Exercise effects on cortical excitability in pain populations: A systematic review and meta-analysis.

BACKGROUND: Transcranial Magnetic Stimulation (TMS) studies examining exercise-induced neuroplasticity in pain populations have produced contradictory findings. We conducted a systematic review to explore how exercise impacts cortical excitability in pain populations using TMS metrics. This review aims to summarize the effect sizes and to understand their sources of heterogeneity. METHODS: We searched multiple databases from inception to December 2022. We included randomized controlled trials (RCTs) with any type of pain population, including acute and chronic pain; exercise interventions were compared to sham exercise or other active interventions. The primary outcomes were TMS metrics, and pain intensity was the secondary outcome. Risk of bias assessment was conducted using the Cochrane tool. RESULTS: This review included five RCTs (n = 155). The main diagnoses were fibromyalgia and cervical dystonia. The interventions included submaximal contractions, aerobic exercise, physical therapy, and exercise combined with transcranial direct current stimulation. Three studies are considered to have a high risk of bias. All five studies showed significant pain improvement with exercise. The neurophysiological data revealed improvements in cortical excitability measured by motor-evoked potentials; standardized mean difference = 2.06, 95% confidence interval 1.35-2.78, I2 = 19%) but no significant differences in resting motor threshold. The data on intracortical inhibition/facilitation (ICI/ICF) was not systematically analyzed, but one study (n = 45) reported higher ICI and lower ICF after exercise. CONCLUSIONS: These findings suggest that exercise interventions positively affect pain relief by modifying corticospinal excitability, but their effects on ICI/ICF are still unclear. While the results are inconclusive, they provide a basis for further exploration in this area of research; future studies should focus on establishing standardized TMS measurements and exercise protocols to ensure consistent and reliable findings. A large-scale RCT that examines various exercise interventions and their effects on cortical excitability could offer valuable insights to optimize its application in promoting neuroplasticity in pain populations.

Decoding the clinical effects of low-grade glioma-induced cortical excitability.

OBJECTIVE: Patients with low-grade glioma (LGG) in eloquent regions often present with seizures, and findings on detailed neuropsychological testing are often abnormal. This study evaluated the association between cortical excitability, seizures, and cognitive function in patients with LGG. METHODS: LGG patients who underwent transcranial magnetic stimulation (TMS) from January 2021 to December 2022 were studied. Cortical excitability was measured using the resting motor thresholds (RMTs) of the upper and lower extremities. Early postoperative seizures served as the seizure endpoint. Neuropsychological assessment was completed prior to surgery contemporaneous with the TMS studies. RESULTS: A total of 31 patients were analyzed for seizure outcome. Median (interquartile range [IQR]) upper-extremity RMT was 39% (34%-46%) of maximum stimulator output, and the median (IQR) lower-extremity RMT was 69% (51%-79%). Lower-extremity RMT was higher in patients with early postoperative seizures, especially in those with motor region tumors (p = 0.02); however, RMT was not associated with seizures at presentation or long-term seizure control. A total of 26 patients completed neuropsychological assessment. There were significant negative correlations between upper-extremity RMT and psychomotor processing speed (Wechsler Adult Intelligence Scale-Fourth Edition [WAIS-IV] Processing Speed Index r = -0.42, p = 0.031; WAIS-IV Coding r = -0.41, p = 0.036; WAIS-IV Symbol Search r = -0.39, p = 0.048), executive function (Trail Making Test Part B r = -0.41, p = 0.036), and hand dexterity (Grooved Pegboard Test r = -0.50, p = 0.047). CONCLUSIONS: RMT was positively correlated with early postoperative seizure risk and negatively correlated with psychomotor processing speed, executive function, and hand dexterity. These findings support the theory of local and regional resting oscillatory network dysfunction from a glioma-brain network.

