Reduction In Cortical Inhibition Research Articles

Exploring the cortical habituation in migraine patients based on contingent negative variation.

Cognitive dysfunction has frequently been found in patients with migraine. The so-called contingent negative variation (CNV) and EEG power spectral densities may be the best choices to explore the underlining pathophysiology, such as cortical inhibition and habituation. Thirty migraine patients without aura and healthy controls matched for sex, age, and education were recruited separately for CNV recording. The amplitudes, latencies, and squares of different CNV components, such as oCNV, iCNV, tCNV, and PINV, were selected and analyzed. Behavioral data, such as manual reaction time (RT), were analyzed. We used the Person correlation coefficient R to analyze different ERP components in relation to clinical characteristics. A multiple regression analysis was conducted for the migraine group. Spectral analysis of EEG data from all channels using the fast Fourier transform (FFT). The migraine group had longer A-latency, C-latency, and iCNV-latency than the control group. The migraine group had higher iCNV-amplitude, oCNV-amplitude, and tCNV-amplitude than the control group, especially those located in the occipital area. The iCNV-square, oCNV-square, tCNV-square, or PINV-square in the migraine group was significantly larger than the control group. Different correlations were found between clinical characteristics and ERP components. The delta or theta activity in the migraine group was statistically lower than in the control group. Our study has revealed that migraine attacks may influence responsivity, pre-activation, habituation, and cortical inhibition not only on the behavioral level but also on the electrophysiological level. Abnormal changes in cortical habituation and inhibition can be interpreted as CNV components. Additionally, analyses have revealed correlations between CNV components and various factors, including age, the clinical course of the condition, attack frequency, pain intensity, and duration. Thus, repetitive migraine attacks can lead to a reduction in cortical inhibition and subsequent impairment in executive function.

In vivo mechanisms of cortical network dysfunction induced by systemic inflammation

Peripheral inflammation is known to impact brain function, resulting in lethargy, loss of appetite and impaired cognitive abilities. However, the channels for information transfer from the periphery to the brain, the corresponding signaling molecules and the inflammation-induced interaction between microglia and neurons remain obscure. Here, we used longitudinal in vivo two-photon Ca2+ imaging to monitor neuronal activity in the mouse cortex throughout the early (initiation) and late (resolution) phases of peripheral inflammation. Single peripheral lipopolysaccharide injection induced a substantial but transient increase in ongoing neuronal activity, restricted to the initiation phase, whereas the impairment of visual processing was selectively observed during the resolution phase of systemic inflammation. In the frontal/motor cortex, the initiation phase-specific cortical hyperactivity was seen in the deep (layer 5) and superficial (layer 2/3) pyramidal neurons but not in the axons coming from the somatosensory cortex, and was accompanied by reduced activity of layer 2/3 cortical interneurons. Moreover, the hyperactivity was preserved after depletion of microglia and in NLRP3−/− mice but absent in TNF-α−/− mice. Together, these data identify microglia-independent and TNF-α-mediated reduction of cortical inhibition as a likely cause of the initiation phase-specific cortical hyperactivity and reveal the resolution phase-specific impairment of sensory processing, presumably caused by activated microglia.

Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I.

Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/- -Lys). Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. SRS were observed in 72% of Gcdh-/- -Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/- -Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/- -Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/- -Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh-/- mice under high lysine diet (Gcdh-/- -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh-/- -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.

Effects of noise-induced hearing loss on parvalbumin and perineuronal net expression in the mouse primary auditory cortex

