Abstract Background In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. ...Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. Objective To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. Findings Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. Conclusions This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.
Transcranial direct current stimulation (tDCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain, and it is increasingly used in experimental and clinical ...settings. Recent studies suggest that the after-effects of tDCS are related to molecular mechanisms of activity-dependent synaptic plasticity. Here we investigated the effect of DCS on the induction of one of the most studied N-methyl-d-aspartate receptor-dependent forms of long-term potentiation (LTP) of synaptic activity at CA3-CA1 synapses in the hippocampus. We show that DCS applied to rat brain slices determines a modulation of LTP that is increased by anodal and reduced by cathodal DCS. Immediate early genes, such as c-fos and zif268 (egr1/NGFI-A/krox24), are rapidly induced following neuronal activation, and a specific role of zif268 in the induction and maintenance of LTP has been demonstrated. We found that both anodal and cathodal DCS produce a marked subregion-specific increase in the expression of zif268 protein in the cornus ammonis (CA) region, whereas the same protocols of stimulation produce a less pronounced increase in c-fos protein expression in the CA and in dentate gyrus regions of the hippocampus. Brain-derived neurotrophic factor expression was also investigated, and it was found to be reduced in cathodal-stimulated slices. The present data demonstrate that it is possible to modulate LTP by using DCS and provide the rationale for the use of DCS in neurological diseases to promote the adaptive and suppress the maladaptive forms of brain plasticity.
Repetitive transcranial magnetic stimulation (rTMS) of human motor cortex can produce long-lasting changes in the excitability of excitatory and inhibitory neuronal networks. The effects of rTMS ...depend critically on stimulus frequency. The aim of our present study was to compare the effects of different rTMS protocols. We compared the aftereffects of 6 different rTMS protocols paired associative stimulation at interstimulus intervals of 25 (PAS(25)) and 10 ms (PAS(10)); theta burst stimulation delivered as continuous (cTBS) or intermittent delivery pattern (iTBS); 1- and 5-Hz rTMS on the excitability of stimulated and contralateral motor cortex in 10 healthy subjects. A pronounced increase of cortical excitability, evaluated by measuring the amplitude of motor evoked potentials (MEPs), was produced by iTBS (+56%) and PAS(25) (+45%). Five-hertz rTMS did not produce a significant increase of MEPs. A pronounced decrease of cortical excitability was produced by PAS(10) (-31%), cTBS (-29%), and 1-Hz rTMS (-20%). Short-interval intracortical inhibition was suppressed by PAS(10). Cortical silent period duration was increased by 1-Hz stimulation. No significant effect was observed in the contralateral hemisphere. Head-to-head comparison of the different protocols enabled us to identify the most effective paradigms for modulating the excitatory and inhibitory circuits activated by TMS.
To determine whether aging is associated with changes in excitability of the cerebral cortex, we evaluated the excitability of the motor cortex with transcranial magnetic stimulation (TMS). We ...compared TMS related measures obtained in a group of young people with those of a group of old people. Motor evoked potential (MEP) amplitude was significantly smaller in older than in younger controls (1.3
±
0.8
mV versus 2.7
±
1.1
mV;
p
<
0.0071). Mean cortical silent period (CSP) duration was shorter in older than in younger controls (87
±
29
ms versus 147
±
39
ms;
p
<
0.0071). SP duration/MEP amplitude ratios were similar in both groups. Our results are consistent with an impaired efficiency of some intracortical circuits in old age.
In four conscious patients who had electrodes implanted in the cervical epidural space for the control of pain, we recorded
corticospinal volleys evoked by single-pulse transcranial magnetic ...stimulation (TMS) over the motor cortex before and after
a 20 s period of continuous theta-burst stimulation (cTBS). It has previously been reported that this form of repetitive TMS
reduces the amplitude of motor-evoked potentials (MEPs), with the maximum effect occurring at 5â10 min after the end of stimulation.
The present results show that cTBS preferentially decreases the amplitude of the corticospinal I1 wave, with approximately
the same time course. This is consistent with a cortical origin of the effect on the MEP. However, other protocols that lead
to MEP suppression, such as short-interval intracortical inhibition, are characterized by reduced excitability of late I waves
(particularly I3), suggesting that cTBS suppresses MEPs through different mechanisms, such as long-term depression in excitatory
synaptic connections.
Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (TMS). When applied to motor cortex
it leads to after-effects on corticospinal and corticocortical excitability ...that may reflect LTP/LTD-like synaptic effects.
