E. Saturno

Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans.

OBJECTIVES The present experiments were designed to compare the understanding of the transcranial electric and magnetic stimulation of the human motorcortex. METHODS The spinal volleys evoked by single transcranial magnetic or electric stimulation over the cerebral motor cortex were recorded from a bipolar electrode inserted into the cervical epidural space of two conscious human subjects. These volleys were termed D- and I waves, according to their latency. Magnetic stimulation was performed with a figure-of-eight coil held over the right motor cortex at the optimum scalp position, in order to elicit motor responses in the contralateral FDI using two different orientations over the motor strip. The induced current flowed either in a postero-anterior or in a latero-medial direction. RESULTS At active motor threshold intensity, the electric anodal stimulation evoked pure D activity. At this intensity, magnetic stimulation with the induced current flowing in a posterior-anterior direction evoked pure I1 activity. When a latero-medial induced current was used, magnetic stimulation evoked both D and I1 activity. Using electric anodal stimulation, at a stimulus intensity of 9% of the stimulator output above the active motor threshold (corresponding approximately to 1.5 active motor threshold), a small I1 wave appeared only in subject 1. Using magnetic stimulation with a posterior-anterior induced current, at a stimulus intensity of 21% of maximum stimulator output above the active motor threshold (corresponding approximately to 1.8 times threshold in subject 1 and to two times threshold in subject 2), a small D wave appeared in subject 1 but not in subject 2. CONCLUSIONS Present results demonstrate that, in conscious humans at threshold intensities, electric stimulation evokes D waves and magnetic stimulation (with a posterior-anterior induced current) evokes I waves, while magnetic stimulation (with a latero-medial induced current) evokes both activities.

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.

Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation

BackgroundA recently devised test of motor cortex excitability (short latency afferent inhibition) was shown to be sensitive to the blockade of muscarinic acetylcholine receptors in healthy subjects. The authors used this test to assess cholinergic transmission in the motor cortex of patients with AD. MethodsThe authors evaluated short latency afferent inhibition in 15 patients with AD and compared the data with those of 12 age-matched healthy controls. ResultsAfferent inhibition was reduced in the patients (mean responses ± SD reduced to 85.7% ± 15.8% of the test size) compared with controls (mean responses ± SD reduced to 45.3% ± 16.2% of the test size;p < 0.001, unpaired t-test). Administration of a single oral dose of rivastigmine improved afferent inhibition in a subgroup of six patients. ConclusionsThe findings suggest that this method can be used as a noninvasive test of cholinergic pathways in AD. Future studies are required to evaluate whether short latency afferent inhibition measurements have any consistent clinical correlates.

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.

The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation

Abstract. Descending corticospinal volleys were recorded from a bipolar electrode inserted into the cervical epidural space of four conscious human subjects after monophasic transcranial magnetic stimulation over the motor cortex with a figure-of-eight coil. We examined the effect of reversing the direction of the induced current in the brain from the usual posterior-anterior (PA) direction to an anterior-posterior (AP) direction. The volleys were compared with D waves evoked by anodal electrical stimulation (two subjects) or medio-lateral magnetic stimulation (two subjects). As reported previously, PA stimulation preferentially recruited I1 waves, with later I waves appearing at higher stimulus intensities. AP stimulation tended to recruit later I waves (I3 waves) in one of the subjects, but, in the other three, I1 or D waves were seen. Unexpectedly, the descending volleys evoked by AP stimulation often had slightly different peak latencies and/or longer duration than those seen after PA stimulation. In addition the relationship between the size of the descending volleys and the subsequent EMG response was often different for AP and PA stimulation. These findings suggest that AP stimulation does not simply activate a subset of the sites activated by PA stimulation. Some sites or neurones that are relatively inaccessible to PA stimulation may be the low-threshold targets of AP stimulation.

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.

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.

The diagnostic value of motor evoked potentials

OBJECTIVE To assess the diagnostic usefulness of motor evoked potentials (MEPs) and to identify the optimal method for calculating the central conduction time. The test results were evaluated in a prospective study of 1023 neurological patients. METHODS We evaluated the correlation between clinical and electrophysiological findings, the accuracy, the sensitivity, the percentage of subclinical abnormalities and the false negative rates of MEPs in different neurological disorders. In patients with lower motor neuron involvement, we compared the central conduction time calculated as the difference between the latency of the cortical and magnetic root stimulation responses with that calculated using the F-wave method. RESULTS The agreement index between electrophysiological and clinical findings was 87%. The overall accuracy of the test was 0.97. The higher sensitivity values were demonstrated in spinal cord disorders (0.85), hereditary spastic paraplegia (0.80) and motor neuron diseases (0.74). The higher percentages of subclinical abnormalities were found in motor neuron disorders (26%) muscular diseases (24%), multiple sclerosis (13.5%) and spinal cord diseases (12.5%). The higher false negative rates were found in sylvian stroke (0.36) and hereditary spastic paraplegia (0.16). Central conduction study using magnetic paravertebral stimulation but not using the F-wave method, resulted in 12% and 10% of false positive values in lower limb multiradiculopathies and in neuropathies, respectively. CONCLUSIONS MEPs represent a highly accurate diagnostic test. MEP clinical value is maximum in motor neuron, muscle and spinal cord diseases. In patients with lower motor neuron involvement, the gold standard for central conduction determination is the F-wave method.

Comparison of descending volleys evoked by monophasic and biphasic magnetic stimulation of the motor cortex in conscious humans.

Abstract. The descending spinal volleys evoked by monophasic and biphasic magnetic stimulation of the motor cortex were recorded from a bipolar electrode inserted into the cervical epidural space of four conscious human subjects. The results suggest that both phases of the biphasic pulse are capable of activating descending motor output. The pattern of recruitment of descending activity depends on the intensity of the stimulus and the relative threshold of each volley to each direction of current flow.

Inhibition of the human primary motor area by painful heat stimulation of the skin

OBJECTIVE To prove whether painful cutaneous stimuli can affect specifically the motor cortex excitability. METHODS The electromyographic (EMG) responses, recorded from the first dorsal interosseous muscle after either transcranial magnetic or electric anodal stimulation of the primary motor (MI) cortex, was conditioned by both painful and non-painful CO2 laser stimuli delivered on the hand skin. RESULTS Painful CO2 laser stimuli reduced the amplitude of the EMG responses evoked by the transcranial magnetic stimulation of both the contralateral and ipsilateral MI areas. This inhibitory effect followed the arrival of the nociceptive inputs to cerebral cortex. Instead, the EMG response amplitude was not significantly modified either when it was evoked by the motor cortex anodal stimulation or when non-painful CO2 laser pulses were used as conditioning stimuli. CONCLUSIONS Since the magnetic stimulation leads to transynaptic activation of pyramidal neurons, while the anodal stimulation activates directly cortico-spinal axons, the differential effect of the noxious stimuli on the EMG responses evoked by the two motor cortex stimulation techniques suggests that the observed inhibitory effect has a cortical origin. The bilateral cortical representation of pain explains why the painful CO2 laser stimuli showed a conditioning effect on MI area of both hemispheres. Non-painful CO2 laser pulses did not produce any effect, thus suggesting that the reduction of the MI excitability was specifically due to the activation of nociceptive afferents.