Sergio Barbieri

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 improves recognition memory in Alzheimer disease

Objective: To evaluate the cognitive effect of transcranial direct current stimulation (tDCS) over the temporoparietal areas in patients with Alzheimer disease (AD). Methods: In 10 patients with probable AD, we delivered anodal tDCS (AtDCS), cathodal tDCS (CtDCS), and sham tDCS (StDCS) over the temporoparietal areas in three sessions. In each session recognition memory and visual attention were tested at baseline (prestimulation) and 30 minutes after tDCS ended (poststimulation). Results: After AtDCS, accuracy of the word recognition memory task increased (prestimulation: 15.5 ± 0.9, poststimulation: 17.9 ± 0.8, p = 0.0068) whereas after CtDCS it decreased (15.8 ± 0.6 vs 13.2 ± 0.9, p = 0.011) and after StDCS it remained unchanged (16.3 ± 0.7 vs 16.0 ± 1.0, p = 0.75). tDCS left the visual attention-reaction times unchanged. Conclusion: Transcranial direct current stimulation (tDCS) delivered over the temporoparietal areas can specifically affect a recognition memory performance in patients with Alzheimer disease (AD). Because tDCS is simple, safe and inexpensive, our finding prompts studies using repeated tDCS, in conjunction with other therapeutic interventions for treating patients with AD.

Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory

How the cerebellum is involved in the practice and proficiency of non-motor functions is still unclear. We tested whether transcranial direct current stimulation (tDCS) over the cerebellum (cerebellar tDCS) induces after-effects on the practice-dependent increase in the proficiency of a working memory (WM) task (Sternberg test) in 13 healthy subjects. We also assessed the effects of cerebellar tDCS on visual evoked potentials (VEPs) in four subjects and compared the effects of cerebellar tDCS on the Sternberg test with those elicited by tDCS delivered over the prefrontal cortex in five subjects. Our experiments showed that anodal or cathodal tDCS over the cerebellum impaired the practice-dependent improvement in the reaction times in a WM task. Because tDCS delivered over the prefrontal cortex induced an immediate change in the WM task but left the practice-dependent proficiency unchanged, the effects of cerebellar tDCS are structure-specific. Cerebellar tDCS left VEPs unaffected, its effect on the Sternberg task therefore seems unlikely to arise from visual system involvement. In conclusion, tDCS over the cerebellum specifically impairs the practice-dependent proficiency increase in verbal WM.

Improved isometric force endurance after transcranial direct current stimulation over the human motor cortical areas

Neuromuscular fatigue is the exercise‐dependent decrease in the ability of muscle fibres to generate force. To investigate whether manipulation of brain excitability by transcranial direct current stimulation (tDCS; 1.5 mA, 10 min, 0.026 C/cm2) modulates neuromuscular fatigue, we evaluated the effect of brain polarization over the right motor areas of the cerebral cortex of healthy subjects on the endurance time for a submaximal isometric contraction of left elbow flexors. In 24 healthy volunteers the study protocol comprised an assessment of the maximum voluntary contraction (MVC) for the left elbow flexors and a fatiguing isometric contraction (35% of MVC), before and immediately after brain polarization. One hour elapsed between baseline (T0) and postconditioning (T1) evaluation. After tDCS, MVC remained unchanged from baseline (mean ± SEM; anodal tDCS: T0, 154.4 ± 18.07; T1, 142.8 ± 16.62 N; cathodal tDCS: T0, 156 ± 18.75; T1, 141.86 ± 17.53 N; controls: T0, 148.8 ± 6.64; T1, 137.6 ± 7.36 N; P > 0.1). Conversely, endurance time decreased significantly less after anodal than after cathodal tDCS or no stimulation (−21.1 ± 5.5%, −35.7 ± 3.3% and −39.3 ± 3.3%, respectively; P < 0.05). None of the evaluated electromyographic variables changed after tDCS. Anodal tDCS could improve endurance time by directly modulating motor cortical excitability, modulating premotor areas, decreasing fatigue‐related muscle pain, increasing motivation and improving synergist muscle coupling. Our findings, showing that anodal tDCS over the motor areas of the cerebral cortex improves muscle endurance, open the way to increasing muscle endurance and decreasing muscle fatigue in normal (i.e. sports medicine) and pathological conditions.

High‐dose intravenous immunoglobulin therapy in multifocal motor neuropathy

We treated five consecutive patients with multifocal motor neuropathy (MMN) with high-dose intravenous immunoglobulin (IVIg). Four patients had increased levels of anti-asialo-GM1 IgM and two of anti-GM1 IgM as well; one patient had no reactivity. We treated them twice with 0.4 g/kg IVIg for 5 consecutive days at a 2-month interval, followed by maintenance infusions up to 6 to 12 months. All patients with high anti-asialo-GM1 had a consistent clinical improvement starting 3 to 10 days after the first IVIg course; in one patient, recovery was complete and persistent for 12 months without additional treatment, while in three patients, improvement only lasted 20 to 30 days. There was a similar improvement in these patients after the second course of IVIg which was maintained by periodic 2-day IVIg infusions. Clinical improvement in these patients was associated with a reduction of conduction block in most, but not all, motor nerves, while antibody titers were not consistently modified by treatment. There was no clinical or electrophysiologic improvement in the patient without antiglycolipid activity after 6 months of IVIg. IVIg may be a safe and effective therapy for MMN.