Noise induced hearing loss is associated with increased excitability in the central auditory system but the cellular correlates of such changes remain to be characterized. Here we tested the hypothesis that noise-induced hearing loss causes deterioration of perineuronal nets (PNNs) in the auditory cortex of mice. PNNs are specialized extracellular matrix components that commonly enwrap cortical parvalbumin (PV) containing GABAergic interneurons. Compared to somatosensory and visual cortex, relatively less is known about PV/PNN expression patterns in the primary auditory cortex (A1). Whether changes to cortical PNNs follow acoustic trauma remains unclear. The first aim of this study was to characterize PV/PNN expression in A1 of adult mice. PNNs increase excitability of PV+ inhibitory neurons and confer protection to these neurons against oxidative stress. Decreased PV/PNN expression may therefore lead to a reduction in cortical inhibition. The second aim of this study was to examine PV/PNN expression in superficial (I-IV) and deep cortical layers (V-VI) following noise trauma. Exposing mice to loud noise caused an increase in hearing threshold that lasted at least 30 days. PV and PNN expression in A1 was analyzed at 1, 10 and 30 days following the exposure. No significant changes were observed in the density of PV+, PNN+, or PV/PNN co-localized cells following hearing loss. However, a significant layer- and cell type-specific decrease in PNN intensity was seen following hearing loss. Some changes were present even at 1 day following noise exposure. Attenuation of PNN may contribute to changes in excitability in cortex following noise trauma. The regulation of PNN may open up a temporal window for altered excitability in the adult brain that is then stabilized at a new and potentially pathological level such as in tinnitus.

Isometric exercise induces analgesia and reduces inhibition in patellar tendinopathy

BackgroundFew interventions reduce patellar tendinopathy (PT) pain in the short term. Eccentric exercises are painful and have limited effectiveness during the competitive season. Isometric and isotonic muscle contractions may have...

Acute systemic LPS-mediated inflammation induces lasting changes in mouse cortical neuromodulation and behavior

Systemic lipopolysaccharide (LPS) is widely used to induce a neuroinflammatory response that is associated with short-term ‘sickness’-behavior that can include fever, loss of activity, loss of appetite, impaired cognition, anxiety and depression. If large enough or left unchecked, this neuroinflammatory response can become self-perpetuating and lead to long-term neurodegenerative processes. In this study, we assess the longer-term effects of a single systemic LPS injection on electrophysiological neuromodulator effects and basic behavioral analysis in mice. Five months after LPS injection, we find a mild reduction in cortical inhibition and altered temporal dynamics of acetylcholine but not norepinephrine or serotonin neuromodulator effects. Consistent with electrophysiological findings, LPS treated mice showed a deficit in memory performance in the novel object recognition test with no effect on measures of anxiety or despair as measured in the open field test and tail suspension test, respectively. Furthermore, LPS-treated mice showed an increase in acetylcholinesterase activity. As increased acetylcholinesterase activity is associated with reduced acetylcholine signaling and impaired cognitive ability, these studies demonstrate the potential for a single inflammatory event to initiate processes that may lead to long-term neurodegeneration.

Cortical inhibition is reduced following short-term training in young and older adults

The purpose of this study was to investigate age-related differences in short-term training adaptations in cortical excitability and inhibition. Thirty young (21.9 ± 3.1years) and 30 older (72.9 ± 4.6years) individuals participated in the study. Each participant was randomly assigned to a control (n = 30) or a resistance training (n = 30) group, with equal numbers of young and older subjects in each group. Participants completed 2days of testing, separated by 2weeks during which time the training group participated in resistance training of the ankle dorsiflexor muscles three times per week. During each testing session, transcranial magnetic stimulation was used to generate motor evoked potentials (MEPs) and silent periods in the tibialis anterior. Hoffmann reflexes (H-reflexes) and compound muscle action potentials (M-waves) were also evoked via electrical stimulation of the peroneal nerve. At baseline, young subjects had higher maximum voluntary contraction (MVC) force (p = 0.002), larger M-wave amplitude (p < 0.001), and longer duration silent periods (p = 0.01) than older individuals, with no differences in the maximal amplitude of the MEP (p = 0.23) or H-reflex (p = 0.57). In the trained group, MVC increased in both young (17.4%) and older (19.8%) participants (p < 0.001), and the duration of the silent period decreased by ~15 and 12ms, respectively (p < 0.001). Training did not significantly impact MEP (p = 0.69) or H-reflex amplitudes (p = 0.38). There were no significant changes in any measures in the control group (p ≥ 0.19) across the two testing sessions. These results indicate that a reduction in cortical inhibition may be an important neural adaptation in response to training in both young and older adults.