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Measures of Cortical Excitability: A Systematic Review and Considerations for Clinical Practice.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative for the treatment of major depressive disorder (MDD), although its clinical effectiveness varies substantially. The effects of sex hormone fluctuations on cortical excitability have been identified as potential factors that can explain this variability. However, data on how sex hormone changes affect clinical response to rTMS is limited. To address this gap, we reviewed the literature examining the effects of sex hormones and hormonal treatments on transcranial magnetic stimulation (TMS) measures of cortical excitability. Results show that variations of endogenous estrogen, testosterone, and progesterone have modulatory effects on TMS-derived measures of cortical excitability. Specifically, higher levels of estrogen and testosterone were associated with greater cortical excitability, while higher progesterone was associated with lower cortical excitability. This highlights the importance of additional investigation into the effects of hormonal changes on rTMS outcomes and circuit-specific physiological variables. These results call for TMS clinicians to consider performing more frequent motor threshold (MT) assessments in patients receiving high doses of estrogen, testosterone, and progesterone in cases such as in vitro fertilization, hormone replacement therapy, and gender-affirming hormonal treatments. It may also be important to consider physiological hormonal fluctuations and their impact on depressive symptoms and the MT when treating female patients with rTMS.

Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability.

Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function. Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeat-associated non-AUG translation. The analysis of postmortem brains of FAME1 expansion (in SAMD12) carriers has revealed the presence of RNA foci that could be formed by the aggregation of RNA molecules with abnormal UUUCA repeats, but evidence is still lacking for other FAME subtypes. Even when the expansion is located in a gene ubiquitously expressed, expression of repeats remains undetectable in peripheral tissues (blood, skin). Therefore, the development of appropriate cellular models (induced pluripotent stem cell-derived neurons) or the study of affected tissues in patients is required to elucidate how FAME repeat expansions located in unrelated genes lead to disease.

Presença de risco de transtorno do estresse pós-traumático em policiais militares feridos por arma de fogo / Presence of risk of posttraumatic stress disorder in military police officers wounded by firearms / Presencia de riesgo de trastorno de estrés postraumático en policías militares heridos por armamiento de fuego

Este estudo teve como objetivo identificar o risco de desenvolvimento de transtorno de estresse pós-traumático (TEPT), bem como sua associação com pensamentos ou tentativas suicidas e a saúde mental de policiais militares feridos por arma de fogo, na Região Metropolitana de Belém (RMB), nos anos de 2017 a 2019. A pesquisa contou com a participação de 30 entrevistados, que responderam o Inventário Demográfico e a Lista de verificação de TEPT para o DSM-5 (PCL-5). Para análise dos dados, utilizou-se a técnica estatística Análise Exploratória de Dados e a técnica multivariada Análise de Correspondência. Os resultados revelaram a existência de risco de desenvolvimento do transtorno de forma parcial ou total em uma expressiva parcela da população entrevistada, tendo homens como maioria dos sintomáticos, com média de 38 anos, exercendo atividades operacionais e vitimados em via pública quando estavam de folga do serviço. O ferimento deixou a maioria com sequelas, com destaque para dores crônicas, limitações de locomoção e/ou mobilidade e perda parcial de um membro. E, ainda, policiais sintomáticos apresentaram comportamentos suicidas, relatando já terem pensado ou tentado tirar a própria vida. Desta forma, conclui-se que policiais militares são expostos constantemente a traumas inerentes a sua profissão. Quando há ameaça de vida, como nos casos de ferimentos por arma de fogo, são suscetíveis a sequelas físicas decorrente do ferimento, somadas a sequelas mentais tardias, como o surgimento de sintomatologias de TEPT e ideação suicida.(AU)

This study aimed to identify the risk of developing post-traumatic stress disorder (PTSD) and its associations around suicidal thoughts or attempts and mental health in military police officers injured by firearms, in the Metropolitan Region of Belem (RMB), from 2017 to 2019. The research had the participation of 30 respondents who answered the Demographic Inventory and the PTSD checklist for DSM-5 (PCL-5). For data analysis, we used the statistical technique Exploratory Data Analysis and the multivariate technique Correspondence Analysis. The results revealed the existence of risk of developing partial or total disorder in a significant portion of the interviewed population, with men as most of the symptomatic individuals, with mean age of 38 years, developing operational activities and victimized on public roads when they were off duty. The injuries left most of them with sequelae, especially chronic pain, limited locomotion and/or mobility, and partial loss of a limb. In addition, symptomatic officers showed suicidal behavior, such as reporting they had thought about or tried to take their own lives. Thus, we conclude that military policemen are constantly exposed to traumas inherent to their profession. When their lives are threatened, as in the case of firearm wounds, they are susceptible to physical sequelae resulting from the injury, in addition to late mental sequelae, such as the appearance of PTSD symptoms and suicidal ideation.(AU)

