poorly understood.AimsTo reveal the differences in long-term potentiation (LTP)-like plasticity...

Abnormal motor cortical plasticity as a useful neurophysiological biomarker for Alzheimer’s disease pathology

ObjectiveAmyloid-beta (Aβ) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer’s disease (AD) diagnosis in subjects with cognitive decline. MethodsTwenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5 ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aβ42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers. ResultsQPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aβ42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate. ConclusionsFindings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects. SignificanceAssessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology.

A comparative transcranial magnetic stimulation study: Assessing cortical excitability and plasticity in Alzheimer's disease, dementia with Lewy bodies and Frontotemporal dementia.

Here, we aimed to investigate the roles of long-term potentiation-like (LTP-like) plasticity using intermittent theta burst (iTBS) protocol and resting motor threshold (rMT) in the differential diagnosis of Alzheimer's disease (AD), diffuse dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We enrolled 21 subjects with AD, 28 subjects with DLB, 14 subjects with FTD, and 33 elderly subjects with normal cognitive functions into the study. We recorded rMT and percentage amplitude change of motor evoked potentials (MEPs) after the iTBS protocol in each group. In patients with AD and DLB, the percentage amplitude change of MEPs, and rMTs were significantly lower than in healthy subjects. However, no significant difference was observed in individuals with FTD. Our findings showed that transcranial magnetic stimulation measures, particularly rMTs and LTP-like plasticity, may be potential biomarkers to distinguish between different dementia subtypes. Impaired motor cortical excitability and synaptic plasticity were more prominent in AD and DLB than in FTD. This aligns with the evidence that cortical motor networks are usually spared in FTDs in early-to-middle stages.

Effects of repetitive transcranial magnetic stimulation on episodic memory in patients with subjective cognitive decline: study protocol for a randomized clinical trial.

Early decline of episodic memory is detectable in subjective cognitive decline (SCD). The left dorsolateral prefrontal cortex (DLPFC) is associated with encoding episodic memories. Repetitive transcranial magnetic stimulation (rTMS) is a novel and viable tool to improve cognitive function in Alzheimer's disease (AD) and mild cognitive impairment, but the treatment effect in SCD has not been studied. We aim to investigate the efficacy of rTMS on episodic memory in individuals with SCD, and to explore the potential mechanisms of neural plasticity. In our randomized, sham-controlled trial, patients (n = 60) with SCD will receive 20 sessions (5 consecutive days per week for 4 weeks) of real rTMS (n = 30) or sham rTMS (n = 30) over the left DLPFC. The primary outcome is the Auditory Verbal Learning Test-Huashan version (AVLT-H). Other neuropsychological examinations and the long-term potentiation (LTP)-like cortical plasticity evaluation serve as the secondary outcomes. These outcomes will be assessed before and at the end of the intervention. If the episodic memory of SCD improve after the intervention, the study will confirm that rTMS is a promising intervention for cognitive function improvement on the early stage of dementia. This study will also provide important clinical evidence for early intervention in AD and emphasizes the significance that impaired LTP-like cortical plasticity may be a potential biomarker of AD prognosis by demonstrating the predictive role of LTP on cognitive improvement in SCD. The study was approved by the Human Research Ethics Committee of the hospital (No. 2023-002-01). The results will be published in peer-review publications. https://www.chictr.org.cn/, identifier ChiCTR2300075517.

Disrupted synaptic homeostasis and partial occlusion of associative long-term potentiation in the human cortex during social isolation

Social isolation often occurs in the military mission of soldiers but has increased in the general population since the COVID-19 epidemic. Overall synaptic homeostasis along with associative plasticity for the activity-dependent refinement of transmission across single synapses represent basic neural network function and adaptive behavior mechanisms. Here, we use electrophysiological and behavioral indices to non-invasively study the net synaptic strength and long-term potentiation (LTP)-like plasticity of humans in social isolation environments. The theta activity of electroencephalography (EEG) signals and transcranial magnetic stimulation (TMS) intensity to elicit a predefined amplitude of motor-evoked potential (MEP) demonstrate the disrupted synaptic homeostasis in the human cortex during social isolation. Furthermore, the induced MEP change by paired associative stimulation (PAS) demonstrates the partial occlusion of LTP-like plasticity, further behavior performances in a word-pair task are also identified as a potential index. Our study indicates that social isolation disrupts synaptic homeostasis and occludes associative LTP-like plasticity in the human cortex, decreasing behavior performance related to declarative memory.

Preventive exercise and physical rehabilitation promote long-term potentiation-like plasticity expression in patients with multiple sclerosis.

Loss of long-term potentiation (LTP) expression has been associated with a worse disease course in relapsing-remitting multiple sclerosis (RR-MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP-like plasticity in patients with multiple sclerosis (MS). In 46 newly diagnosed RR-MS patients, we explored the impact of preventive exercise on LTP-like plasticity as assessed by intermittent theta-burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8-week inpatient neurorehabilitation program on clinical scores and LTP-like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects. Reduced LTP expression was found in RR-MS patients compared with controls. Exercising RR-MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity. Both preventive exercise and physical rehabilitation may enhance the expression of LTP-like synaptic plasticity in MS, with potential beneficial effects on disability accumulation.