Corticomotor Responses to Attentionally Demanding Motor Performance: A Mini-Review

Increased attentional demand has been shown to reduce motor performance, leading to increases in accidents, particularly in elderly populations. While these deficits have been well documented behaviorally, their cortical correlates are less well known. Increased attention has been shown to affect activity in prefrontal regions of the cortex. However there have been varying results within past research investigating corticomotor regions, mediating motor performance. This mini-review initially discusses past behavioral research, before moving to studies investigating corticomotor areas in response to changes in attention. Recent dual task studies have revealed a possible decline in the ability of older, but not younger, adults to activate inhibitory processes within the motor cortex, which may be correlated with poor motor performance, and thus accidents. A reduction in cortical inhibition may be caused by neurodegeneration within prefrontal regions of the cortex with age, rendering older adults less able to allocate attention to corticomotor regions.

Understanding the mechanisms of neuromuscular fatigue with paired‐pulse stimulation

Transcranial magnetic stimulation (TMS), using both single and paired-pulse techniques, has provided insight in understanding the balance of excitation and inhibition within the corticomotor system during maximal and submaximal exercise. A single pulse of TMS produces a short-latency motor-evoked potential (MEP), indicating the net excitation of the motor pathway which includes the balance within supraspinal (cortical) and spinal sources. The MEP is followed by an interruption of ongoing electromyographic (EMG) activity known as the silent period. Classically, the silent period has been interpreted to represent the inhibition within the motor cortex (i.e. intracortical inhibition) which probably involves γ-aminobutyric acid (GABAB) receptors. Intracortical inhibition is clinically important to understand because chronic pain disorders (migraines) and psychiatric disorders (post-traumatic stress disorder) have demonstrated less cortical inhibition during a voluntary contraction while other disorders such as Parkinson's and Alzheimer's diseases have demonstrated abnormal corticospinal excitatory circuits at rest. Additionally, the fatigue-induced reduction in cortical inhibition may be related to the motor impairments during exercise. The alterations in the MEP and silent period during exercise indicate that the central nervous system (CNS) may necessitate increases in both excitatory and inhibitory activity during fatiguing contractions; however, the mechanisms underlying these effects are yet to be completely understood.

What Has Transcranial Magnetic Stimulation Taught Us About Neural Adaptations To Strength Training? A Brief Review

The evidence for neural mechanisms underpinning rapid strength increases has been investigated and discussed for over 30 years using indirect methods, such as surface electromyography, with inferences made toward the nervous system. Alternatively, electrical stimulation techniques such as the Hoffman reflex, volitional wave, and maximal wave have provided evidence of central nervous system changes at the spinal level. For 25 years, the technique of transcranial magnetic stimulation (TMS) has allowed for noninvasive supraspinal measurement of the human nervous system in a number of areas such as fatigue, skill acquisition, clinical neurophysiology, and neurology. However, it has only been within the last decade that this technique has been used to assess neural changes after strength training. The aim of this brief review is to provide an overview of TMS, discuss specific strength training studies that have investigated changes, after short-term strength training in healthy populations in upper and lower limbs, and conclude with further research suggestions and the application of this knowledge for the strength and conditioning coach.

A Transcranial Magnetic Stimulation Study of the Effects of Cannabis Use on Motor Cortical Inhibition and Excitability

Active compounds in cannabis such as tetrahydrocannabinol (THC) interact with the inhibitory neurotransmitter delta-aminobutyric acid (GABA) but little is known about the functional effects of cannabis on human cortical brain processes. Therefore, the aim of the study was to investigate whether patients with chronic cannabis use demonstrate abnormalities in cortical inhibition or excitability. In all, 42 chronic cannabis using subjects (divided into heavy and light using subjects) and 19 controls were included in the study. Single and paired pulse transcranial magnetic stimulation were used to assess a number of parameters of cortical inhibition and cortical excitability. In addition, psychomotor function and THC plasma levels were measured. Both cannabis using groups (heavy and light use) demonstrated a reduction in short interval cortical inhibition compared with healthy controls, but there was no difference in other measures of cortical inhibition or cortical excitability. There was also no difference between the two groups on measures of psychomotor performance. Chronic cannabis use is associated with a reduction in cortical inhibition potentially related to activity at the GABA(A) receptors. Further research is required to explore whether this results from chronic cannabis use or reflects an underlying predisposition to developing chronic substance use problems.

Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

Mutations in the GABA(A) receptor gamma2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a gamma2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of gamma2(R43Q) was seen in heterozygous mice in the absence of any change in alpha1 subunit surface expression, ruling out a dominant-negative effect. GABA(A)-mediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.