Este estudio tuvo como objetivo identificar el riesgo de desarrollo de trastorno de estrés postraumático (TEPT) y sus asociaciones con pensamientos o tentativas suicidas y la salud mental en policías militares heridos por armamiento de fuego, en la Región Metropolitana de Belém (Brasil), en el período entre 2017 y 2019. En el estudio participaron 30 entrevistados que respondieron el Inventario Demográfico y la Lista de verificación de TEPT para el DSM-5 (PCL-5). Para el análisis de datos se utilizaron la técnica estadística Análisis Exploratoria de Datos y la técnica multivariada Análisis de Correspondencia. Los resultados revelaron que existen riesgos de desarrollo de trastorno de estrés postraumático de forma parcial o total en una expresiva parcela de la población de policías entrevistados, cuya mayoría de sintomáticos eran hombres, de 38 años en media, que ejercen actividades operacionales y fueron victimados en vía pública cuándo estaban de día libre del servicio. La lesión dejó la mayoría con secuelas, especialmente con dolores crónicos, limitaciones de locomoción y/o movilidad y la pierda parcial de un miembro. Aún los policías sintomáticos presentaran comportamiento suicida, tales como relataran qué ya pensaron o tentaron quitar la propia vida. Se concluye que los policías militaran se exponen constantemente a los traumas inherentes a su profesión. Cuando existe amenaza de vida, como en los casos de heridas por armamiento de fuego, son expuestos a secuelas físicas transcurridas de la herida, sumado a secuelas mentales tardías, como el surgimiento de sintomatologías de TEPT y la ideación suicida.(AU)

[Effect of electroacupuncture at back-shu points of five zang on fatigue status and cortical excitability in chronic fatigue syndrome].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at back-shu points of five zang on fatigue status, quality of life and motor cortical excitability in patients with chronic fatigue syndrome (CFS), so as to explore the possible mechanism of EA for CFS. METHODS: A total of 72 patients with CFS were randomized into an EA group (36 cases, 4 cases dropped off) and a sham EA group (36 cases, 3 cases dropped off). In the EA group, EA at Ganshu (BL 18), Xinshu (BL 15), Pishu (BL 20), Feishu (BL 13) and Shenshu (BL 23) was adopted, with continuous wave, 2 Hz in frequency. In the sham EA group, sham EA at non-acupoints (1.5-2.0 cm lateral to back-shu points of five zang) was applied, with shallow needling, and no current was connected. The treatment in the both groups was 20 min each time, once every other day, 2 weeks as one course, 3 courses were required. Before and after treatment, the scores of fatigue scale-14 (FS-14) and the MOS 36-item short form health survey (SF-36) were observed, and cortical excitability (the resting motor threshold [RMT], amplitude of motor-evoked potential [MEP-A] and latency of motor-evoked potential [MEP-L]) was detected in the two groups. RESULTS: After treatment, the physical fatigue score, mental fatigue score and total score of FS-14, as well as RMT of motor cortex in the EA group were decreased compared with those before treatment (P<0.01), the physical fatigue score and total score of FS-14 in the sham EA group were decreased compared with those before treatment (P<0.05); each item score and total score of FS-14 and RMT of motor cortex in the EA group were lower than those in the sham EA group (P<0.01, P<0.05). After treatment, each item score and total score of SF-36 and MEP-A of motor cortex in the EA group were increased compared with those before treatment (P<0.01), which were higher than those in the sham EA group (P<0.01, P<0.05). CONCLUSION: EA at back-shu points of five zang can effectively improve the fatigue status and quality of life in patients with CFS, its mechanism may be related to the up-regulating excitability of cerebral motor cortex.

Astrocyte Ca2+-evoked ATP release regulates myelinated axon excitability and conduction speed.

In the brain's gray matter, astrocytes regulate synapse properties, but their role is unclear for the white matter, where myelinated axons rapidly transmit information between gray matter areas. We found that in rodents, neuronal activity raised the intracellular calcium concentration ([Ca2+]i) in astrocyte processes located near action potential­generating sites in the axon initial segment (AIS) and nodes of Ranvier of myelinated axons. This released adenosine triphosphate, which was converted extracellularly to adenosine and thus, through A2a receptors, activated HCN2-containing cation channels that regulate two aspects of myelinated axon function: excitability of the AIS and speed of action potential propagation. Variations in astrocyte-derived adenosine level between wake and sleep states or during energy deprivation could thus control white matter information flow and neural circuit function.

