Intracortical Circuits Research Articles

Seizure pathways: A model-based investigation.

We present the results of a model inversion algorithm for electrocorticography (ECoG) data recorded during epileptic seizures. The states and parameters of neural mass models were tracked during a total of over 3000 seizures from twelve patients with focal epilepsy. These models provide an estimate of the effective connectivity within intracortical circuits over the time course of seizures. Observing the dynamics of effective connectivity provides insight into mechanisms of seizures. Estimation of patients seizure dynamics revealed: 1) a highly stereotyped pattern of evolution for each patient, 2) distinct sub-groups of onset mechanisms amongst patients, and 3) different offset mechanisms for long and short seizures. Stereotypical dynamics suggest that, once initiated, seizures follow a deterministic path through the parameter space of a neural model. Furthermore, distinct sub-populations of patients were identified based on characteristic motifs in the dynamics at seizure onset. There were also distinct patterns between long and short duration seizures that were related to seizure offset. Understanding how these different patterns of seizure evolution arise may provide new insights into brain function and guide treatment for epilepsy, since specific therapies may have preferential effects on the various parameters that could potentially be individualized. Methods that unite computational models with data provide a powerful means to generate testable hypotheses for further experimental research. This work provides a demonstration that the hidden connectivity parameters of a neural mass model can be dynamically inferred from data. Our results underscore the power of theoretical models to inform epilepsy management. It is our hope that this work guides further efforts to apply computational models to clinical data.

Verbal working memory modulates afferent circuits in motor cortex.

Verbal instruction and strategies informed by declarative memory are key to performance and acquisition of skilled actions. We previously demonstrated that anatomically distinct sensory-motor inputs converging on the corticospinal neurons of motor cortex are differentially sensitive to visual attention load. However, how loading of working memory shapes afferent input to motor cortex is unknown. This study used short-latency afferent inhibition (SAI) to probe the effect of verbal working memory upon anatomically distinct afferent circuits converging on corticospinal neurons in the motor cortex. SAI was elicited by preceding a suprathreshold transcranial magnetic stimulus (TMS) with electrical stimulation of the median nerve at the wrist while participants mentally rehearsed a two- or six-digit numeric memory set. To isolate different afferent intracortical circuits in motor cortex SAI was elicited, using TMS involving posterior-anterior (PA) or anterior-posterior (AP) monophasic current. Both PA and AP SAI were significantly reduced during maintenance of the six-digit compared to two-digit memory set. The generalized effect of working memory across anatomically distinct circuits converging upon corticospinal neurons in motor cortex is in contrast to the specific sensitivity of AP SAI to increased attention load. The common response across the PA and AP SAI circuits to increased working memory load may reflect an indiscriminate perisomatic mechanism involved in the voluntary facilitation of desired and/or suppression of unwanted actions during action selection or response conflict.

Imbalance of cortical facilitatory and inhibitory circuits underlies hyperexcitability in ALS.

To determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS). In this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits. There was a significant increase in SICF (ALS -18.51 ± 1.56%, controls -8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R 2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score (R 2 = 0.335, p = 0.002). The present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.

Effects of bilateral priming on motor cortex function in healthy adults.

Bilateral priming is a rehabilitation adjuvant that can improve upper limb motor recovery poststroke. It uses a table-top device to couple the upper limbs together such that active flexion and extension of one wrist leads to passive movement of the opposite wrist in a mirror symmetric pattern. Bilateral priming increases corticomotor excitability (CME) in the primary motor cortex (M1) of the passively driven wrist; however, the neurophysiological mechanisms underlying this increase remain unclear. This study explored these mechanisms by using transcranial magnetic stimulation over the right M1 and recording motor-evoked potentials from the passively driven left extensor carpi radialis of healthy adults. Intracortical measures were recorded before and 5 and 35 min after a single 15-min session of priming. One-millisecond short-interval intracortical inhibition, long-interval intracortical inhibition, late cortical disinhibition (LCD), and intracortical facilitation were recorded with a posterior-anterior (PA) intracortical current, whereas CME and short-interval intracortical facilitation (SICF) were recorded with both PA and anterior-posterior (AP) currents. CME with PA stimulation was also recorded ~1 h postpriming. PA CME was elevated 35 min postpriming and remained elevated ~1 h postpriming. LCD decreased, and AP SICF increased at both 5 and 35 min postpriming. However, these changes in LCD and AP SICF are unlikely to be the cause of the increased PA CME because of the differing timelines of their effects and AP and PA currents activating separate interneuron circuits. These results suggest that bilateral priming does not increase CME through alterations of the intracortical circuits investigated here. NEW & NOTEWORTHY This is the first study to measure how bilateral priming modulates corticomotor excitability with posterior-anterior and anterior-posterior intracortical currents, 1-ms short-interval intracortical inhibition, late cortical disinhibition, intracortical facilitation, and short-interval intracortical facilitation. We found corticomotor excitability with a posterior-anterior current increased by 35 min until ~1 h postpriming. Short-interval intracortical facilitation with an anterior-posterior current was greater for at least 35 min postpriming. This provides further insight into the neurophysiological mechanisms underlying bilateral priming.

