Vincenzo Di Lazzaro

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

The clinical diagnostic utility of transcranial magnetic stimulation: Report of an IFCN committee

The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimers disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Inhibition of motor system excitability at cortical and spinal level by tonic muscle pain

OBJECTIVE To assess whether the motor system excitability can be modified by experimental tonic pain induced either in muscles or in subcutis. METHODS Transcranial magnetic stimulation of the left primary motor cortex was used to record motor evoked potentials (MEPs) from the right abductor digiti minimi (ADM) muscle. Recordings were made before, during and after experimental pain induced by (1) injection of hypertonic (5%) saline into the right ADM, the right first dorsal interosseum (FDI) and the left ADM muscles, and (2) injection of hypertonic saline in the subcutaneous region of the right ADM. Both MEPs and H-reflex were recorded also from the right flexor carpi radialis (FCR) before, during and after muscle pain. RESULTS MEPs recorded from the ADM muscle were significantly reduced in amplitude during pain induced in the right ADM and right FDI muscles, but not during pain in the left ADM muscle or during subcutaneous pain. This inhibitory effect was observed during the peak-pain and persisted also after the disappearance of the pain sensation. In the FCR muscle, the MEP inhibition was observed during the peak-pain, while a significant reduction of the H-reflexs amplitude was observed starting 1 min after the peak-pain. CONCLUSIONS Tonic muscle pain can inhibit the motor system. The motor cortex inhibition observed at an early phase is followed by a reduction of the excitability of both cortical and spinal motoneurones.

Physiology of repetitive transcranial magnetic stimulation of the human brain

During the last two decades, transcranial magnetic stimulation (TMS) has rapidly become a valuable method to investigate noninvasively the human brain. In addition, repetitive TMS (rTMS) is able to induce changes in brain activity that last after stimulation. Therefore, rTMS has therapeutic potential in patients with neurologic and psychiatric disorders. It is, however, unclear by which mechanism rTMS induces these lasting effects on the brain. The effects of rTMS are often described as LTD- or LTP-like, because the duration of these alterations seems to implicate changes in synaptic plasticity. In this review we therefore discuss, based on rTMS experiments and knowledge about synaptic plasticity, whether the physiologic basis of rTMS-effects relates to changes in synaptic plasticity. We present seven lines of evidence that strongly suggest a link between the aftereffects induced by rTMS and the induction of synaptic plasticity. It is, nevertheless, important to realize that at present it is impossible to demonstrate a direct link between rTMS on the one hand and synaptic plasticity on the other. Therefore, we provide suggestions for future, innovating research, aiming to investigate both the local effects of rTMS on the synapse and the effects of rTMS on other, more global levels of brain organization. Only in that way can the aftereffects of rTMS on the brain be completely understood.

State of the art: Pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation

The combination of brain stimulation techniques like transcranial magnetic stimulation (TMS) with CNS active drugs in humans now offers a unique opportunity to explore the physiologic effects of these substances in vivo in the human brain. Motor threshold, motor evoked potential size, motor evoked potential intensity curves, cortical silent period, short-interval intracortical inhibition, intracortical facilitation, short-interval intracortical facilitation, long-interval intracortical inhibition and short latency afferent inhibition represent the repertoire for investigating drug effects on motor cortical excitability by TMS. Here we present an updated overview on the pharmacophysiologic mechanisms with special emphasis on methodologic pitfalls and possible future developments or requirements.

State of the art: Physiology of transcranial motor cortex stimulation

The motor cortex can be stimulated transcranially producing excitatory and inhibitory phenomena in muscles controlled by the activated cortical areas. The physiologic bases of these effects are still relatively poorly understood because of the complexity of the interactions between the currents induced in the brain with an intricate arrangement of neural circuits in the cerebral cortex, which is composed of multiple excitatory and inhibitory networks of cell bodies and axons of different size, location, orientation and function. All forms of stimulation of the intact motor cortex tend to produce repetitive discharge of corticospinal neurones; however, different structures of these central motor circuits seem to be preferentially targeted by the available different techniques of stimulation. Direct recording of the evoked corticospinal output has provided important insight into the excitatory and inhibitory phenomena produced by cerebral cortex stimulation. An updated overview of human and animal studies on the physiologic mechanisms of intact motor cortex stimulation is presented.

Modulation of brain plasticity in stroke: a novel model for neurorehabilitation

Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL AF): design and rationale.

BACKGROUND Patients with atrial fibrillation (AF) are at increased risk for ischemic stroke. In patients who have suffered a stroke, screening for AF is routinely performed only for a short period after the stroke as part of the evaluation for possible causes. If AF is detected after an ischemic stroke, oral anticoagulation therapy is recommended for secondary stroke prevention. In 25% to 30% of stroke patients, the stroke mechanism cannot be determined (cryptogenic stroke). The incidence of paroxysmal AF undetected by short-term monitoring in patients with cryptogenic stroke is unknown, but has important therapeutic implications on patient care. The optimum monitoring duration and method of AF detection after stroke are unknown. The purpose of this study is to evaluate the incidence of AF and time to AF detection in patients with cryptogenic stroke using an insertable cardiac monitor. STUDY DESIGN The CRYSTAL AF trial is a randomized prospective study to evaluate a novel approach to long-term monitoring for AF detection in patients with cryptogenic stroke. Four hundred fifty cryptogenic stroke patients (by definition, without a history of AF) will be enrolled at approximately 50 sites in Europe, Canada, and the United States. Patients will be randomized in a 1:1 fashion to standard arrhythmia monitoring (control arm) or implantation of the subcutaneous cardiac monitor (Reveal XT; Medtronic, Inc, Minneapolis, MN) (continuous monitoring arm). OUTCOMES The primary end point is time to detection of AF within 6 months after stroke. The clinical follow-up period will be at least 12 months. Study completion is expected at the end of 2012.

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.

Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition

Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short‐latency afferent inhibition, SAI). This can be tested by coupling electrical stimulation of peripheral nerve with transcranial magnetic stimulation (TMS) of the motor cortex. SAI is reduced by the anticholinergic drug scopolamine, and in patients with Alzheimers disease. Therefore, it is possible that SAI is a marker of central cholinergic activity important for memory function. The benzodiazepine lorazepam also reduces SAI. Since benzodiazepines impair memory formation, but do not do so uniformly, with a maximum amnesic effect after lorazepam but less or no effect after diazepam, we were interested in testing in this non‐behavioural study to what extent the effects of lorazepam and diazepam on circuits involved in SAI could be dissociated. In addition, and for control, we tested the effects of lorazepam and diazepam on short‐interval intracortical inhibition (SICI), a motor cortical inhibition mediated through the GABAA receptor. Lorazepam markedly reduced SAI, whereas diazepam slightly increased it. In contrast, both benzodiazepines uniformly increased SICI. Our findings demonstrate opposite effects of lorazepam and diazepam on SAI, an inhibition modulated by central cholinergic activity, but the same effects on SICI, a marker of neurotransmission through the GABAA receptor. This dissociation suggests, for the first time, that TMS measures of cortical inhibition provide the opportunity to segregate differences of benzodiazepine action in human central nervous system circuits.