Massimiliano Oliveri

Efficacy of repetitive transcranial magnetic stimulation/transcranial direct current stimulation in cognitive neurorehabilitation

Cognitive deficits are a common consequence of neurologic disease, in particular, of traumatic brain injury, stroke, and neurodegenerative disorders, and there is evidence that specific cognitive training may be effective in cognitive rehabilitation. Several investigations emphasize the fact that interacting with cortical activity, by means of cortical stimulation, can positively affect the short-term cognitive performance and improve the rehabilitation potential of neurologic patients. In this respect, preliminary evidence suggests that cortical stimulation may play a role in treating aphasia, unilateral neglect, and other cognitive disorders. Several possible mechanisms can account for the effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) on cognitive performance. They all reflect the potential of these methods to improve the subjects ability to relearn or to acquire new strategies for carrying out behavioral tasks. The responsible mechanisms remain unclear but they are most likely related to the activation of impeded pathways or inhibition of maladaptive responses. Modifications of the brain activity may assist relearning by facilitating local activity or by suppressing interfering activity from other brain areas. Notwithstanding the promise of these preliminary findings, to date no systematic application of these methods to neurorehabilitation research has been reported. Considering the potential benefit of these interventions, further studies taking into consideration large patient populations, long treatment periods, or the combination of different rehabilitation strategies are needed. Brain stimulation is indeed an exciting opportunity in the field of cognitive neurorehabilitation, which is clearly in need of further research.

Interhemispheric Asymmetries of Motor Cortex Excitability in the Postacute Stroke Stage A Paired-Pulse Transcranial Magnetic Stimulation Study

Background and Purpose— Changes in the intracortical inhibition (ICI) and facilitation (ICF) of motor cortex paired-pulse transcranial magnetic stimulation were reported in the affected (AH) and unaffected (UH) hemispheres of stroke patients and reflect some of the mechanisms related to motor cortex plasticity and different degrees of functional recovery. The interhemispheric differences of the ICI/ICF slopes have been found to have a nearly identical time course in the 2 hemispheres of healthy subjects, and whether such symmetry is modified after monohemispheric stroke has not yet been examined. Our goal was to investigate the interhemispheric asymmetries of the time course of ICI/ICF between the AH and UH of stroke patients in the postacute phase of recovery. Methods— ICI/ICF recovery curves to subthreshold-conditioning suprathreshold-test magnetic stimuli were recorded from the paretic and nonparetic hand muscles of 10 well-recovered stroke patients and compared with those of a population of 10 control subjects. Results— In the healthy subjects, ICI/ICF showed a symmetrical time evolution between the 2 hemispheres. In stroke patients, the ICI/ICF slopes were significantly different between the UH and AH; the intracortical inhibition was reduced in the AH and normal in the UH. Conclusions— The defective AH ICI associated with the effective UH ICI could represent a marker of poststroke cortical plasticity implicated as a mechanism relevant to functional recovery. Analysis of the interhemispheric asymmetries of the ICI/ICF recovery curves might provide a valuable neurophysiological parameter in the prognosis and follow-up of patients with monohemispheric stroke.

Influence of the supplementary motor area on primary motor cortex excitability during movements triggered by neutral or emotionally unpleasant visual cues

The stronger anatomo-functional connections of the supplementary motor area (SMA), as compared with premotor area (PM), with regions of the limbic system, suggest that SMA could play a role in the control of movements triggered by visual stimuli with emotional content. We addressed this issue by analysing the modifications of the excitability of the primary motor area (M1) in a group of seven healthy subjects, studied with transcranial magnetic stimulation (TMS), after conditioning TMS of SMA, during emotional and non-emotional visually cued movements. Conditioning TMS of the PM or of contralateral primary motor cortex (cM1) were tested as control conditions. Single-pulse TMS over the left M1 was randomly intermingled with paired TMS, in which a conditioning stimulation of the left SMA, left PM or right M1 preceded test stimulation over the left M1. The subjects carried out movements in response to computerised visual cues (neutral pictures and pictures with negative emotional content). The amplitudes of motor-evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle after paired TMS were measured and compared with those obtained after single-pulse TMS of the left M1 under the various experimental conditions. Conditioning TMS of the SMA in the paired-pulse paradigm selectively enhanced MEP amplitudes in the visual-emotional triggered movement condition, compared with single-pulse TMS of M1 alone or with paired TMS during presentation of neutral visual cues. On the other hand, conditioning TMS of the PM or cM1 did not differentially influence MEP amplitudes under visual-emotional triggered movement conditions. This pattern of effects was related to the intensity of the conditioning TMS over the SMA, being most evident with intensities ranging from 110% to 80% of motor threshold. These results suggest that the SMA in humans could interface the limbic and the motor systems in the transformation of emotional experiences into motor actions.

