Gianluca Ardolino

Non‐synaptic mechanisms underlie the after‐effects of cathodal transcutaneous direct current stimulation of the human brain

Although cathodal transcranial direct current stimulation (tDCS) decreases cortical excitability, the mechanisms underlying DC‐induced changes remain largely unclear. In this study we investigated the effect of cathodal DC stimulation on spontaneous neural activity and on motor responses evoked by stimulation of the central and peripheral nervous system. We studied 17 healthy volunteers. Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the motor area were used to study the effects of cathodal tDCS (1.5 mA, 10 min) on resting motor threshold and motor evoked potentials (MEPs) recorded from the contralateral first dorsal interosseous muscle (FDI). The electroencephalographic (EEG) activity in response to cathodal tDCS was analysed by power spectral density (PSD). Motor axonal excitability changes in response to transcutaneous DC stimulation of the ulnar nerve (0.3 mA, 10 min) were assessed by testing changes in the size of the compound muscle action potential (CMAP) elicited by submaximal nerve stimulation. Cathodal tDCS over the motor area for 10 min increased the motor threshold and decreased the size of MEPs evoked by TMS for at least 60 min after current offset (t0 71.7 ± 5%, t20 50.8 ± 11%, t40 47.7 ± 7.7%, and t60 39.7 ± 6.4%, P < 0.01). The tDCS also significantly decreased the size of MEPs elicited by TES (t0 64 ± 16.4%, P= 0.09; t20 67.6 ± 10.8%, P= 0.06; and t40 58.3 ± 9.9%, P < 0.05). At the same time in the EEG the power of delta (2–4 Hz) and theta (4–7 Hz) rhythms increased (delta 181.1 ± 40.2, P < 0.05; and theta 138.7 ± 27.6, P= 0.07). At the peripheral level cathodal DC stimulation increased the size of the ulnar nerve CMAP (175 ± 34.3%, P < 0.05). Our findings demonstrate that the after‐effects of tDCS have a non‐synaptic mechanism of action based upon changes in neural membrane function. These changes apart from reflecting local changes in ionic concentrations, could arise from alterations in transmembrane proteins and from electrolysis‐related changes in [H+] induced by exposure to constant electric field.

Transcranial direct current stimulation (tDCS) and language

Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique inducing prolonged brain excitability changes and promoting cerebral plasticity, is a promising option for neurorehabilitation. Here, we review progress in research on tDCS and language functions and on the potential role of tDCS in the treatment of post-stroke aphasia. Currently available data suggest that tDCS over language-related brain areas can modulate linguistic abilities in healthy individuals and can improve language performance in patients with aphasia. Whether the results obtained in experimental conditions are functionally important for the quality of life of patients and their caregivers remains unclear. Despite the fact that important variables are yet to be determined, tDCS combined with rehabilitation techniques seems a promising therapeutic option for aphasia.

Altered subthalamo-pallidal synchronisation in parkinsonian dyskinesias

The aim of this work was to study the role of subthalamo-pallidal synchronisation in the pathophysiology of dyskinesias. We recorded local field potentials (LFPs) in a patient with Parkinson’s disease and left surgery induced dyskinesias with double, bilateral deep brain stimulation electrode implants in the subthalamic nucleus (STN) and the globus pallidus internus (GPi). Synchronisation was studied through coherence analysis. In the nuclei contralateral to the dyskinetic side of the body there was decreased STN-GPi coherence in the high beta range (20–30 Hz) and an enhanced coherence at low frequencies (<10 Hz). Despite the possible limitations arising from single-case observations, our findings suggest that parkinsonian dyskinesias are related to altered synchronisation between different structures of the basal ganglia. Firing abnormalities within individual basal ganglia nuclei are probably not enough to account for the complex balance between hypokinetic and hyperkinetic symptoms in human parkinsonian dyskinesias and altered interactions between nuclei should also be considered.

Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings

&NA; Aiming at developing a new, noninvasive approach to spinal cord neuromodulation, we evaluated whether transcutaneous direct current (DC) stimulation induces long‐lasting changes in the central pain pathways in human beings. A double‐blind crossover design was used to investigate the effects of anodal direct current (2 mA, 15 min) applied on the skin overlying the thoracic spinal cord on the lower‐limb flexion reflex in a group of 11 healthy volunteers. To investigate whether transcutaneous spinal cord DC stimulation (tsDCS) acts indirectly on the nociceptive reflex by modulating excitability in mono‐oligosynaptic segmental reflex pathways, we also evaluated the H‐reflex size from soleus muscle after tibial nerve stimulation. In our healthy subjects, anodal thoracic tsDCS reduced the total lower‐limb flexion reflex area by 40.25% immediately after stimulation (T0) and by 46.9% 30 min after stimulation offset (T30). When we analyzed the 2 lower‐limb flexion reflex components (RII tactile and RIII nociceptive) separately, we found that anodal tsDCS induced a significant reduction in RIII area with a slight but not significant effect on RII area. After anodal tsDCS, the RIII area decreased by 27% at T0 and by 28% at T30. Both sham and active tsDCS left all the tested H‐reflex variables unchanged. None of our subjects reported adverse effects after active stimulation. These results suggest that tsDCS holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain. Thoracic transcutaneous direct current stimulation induces depression of nociceptive lower limb flexion reflex in human beings that persists after stimulation offset; this form of stimulation holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain.

