Modulation Of Cortical Inhibition Research Articles

Cortical inhibition in neurofibromatosis type 1 is modulated by lovastatin, as demonstrated by a randomized, triple-blind, placebo-controlled clinical trial

Neurofibromatosis type 1 (NF1) is associated with GABAergic dysfunction which has been suggested as the underlying cause of cognitive impairments. Previous intervention trials investigated the statins’ effects using cognitive outcome measures. However, available outcome measures have led to inconclusive results and there is a need to identify other options. Here, we aimed at investigating alternative outcome measures in a feasibility trial targeting cortical inhibition mechanisms known to be altered in NF1. We explored the neurochemical and physiological changes elicited by lovastatin, with magnetic resonance spectroscopy and transcranial magnetic stimulation (TMS). Fifteen NF1 adults participated in this randomized, triple-blind, placebo-controlled crossover trial (Clinicaltrials.gov NCT03826940) composed of one baseline and two reassessment visits after lovastatin/placebo intake (60 mg/day, 3-days). Motor cortex GABA+ and Glx concentrations were measured using HERMES and PRESS sequences, respectively. Cortical inhibition was investigated by paired-pulse, input–output curve, and cortical silent period (CSP) TMS protocols. CSP ratios were significantly increased by lovastatin (relative: p = 0.027; absolute: p = 0.034) but not by placebo. CSP durations showed a negative correlation with the LICI 50 ms amplitude ratio. Lovastatin was able to modulate cortical inhibition in NF1, as assessed by TMS CSP ratios. The link between this modulation of cortical inhibition and clinical improvements should be addressed by future large-scale studies.

Older Adults Differentially Modulate Transcranial Magnetic Stimulation–Electroencephalography Measures of Cortical Inhibition during Maximal Single-joint Exercise

The effects of muscle fatigue are known to be altered in older adults, and age-related changes in the brain are likely to be a contributing factor. However, the neural mechanisms underlying these changes are not known. The aim of the current study was to use transcranial magnetic stimulation combined with electroencephalography (TMS–EEG) to investigate age-related changes in cortical excitability with muscle fatigue. In 23 young (mean age ± SD: 22 ± 2 years) and 17 older (mean age ± SD: 68.3 ± 5.6 years) adults, single-pulse TMS–EEG was applied before, during and after the performance of fatiguing, intermittent isometric abduction of the index finger. Motor-evoked potential (MEP) measures of cortical excitability were increased during (estimated mean difference, 123.3%; P < 0.0001) and after (estimated mean difference, 117.5%; P = 0.001) fatigue and this was not different between groups (P > 0.5). For TMS–EEG, the amplitude of the P30 and P180 potentials were unaffected by fatigue in older participants (P > 0.05). In contrast, the amplitude of the N45 potential in older adults was significantly reduced both during (positive cluster: mean voltage difference = 0.7 µV, P < 0.005; negative cluster: mean voltage difference = 0.9 µV, P < 0.0005) and after (mean voltage difference = 0.5 µV, P < 0.005) fatiguing exercise, whereas this response was absent in young participants. These results suggest that performance of maximal intermittent isometric exercise in old but not young adults is associated with modulation of cortical inhibition likely mediated by activation of gamma-aminobutyric acid type A receptors.

Assessment and modulation of cortical inhibition using transcranial magnetic stimulation

Abstract:Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique, which is used for diagnostic, therapeutic and scientific purposes in the field of neurology and psychiatry. It is based on the physical principle of electromagnetic induction and allows for the local activation of cortical areas through the intact skull of conscious humans. When applied repeatedly (repetitive TMS; rTMS) sustained changes of cortical excitability can be observed. Hence, TMS resembles a promising approach for assessing and modulating neuronal networks in a non-invasive manner. However, despite its broad clinical application, the cellular and molecular mechanisms of rTMS-based therapies remain not well understood. Established therapeutic concepts assume that pathologically altered cortical excitability is normalised, which may involve ‘long-term potentiation’ or ‘long-term depression’ of excitatory synapses. Indeed, animal studies demonstrate that rTMS induces long-term changes of excitatory neurotransmission. However, it is unclear through which mechanisms synaptic changes, which are caused by external electromagnetic activation of the cortex and therefore are not specific for context or behaviour, could have a positive impact on complex brain function. More recent findings suggest that not only excitatory but also inhibitory neuronal networks are modulated by rTMS. It was shown for example that 10 Hz rTMS leads to a calcium-dependent long-term depression of inhibitory GABAergic synapses. Since the reduction of inhibitory neurotransmission (= disinhibition) is considered important for the expression of associative plasticity at excitatory synapses, it is conceivable that rTMS-induced disinhibition may promote context- and behaviour-specific synaptic changes. Hence, the model of

Repetition suppression in transcranial magnetic stimulation-induced motor-evoked potentials is modulated by cortical inhibition

