Dopamine-dependent changes of cortical excitability induced by transcranial static magnetic field stimulation in Parkinson's disease.

Transcranial static magnetic field stimulation (tSMS) is a recent low-cost non-invasive brain stimulation technique that decreases cortical excitability in healthy subjects. The objective of the present study was to test the ability of tSMS to modulate cortical excitability in patients with Parkinson's disease. We performed a randomized double-blind sham-controlled cross-over study to assess cortical excitability before and immediately after tSMS (or sham) applied for 10 min to the more affected motor cortex of patients with Parkinson's disease. Cortical excitability was quantified by the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS). tSMS significantly decreased MEP amplitudes in patients OFF medication (after overnight withdrawal of dopaminergic drugs), but not ON medication (after an acute dose of levodopa). The between-patients variability of tSMS-induced changes was significantly greater ON medication. The variability ON medication could be partly explained by disease progression, i.e. the more advanced the patient, the more likely it was to observe a switch from inhibitory tSMS plasticity OFF medication to paradoxical facilitatory plasticity ON medication. These results suggest that tSMS induces dopamine-dependent changes of cortical excitability in patients with Parkinson's disease.

The effects of prolonged cathodal direct current stimulation on the excitatory and inhibitory circuits of the ipsilateral and contralateral motor cortex.

Weak cathodal transcranial direct current stimulation (tDCS) of the human hand area modulates corticospinal excitability with a suppression of motor-evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS). The changes in excitability persist beyond the time of stimulation if tDCS is given for several minutes and can remain stable for an hour or more. The aim of present study was to evaluate whether a long-lasting suppression of cortical excitability could be induced by prolonged cathodal tDCS (20 min of stimulation). We also explored the impact of brain-derived neurotrophic factor (BDNF) gene polymorphisms, on tDCS after-effects. Cortical excitability to single and paired-pulse TMS was evaluated both for the stimulated and contralateral hemisphere, before and up to 24 h after 20 min of cathodal tDCS. We evaluated threshold and amplitude of MEPs, short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). tDCS produced a pronounced suppression of MEP amplitude that was still significant at 3 h after the end of stimulation. The BDNF genotype had not influence on tDCS after-effects. Thresholds for MEPs, SICI and ICF were not affected. No significant effect was observed in the contralateral hemisphere. Twenty minutes of cathodal tDCS is capable of inducing a long-lasting suppression of the excitability of the human motor cortex.

Dystonia in Costello syndrome.

BACKGROUND: Costello Syndrome is a rare multiple congenital anomaly disorder caused by de novo heterozygous mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) gene. Recent studies seem to support apparent autosomal dominant inheritance and somatic mosaicism and an association with advanced parental age. Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear. METHODS: We evaluated and described posture and movement in six consecutive subjects with genetically proven Costello Syndrome, in order to better characterize the phenomenology of the associated postural abnormalities and any related motor abnormalities. We also evaluated motor cortex plasticity by applying Paired Associative Stimulation. RESULTS: All the patients presented the typical postural abnormalities reported in Costello Syndrome, in particular the ulnar deviation of fingers. The latter was reducible and not fixed. In addition, patients exhibited more explicit dystonic features of the face, limbs and trunk and altered sensorimotor plasticity consistent with generalized dystonia. CONCLUSIONS: These findings suggest that dystonia may underlie the abnormal postures described in Costello Syndrome patients.

Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation.

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.

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 evaluation of the pedunculopontine nucleus in humans.

The pedunculopontine nucleus (PPTg) is constituted by a heterogeneous cluster of neurons located in caudal mesencephalic tegmentum which projects to the thalamus to trigger thalamocortical rhythms and the brainstem to modulate muscle tone and locomotion. It has been investigated as potential deep brain stimulation (DBS) target for treating Parkinson's disease (PD) symptoms. Neurophysiological studies conducted in humans using DBS electrodes for exploring functional properties of PPTg in vivo, reviewed in this paper, demonstrated that the functional connections between PPTg and cortex, basal ganglia, brainstem network involved in sleep/wake control, and spinal cord can be explored in vivo and provided useful insights about the physiology of this nucleus and pathophysiology of PD.

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.

Enhanced human brain associative plasticity in Costello syndrome.

Costello syndrome (CS) is a rare multiple congenital anomaly disorder which is caused by germline mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homologue (HRAS) proto-oncogene. Experimental data suggest perturbing effects of the mutated protein on the functional and structural organization of networks of cerebral cortex and on the activity-dependent strengthening of synaptic transmission known as long term potentiation (LTP). In five patients with molecularly proven diagnosis of CS and in a group of 13 age-matched control subjects we investigated activity-dependent synaptic plasticity. To this end, we used a paired associative stimulation (PAS) protocol, in which left ulnar nerve stimuli were followed by transcranial magnetic stimulation (TMS) pulses to right cortical hand area, and recorded motor evoked potentials (MEPs) by single pulse TMS from left first dorsal interosseus (FDI) muscle before and after PAS. In 4 out of 5 CS patients and in a subgroup of nine control subjects we also evaluated the time course and the topographical specificity of PAS after-effects. In these two subgroups, MEPs were measured before, immediately after and 30 min after PAS in the left FDI and left abductor pollicis brevis (APB). While the PAS protocol led to a 65% increase of the FDI MEP amplitude in controls, the LTP-like phenomenon was significantly more pronounced in CS patients, with motor responses increased by 230%. In addition, CS patients showed a similar MEP increase in both muscles while control subjects showed a slight increase in APB and only immediately after PAS. We hypothesize that the extremely enhanced PAS after-effects could be due to the influence of HRAS activity on the susceptibility of synapses to undergo LTP.

Repetitive transcranial magnetic stimulation for ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons characterized by progressive weakness, respiratory failure and death within 3-5 years. It has been proposed that glutamate-related excitotoxicity may promote motor neuron death in ALS. Glutamatergic circuits of the human motor cortex can be activated noninvasively using transcranial magnetic stimulation (TMS) of the brain, and repetitive TMS (rTMS) can produce changes in neurotransmission that outlast the period of stimulation. In recent years a remarkable number of papers about the potential effects of rTMS in several neurological disorders including ALS has been published. Preliminary studies have shown that rTMS of the motor cortex, at frequencies that decrease cortical excitability, causes a slight slowing in the progression rate of ALS, suggesting that these effects might be related to a diminution of glutamate-driven excitotoxicity. RTMS could also interfere with motor neuron death through different mechanisms: rTMS could modulate the production of brain-derived neurotrophic factor (BDNF), a potent survival factor for neurons, that in turn might represent a promoter of motor neuron sparing in ALS. Despite some promising preliminary data, recent studies have demonstrated a lack of significant long-term beneficial effects of rTMS on neurological deterioration in ALS. However, further studies are warranted to evaluate the potential efficacy of different protocols of motor cortex stimulation (in terms of technique, duration and frequency of stimulation), particularly during the early stages of the disease when the progression rate is more pronounced.

Standardizing the intensity of upper limb treatment in rehabilitation medicine.

OBJECTIVE: To describe a treatment protocol for the upper limb that standardizes intensity of therapy input regardless of the severity of presentation. DESIGN: The protocol is described (Part 1) and feasibility and effect explored (Part 2). SUBJECTS: Participants (n = 11) had a single ischaemic stroke in the middle cerebral artery territory more than one year previously, and had residual weakness of the hand with some extension present at the wrist and the ability to grasp. INTERVENTIONS: Following two baseline assessments, participants attended therapy for 1 hour a day for 10 consecutive working days. Treatment consisted of a combination of strength and functional task training. Outcomes were measured immediately after training, at one month and three months. OUTCOME MEASURES: Intensity was measured with Borg Rating of Perceived Exertion. Secondary outcome measures included Action Research Arm Test (ARAT), nine-hole peg test, and Goal Attainment Scale. RESULTS: Borg scores indicated that the level of intensity was appropriate and similar across all participants despite individual differences in the severity of their initial presentation (median (interquartile range) = 14 (13-15)). The mean ARAT score significantly increased by 6.8 points (chi(2)(3) = 15.618, P<0.001), and was maintained at three-month follow-up (z = - 2.384, P = 0.016). The nine-hole peg test also showed a main effect of time and 88% of goals set were achieved. CONCLUSIONS: The physiotherapy protocol standardized intensity of treatment by grading exercise and task-related practice according to the person's residual ability, rather than simply standardizing treatment times. It was feasible and well tolerated in this group.

The effects of motor cortex rTMS on corticospinal descending activity.

Repetitive transcranial magnetic stimulation (rTMS) of the human motor cortex can produce long-lasting changes in the excitability of the motor cortex to single pulse transcranial magnetic stimulation (TMS). rTMS may increase or decrease motor cortical excitability depending critically on the characteristics of the stimulation protocol. However, it is still poorly defined which mechanisms and central motor circuits contribute to these rTMS induced long-lasting excitability changes. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by single pulse TMS from the epidural space of conscious patients with chronically implanted spinal electrodes before and after several protocols of rTMS that increase or decrease brain excitability. These recordings provided insight into the physiological basis of the effects of rTMS and the specific motor cortical circuits involved.

Motor cortex plasticity predicts recovery in acute stroke.

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.

LTD-like plasticity induced by paired associative stimulation: direct evidence in humans.

Paired associative stimulation (PAS), in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex, may produce a long lasting change in cortical excitability. At an interstimulus interval slightly shorter than the time needed for the afferent inputs to reach cerebral cortex (10 ms), motor cortex excitability decreases. Indirect data support the hypothesis that PAS at this interval (PAS10) involves LTD like-changes in cortical synapses. The aim of present paper was to investigate more directly PAS10 effects. We recorded corticospinal descending volleys evoked by single pulse TMS before and after PAS10 in two conscious subjects who had a high cervical epidural electrode implanted for pain control. These synchronous volleys provide a measure of cortical synaptic activity. PAS10 significantly reduced the amplitude of later descending waves while the earliest descending wave was not modified. Present results confirm the cortical origin of the effect of PAS10.

Reduced cerebral cortex inhibition in dystonia: direct evidence in humans.

OBJECTIVE: A loss of inhibition in central motor circuits resulting in abnormal motor control is the hypothesised cause of dystonia. So far, changes in inhibitory function of cerebral cortex in dystonia, have been revealed only indirectly by recording muscle responses evoked by transcranial magnetic stimulation (TMS) of the brain. The aim of present study was to evaluate more directly cerebral cortex changes in dystonia. We had the almost unique opportunity to record directly motor cortex output after brain stimulation, in a dystonic patient who had epidural electrodes implanted in the upper cervical cord. METHODS: We evaluated descending activity evoked by single and paired pulse TMS together with the inhibitory effects produced by afferent stimuli on TMS evoked activity, and compared the results with those obtained in thirteen subjects with no central nervous system abnormality who also had cervical spinal electrodes. RESULTS: The intrinsic inhibitory activity produced by paired TMS of the motor cortex, and the inhibitory effects produced by afferent inputs, were suppressed in the patient with dystonia. CONCLUSIONS: These findings provide a direct evidence of the abnormality in motor cortex inhibitory systems in dystonia. SIGNIFICANCE: The abnormality in cortical inhibitory system might have a role in the pathophysiology of dystonia.

Does exposure to extremely low frequency magnetic fields produce functional changes in human brain?

Behavioral and neurophysiological changes have been reported after exposure to extremely low frequency magnetic fields (ELF-MF) both in animals and in humans. The physiological bases of these effects are still poorly understood. In vitro studies analyzed the effect of ELF-MF applied in pulsed mode (PEMFs) on neuronal cultures showing an increase in excitatory neurotransmission. Using transcranial brain stimulation, we studied noninvasively the effect of PEMFs on several measures of cortical excitability in 22 healthy volunteers, in 14 of the subjects we also evaluated the effects of sham field exposure. After 45 min of PEMF exposure, intracortical facilitation produced by paired pulse brain stimulation was significantly enhanced with an increase of about 20%, while other parameters of cortical excitability remained unchanged. Sham field exposure produced no effects. The increase in paired-pulse facilitation, a physiological parameter related to cortical glutamatergic activity, suggests that PEMFs exposure may produce an enhancement in cortical excitatory neurotransmission. This study suggests that PEMFs may produce functional changes in human brain.