Differences between motor execution and motor imagery of grasping movements in the motor cortical excitatory circuit.

BackgroundBoth motor imagery (MI) and motor execution (ME) can facilitate motor cortical excitability. Although cortical excitability is modulated by intracortical inhibitory and excitatory circuits in the human primary motor cortex, it is not clear which intracortical circuits determine the differences in corticospinal excitability between ME and MI.MethodsWe recruited 10 young healthy subjects aged 18−28 years (mean age: 22.1 ± 3.14 years; five women and five men) for this study. The experiment consisted of two sets of tasks involving grasp actions of the right hand: imagining and executing them. Corticospinal excitability and short-interval intracortical inhibition (SICI) were measured before the interventional protocol using transcranial magnetic stimulation (baseline), as well as at 0, 20, and 40 min (T0, T20, and T40) thereafter.ResultsFacilitation of corticospinal excitability was significantly greater after ME than after MI in the right abductor pollicis brevis (APB) at T0 and T20 (p < 0.01 for T0, and p < 0.05 for T20), but not in the first dorsal interosseous (FDI) muscle. On the other hand, no significant differences in SICI between ME and MI were found in the APB and FDI muscles. The facilitation of corticospinal excitability at T20 after MI correlated with the Movement Imagery Questionnaire (MIQ) scores for kinesthetic items (Rho = −0.646, p = 0.044) but did not correlate with the MIQ scores for visual items (Rho = −0.265, p = 0.458).DiscussionThe present results revealed significant differences between ME and MI on intracortical excitatory circuits of the human motor cortex, suggesting that cortical excitability differences between ME and MI may be attributed to the activation differences of the excitatory circuits in the primary motor cortex.

Intracortical facilitation within the migraine motor cortex depends on the stimulation intensity. A paired-pulse TMS study

IntroductionConnectivity within the primary motor cortex can be measured using the paired-pulse transcranial magnetic stimulation (TMS) paradigm. This evaluates the effect of a first conditioning stimulus on the motor evoked potential (MEP) elicited by a second test stimulus when different interstimulus intervals are used. Aim of the present study was to provide, in patients suffering from migraine without aura (MwoA), additional information on intracortical facilitation (ICF), short intracortical inhibition (SICI), and long intracortical inhibition (LICI), using different intensities of the test stimulus (TS).MethodsWe enrolled 24 patients with episodic MwoA and 24 age- and sex-matched healthy volunteers. Both patients and controls were randomly assigned to two different experimental groups: the first group underwent evaluation of ICF, while in the second group we assessed SICI and LICI. All these measures were assessed by using three different suprathreshold intensities of the TS (110%, 130% and 150% of the resting motor threshold, RMT). Interstimulus intervals (ISIs) of 10 ms were used for testing ICF, while SICI and LICI were carried out by using 2 ms and 100 ms ISIs respectively. All migraine patients underwent the experimental protocol while in the interictal pain-free state.ResultsA main finding of the study was that an increased ICF could be seen in migraineurs as compared to the healthy subjects only by using a 110% intensity of the TS. Instead, no significant differences were observed between patients and controls as regards both measures of intracortical inhibition.ConclusionWe show that hyperresponsivity of the glutamatergic intracortical circuits can be detected in the migraine motor cortex only by applying a low suprathreshold intensity of stimulation. Our results strengthen the notion that, to be reliable, the assessment of cortical excitability in migraine should always include evaluation of the cortical response to different stimulation intensities.

Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease with Transcranial Magnetic Stimulation.

Considering the increasing evidence that disease-modifying treatments for Alzheimer's disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia. To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI). A sample of 69 subjects with MCI were included and classified as AD MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed. We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%. The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis.

