Michele Dileone

Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex

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 5–10 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.

Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation

Subanaesthetic doses of the N‐methyl‐d‐aspartate (NMDA) antagonist ketamine have been shown to determine a dual modulating effect on glutamatergic transmission in experimental animals, blocking NMDA receptor activity and enhancing non‐NMDA transmission through an increase in the release of endogenous glutamate. Little is known about the effects of ketamine on the excitability of the human central nervous system. The effects of subanaesthetic, graded incremental doses of ketamine (0.01, 0.02 and 0.04 mg kg−1 min−1, i.v.) on the excitability of cortical networks of the human motor cortex were examined with a range of transcranial magnetic and electric stimulation protocols in seven normal subjects. Administration of ketamine at increasing doses produced a progressive reduction in the mean resting motor threshold (RMT) (F(3, 18) = 22.33, P < 0.001) and active motor threshold (AMT) (F(3, 18) = 12.17, P < 0.001). Before ketamine administration, mean RMT ±s.d. was 49 ± 3.3 % of maximum stimulator output and at the highest infusion level it was 42.6 ± 2.6 % (P < 0.001). Before ketamine administration, AMT ±s.d. was 38 ± 3.3 % of maximum stimulator output and at the highest infusion level it was 33 ± 4.4 % (P < 0.002). Ketamine also led to an increase in the amplitude of EMG responses evoked by magnetic stimulation at rest; this increase was a function of ketamine dosage (F(3, 18) = 5.29, P= 0.009). In contrast to responses evoked by magnetic stimulation, responses evoked by electric stimulation were not modified by ketamine. The differential effect of ketamine on responses evoked by magnetic and electric stimulation demonstrates that subanaesthetic doses of ketamine enhance the recruitment of excitatory cortical networks in motor cortex. Transcranial magnetic stimulation produces a high‐frequency repetitive discharge of pyramidal neurones and for this reason probably depends mostly on short‐lasting AMPA transmission. An increase in this transmission might facilitate the repetitive discharge of pyramidal cells after transcranial magnetic stimulation which, in turn, results in larger motor responses and lower thresholds. We suggest that the enhancement of human motor cortex excitability to transcranial magnetic stimulation is the effect of an increase in glutamatergic transmission at non‐NMDA receptors similar to that described in experimental studies.

The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex

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.

Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease

Objectives: Recent transcranial magnetic stimulation (TMS) studies demonstrate that motor cortex excitability is increased in Alzheimer’s disease (AD) and that intracortical inhibitory phenomena are impaired. The aim of the present study was to determine whether hyperexcitability is due to the impairment of intracortical inhibitory circuits or to an independent abnormality of excitatory circuits. Methods: We assessed the excitability of the motor cortex with TMS in 28 patients with AD using several TMS paradigms and compared the data of cortical excitability (evaluated by measuring resting motor threshold) with the amount of motor cortex disinhibition as evaluated using the test for motor cortex cholinergic inhibition (short latency afferent inhibition) and GABAergic inhibition (short latency intracortical inhibition). The data in AD patients were also compared with that from 12 age matched healthy individuals. Results: The mean resting motor threshold was significantly lower in AD patients than in controls. The amount of short latency afferent inhibition was significantly smaller in AD patients than in normal controls. There was also a tendency for AD patients to have less pronounced short latency intracortical inhibition than controls, but this difference was not significant. There was no correlation between resting motor threshold and measures of either short latency afferent or intracortical inhibition (r = −0.19 and 0.18 respectively, NS). In 14 AD patients the electrophysiological study was repeated after a single oral dose of the cholinesterase inhibitor rivastigmine. Resting motor threshold was not significantly modified by the administration of rivastigmine. In contrast, short latency afferent inhibition from the median nerve was significantly increased by the administration of rivastigmine. Conclusions: The change in threshold did not seem to correlate with dysfunction of inhibitory intracortical cholinergic and GABAergic circuits, nor with the central cholinergic activity. We propose that the hyperexcitability of the motor cortex is caused by an abnormality of intracortical excitatory circuits.

Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans

Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABAA 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 GABAA 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 GABAA 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 (F3,9= 3.19, P= 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F3,9= 9.39, P= 0.0002). Our findings demonstrate that GABAA activity enhancement determines a suppression of SAI and an increase of SICI.

Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation

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.

I-wave origin and modulation

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.

Neurophysiological predictors of long term response to AChE inhibitors in AD patients

Background: In vivo evaluation of cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI). SAI is reduced in Alzheimer’s disease (AD) and drugs enhancing cholinergic transmission increase SAI. Methods: We evaluated whether SAI testing, together with SAI test-retest, after a single dose of the acetylcholinesterase (AChE) inhibitor rivastigmine, might be useful in predicting the response after 1 year treatment with rivastigmine in 16 AD patients. Results: Fourteen AD patients had pathologically reduced SAI. SAI was increased after administration of a single oral dose of rivastigmine in AD patients with abnormal baseline SAI, but individual responses to rivastigmine varied widely, with SAI change ranging from an increase in inhibition of ∼50% of test size to no change. Baseline SAI and the increase in SAI after a single dose of rivastigmine were correlated with response to long term treatment. A normal SAI in baseline conditions, or an abnormal SAI in baseline conditions that was not greatly increased by a single oral dose of rivastigmine, were invariably associated with poor response to long term treatment, while an abnormal SAI in baseline conditions in conjunction with a large increase in SAI after a single dose of rivastigmine was associated with good response to long term treatment in most of the patients. Conclusions: Evaluation of SAI may be useful for identifying AD patients likely to respond to treatment with AChE inhibitors.

GABAA receptor subtype specific enhancement of inhibition in human motor cortex.

Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and γ‐aminobutyric acid A receptor (GABAAR) subtypes. Here we employed paired‐pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABAAR‐mediated inhibition in human motor cortex, to address the question of which GABAAR subtype is responsible for this form of inhibition. It has been shown that classical benzodiazepines (diazepam and lorazepam) have a non‐selective affinity profile at different α‐subunit‐bearing subtypes of the GABAAR while zolpidem has a 10‐fold greater affinity to the α1‐subunit‐bearing GABAAR compared with those bearing the α2‐ or α3‐subunit. We found that, in seven healthy subjects, a single oral dose of 20 mg of diazepam or 2.5 mg of lorazepam significantly increased SICI, whereas 10 mg of zolpidem did not change SICI. This dissociation occurred despite equal sedation by all three drugs, an α1‐subunit GABAAR‐mediated effect. The findings strongly suggest that SICI is not mediated by the α1‐subunit‐bearing subtype of the GABAAR but by those bearing either the α2‐ or α3‐subunit. This study represents an attempt by means of TMS to identify GABAAR subtype‐specific action at the systems level of human cortex, a highly relevant issue because the different α‐subunit‐bearing subtypes of the GABAAR are differently involved in benzodiazepine‐mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy.

Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study.

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 alpha-subunit bearing subtypes of the GABAAR (diazepam: non-selective, lorazepam: unknown, zolpidem: 10-fold higher affinity to alpha1- than alpha2- or alpha3-subunit bearing GABAARs, no affinity to alpha5-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.