The influence of high-frequency repetitive transcranial magnetic stimulation on endogenous estrogen in patients with disorders of consciousness.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a promising therapeutic intervention for neurological disorders. However, the precise mechanisms of rTMS in neural excitability remains poorly understood. Estradiol is known to have strong influence on cortical excitability. This study aimed to determine whether high-frequency (HF) rTMS influences endogenous estradiol in male patients with disorders of consciousness (DOC). METHODS: A randomized controlled trial was conducted with a total of 57 male patients with DOC. Eventually, 50 patients completed the study. Twenty-five patients underwent real rTMS, and 25 patients underwent sham rTMS, which were delivered over the dorsolateral prefrontal cortex. The primary outcome measure was the change in serum estradiol from baseline to after 10 sessions of HF-rTMS. The improvement in the total score of the JFK Coma Recovery Scale-Revised (CRS-R) was also assessed. RESULTS: Changes in estradiol levels and CRS-R scores from pre-to post-treatment were significantly different between the active rTMS and sham stimulation conditions. A significant enhancement of CRS-R scores in the patients receiving rTMS stimulation was observed compared to the sham group. Serum estradiol levels in patients following HF-rTMS were significantly higher than their baseline levels, whereas no significant changes were found in the sham group from pre-to post-stimulation. The rise in estradiol levels was greater in responders than in non-responders. The changes in estradiol levels were significantly positively correlated with the improvement in CRS-R scores. CONCLUSION: These preliminary findings indicate that serum estradiol levels are affected by HF-rTMS and positively related to clinical responses in male patients with DOC. The elevation of estradiol levels may lay a physiological foundation for successful rTMS treatment for DOC patients by increasing cortical excitability.

Correlating cognition and cortical excitability with pain in fibromyalgia: a case control study.

BACKGROUND: Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal symptoms, primarily attributed to sensitization of somatosensory system carrying pain. Few reports have investigated the impact of fibromyalgia symptoms on cognition, corticomotor excitability, sleepiness, and the sleep quality - all of which can deteriorate the quality of life in fibromyalgia. However, the existing reports are underpowered and have conflicting directions of findings, limiting their generalizability. Therefore, the present study was designed to compare measures of cognition, corticomotor excitability, sleepiness, and sleep quality using standardized instruments in the recruited patients of fibromyalgia with pain-free controls. METHODS: Diagnosed cases of fibromyalgia were recruited from the Rheumatology department for the cross-sectional, case-control study. Cognition (Mini-Mental State Examination, Stroop color-word task), corticomotor excitability (Resting motor threshold, Motor evoked potential amplitude), daytime sleepiness (Epworth sleepiness scale), and sleep quality (Pittsburgh sleep quality index) were studied according to the standard procedure. RESULTS: Thirty-four patients of fibromyalgia and 30 pain-free controls were recruited for the study. Patients of fibromyalgia showed decreased cognitive scores (p = 0.05), lowered accuracy in Stroop color-word task (for color: 0.02, for word: 0.01), and prolonged reaction time (< 0.01, < 0.01). Excessive daytime sleepiness in patients were found (< 0.01) and worsened sleep quality (< 0.01) were found. Parameters of corticomotor excitability were comparable between patients of fibromyalgia and pain-free controls. CONCLUSIONS: Patients of fibromyalgia made more errors, had significantly increased reaction time for cognitive tasks, marked daytime sleepiness, and impaired quality of sleep. Future treatment strategies may include cognitive deficits and sleep disturbances as an integral part of fibromyalgia management.

Athletes after anterior cruciate ligament reconstruction demonstrate asymmetric intracortical facilitation early after surgery.