Non-invasive Brain Stimulation: Probing Intracortical Circuits and Improving Cognition in the Aging Brain.

The impact of cognitive aging on brain function and structure is complex, and the relationship between aging-related structural changes and cognitive function are not fully understood. Physiological and pathological changes to the aging brain are highly variable, making it difficult to estimate a cognitive trajectory with which to monitor the conversion to cognitive decline. Beyond the information on the structural and functional consequences of cognitive aging gained from brain imaging and neuropsychological studies, non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can enable stimulation of the human brain in vivo, offering useful insights into the functional integrity of intracortical circuits using electrophysiology and neuromodulation. TMS measurements can be used to identify and monitor changes in cortical reactivity, the integrity of inhibitory and excitatory intracortical circuits, the mechanisms of long-term potentiation (LTP)/depression-like plasticity and central cholinergic function. Repetitive TMS and tDCS can be used to modulate neuronal excitability and enhance cortical function, and thus offer a potential means to slow or reverse cognitive decline. This review will summarize and critically appraise relevant literature regarding the use of TMS and tDCS to probe cortical areas affected by the aging brain, and as potential therapeutic tools to improve cognitive function in the aging population. Challenges arising from intra-individual differences, limited reproducibility, and methodological differences will be discussed.

Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury.

The plasticity of sensorimotor systems in mammals underlies the capacity for motor learning as well as the ability to relearn following injury. Spinal cord injury, which both deprives afferent input and interrupts efferent output, results in a disruption of cortical somatotopy. While changes in corticospinal axons proximal to the lesion are proposed to support the reorganization of cortical motor maps after spinal cord injury, intracortical horizontal connections are also likely to be critical substrates for rehabilitation-mediated recovery. Intrinsic connections have been shown to dictate the reorganization of cortical maps that occurs in response to skilled motor learning as well as after peripheral injury. Cortical networks incorporate changes in motor and sensory circuits at subcortical or spinal levels to induce map remodeling in the neocortex. This review focuses on the reorganization of cortical networks observed after injury and posits a role of intracortical circuits in recovery.

TDCS effects on cortical excitability in multiple sclerosis fatigue

Objectives Fatigue could affect up to 90% of patients with multiple sclerosis (MS) [1] . Facing the modest benefits and numerous side effects of pharmacological therapies, transcranial direct current stimulation (tDCS) has recently emerged as an appealing tool to treat several neuropsychiatric complaints, including MS fatigue [3] . Previous tDCS protocols did not assess long-term effects of tDCS on MS fatigue, neither did they investigate its potential mechanism of action in this context. Methods We hereby present the case of a 37-year-old MS patient who sought medical attention for debilitating fatigue. The patient has previously participated in a sham-controlled tDCS trial and was found to be among responders to real but not sham stimulation [3] . At presentation, he did not have secondary causes of fatigue. The protocol lasted for 9 weeks (5 consecutive daily sessions in week 1; 4 sessions per week in week 2 and 3; 3 sessions in week 4; 2 sessions in week 5; 1 session in week 6 and a follow-up in week 9). We tested tDCS effects over fatigue as well as other neuropsychological symptoms. Cortical excitability measures were obtained at baseline [2] and then at the end of week 1, week 3 and week 6. Results tDCS resulted in a significant improvement of fatigue which was obtained after the first week, but the most important anti-fatigue effects were documented after week 5. This effect was paralleled by amelioration of cognition and mood scores as well as changes in cortical excitability parameters (increase in short-interval intracortical inhibition and decrease in short-interval intracortical facilitation). Conclusion This is the first report that presents long-term assessment of tDCS effects in the context of fatigue and other MS-related symptoms. Left prefrontal tDCS appears to improve MS fatigue and seems to have a modulatory effect on inhibitory and facilitatory intracortical circuits.