Changes in intracortical circuits of the human motor cortex following theta burst stimulation of the lateral cerebellum

OBJECTIVE The cerebellum takes part in several motor functions through its influence on the motor cortex (M1). Here, we applied the theta burst stimulation (TBS) protocol, a novel form of repetitive Transcranial Magnetic Stimulation (rTMS) over the lateral cerebellum. The aim of this study was to test whether TBS of the lateral cerebellum could be able to modulate the excitability of the contralateral M1 in healthy subjects. METHODS Motor-evoked potentials (MEPs) amplitude, short intracortical inhibition (SICI), long intracortical inhibition (LICI) and short intracortical facilitation (SICF) were tested in the M1 before and after cerebellar continuous TBS (cTBS) or intermittent TBS (iTBS). RESULTS We found that cTBS induced a reduction of SICI and an increase of LICI. On the other hand, cerebellar iTBS reduced LICI. MEPs amplitude also differently vary following cerebellar stimulation with cTBS or iTBS, resulting in a decrease by the former and an increase by the latter. CONCLUSIONS Although the interpretation of these data remains highly speculative, these findings reveal that the cerebellar cortex undergoes bidirectional plastic changes that modulate different intracortical circuits within the contralateral primary motor cortex. SIGNIFICANCE Long-lasting modifications of these pathways could be useful to treat various pathological conditions characterized by an altered cortical excitability.

Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease

Background: The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia (LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern or code of activity that originates and is conveyed from the basal ganglia to the thalamus and the cortical motor areas. However, not only striatothalamocortical motor circuits but also other interconnected pathways could be implicated in its pathogenesis. Methods: In a series of experiments, we applied repetitive transcranial magnetic stimulation (rTMS) over the lateral cerebellum in a group of patients with advanced Parkinson disease, to investigate whether modulation of cerebellothalamocortical circuits by means of rTMS may result in a modification of a dyskinetic state induced by levodopa ingestion. Results: We found that a single session of cerebellar continuous theta burst stimulation (cTBS) was capable of transiently reducing LID. In the same patients, we observed that cerebellar cTBS changed the profile of activation of intracortical circuits in the contralateral primary motor cortex. Cerebellar cTBS reduced short intracortical inhibition and increased long intracortical inhibition, inducing a cortical reorganization that is associated with a reduction of LID. Furthermore, in another experiment, we observed that a 2-week course of bilateral cerebellar cTBS induced persistent clinical beneficial effects, reducing peak-dose LID for up to 4 weeks after the end of the daily stimulation period. Conclusions: Our study demonstrates that cerebellar continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia, possibly due to modulation of cerebellothalamocortical pathways.

Perceiving numbers alters time perception.

The representation of time, space and numbers are strictly linked in the primates cognitive system. Here we show that merely looking at number symbols biases a temporal judgment on their duration depending upon the numbers magnitude. In a first experiment, a group of healthy subjects was submitted to a time estimation task, requiring to judge whether the duration of a test stimulus was longer or shorter than that of a previous reference fixed stimulus (digit 5; duration 300 ms). Test stimuli were the digits 1, 5 and 9 ranging between 250 and 350 ms. The main results showed that temporal perception was biased according to the magnitude expressed by the digit: low digits (i.e. 1) leading to underestimation and high digits (i.e. 9) an overestimation of perceived duration. Control experiments showed that this result was consistent whatever digits were tested but not when letters of the alphabet were used. These findings argue for a functional interaction between time and numbers in the cognitive system.