Practice Makes Plasticity: 10-Hz rTMS Enhances LTP-like Plasticity in Musicians and Athletes

Practice Makes Plasticity: 10-Hz rTMS Enhances LTP-like Plasticity in Musicians and Athletes

Innovative Therapy Combining Neck Muscle Vibration and Transcranial Direct Current Stimulation in Association with Conventional Rehabilitation in Left Unilateral Spatial Neglect Patients: HEMISTIM Protocol for a Randomized Controlled Trial

Unilateral spatial neglect (USN) rehabilitation requires the development of new methods that can be easily integrated into conventional practice. The aim of the HEMISTIM protocol is to assess immediate and long-term recovery induced by an innovative association of left-side neck-muscle vibration (NMV) and anodal transcranial Direct Current Stimulation (tDCS) on the ipsilesional posterior parietal cortex during occupational therapy sessions in patients with left USN. Participants will be randomly assigned to four groups: control, Left-NMV, Left-NMV + sham-tDCS or Left-NMV + anodal-tDCS. NMV and tDCS will be applied during the first 15 min of occupational therapy sessions, three days a week for three weeks. USN will be assessed at baseline, just at the end of the first experimental session, after the first and third weeks of the protocol and three weeks after its ending. Our primary outcome will be the evolution of the functional Catherine Bergego Scale score. Secondary outcome measures include five tests that investigate different neuropsychological aspects of USN. Left NMV, by activating multisensory integration neuronal networks, might enhance effects obtained by conventional therapy since post-effects were shown when it was combined with upper limb movements. We expect to reinforce lasting intermodal recalibration through LTP-like plasticity induced by anodal tDCS.

Hippocampal-prefrontal long-term potentiation-like plasticity with transcranial direct current stimulation in rats

Transcranial direct current stimulation (tDCS) has been explored as a new treatment method for improving cognitive and motor functions. However, the neuronal mechanisms of tDCS in modulating brain functions, especially cognitive and memory functions, are not well understood. In the present study, we assessed whether tDCS could promote neuronal plasticity between the hippocampus and prefrontal cortex in rats. This is important because the hippocampus-prefrontal pathway is a key pathway in cognitive and memory functions and is involved in various psychiatric and neurodegenerative disorders. Specifically, the effect of anodal or cathodal tDCS on the medial prefrontal cortex was investigated in rats by measuring the medial prefrontal cortex response to electrical stimulation applied to the CA1 region of the hippocampus. Following anodal tDCS, the evoked prefrontal response was potentiated compared to that in the pre-tDCS condition. However, the evoked prefrontal response did not show any significant changes following cathodal tDCS. Furthermore, the plastic change of the prefrontal response following anodal tDCS was only induced when hippocampal stimulation was continuously applied during tDCS. Anodal tDCS without hippocampal activation showed little or no changes. These results indicate that combining anodal tDCS of the prefrontal cortex with hippocampal activation induces long-term potentiation (LTP)-like plasticity in the hippocampus-prefrontal pathway. This LTP-like plasticity can facilitate smooth information transmission between the hippocampus and the prefrontal cortex and may lead to improvements in cognitive and memory function.

Practice makes plasticity: 10-Hz rTMS enhances LTP-like plasticity in musicians and athletes.

Motor skill learning has been linked to functional and structural changes in the brain. Musicians and athletes undergo intensive motor training through the practice of an instrument or sport and have demonstrated use-dependent plasticity that may be subserved by long-term potentiation (LTP) processes. We know less, however, about whether the brains of musicians and athletes respond to plasticity-inducing interventions, such as repetitive transcranial magnetic stimulation (rTMS), differently than those without extensive motor training. In a pharmaco-rTMS study, we evaluated motor cortex excitability before and after an rTMS protocol in combination with oral administration of D-cycloserine (DCS) or placebo. In a secondary covariate analysis, we compared results between self-identified musicians and athletes (M&As) and non-musicians and athletes (non-M&As). Three TMS measures of cortical physiology were used to evaluate plasticity. We found that M&As did not have higher baseline corticomotor excitability. However, a plasticity-inducing protocol (10-Hz rTMS in combination with DCS) strongly facilitated motor-evoked potentials (MEPs) in M&As, but only weakly in non-M&As. Placebo and rTMS produced modest facilitation in both groups. Our findings suggest that motor practice and learning create a neuronal environment more responsive to plasticity-inducing events, including rTMS. These findings may explain one factor contributing to the high inter-individual variability found with MEP data. Greater capacity for plasticity holds implications for learning paradigms, such as psychotherapy and rehabilitation, by facilitating LTP-like activation of key networks, including recovery from neurological/mental disorders.

