Patrizia Giacomini

Ipsilateral activation of the unaffected motor cortex in patients with hemiparetic stroke

BACKGROUND AND PURPOSE Recent research has shown that following stroke patients can display ipsilateral activity reflecting a functional link between the undamaged hemisphere and the affected upper limb on the same side of the body. In the present study the capacity for ipsilateral activation is documented during recovery by using transcranial magnetic stimulation (TMS) and transcranial Doppler (TCD). METHODS Fourteen patients affected by hemispheric stroke were examined with TMS and TCD within 48 h of onset, and again 6 months later. Neurological signs were scored with reference to the NIHSS, and patients executed a thumb to finger opposition task so as to further estimate the motor deficit. Twenty healthy volunteers represented the control population. RESULTS (1) Both TMS and TCD yielded homogeneous results showing ipsilateral activity between affected hands and undamaged hemispheres. On stimulating the motor cortex 3 cm anterior and 3 cm lateral to Cz, a scalp site remote from the primary motor area, ipsilateral motor evoked potentials (iMEPs) from hand muscles were found in recovered patients. (2) In 8 controls iMEPs with smaller amplitudes than patients could be obtained by stimulating only the left hemisphere. (3) TCD revealed increased blood flow velocity in the ipsilateral MCA by activating the recovering hand (10.5+/-3.3%; P<0.001). CONCLUSION TMS reveals a specific area in the motor cortex from which ipsilateral MEPs can be elicited and both TMS and TCD indicate that an ipsilateral corticospinal tract can be accessible in some adult controls or becomes unmasked after cerebral damage.

The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons.

A clear picture of the mechanisms of action of the anti-epileptic agent gabapentin is far from being accomplished. We have analyzed the effects of gabapentin on ligand- and voltage-gated currents in isolated adult rat cortical neurons. Gabapentin failed to modify glutamate currents and produced a slight reduction of GABA responses. Negligible inhibition of sodium, but consistent inhibition of high-voltage-activated calcium conductance was promoted by gabapentin. In addition, gabapentin reduced calcium current sensitivity to dihydropyridine agonist and antagonists. Interestingly, gabapentin also decreased a not-inactivating, cadmium-sensitive, potassium current. These unconventional effects might underlie its efficacy in a variety of diseases which involve periodic discharge patterns as neuropathic pain or essential tremor.

Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study

OBJECTIVE We investigated the effect of bilateral subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on intracortical inhibition (ICI) in patients with advanced Parkinsons disease (PD). METHODS The activity of intracortical inhibitory circuits was studied in 4 PD patients implanted with stimulating electrodes both in STN and GPi by means of paired-pulse transcranial magnetic stimulation, delivered in a conditioning-test design at short (1-6 ms) interstimulus intervals (ISI). The effect of apomorphine on the same PD patients was also investigated. RESULTS We observed that implanted PD patients showed a significant increase in ICI during either bilateral STN or GPi DBS at 3 ms ISI, and during bilateral STN DBS at 2 ms ISI in comparison to their off DBS condition. The same statistical improvement was observed during apomorphine infusion at 3 and 2 ms ISI. In each condition, the electrophysiological changes were associated with a significant clinical improvement as measured by the Unified Parkinsons Disease Rating Scale motor examination. CONCLUSIONS These results are consistent with the hypothesis that basal ganglia DBS can mimic the effects of pharmacological dopaminergic therapy on PD patients cortical activity. We propose that in PD patients, the basal ganglia DBS-induced improvement of ICI may be related to a recovery in modulation of thalamo-cortical motor pathway.

Ionic mechanisms underlying differential vulnerability to ischemia in striatal neurons

Brain cells express extremely different sensitivity to ischemic insults. The reason for this differential vulnerability is still largely unknown. Here we discuss the ionic bases underlying the physiological responses to in vitro ischemia in two neostriatal neuronal subtypes exhibiting respectively high sensitivity and high resistance to energy deprivation. Vulnerable neostriatal neurons respond to ischemia with a membrane depolarization. This membrane depolarization mainly depends on the increased permeability to Na+ ions. In contrast, resistant neostriatal neurons respond to ischemia with a membrane hyperpolarization due to the opening of K+ channels. Interestingly, in both neuronal subtypes the ischemia-dependent membrane potential changes can be significantly enhanced or attenuated by a variety of pharmacological agents interfering with intracellular Ca2+ entry, ATP-dependent K+ channels opening, and Na+/Ca2+ exchanger functioning. The understanding of the ionic mechanisms underlying the differential membrane responses to ischemia represents the basis for the development of rational neuroprotective treatments during acute cerebrovascular insults.