All Talk and No Action: A Transcranial Magnetic Stimulation Study of Motor Cortex Activation during Action Word Production

A number of researchers have proposed that the premotor and motor areas are critical for the representation of words that refer to actions, but not objects. Recent evidence against this hypothesis indicates that the left premotor cortex is more sensitive to grammatical differences than to conceptual differences between words. However, it may still be the case that other anterior motor regions are engaged in processing a words sensorimotor features. In the present study, we used singleand paired-pulse transcranial magnetic stimulation to test the hypothesis that left primary motor cortex is activated during the retrieval of words (nouns and verbs) associated with specific actions. We found that activation in the motor cortex increased for action words compared with non-action words, but was not sensitive to the grammatical category of the word being produced. These results complement previous findings and support the notion that producing a word activates some brain regions relevant to the sensorimotor properties associated with that word regardless of its grammatical category.

Neural networks engaged in milliseconds and seconds time processing: evidence from transcranial magnetic stimulation and patients with cortical or subcortical dysfunction

Here, we review recent transcranial magnetic stimulation studies and investigations in patients with neurological disease such as Parkinsons disease and stroke, showing that the neural processing of time requires the activity of wide range-distributed brain networks. The neural activity of the cerebellum seems most crucial when subjects are required to quickly estimate the passage of brief intervals, and when time is computed in relation to precise salient events. Conversely, the circuits involving the striatum and the substantia nigra projecting to the prefrontal cortex (PFC) are mostly implicated in supra-second time intervals and when time is processed in conjunction with other cognitive functions. A conscious representation of temporal intervals relies on the integrity of the prefrontal and parietal cortices. The role of the PFC becomes predominant when time intervals have to be kept in memory, especially for longer supra-second time intervals, or when the task requires a high cognitive level. We conclude that the contribution of these strongly interconnected anatomical structures in time processing is not fixed, depending not only on the duration of the time interval to be assessed by the brain, but also on the cognitive set, the chosen task and the stimulus modality.

Neurophysiological follow-up of motor cortical output in stroke patients

BACKGROUND AND PURPOSE Transcranial magnetic stimulation (TMS) has been employed in following up a population of 20 stroke patients in a post-acute, apparently stabilized stage. Neurophysiological and clinical data were recorded in 5 different recording sessions, from the beginning of a neuro-rehabilitation treatment (T0, at about 5 weeks from the ictal event.), followed up for about 4 months (T4), with the purpose to study any modification of the cortical motor output in the course of a neuro-rehabilitation treatment. METHODS Motor evoked potentials (MEPs) were simultaneously recorded from 10 muscles of both upper limbs (affected and not-affected); meanwhile, clinical and functional scores were gathered. Spinal responsiveness was investigated via H-reflex and F-wave recordings. RESULTS We describe a pattern of improving changes still taking place four months after the stroke, even if the maximal amelioration burden was concentrated between T0 and T1 and T1 and T2 recording sessions (T0/admission to T2/42 days from T0=about 80 days from stroke occurrence). In particular, the excitability threshold (ETh) was progressively decreasing in the affected hemisphere (AH; P<0.001 between T0 and T4), while MEPs amplitude and latency tended toward normality, more in the resting state than during voluntary contraction. Slopes of neurophysiological and clinical data evolution were taken and trends of amelioration described. CONCLUSIONS These findings suggest that rearrangements of motor cortical neural circuitries are still operating after several months from an acute vascular monohemispheric insult, coupled with a clinical improvement in disability and neurological scores. The steepest part of the slopes were evident in the first 80 days, suggesting that this period is the one in which plastic changes of cortical motor areas are mainly active.

rTMS of supplementary motor area modulates therapy-induced dyskinesias in Parkinson disease

The neural mechanisms and circuitry involved in levodopa-induced dyskinesia are unclear. Using repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in a group of patients with advanced Parkinson disease, the authors investigated whether modulation of SMA excitability may result in a modification of a dyskinetic state induced by continuous apomorphine infusion. rTMS at 1 Hz was observed to markedly reduce drug-induced dyskinesias, whereas 5-Hz rTMS induced a slight but not significant increase.