Quadriceps dysfunction persists after anterior cruciate ligament reconstruction (ACLR), yet the etiology remains elusive. Inhibitory and facilitatory intracortical networks (ie, intracortical excitability) may be involved in quadriceps dysfunction, yet the investigation of these networks early after ACLR is sparse. The purposes of this study were to examine (a) changes in intracortical excitability in athletes after ACLR compared to uninjured athletes during the course of postoperative rehabilitation, (b) the association between intracortical excitability and quadriceps strength in athletes after ACLR. Eighteen level I/II athletes after ACLR between the ages of 18 to 30 years and eighteen healthy sex, age, and activity matched athletes were tested at three-time points: (a) 2 weeks after surgery, (b) achievement of a "quiet knee" defined as full range of motion and minimal effusion, (c) return to running time point defined as achievement of a quadriceps index ≥80% and at least 12 weeks post-ACLR. Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), measured via transcranial magnetic stimulation and isometric quadriceps strength were examined bilaterally at each time point. There was a significant group × limb interaction (P = .017) for ICF. The ACLR group demonstrated asymmetric ICF (greater in the nonsurgical limb) compared to controls and a significant relationship between SICI and quadriceps strength of the surgical limb at the quiet knee time point (P = .018). ACLR individuals demonstrate differential effects on ICF between limbs. Also, SICI is associated with isometric quadriceps strength after ACLR, suggesting increased inhibition of the motor cortex may contribute to impaired quadriceps strength following ACLR.

Correlating cognition and cortical excitability with pain in fibromyalgia: a case control study

Abstract Background: Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal symptoms, primarily attributed to sensitization of somatosensory system carrying pain. Few reports have investigated the impact of fibromyalgia symptoms on cognition, corticomotor excitability, sleepiness, and the sleep quality — all of which can deteriorate the quality of life in fibromyalgia. However, the existing reports are underpowered and have conflicting directions of findings, limiting their generalizability. Therefore, the present study was designed to compare measures of cognition, corticomotor excitability, sleepiness, and sleep quality using standardized instruments in the recruited patients of fibromyalgia with pain-free controls. Methods: Diagnosed cases of fibromyalgia were recruited from the Rheumatology department for the cross-sectional, case-control study. Cognition (Mini-Mental State Examination, Stroop color-word task), corticomotor excitability (Resting motor threshold, Motor evoked potential amplitude), daytime sleepiness (Epworth sleepiness scale), and sleep quality (Pittsburgh sleep quality index) were studied according to the standard procedure. Results: Thirty-four patients of fibromyalgia and 30 pain-free controls were recruited for the study. Patients of fibromyalgia showed decreased cognitive scores (p = 0.05), lowered accuracy in Stroop color-word task (for color: 0.02, for word: 0.01), and prolonged reaction time (< 0.01, < 0.01). Excessive daytime sleepiness in patients were found (< 0.01) and worsened sleep quality (< 0.01) were found. Parameters of corticomotor excitability were comparable between patients of fibromyalgia and pain-free controls. Conclusions: Patients of fibromyalgia made more errors, had significantly increased reaction time for cognitive tasks, marked daytime sleepiness, and impaired quality of sleep. Future treatment strategies may include cognitive deficits and sleep disturbances as an integral part of fibromyalgia management.(AU)

Motor cortical excitability and plasticity in patients with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1. METHODS: We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS). RESULTS: The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009). CONCLUSIONS: Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients. SIGNIFICANCE: These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1.

Amygdala stimulation ameliorates memory impairments and promotes c-Fos activity in fimbria-fornix-lesioned rats.

Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria-fornix (FF). The mechanisms for this improvement involve early gene expression and synthesis of BDNF, MAP-2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c-Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF-lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c-Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF-lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF-lesioned, but not stimulated group, like the c-Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.

BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons.