An inhibitory form of TBS (continuous, cTBS) suppresses MEPs, and spinal epidural recordings show this is due to suppression
of the I1 volley evoked by TMS. Here we investigate whether the excitatory form of TBS (intermittent, iTBS) affects the same
I-wave circuitry. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after iTBS in
three conscious patients who had an electrode implanted in the cervical epidural space for the control of pain. As in healthy
subjects, iTBS increased MEPs, and this was accompanied by a significant increase in the amplitude of later I-waves, but not
the I1 wave. In two of the patients we tested the excitability of the contralateral cortex and found a significant suppression
of the late I-waves. The extent of the changes varied between the three patients, as did their age. To investigate whether
age might be a significant contributor to the variability we examined the effect of iTBS on MEPs in 18 healthy subjects. iTBS
facilitated MEPs evoked by TMS of the conditioned hemisphere and suppressed MEPs evoked by stimulation of the contralateral
hemisphere. There was a slight but non-significant decline in MEP facilitation with age, suggesting that interindividual variability
was more important than age in explaining our data. In a subgroup of 10 subjects we found that iTBS had no effect on the duration
of the ipsilateral silent period suggesting that the reduction in contralateral MEPs was not due to an increase in ongoing
transcallosal inhibition. In conclusion, iTBS affects the excitability of excitatory synaptic inputs to pyramidal tract neurones
that are recruited by a TMS pulse, both in the stimulated hemisphere and in the contralateral hemisphere. However the circuits
affected differ from those influenced by the inhibitory, cTBS, protocol. The implication is that cTBS and iTBS may have different
therapeutic targets.
Repetitive transcranial magnetic stimulation of the brain given as intermittent theta burst stimulation (iTBS) can induce long-term potentiation (LTP)-like changes in the stimulated hemisphere and ...long-term depression (LTD)-like changes in the opposite hemisphere. We evaluated whether LTP- and LTD-like changes produced by iTBS in acute stroke correlate with outcome at 6 months. We evaluated the excitability of affected hemisphere (AH) and unaffected hemisphere (UH) by measuring motor threshold and motor-evoked potential (MEP) amplitude under baseline conditions and after iTBS of AH in 17 patients with acute ischemic stroke. Baseline amplitude of MEPs elicited from AH was significantly smaller than that of MEPs elicited from UH, and baseline motor threshold was higher for the AH. Higher baseline MEP values in UH correlated with poor prognosis. iTBS produced a significant increase in MEP amplitude for AH that was significantly correlated with recovery. A nonsignificant decrease in MEP amplitude was observed for the UH. When the decrease in the amplitude of UH MEPs was added to the regression model, the correlation was even higher. Functional recovery is directly correlated with LTP-like changes in AH and LTD-like changes in UH and inversely correlated with the baseline excitability of UH.
I-wave origin and modulation Di Lazzaro, V; Profice, P; Ranieri, F ...
Brain stimulation,
10/2012, Letnik:
5, Številka:
4
Journal Article
Recenzirano
The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing ...the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.
Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA A receptors, tonically inhibits cholinergic activity. Little is known about the ...effects of GABA on the cholinergic activity
in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation
(TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an
inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated
whether GABA A activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol
of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA A activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic
drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those
of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in
SICI ( F 3,9
= 3.19, P
= 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam ( F 3,9
= 9.39, P
= 0.0002). Our findings demonstrate that GABA A activity enhancement determines a suppression of SAI and an increase of SICI.
Abstract Objective To investigate if different interneuronal circuits in human motor cortex mediate inhibition through different subtypes of the gamma-aminobutyric acid A receptor (GABAAR). Methods ...Two distinct forms of motor cortical inhibition were measured in 10 healthy subjects by established transcranial magnetic stimulation (TMS) protocols: short interval intracortical inhibition (SICI) and short latency afferent inhibition (SAI). Their modification by a single oral dose of three different positive GABAAR modulators (20 mg of diazepam, 2.5 mg of lorazepam and 10 mg of zolpidem) with different affinity profiles at the various α-subunit bearing subtypes of the GABAAR (diazepam: non-selective, lorazepam: unknown, zolpidem: 10-fold higher affinity to α1- than α2- or α3-subunit bearing GABAARs, no affinity to α5-subunits) was tested in a randomized crossover design. In addition, the sedative drug effects were recorded by a visual analogue scale. Results Diazepam and lorazepam increased SICI, whereas zolpidem did not change SICI. In contrast, diazepam had no effect on SAI, whereas lorazepam and zolpidem decreased SAI. The sedative effects were not different between drugs. Conclusions The dissociating patterns of drug modification of SICI versus SAI strongly suggest that different GABAAR subtypes are involved in SICI and SAI. Significance We provide evidence, for the first time, for a dissociation of effects of diazepam and zolpidem on SAI and confirm the previously reported differential effect of zolpidem and of diazepam and lorazepam on SICI. The differential effects of the three benzodiazepines on SAI and SICI suggest that neuronal circuits in human motor cortex that mediate inhibition through different GABAAR subtypes can be segregated by TMS.
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