Movement-related modulation of neural activity in human basal ganglia and its L-DOPA dependency: recordings from deep brain stimulation electrodes in patients with Parkinson's disease.

Abstract. Through electrodes implanted for deep brain stimulation in three patients (5 sides) with Parkinsons disease, we recorded the electrical activity from the human basal ganglia before, during and after voluntary contralateral finger movements, before and after L-DOPA. We analysed the movement-related spectral changes in the electroencephalographic signal from the subthalamic nucleus (STN) and from the internal globus pallidus (GPi). Before, during and after voluntary movements, signals arising from the human basal ganglia contained two main frequencies: a high β (around 26 Hz), and a low β (around 18 Hz). The high β (around 26 Hz) power decreased in the STN and GPi, whereas the low β (around 18 Hz) power decrease was consistently found only in the GPi. Both frequencies changed their power with a specific temporal modulation related to the different movement phases. L-DOPA specifically and selectively influenced the spectral power changes in these two signal bands.

Limb immobilization for the treatment of focal occupational dystonia

Background: Occupational focal upper-limb dystonia is characterized by involuntary muscle contractions that selectively interfere with the execution of specific motor tasks such as writing or playing a musical instrument. Occupational dystonias have a severe social impact, especially in certain professions. The available medical treatments offer little benefit. Methods: In eight patients with idiopathic occupational focal dystonia of the upper limb, the dystonic forearm and hand were immobilized with a plastic splint for mean (±SD) 4.5 ± 0.75 weeks. Before splinting (base line) and at various intervals afterwards (4, 12, and 24 weeks), the authors assessed the severity of dystonia and the patients’ motor performance objectively (Arm Dystonia Disability Scale and Tubiana and Chamagne Score) and subjectively (Self-Rating Score). Results: Assessment 4 weeks after splint removal, when patients had regained normal voluntary movements, showed that the severity of dystonia and the patients’ performance of the impaired motor task had improved; the benefit persisted unchanged at later follow-up visits (Arm Dystonia Disability Scale: base line 20.6 ± 30.2%; after 4 weeks 83.9 ± 23.8%, p = 0.007; after 12 weeks 83.9 ± 23.8%, p = 0.007; after 24 weeks 79.7 ± 29.5%, p = 0.015. Tubiana and Chamagne Score: base line 28.6 ± 22.7%; after 4 weeks 80.0 ± 23.1%, p = 0.015; after 12 weeks 80.0 ± 23.1%, p = 0.015; after 24 weeks 74.3 ± 32.1%, p = 0.031. Self-Rating Score: base line 20.6 ± 19.3%; after 4 weeks 63.7 ± 25.2%, p = 0.015; after 12 weeks 66.9 ± 28.1%, p = 0.015; after 24 weeks 70.6 ± 31.8%, p = 0.015). At the 24-week visit the improvement disappeared in one patient, was moderate in three, and marked in four. Conclusions: Limb immobilization can be a simple, effective, safe, and inexpensive treatment for focal occupational upper-limb dystonia.

Peripheral neuropathy in macroglobulinemia: Incidence and antigen‐specificity of M proteins

Peripheral neuropathy was found in 12 (46%) of 26 patients with macroglobulinemia. The neuropathy was subclinical in two. Anti-myelin-associated glycoprotein (MAG) activity was found in six (50%) patients with neuropathy. Sural nerve biopsies showed demyelination and IgM deposits on the myelin sheath. In one patient who had no anti-MAG activity, the serum IgM bound to peripheral myelin by indirect immunofluorescence and to several protein bands in peripheral nerve and other tissues by immunoblot. In the other five patients with neuropathy, we found no binding of M proteins to nerve components, but in three patients there were endoneurial IgM deposits in nerve biopsy. Peripheral neuropathy may be related to the antigen-specificity of M proteins.

How long is IVIg effective in multifocal motor neuropathy

The authors treated 10 patients with multifocal motor neuropathy (MMN) responding to an initial course of IV immunoglobulin (IVIg) with periodic infusion for 5 to 12 years (mean 8.2 years). At last follow-up, only two patients had maintained the maximal improvement achieved during therapy while eight worsened despite increasing Ig dosage. This decline started after 3 to 7 years (mean 4.8 years) of therapy and correlated with a reduction of distal compound muscle action potential amplitudes (p < 0.019). The effectiveness of IVIg in MMN often declines after several years possibly associated with the development of axonal degeneration.

Deterioration of multifocal motor neuropathy after plasma exchange

We report a patient with motor neuropathy in whom plasma exchange (PE) was followed by a pronounced clinical worsening with the appearance of conduction blocks in previously clinically unaffected motor nerves, leading to the diagnosis of multifocal motor neuropathy (MMN). This report highlights the different response to therapy of MMN and chronic inflammatory demyelinating polyneuropathy (CIDP) because not only steroids but also PE, which is often effective in CIDP, do not improve and at times may even worsen MMN.