Somatic mutations have emerged as the likely cause of focal epilepsies associated with developmental malformations and epilepsy-associated glioneuronal tumors (GNT). Somatic BRAFV600E mutations in particular have been detected in the majority of low-grade neuroepithelial tumors (LNETS) and in neurons in focal cortical dysplasias adjacent to epilepsy-associated tumors. Furthermore, conditional expression of an activating BRAF mutation in neocortex causes seizures in mice. In this study we characterized the cellular electrophysiology of layer 2/3 neocortical pyramidal neurons induced to express BRAFV600E from neural progenitor stages. In utero electroporation of a piggyBac transposase plasmid system was used to introduce transgenes expressing BRAF wild type (BRAFwt), BRAFV600E, and/or enhanced green fluorescent protein (eGFP) and monomeric red fluorescent protein (mRFP) into radial glia progenitors in mouse embryonic cortex. Whole cell patch-clamp recordings of pyramidal neurons in slices prepared from both juvenile and adult mice showed that BRAFV600E resulted in neurons with a distinct hyperexcitable phenotype characterized by depolarized resting membrane potentials, increased input resistances, lowered action potential (AP) thresholds, and increased AP firing frequencies. Some of the BRAFV600E-expressing neurons normally destined for upper cortical layers by their birthdate were stalled in their migration and occupied lower cortical layers. BRAFV600E-expressing neurons also displayed increased hyperpolarization-induced inward currents (Ih) and decreased sustained potassium currents. Neurons adjacent to BRAFV600E transgene-expressing neurons, and neurons with TSC1 genetically deleted by CRISPR or those induced to carry PIK3CAE545K transgenes, did not show an excitability phenotype similar to that of BRAFV600E-expressing neurons. Together, these results indicate that BRAFV600E leads to a distinct hyperexcitable neuronal phenotype.NEW & NOTEWORTHY This study is the first to report the cell autonomous effects of BRAFV600E mutations on the intrinsic neuronal excitability. We show that BRAFV600E alters multiple electrophysiological parameters in neocortical neurons. Similar excitability changes did not occur in cells neighboring BRAFV600E-expressing neurons, after overexpression of wild-type BRAF transgenes, or after introduction of mutations affecting the mammalian target of rapamycin (mTOR) or the catalytic subunit of phosphoinositide 3-kinase (PIK3CA). We conclude that BRAFV600E causes a distinct, cell autonomous, highly excitable neuronal phenotype when introduced somatically into neocortical neuronal progenitors.

Utilizing transcranial direct current stimulation to enhance laparoscopic technical skills training: A randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that delivers constant, low electrical current resulting in changes to cortical excitability. Prior work suggests it may enhance motor learning giving it the potential to augment surgical technical skill acquisition. OBJECTIVES: The aim of this study was to test the efficacy of tDCS, coupled with motor skill training, to accelerate laparoscopic skill acquisition in a pre-registered (NCT03083483), double-blind and placebo-controlled study. We hypothesized that relative to sham tDCS, active tDCS would accelerate the development of laparoscopic technical skills, as measured by the Fundamentals of Laparoscopic Surgery (FLS) Peg Transfer task quantitative metrics. METHODS: In this study, sixty subjects (mean age 22.7 years with 42 females) were randomized into sham or active tDCS in either bilateral primary motor cortex (bM1) or supplementary motor area (SMA) electrode configurations. All subjects practiced the FLS Peg Transfer Task during six 20-min training blocks, which were preceded and followed by a single trial pre-test and post-test. The primary outcome was changes in laparoscopic skill performance over time, quantified by group differences in completion time from pre-test to post-test and learning curves developed from a calculated score accounting for errors. RESULTS: Learning curves calculated over the six 20-min training blocks showed significantly greater improvement in performance for the bM1 group than the sham group (t = 2.07, p = 0.039), with the bM1 group achieving approximately the same amount of improvement in 4 blocks compared to the 6 blocks required of the sham group. The SMA group also showed greater mean improvement than sham, but exhibited more variable learning performance and differences relative to sham were not significant (t = 0.85, p = 0.400). A significant main effect was present for pre-test versus post-test times (F = 133.2, p < 0.001), with lower completion times at post-test, however these did not significantly differ for the training groups. CONCLUSION: Laparoscopic skill training with active bilateral tDCS exhibited significantly greater learning relative to sham. The potential for tDCS to enhance the training of surgical skills, therefore, merits further investigation to determine if these preliminary results may be replicated and extended.

Chlorpromazine binding to the PAS domains uncovers the effect of ligand modulation on EAG channel activity.