T51. TMS evaluation in cognitive impaired patients according to new criteria for AD

Alzheimer‘s disease (AD) is characterized by loss of synaptic connections, cell death and disruption of structural and functional networks. One of the most consistent findings is the impairment of cortical plasticity, especially Long Term Potentiation (LTP) mechanisms. Recently, the use of a new lexicon and new diagnostic criteria allowed to considered AD as a clinico-biological entity identifiable in vivo on the presence of biomarkers. In light of the new lexicon and the new diagnostic criteria, aim of the current work is to investigate cortical plasticity in cognitive impaired (CI) patients admitted for the first time in the memory clinic and stratified according to CSF biomarker profile; moreover we followed patients up to a period of three years to explore the relationship between neurophysiological, neuropsychological and CSF biomarker and clinical progression. Seventy-one consecutive patients recruited at the memory clinic admitted for their first visit for complaining memory symptoms and underwent CSF sampling. Then they undertake TMS examination, investigating mechanisms of long term potentiation (LTP) with intermittent Theta Busrt Stimluation (iTBS) and intracortical circuits. Patients were followed longitudinally with MMSE testing up to 36 months. According to the new criteria AD proposed we divided CI patients in basis of evidence ofin vivobiomarkers (as assessed by CSF analysis) and the presence of dementia. Resulting in three groups: (1) Mild Cognitive Impaired (MCI) patients (n = 22); Prodromal AD (PROAD) patients (n = 25); AD Dementia (ADD) patients (n = 25). Univariate regression analyses were performed to characterize the association between each clinical and neurophysiological variable with clinical progression (delta MMSE score at 36 months respect to baseline). A control group of 23 healthy subjects (HS) was recruited for control. For neurophysiological evaluations only iTBS protocol was different among the different groups showing a paradoxical reversal of LTP for ADD and PROAD and a poor response for MCI patients. ProAD worsened faster than MCI. Regression analyses showed that LTP impairment was related to clinical progression. Kaplan-Meyer analyses showed that CI patients expressing the worst LTP values were the ones to progress faster in a 3 year time. the new criteria based on the presence of biomarkers and dementia allow us to identify CI patients at a prodromal stage that will develop dementia due to AD. LTP impairment drives the clinical progression in CI patients at prodromal stages even without evidence of biomarker positivity, confirming its pivotal role in determining cognitive decline.

Acute intermittent hypoxia enhances corticospinal synaptic plasticity in humans

Acute intermittent hypoxia (AIH) enhances voluntary motor output in humans with central nervous system damage. The neural mechanisms contributing to these beneficial effects are unknown. We examined corticospinal function by evaluating motor evoked potentials (MEPs) elicited by cortical and subcortical stimulation of corticospinal axons and the activity in intracortical circuits in a finger muscle before and after 30 min of AIH or sham AIH. We found thatthe amplitude of cortically and subcortically elicited MEPs increased for 75 min after AIH but not sham AIH while intracortical activity remained unchanged. To examine further these subcortical effects, we assessed spike-timingdependent plasticity (STDP) targeting spinal synapses and the excitability of spinal motoneurons. Notably, AIH increased STDP outcomes while spinal motoneuron excitability remained unchanged. Our results provide the first evidence that AIH changes corticospinal function in humans, likely by altering corticospinal-motoneuronal synaptic transmission. AIH may represent a novel noninvasive approach for inducing spinal plasticity in humans.

Physiological Processes Underlying Short Interval Intracortical Facilitation in the Human Motor Cortex

Short interval intracortical facilitation (SICF) may be elicited by a paired pulse transcranial magnetic stimulation (TMS) paradigm, whereby a suprathreshold first stimulus (S1) precedes a perithreshold second stimulus (S2). Other facilitatory circuits can be probed by TMS such as intracranial facilitation, however the cortical contributions to these circuits may lie partially outside of M1. SICF as such represents a unique analog to M1 inhibitory circuits such as short interveal intracortical circuits. The aim of the present study was to provide insight into the physiological processes underlying the development of SICF using the threshold tracking TMS technique which was recently demonstrated to have significant reliability. TMS studies were undertaken on 35 healthy controls, using either a 90 mm circular and 70 mm figure of eight coil, and one of two targets (0.2 and 1.0 mV) tracked. The motor evoked potential (MEP) responses were recorded from the abductor pollicis brevis. SICF was consistently evident between interstimulus intervals (ISI) of 1–5 ms (P < 0.001), with two peaks occurring ISIs 1.5 and 3 ms when using the circular coil. A significant SICF reduction (F = 5.631, P < 0.05) was evident with the higher tracking target, while SICF increased when stimulating with the figure of eight coil. While there was a correlation between SICF and CSP duration, there was no relationship between SICF and SICI or ICF. Age appeared to have no influence on SICF, SICI, or ICF. Findings from the present work suggest that SICF appears to be mediated by I-wave facilitation.

Neural Correlates to the Increase in Maximal Force after Dexamethasone Administration.