Transcranial magnetic stimulation (TMS) can be applied to modulate cortical phenomena. The modulation effect is dependent on the applied stimulation frequency. Repetition suppression (RS) has been demonstrated in the motor system using TMS with short suprathreshold 1-Hz stimulation trains repeated at long inter-train intervals. RS has been reported to occur in the resting motor-evoked potentials (MEPs) with respect to the first pulse in a train of stimuli. Although this RS in the motor system has been described in previous studies, the neuronal origin of the phenomenon is still poorly understood. The present study evaluated RS in three TMS-induced motor responses; resting and active MEPs as well as corticospinal silent periods (SPs) in order to clarify the mechanism behind TMS-induced RS. We studied 10 healthy right-handed subjects using trains of four stimuli with stimulation intensities of 120% of the resting motor threshold (rMT) and 120% of the silent period threshold for an SP duration of 30ms (SPT30). Inter-trial interval was 20s, with a 1-s inter-stimulus interval within the trains. We confirmed that RS appears in resting MEPs (p<0.001), whereas active MEPs did not exhibit RS (p>0.792). SPs, on the contrary, lengthened (p<0.001) indicating modulation of cortical inhibition. The effects of the two stimulation intensities exhibited a similar trend; however, the SPT30 evoked a more profound inhibitory effect compared to that achieved by rMT. Moreover, the resting MEP amplitudes and SP durations correlated (rho⩽−0.674, p<0.001) and the pre-TMS EMG level did not differ between stimuli in resting MEPs (F=0.0, p⩾0.999). These results imply that the attenuation of response size seen in resting MEPs might originate from increasing activity of inhibitory GABAergic interneurons which relay the characteristics of SPs.

IS 9. Modulation of cortical inhibition by rTMS-a rat model

Introduction Human cortical excitability can be modified by repetitive transcranial magnetic stimulation (rTMS) but the factors that determine the direction of change remain still elusive. Classical forms of synaptic plasticity and metaplastic processes like homeostatic synaptic scaling and priming-dependent synaptic plasticity are possible mechanistic scenarios. Although the activity of excitatory neurons finally represents the degree of cortical activation, a multitude of inhibitory cortical systems governs about magnitude and pattern of cortical activity and the degree of plasticity allowed without loosing essential excitation-inhibition balance. It is thus likely that rTMS-induced changes in cortical excitability are associated with changes in cortical inhibition and that classes of interneurons differently contribute. Objectives We established a rat model of rTMS enabling to study cellular effects of rTMS in more detail and with possible relation to behavioural changes. To focus on changes in inhibitory cortical activity, we studied the expression of certain activity markers which are specific to inhibitory neurons in general, like the two isoforms of the glutamic acid decarboxylase GAD65 and GAD67, or relate to a certain class of interneurons, like the expression of the calcium-binding proteins parvalbumin (PV), calbindin (CB) and calretinin (CR). Our recent studies focus on the temporal dynamics of these activity markers which is of particular interest in case of combining rTMS with other artificial or natural interventions or repeated rTMS. Materials and methods Adult male Sprague–Dawley rats ( n = 42.15 weeks old) were trained to tolerate the procedure of manual restrain and rTMS without signs of stress before receiving a single block (600 pulses) of either verum or sham intermittent theta-burst stimulation protocol (iTBS) at an intensity just subthreshold for evoking motor responses (MagStim rapid, 70 mm figure-of-eight coil). Then, rat were deeply anesthetized and perfused at different intervals post-rTMS (10, 20, 40, 80, 160 min) for immunohistochemical analysis of neuronal activity marker expression (GAD65/67, PV, CB for inhibitory neurons; c-Fos and zif268 mainly for excitatory neurons). Results Three phases of changes in neuronal activity marker expression could be distinguished: an early phase (10–20 min) of strongly increased c-Fos and GAD65 expression, a following phase (40–80 min) of reduced GAD67, PV and CB expression and a late phase (>160 min) of reduced c-Fos and GAD65 expression. Conclusion Early increased levels of c-Fos and GAD65 indicate a strong co-activation of excitatory and inhibitory neurons due to iTBS. The delayed decrease in GAD67, PV and CB expression indicates a secondary depression of activity of inhibitory neurons without signs of increased excitatory activity (c-Fos, zif268). The late decrease in c-Fos and GAD65 finally indicates a matched reduction in the activity of both excitatory and inhibitory activities. Obviously, excitation-inhibition balance is never violated but the phases of changed synaptic (GAD65) and somatic (GAD67, PV, CB) inhibitory neuron activity to not co-vary in time. This study has been supported by the Deutsche Forschungsgemeinschaft, DFG (FU 256/3-2, SFB 874, TP A4).

Modulation of cortical inhibition by rTMS – findings obtained from animal models

Transcranial magnetic stimulation (TMS) has become a popular method to non-invasively stimulate the human brain. The opportunity to modify cortical excitability with repetitive stimulation (rTMS) has especially gained interest for its therapeutic potential. However, details of the cellular mechanisms of the effects of rTMS are scarce. Currently favoured are long-term changes in the efficiency of excitatory synaptic transmission, with low-frequency rTMS depressing it, but high-frequency rTMS augmenting. Only recently has modulation of cortical inhibition been considered as an alternative way to explain lasting changes in cortical excitability induced by rTMS. Adequate animal models help to highlight stimulation-induced changes in cellular processes which are not assessable in human rTMS studies. In this review article, we summarize findings obtained with our rat models which indicate that distinct inhibitory cell classes, like the fast-spiking cells characterized by parvalbumin expression, are most sensitive to certain stimulation protocols, e.g. intermittent theta burst stimulation. We discuss how our findings can support the recently suggested models of gating and homeostatic plasticity as possible mechanisms of rTMS-induced changes in cortical excitability.