Ether-a-go-go (EAG) potassium selective channels are major regulators of neuronal excitability and cancer progression. EAG channels contain a Per-Arnt-Sim (PAS) domain in their intracellular N-terminal region. The PAS domain is structurally similar to the PAS domains in non-ion channel proteins, where these domains frequently function as ligand-binding domains. Despite the structural similarity, it is not known whether the PAS domain can regulate EAG channel function via ligand binding. Here, using surface plasmon resonance, tryptophan fluorescence, and analysis of EAG currents recorded in Xenopus laevis oocytes, we show that a small molecule chlorpromazine (CH), widely used as an antipsychotic medication, binds to the isolated PAS domain of EAG channels and inhibits currents from these channels. Mutant EAG channels that lack the PAS domain show significantly lower inhibition by CH, suggesting that CH affects currents from EAG channels directly through the binding to the PAS domain. Our study lends support to the hypothesis that there are previously unaccounted steps in EAG channel gating that could be activated by ligand binding to the PAS domain. This has broad implications for understanding gating mechanisms of EAG and related ERG and ELK K+ channels and places the PAS domain as a new target for drug discovery in EAG and related channels. Up-regulation of EAG channel activity is linked to cancer and neurological disorders. Our study raises the possibility of repurposing the antipsychotic drug chlorpromazine for treatment of neurological disorders and cancer.

Corticomotor function is associated with quadriceps rate of torque development in individuals with ACL surgery.

Impaired corticomotor function arising from altered intracortical and corticospinal pathways are theorized to impede muscle recovery following anterior cruciate ligament (ACL) surgery, yet functional implications of centrally driven adaptations remain unclear. We aimed to assess relationships between quadriceps corticomotor and neuromechanical function after ACL surgery, and to compare with contralateral and control limbs. 16 individuals after primary, unilateral ACL surgery and 16 sex- and age-matched controls participated. Corticomotor function was assessed using transcranial magnetic stimulation, and quantified via active motor thresholds (AMT), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Neuromechanical function was quantified via electromechanical delay, early and late-phase rate of torque development (RTD0-50, RTD100-200), coefficient of variation, maximal voluntary isometric contraction (MVIC) torque, and central activation ratio. We observed significant correlations in the ACL limbs between: AMT and RTD0-50 (r = - 0.513, p = 0.031), SICI and RTD100-200 (r = 0.501, p = 0.048), AMT and SICI (r = - 0.659, p = 0.010), AMT and ICF (r = 0.579, p = 0.031), RTD0-50 and MVIC (r = 0.504, p = 0.023), and RTD100-200 and MVIC (r = 0.680, p = 0.002). The ACL limbs demonstrated higher AMT compared to controls (44.9 ± 8.4 vs. 30.1 ± 8.2%, p < 0.001), and lesser MVIC torque (2.37 ± 0.52 vs. 2.80 ± 0.59 Nm/kg, p = 0.005) and RTD100-200 (6.79 ± 1.72 vs. 7.90 ± 1.98 Nm/kg/s, p = 0.006) compared to the contralateral limbs. Our findings indicate that lesser corticospinal excitability is associated with lesser early-phase RTD, and greater intracortical inhibition is associated with lesser late-phase RTD. These findings provide evidence of implications of altered intracortical and corticospinal pathways relative to the ability to rapidly generate quadriceps torque following ACL surgery.

Application of oxytocin with low-level laser irradiation suppresses the facilitation of cortical excitability by partial ligation of the infraorbital nerve in rats: An optical imaging study.

The effects of current treatments for neuropathic pain are limited. Oxytocin is a novel candidate substance to relieve neuropathic pain, as demonstrated in various animal models with nerve injury. Low-level laser therapy (LLLT) is another option for the treatment of neuropathic pain. In this study, we quantified the effects of oxytocin or LLLT alone and the combination of oxytocin and LLLT on cortical excitation induced by electrical stimulation of the dental pulp using optical imaging with a voltage-sensitive dye in the neuropathic pain model with partial ligation of the infraorbital nerve (pl-ION). We applied oxytocin (OXT, 0.5 µmol) to the rat once on the day of pl-ION locally to the injured nerve. LLLT using a diode laser (810 nm, 0.1 W, 500 s, continuous mode) was performed daily via the skin to the injured nerve from the day of pl-ION to 2 days after pl-ION. Cortical responses to electrical stimulation of the mandibular molar pulp under urethane anesthesia were recorded 3 days after pl-ION. Both the amplitude and area of excitation in the primary and secondary somatosensory and insular cortices in pl-ION rats were larger than those in sham rats. The larger amplitude of cortical excitation caused by pl-ION was suppressed by OXT or LLLT. The expanded area of cortical excitation caused by pl-ION was suppressed by OXT with LLLT but not by OXT or LLLT alone. These results suggest that the combined application of OXT and LLLT is effective in relieving the neuropathic pain induced by trigeminal nerve injury.