This study investigated the effects of short-term glucocorticoid administration on voluntary activation and intracortical inhibitory and facilitatory circuits. Seventeen healthy men participated in a pseudorandomized double-blind study to receive either dexamethasone (8 mg·d, n = 9 subjects) or placebo (n = 8 subjects) for 7 d. The ankle dorsiflexion torque, corresponding EMG of the tibialis anterior, and voluntary activation assessed by the interpolated twitch method using transcranial magnetic stimulation (TMS) were measured during a maximal voluntary contraction (MVC). Short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed at rest and during submaximal contraction (50% MVC torque) by paired-pulse TMS with the conditioning stimulus set at 0.8× of motor threshold and delivered 2 ms (SICI) and 13 ms (ICF) before the test stimulus (1.2× motor threshold). The MVC torque (+14%), tibialis anterior EMG (+31%), and voluntary activation (+3%) increased after glucocorticoid treatment (P < 0.05). The increase in voluntary activation was associated with the gain in MVC torque (r = 0.56; P = 0.032). The level of SICI and the duration of the EMG silent period that followed the test TMS decreased (-18.6% and -13.5%, respectively) during the 50% MVC after treatment (P < 0.05), whereas no significant change was observed for ICF. Neither SICI nor ICF changed after treatment when assessed at rest. Short-term dexamethasone treatment induced specific decrease in the excitability of intracortical inhibitory circuits that likely contributed to the increase in the voluntary activation and associated MVC torque.

Chapter 4 - Somatosensory maps

Somatosensory areas containing topographic maps of the body surface are a major feature of parietal cortex. In primates, parietal cortex contains four somatosensory areas, each with its own map, with the primary cutaneous map in area 3b. Rodents have at least three parietal somatosensory areas. Maps are not isomorphic to the body surface, but magnify behaviorally important skin regions, which include the hands and face in primates, and the whiskers in rodents. Within each map, intracortical circuits process tactile information, mediate spatial integration, and support active sensation. Maps may also contain fine-scale representations of touch submodalities, or direction of tactile motion. Functional representations are more overlapping than suggested by textbook depictions of map topography. The whisker map in rodent somatosensory cortex is a canonic system for studying cortical microcircuits, sensory coding, and map plasticity. Somatosensory maps are plastic throughout life in response to altered use or injury. This chapter reviews basic principles and recent findings in primate, human, and rodent somatosensory maps.

Discrimination of atypical parkinsonisms with transcranial magnetic stimulation

BackgroundDifferential diagnosis of atypical parkinsonian disorders, i.e. dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) still remains problematic. Furthermore, DLB may overlap with Alzheimer's disease (AD) in the early stages of disease. ObjectiveTo determine whether transcranial magnetic stimulation (TMS) can be used to classify atypical parkinsonian disorders and AD. MethodsA paired-pulse TMS multi-paradigm approach assessing multiple intracortical circuits, as short interval intracortical inhibition-facilitation and short latency afferent inhibition, was used to model a decision tree analysis and determine diagnostic accuracy in classifying different neurodegenerative disorders. ResultsWe observed a significant impairment in short latency afferent inhibition in AD and DLB and a significant impairment in short interval intracortical inhibition-facilitation in DLB, PSP and CBS patients. These parameters were used to model a decision tree analysis which yielded an overall diagnostic accuracy of 88.3%, with 90.5% for AD, 85.2% for DLB, 76.0% for CBS-PSP, and 94.9% for healthy controls. ConclusionsThe assessment of intracortical connectivity with TMS may aid in the differential diagnosis of AD and the atypical parkinsonian disorders.

Transient Hypoxemia Chronically Disrupts Maturation of Preterm Fetal Ovine Subplate Neuron Arborization and Activity.