NMDA receptor–related mechanisms of dopaminergic modulation of tDCS-induced neuroplasticity

Abstract Background: Dopamine is a key neuromodulator of neuroplasticity, and an important neuronal substrate of learning, and memory formation, which critically involves glutamatergic N-Methyl-D-aspartate (NMDA) receptors. Dopamine modulates NMDA receptor activity via dopamine D1 and D2 receptor subtypes. It is hypothesized that dopamine focuses long term potentiation (LTP)-like plasticity, i.e. reduces diffuse widespread but enhances locally restricted plasticity via a D2 receptor-dependent NMDA receptor activity reduction. Here, we explored NMDA receptor-dependent mechanisms underlying DAergic modulation of LTP-like plasticity induced by transcranial direct current stimulation (tDCS). Methods: Eleven healthy, right-handed volunteers received anodal tDCS (1 mA, 13 min) over the left motor cortex combined with DAergic agents (the D2 receptor agonist bromocriptine, levodopa (L-Dopa) for general dopamine enhancement, or placebo), and the partial NMDA receptor agonist D-cycloserine (CYC; dosages of 50, 100 and 200 mg, or placebo). Cortical excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potentials. Results: Low-dose CYC alone did not relevantly change anodal tDCS-generated LTP-like plasticity, while medium dosage prolonged and high dosage CYC diminished aftereffects of stimulation. L-Dopa or bromocriptine alone reversed or abolished anodal tDCS-induced excitatory plasticity respectively, which was re-established by medium-dose CYC. Adding low dosage CYC did not alter the effects of bromocriptine and L-Dopa, while high-dose CYC abolished the after-effects. Conclusions: Our results suggest that the focusing effect of dopamine on LTP-like plasticity is caused by D2 receptor-generated reduction of NMDA receptor activity. Medium-dose CYC, as compared to low and high dosages, restored anodal tDCS-induced after-effects possibly due to optimizing calcium influx via enhancement of NMDA receptor activity Research Category and Technology and Methods Basic Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: transcranial direct current stimulation, dopamine, NMDA receptor, plasticity

A family study of symbolic learning and synaptic plasticity in autism spectrum disorder.

The current study presents a male with autism spectrum disorder (ASD) and a 3q29 deletion, and three healthy first-degree relatives. Our magnetic resonance imaging (MRI) dataset included a healthy control subset. We describe a comprehensive multimodal approach, including equivalence class formation, neurocognitive testing, MRI, and electroencephalography (EEG)-based cortical plasticity, which can provide new insights into socio-communicative and learning impairments and neural underpinnings in ASD. On neurocognitive testing, the proband showed reduced processing speed, attending behavior, and executive function. He required more training trials in equivalence class training compared with family members and exhibited impaired priming of words compared with priming with images. The proband had smaller intracranial volume and surface area and a larger visual evoked potential (VEP) C1 amplitude than family members and intact long-term potentiation (LTP)-like visual cortex plasticity. Together, these results suggest that 3q29 deletion-related ASD is associated with impaired problem-solving strategies in complex socio-communicative and learning tasks, smaller intracranial and surface area, altered VEP amplitude, and normal LTP-like visual cortex plasticity. Further studies are needed to clarify whether this multimodal approach can be used to identify ASD subgroups with distinct neurobiological alterations and to uncover mechanisms underlying socio-communicative and learning impairments. Lay Summary: We studied learning, brain activity, and brain structure in a person with autism and a genetic aberration, and his close relatives. Compared with relatives, the person with autism required more training for learning, and visual learning was better than verbal learning. This person had some changes in the activity of the visual cortex, and the size and the surface area of the brain were reduced. Knowledge about learning and brain mechanisms is valuable for the development of training programs for individuals with autism.

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (θtACS) or gamma (γtACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with γtACS but not with θtACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions.

Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome

ObjectiveTranscranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI).Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. MethodsThirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. ResultsPatients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. ConclusionsEight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. SignificanceThis study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

Long term potentiation-like neural plasticity and performance-based memory function

ObjectiveExperience-dependent modulation of the visual evoked potential (VEP) has emerged as a promising non-invasive proxy for assaying long term potentiation (LTP)-like plasticity in the cerebral cortex. LTP is considered the principal candidate mechanism underlying learning and memory. There is, however, a paucity of evidence exploring associations between LTP-like plasticity and performance-based learning and memory. The present study aimed to explore the relationship between VEP-plasticity and higher-order learning and memory in healthy adults. MethodVisual and verbal learning and memory was assessed using the Aggie Figures Learning Test (AFLT) and the Rey Auditory Verbal Learning Test (RAVLT). The study included 111 healthy adults (61.1% females; mean age 37.6 years, range 17–71) who underwent a VEP paradigm employing visual high-frequency stimulation to induce a change in visual evoked responses recorded by scalp EEG. In addition, a more comprehensive neuropsychological assessment was administered. ResultsSeveral significant moderate age-corrected positive correlations were found between modulation of the later VEP components (N1 and P1-N1 peak-to-peak) and both visual and verbal learning and memory performance. Further, there were significant differences in learning and memory performance between participants showing a higher degree of modulation (>1 SD above mean) compared to participants showing a lower degree of modulation. No significant associations were found between VEP-plasticity and other neurocognitive domains. ConclusionsThe current results suggest that LTP-like plasticity indexed by VEP modulation reflect processes specific to learning and memory. Future research is needed to further delineate the complex relationship between neural plasticity and learning and memory, specifically concerning possible clinical implications in populations with deficits in learning and memory function.