Adaptive deep brain stimulation in a freely moving parkinsonian patient

The future of deep brain stimulation (DBS) for Parkinsons disease (PD) lies in new closed‐loop systems that continuously supply the implanted stimulator with new settings obtained by analyzing a feedback signal related to the patients current clinical condition.1 The most suitable feedback for PD is subthalamic local field potential (LFP) activity recorded from the stimulating electrode itself.2, 3, 4 This closed‐loop technology known as adaptive DBS (aDBS) recently proved superior to conventional open‐loop DBS (cDBS) in patients with PD.2

Low-frequency subthalamic oscillations increase after deep brain stimulation in Parkinson's disease

This work is the second of a series of papers in which we investigated the neurophysiological basis of deep brain stimulation (DBS) clinical efficacy using post-operative local field potential (LFP) recordings from DBS electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinsons disease. We found that low-frequency (1-1.5Hz) oscillations in LFP recordings from the STN of patients with Parkinsons disease dramatically increase after DBS of the STN itself (log power change=0.93+/-0.62; Wilcoxon: p=0.0002, n=13), slowly decaying to baseline levels after turning DBS off. The DBS-induced increase of low-frequency LFP oscillations is highly reproducible and appears only after the delivery of DBS for a time long enough to induce clinical improvement. This increase of low-frequency LFP oscillations could reflect stimulation-induced modulation of network activity or could represent changes of the electrochemical properties at the brain-electrode interface.

The human astrocytoma cell line U373MG produces monocyte chemotactic protein (MCP)-1 upon stimulation with β-amyloid protein

Astrocytes associated with beta-amyloid (Abeta) accumulate in senile plaques of Alzheimers disease (AD). To investigate the biological effects of Abeta/astrocyte interaction, we examined chemokine production by the human astrocytoma cell line U373MG stimulated with Abeta peptides. Northern blot analysis and specific immunoassays demonstrate that Abeta [1-42] and Abeta [25-35] induce mRNA expression and release of monocyte chemotactic protein (MCP)-1 but not of gamma-interferon inducible protein (IP)-10 by U373MG cells. The observation that Abeta induces astrocyte production of the potent microglia chemoattractant MCP-1 contributes to understanding mechanism of damage exerted by Abeta in AD senile plaques.

Transcutaneous spinal direct current stimulation

In the past 10 years renewed interest has centered on non-invasive transcutaneous weak direct currents applied over the scalp to modulate cortical excitability (“brain polarization” or transcranial direct current stimulation, tDCS). Extensive literature shows that tDCS induces marked changes in cortical excitability that outlast stimulation. Aiming at developing a new, non-invasive, approach to spinal cord neuromodulation we assessed the after-effects of thoracic transcutaneous spinal DC stimulation (tsDCS) on somatosensory potentials (SEPs) evoked in healthy subjects by posterior tibial nerve (PTN) stimulation. Our findings showed that thoracic anodal tsDCS depresses the cervico-medullary PTN-SEP component (P30) without eliciting adverse effects. tsDCS also modulates post-activation H-reflex dynamics. Later works further confirmed that transcutaneous electric fields modulate spinal cord function. Subsequent studies in our laboratory showed that tsDCS modulates the flexion reflex in the human lower limb. Besides influencing the laser evoked potentials (LEPs), tsDCS increases pain tolerance in healthy subjects. Hence, though the underlying mechanisms remain speculative, tsDCS modulates activity in lemniscal, spinothalamic, and segmental motor systems. Here we review currently available experimental evidence that non-invasive spinal cord stimulation (SCS) influences spinal function in humans and argue that, by focally modulating spinal excitability, tsDCS could provide a novel therapeutic tool complementary to drugs and invasive SCS in managing various pathologic conditions, including pain.

Guillain-Barré syndrome after combined CHOP and rituximab therapy in non-Hodgkin lymphoma.