Preterm infants are at risk for a broad spectrum of neurobehavioral disabilities associated with diffuse disturbances in cortical growth and development. During brain development, subplate neurons (SPNs) are a largely transient population that serves a critical role to establish functional cortical circuits. By dynamically integrating into developing cortical circuits, they assist in consolidation of intracortical and extracortical circuits. Although SPNs reside in close proximity to cerebral white matter, which is particularly vulnerable to oxidative stress, the susceptibility of SPNs remains controversial. We determined SPN responses to two common insults to the preterm brain: hypoxia-ischemia and hypoxia. We used a preterm fetal sheep model using both sexes that reproduces the spectrum of human cerebral injury and abnormal cortical growth. Unlike oligodendrocyte progenitors, SPNs displayed pronounced resistance to early or delayed cell death from hypoxia or hypoxia-ischemia. We thus explored an alternative hypothesis that these insults alter the maturational trajectory of SPNs. We used DiOlistic labeling to visualize the dendrites of SPNs selectively labeled for complexin-3. SPNs displayed reduced basal dendritic arbor complexity that was accompanied by chronic disturbances in SPN excitability and synaptic activity. SPN dysmaturation was significantly associated with the level of fetal hypoxemia and metabolic stress. Hence, despite the resistance of SPNs to insults that trigger white matter injury, transient hypoxemia disrupted SPN arborization and functional maturation during a critical window in cortical development. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in cerebral growth and maturation related to SPN dysmaturation.SIGNIFICANCE STATEMENT The human preterm brain commonly sustains blood flow and oxygenation disturbances that impair cerebral cortex growth and cause life-long cognitive and learning disabilities. We investigated the fate of subplate neurons (SPNs), which are a master regulator of brain development that plays critical roles in establishing cortical connections to other brain regions. We used a preterm fetal sheep model that reproduces key features of brain injury in human preterm survivors. We analyzed the responses of fetal SPNs to transient disturbances in fetal oxygenation. We discovered that SPNs are surprisingly resistant to cell death from low oxygen states but acquire chronic structural and functional changes that suggest new strategies to prevent learning problems in children and adults that survive preterm birth.

Valeriana officinalis Root Extract Modulates Cortical Excitatory Circuits in Humans

Background:Valeriana officinalis extract (VE) is a popular herbal medicine used for the treatment of anxiety and sleep disorders. Although the anxiolytic and sedative effects are mainly attributed to the modulation of GABA-ergic transmission, the mechanism of action has not been fully investigated in humans. Noninvasive brain stimulation protocols can be used to elucidate the mechanisms of action of psychoactive substances at the cortical level in humans. In this study, we investigated the effects of a single dose of VE on cortical excitability as assessed with transcranial magnetic stimulation (TMS). Methods: Fifteen healthy volunteers participated in a double-blind, randomized, cross-over, placebo-controlled study. Subjects were required to take either 900 mg of VE (valerenic acid 0.8%) or placebo (an equal dose of vitamin E). Motor cortex excitability was studied by single and paired TMS before and at 1 h and 6 h after the oral administration. Cortical excitability was assessed using different TMS parameters: resting motor threshold, motor-evoked potential amplitude, cortical silent period, short-interval intracortical inhibition, and intracortical facilitation. Furthermore, we assessed sensorimotor integration by short-latency and long-latency afferent inhibition. Results: We found a significant reduction in ICF, without any significant changes in other TMS measures of motor cortex excitability. The amount of ICF returned to baseline value 6 h after the intake of the VE. Conclusion: A single oral dose of VE modulates intracortical facilitatory circuits. Our results in healthy subjects could be predictive markers of treatment response in patients and further support the use of pharmaco-TMS to investigate the neuropsychiatric effects of herbal therapies in humans.

Active and resting motor threshold are efficiently obtained with adaptive threshold hunting.

Transcranial magnetic studies typically rely on measures of active and resting motor threshold (i.e. AMT, RMT). Previous work has demonstrated that adaptive threshold hunting approaches are efficient for estimating RMT. To date, no study has compared motor threshold estimation approaches for measures of AMT, yet this measure is fundamental in transcranial magnetic stimulation (TMS) studies that probe intracortical circuits. The present study compared two methods for acquiring AMT and RMT: the Rossini-Rothwell (R-R) relative-frequency estimation method and an adaptive threshold-hunting method based on maximum-likelihood parameter estimation by sequential testing (ML-PEST). AMT and RMT were quantified via the R-R and ML-PEST methods in 15 healthy right-handed participants in an experimenter-blinded within-subject study design. AMT and RMT estimations obtained with both the R-R and ML-PEST approaches were not different, with strong intraclass correlation and good limits of agreement. However, ML-PEST required 17 and 15 fewer stimuli than the R-R method for the AMT and RMT estimation, respectively. ML-PEST is effective in reducing the number of TMS pulses required to estimate AMT and RMT without compromising the accuracy of these estimates. Using ML-PEST to estimate AMT and RMT increases the efficiency of the TMS experiment as it reduces the number of pulses to acquire these measures without compromising accuracy. The benefits of using the ML-PEST approach are amplified when multiple target muscles are tested within a session.

Rapid plasticity of visually evoked responses in rat monocular visual cortex.

Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs.