Cardiovascular impairment in a patient with acute myelitis.

STUDY DESIGN: Case report. OBJECTIVE: to report and discuss the development of sudden symptomatic sinus bradycardia in a 35-year-old woman with acute myelitis. CASE REPORT: A 35-year-old woman presented rapidly progressive weakness and hypoesthesia in the left hemibody. Five days after symptom onset, she developed symptomatic sinus bradycardia up to 30 b.p.m. Bradycardia was completely resolved ∼36 h after its onset. RESULTS: Cervical spine magnetic resonance imaging showed a focal T2-hyperintense intramedullary lesion at C2 level, with moderate cord swelling. The lesion involved bilaterally dorsal funiculi, and left lateral and ventral funiculi. Cardiac I-123 metaiodobenzylguanidine (MIBG) scintigraphy showed a decreased cardiac MIBG uptake suggesting sympathetic denervation. CONCLUSION: The most likely explanation for bradycardia in our patient is the myelitis-related disruption of descending vasomotor pathways, resulting in sympathetic hypoactivity. Our case extends the spectrum of the clinical presentations of cervical myelitis and emphasizes the importance of careful cardiac monitoring in acute phase of cervical myelitis.

Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques.

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.

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.

Recurrent subarachnoid bleeding and superficial siderosis in a patient with histopathologically proven cerebral amyloid angiopathy.

A 68-year-old man with a history of hypertension presented with recurrent subarachnoid bleeding. Brain MRI showed superficial siderosis, and diagnostic cerebral angiograms did not show any intracranial vascular malformation or arterial aneurism. Post mortem neuropathological examination of the brain was consistent with a diagnosis of cerebral amyloid angiopathy. Clinicians should be aware that cerebral amyloid angiopathy should be considered in patients with unexplained recurrent subarachnoid bleeding, even in cases without familial clustering or transthyretin variant.

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.

Light chain deposition in peripheral nerve as a cause of mononeuritis multiplex in Waldenström's macroglobulinaemia.

Waldenström's macroglobulinaemia is a form of monoclonal IgM gammopathy associated with a rare B-cell lympho-plasmacytic lymphoma, characterized by the involvement of bone marrow, lymph nodes and spleen. Neurological complications involving peripheral nerves are common and different pathogenic mechanisms have been reported. We describe a patient with severe multineuropathy associated with Waldenström's macroglobulinaemia. Nerve biopsy revealed copious light chain deposition which subverted the normal architecture of the endoneurium and epineurium resulting in massive fascicular hyalinosis and epineural arteries disruption, respectively. This report confirms that massive immunoglobulin deposition is one of the several mechanisms of nerve damage in IgM-related neuropathy. Since their recognition has important therapeutical consequences, nerve biopsy is an essential diagnostic tool in patients with an unusual clinical presentation of IgM-related neuropathies.

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.

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.

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.

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.