Associative motor cortex plasticity: direct evidence in humans.

Previous studies have shown that paired associative stimulation (PAS) protocol, in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex at intervals that produce an approximately synchronous activation of cortical networks, enhances the amplitude of motor evoked potentials (MEPs) evoked by cortical stimulation. Indirect data support the hypothesis that the enhancement of MEPs produced by PAS involves long-term potentiation like changes in cortical synapses. The aim of present paper was to investigate the central nervous system level at which PAS produces its effects. We recorded corticospinal descending volleys evoked by single pulse TMS of the motor cortex before and after PAS in 4 conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. The descending volleys evoked by TMS represent postsynaptic activity of corticospinal neurones that can provide indirect information about the effectiveness of synaptic inputs to these neurones. PAS significantly enhanced the amplitude of later descending waves, whereas the earliest descending wave was not significantly modified by PAS. The present results show that PAS may increase the amplitude of later corticospinal volleys, consistent with a cortical origin of the effect of PAS.

Stroke in critically ill patients.

Advances in critical care medicine have led to improved survival rates among patients admitted to the Intensive Care unit (ICU), but complications experienced during admittance in an ICU may influence long-term outcome and the neurocognitive state of these patients. Coagulation disorders, glucose intolerance, diabetes, pro-inflammatory state and underlying severe pathologies are common risk factors for stroke development in ICU patients. Stroke may result in very serious consequences like motor function impairment, neglect and aphasia, but in some cases, stroke may not result in any clinical sign in acute phase. Recently, more attention has been given to this condition called ''silent stroke.'' ''Silent stroke'' could be the foundation of the development of neurocognitive impairment and vascular dementia. In ICU survivors, approximately 1/3 of patients or more will develop chronic neurocognitive impairment. With the advent of sensitive techniques for brain imaging, silent brain lesions, including brain infarct and white matter changes, have been frequently recognized. Until now, epidemiological studies in this field evaluating incidence and consequences of stroke in ICU setting are lacking, and prospective studies are required to evaluate the impact of this condition on the quality of life, neurocognitive outcome and mortality of ICU patients. We believe that when stroke occurs in critically ill patients, more attention is typically given to the underlying pathologies than stroke, and this may influence the long-term outcome. Guidelines for the early management of stroke, commonly used in Stroke Units, should be followed, even in critically ill patients in an ICU setting.

In vivo functional evaluation of central cholinergic circuits in vascular dementia.

OBJECTIVE: Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of motor cortex. This test, named short latency afferent inhibition (SAI) has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in Alzheimer disease (AD) patients, a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. The objective of present study was to evaluate central cholinergic circuits in patients with Vascular Dementia (VaD). METHODS: We evaluated SAI in a group of patients with VaD and compared the data with those from a group of AD patients and a control group of age-matched healthy individuals. RESULTS: Mean SAI was normal in VaD patients while it was significantly reduced in AD patients. The analysis of individual data showed abnormal SAI in 75% of AD and in only 25% of VaD. CONCLUSIONS: SAI is normal in most of VaD patients in contrast with AD patients. This test might be used for the functional evaluation of central cholinergic circuits in VaD patients. SIGNIFICANCE: SAI testing may represent a useful additional tool for the evaluation of patients with VaD however, further studies are required in order to evaluate whether this method can be used for the differential diagnosis between pure VaD and different forms of dementia.

Low-frequency repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex.

Previous studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) suppresses motor-evoked potentials (MEPs) evoked by single pulse TMS. The aim of the present paper was to investigate the central nervous system level at which rTMS produces a suppression of MEP amplitude. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after 1 Hz rTMS in five conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. One of the patients had Parkinson's disease and was studied on medication. Repetitive TMS significantly suppressed the amplitude of later I-waves, and reduced the amplitude of concomitantly recorded MEPs. The earliest I-wave was not significantly modified by rTMS. The present results show that 1 Hz rTMS may decrease the amplitude of later descending waves, consistent with a cortical origin of the effect of 1 Hz rTMS on MEPs.