Different patterns of electrophysiological deficits in manifesting and non-manifesting carriers of the DYT1 gene mutation.

A mutation in the DYT1 gene on chromosome 9q34 causes early-onset primary torsion dystonia with autosomal dominant inheritance but low phenotypic penetrance. The aim of the present study was to assess the functional consequences of the DYT1 gene, by comparing the electrophysiology of cortical and spinal circuits in clinically affected and unaffected carriers of the DYT1 gene mutation. We assessed intracortical inhibition (ICI), intracortical facilitation (ICF), the cortical silent period (SP) and spinal reciprocal inhibition (RI) in 10 manifesting DYT1 gene carriers (MDYT1), seven non-manifesting DYT1 gene carriers (NMDYT1) and 13 healthy controls. The MDYT1 subjects had abnormalities similar to those seen in previous studies of non-genetically characterized individuals with primary dystonia. They had reduced ICI, shorter SP and absent presynaptic phase of RI compared with the healthy controls. NMDYT1 subjects also had a significant reduction in cortical inhibition (ICI and SP), but their spinal RI was not different from controls. We conclude that clinical expression of dystonia depends on widespread electrophysiological deficits, and the presence of the DYT1 gene mutation itself leads only to a subset of these changes. This is consistent with the hypothesis that additional environmental/genetic insults may be needed to reveal clinical symptoms in DYT1 gene carriers.

A transcranial magnetic stimulation study of inhibitory deficits in the motor cortex in patients with schizophrenia

It has been proposed that inhibitory deficits play a crucial role in the pathophysiological process of schizophrenia as suggested by post-mortem, neuropsychological and neurophysiological evidence. We hypothesised that patients with schizophrenia would demonstrate abnormalities of cortical inhibition in the motor cortex with single and paired pulse transcranial magnetic stimulation (TMS). Patients with DSM-IV schizophrenia ( n=22) and normal volunteers ( n=21) participated in the study. Electromyographic recordings from the abductor pollicis brevis (APB) muscle were made during focal TMS stimulation to the contra-lateral motor cortex. The threshold intensity to produce a motor response, the size of the motor evoked potential, the duration of the silent period, and the cortical inhibition and facilitation to paired pulse TMS were measured. The patient group demonstrated a reduction in length of the silent period and a reduction in cortical inhibition with paired stimuli. No changes were found in motor threshold, motor evoked potential size, or cortical facilitation. The study demonstrated deficits of cortical inhibition in the motor cortex of patients with schizophrenia. These deficits appear to be of cortical origin. Their relationship to dysfunction in other cortical networks requires further elucidation.

ECoG and breathing activity in fetal lambs after undercut of cerebral cortex.

Reduction of cortical inhibition has been suggested as a possible mechanism for the transition from episodic fetal to continuous postnatal breathing. Twelve fetal lambs were chronically decorticated at 112-115 days gestation. Lateral rectus, neck, and diaphragmatic electromyogram (EMG), electrocorticogram (ECoG), and tracheal and arterial blood pressure were monitored after allowing 3 days for recovery. The fetal lambs were studied for 4-28 days in 2- to 4-h sessions/day. There were no episodes of low-voltage high-frequency ECoG activity. The mean duration (+/- SD) of rapid eye movements (REM) measured by lateral rectus EMG [11 +/- 7.9 min and periods of tonic activity or silence [non-REM (NREM)], 14 +/- 7.4 min] in decorticated fetuses were not statistically different from REM (12 +/- 5.1 min) and NREM (15 +/- 6.8 min) sleep periods in intact fetuses. After decortication, the percentage of time (+/- SD) occupied by different states were phasic diaphragmatic EMG activity 36 +/- 7.8%, tonic diaphragmatic EMG 21 +/- 8.6%, and diaphragmatic silence 43 +/- 14.2%. Phasic diaphragmatic EMG activity occurred together with REM, the latter being present 45 +/- 3.7% of the time. Despite decortication, between 115 and 125 days gestation ECoG changed from a trace alternans to a high-voltage low-frequency pattern. We conclude that the cerebral cortex is not responsible for apnea during fetal life. In addition, these data suggest that the cerebral cortex may normally be the source of ECoG synchrony.