Dear Editor, Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy characterised by rapidly progressive predominantly motor impairment and areflexia. The pathogenesis of GBS remains unclear even if there is strong evidence for an immune-mediated process (Hughes et al., 1999). GBS has been reported in patients with Hodgkin’s (Kelly and Karcher, 2005) and, less frequently, non-Hodgkin’s lymphoma (NHL) (Vallat et al., 1995; Magne et al., 2005) where it is thought to be caused by an immune dysfunction caused by the disease or its therapy. A 51-year-old man was diagnosed with B-cell NHL in August 2005 after biopsy of a symptomatic inguinal lymph node. Therapy was immediately initiated. After an initial course of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and methylprednisolone 100 mg (CHOP), he received four cycles of combined CHOP and rituximab (375 mg/m2) (R-ICHOP) at 2-week intervals ending in October 2005. After the first three courses, the patient complained of mild paresthesias at the fingertips. Three weeks after the fourth course and a 2 weeks after transient fever without additional symptoms, he reported worsening of finger paresthesias followed by rapidly progressive leg weakness extending within 2 days to the arms and bulbar muscles with difficulty in swallowing. Neurological examination 3 days after onset of weakness showed severe, symmetrical, predominantly distal, flaccid quadriparesis more pronounced in the legs (Medical Research Council [MRC] score 3/5 in the upper and 4/5 in the lower limbs), with absent deep tendon reflexes and normal sensation. Forced vital capacity was normal. Routine laboratory tests were normal apart from reduced white blood cell and lymphocyte counts (Fig. 1). Serum immunoglobulin (Ig)M antibodies to cytomegalovirus, herpes simplex virus 1 and 2, varicella-zoster virus, Ebstein-Barr virus, mycoplasma pneumoniae, IgG and IgM antibodies to Campylobacter Jejuni, and anti-GM1, -GM2, -GD1b, -GD1a and -GQ1b IgG antibodies were normal. Cerebrospinal fluid proteins were increased (72 mg/dl) while cell count was normal. Nerve conduction studies performed 4 days after onset showed conduction blocks in the right peroneal (50%, distal compound muscle action potential [CMAP] amplitude 1.6 mV), right tibialis posterior (50%, distal CMAP amplitude 1.6 mV) and left posterior tibialis nerves (55%, distal CMAP amplitude 3.1 mV), reduced motor conduction velocities (34 m/sec on the right and 33 m/sec on the left) and increased distal (14.8 and 19 msec), and F wave latencies (44 msec and absent) in the median nerves, where distal CMAP amplitudes were also reduced (0.5 and 0.6 mV, respectively). Despite three daily plasma exchanges started 5 days after disease onset, the patient continued to worsen and became bedridden. He was then treated with high-dose intravenous immunoglobulin (IVIg) therapy (0.5 g/kg/day) and IV methylprednisolone (500 mg) for four consecutive days with moderate improvement followed after 1 week by further deterioration (MRC score 2/5 in the upper and 0/5 in the lower limbs), with progressive respiratory insufficiency (forced vital capacity of 0.9 l). He was transferred to the intensive care unit and placed on non-invasive assisted ventilation. The patient was treated again with IVIg and IV methylprednisolone for 2 days. The patient gradually and steadily improved over the following 3 weeks when a slight worsening was treated again with the same 2day regimen with further progressive improvement. At the follow-up 2 months later, the patient could walk normally for several meters without support. His NHL is in remission. The clinical, electrophysiological, and laboratory features were diagnostic of GBS, possibly superimposed on an underlying neuropathy induced by chemotherapy. Several factors may have contributed to the development of GBS in this patient, including NHL itself, a possible antecedent infection suggested by the transient fever, and chemotherapy with CHOP Address correspondence to: Eduardo Nobile-Orazio, MD, PhD, Department of Neurological Sciences, Milan University, IRCCS Istituto Clinico Humanitas, Via Manzoni 56, 20089, Rozzano Milan, Italy. Tel: þ390282242209; Fax: þ390282242298; E-mail: eduardo.nobile@ unimi.it Journal of the Peripheral Nervous System 12:142–143 (2007)

Increased short latency afferent inhibition after anodal transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS), a technique for central neuromodulation, has been recently proposed as possible treatment in several neurological and psychiatric diseases. Although shifts on focal brain excitability have been proposed to explain the clinical effects of tDCS, how tDCS-induced functional changes influence cortical interneurones is still largely unknown. The assessment of short latency afferent inhibition (SLAI) of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS), provides the opportunity to test non-invasively interneuronal cholinergic circuits in the human motor cortex. The aim of the present study was to assess whether anodal tDCS can modulate interneuronal circuits involved in SLAI. Resting motor threshold (RMT), amplitude of unconditioned MEPs and SLAI were assessed in the dominant hemisphere of 12 healthy subjects (aged 21-37) before and after anodal tDCS (primary motor cortex, 13min, 1mA). SLAI was assessed delivering electrical conditioning stimuli to the median nerve at the wrist prior to test TMS given at the interstimulus interval (ISI) of 2ms. Whereas RMT and the amplitude of unconditioned MEPs did not change after anodal tDCS, SLAI significantly increased. In conclusion, anodal tDCS-induced effects depend also on the modulation of cortical interneuronal circuits. The enhancement of cortical cholinergic activity assessed by SLAI could be an important mechanism explaining anodal tDCS action in several pathological conditions.