Quantitative EEG and dynamic susceptibility contrast MRI in Alzheimer's disease: a correlative study

OBJECTIVE To investigate the relationship between the electroencephalographic (EEG) power spectra features obtained by quantitative EEG (qEEG) and the hemodynamic parameters detected by dynamic susceptibility contrast-enhanced MR imaging (DSC MRI) in patients with Alzheimers disease (AD). METHODS Fourteen patients with probable AD and 15 elderly healthy controls were included in the study. All subjects underwent both EEG recording in a rest condition and perfusion MRI. Three EEG scalp areas were defined (anterior, central and posterior) and power spectra values were obtained from each scalp area. Relative values of temporoparietal and sensorimotor regional cerebral blood volume (rCBV) were measured bilaterally and successively averaged to obtain a total perfusion index. The brain atrophy index was calculated and used as a covariate to rCBV. Correlation analysis was performed between EEG variables and hemodynamic-morphological parameters. RESULTS qEEG power spectra of AD patients were characterized by an increase in mean relative power of theta (4-7.75 Hz) associated with a decrease in alpha (8-12.75 Hz) frequency bands with a topographic distribution over the central and posterior EEG scalp regions, when compared with controls; beta (13-31 Hz) frequency band also displayed a significant decrease over the anterior and posterior EEG scalp regions of AD patients with respect to controls. The DSC MRI revealed a bilateral reduction in the temporoparietal and sensorimotor rCBV with respect to controls. Correlation analysis showed that the total level of hypoperfusion selectively correlates with the EEG power spectra in theta and alpha frequency bands distributed over anterior/central and central region, respectively. Within AD patients, the lower the level of hypoperfusion, the higher the content of EEG power spectra in theta frequency band, and the lower the level of hypoperfusion, the lower the content of EEG power spectra in alpha band. CONCLUSIONS The combined qEEG and DSC MRI technology unveiled a selective correlation between neurophysiological and hemodynamical patterns in AD patients. Further investigations will ascertain the relevance of this multi-modal approach in the heterogeneous clinical context of AD.

Stimulation of Nitric Oxide–cGMP Pathway Excites Striatal Cholinergic Interneurons via Protein Kinase G Activation

Conflicting data have been collected so far on the action of nitric oxide (NO) on cholinergic interneurons of the striatum. In the presentin vitro electrophysiological study, we reported that intracellularly recorded striatal cholinergic interneurons are excited by both hydroxylamine andS-nitroso-N-acetylpenicillamine, two NO donors. This excitation persisted unchanged in the presence of glutamate, dopamine, and substance P receptor antagonists as well as after blockade of tetrodotoxin (TTX)- and calcium channel-sensitive transmitter release, suggesting that NO produces its effects by modulating directly resting ion conductances in the somatodendritic region of striatal cholinergic cells. The depolarizing effect of hydroxylamine was greatly reduced by lowering external concentrations of sodium ions (from 126 to 38 mm) and did not reverse polarity in the voltage range from −120 to −40 mV. The sodium transporter blockers bepridil and 3′,4′-dichlorobenzamil were conversely ineffective in preventing NO-induced membrane depolarization. Intracellular cGMP elevation is required for the action of hydroxylamine on striatal cholinergic cells, as demonstrated by the findings that the membrane depolarization produced by this pharmacological agent was prevented by bath and intracellular application of two inhibitors of soluble guanylyl cyclase and was mimicked and occluded by zaprinast, a cGMP phosphodiesterase inhibitor. Finally, intracellular Rp-8-Br-cGMPS, a protein kinase G (PKG) inhibitor, blocked the hydroxylamine-induced membrane depolarization of cholinergic interneurons, whereas both okadaic acid and calyculin A, two protein phosphatase inhibitors, enhanced it, indicating that intracellular PKG and phosphatases oppositely regulate the sensitivity of striatal cholinergic interneurons to NO. The characterization of the cellular mechanisms involved in the regulation of striatal interneuron activity is a key step for the understanding of the role of these cells in striatal microcircuitry.

Nitrergic neurons make synapses on dual-input dendritic spines of neurons in the cerebral cortex and the striatum of the rat: Implication for a postsynaptic action of nitric oxide

Pre-embedding electron microscopic immunocytochemistry was used to examine the ultrastructure of neurons containing nitric oxide synthase and to evaluate their synaptic relationships with target neurons in the striatum and sensorimotor cerebral cortex. Intense nitric oxide synthase immunoreactivity was found by light and electron microscopy in a type of aspiny neuron scattered in these two regions. The intensity of the labeling was uniform in the soma, dendrites and axon terminals of these neurons. In both forebrain regions, nitric oxide synthase-immunoreactive neurons received synaptic contacts from unlabeled terminals, which were mostly apposed to small-caliber dendrites. The unlabeled symmetric contacts were generally about four times as abundant as the unlabeled asymmetric contacts on the nitric oxide synthase-immunoreactive neurons. Terminals labeled for nitric oxide synthase were filled with synaptic vesicles and were observed to contact unlabeled neurons. Only 54% (in the cerebral cortex) and 44.3% (in the striatum) of the nitric oxide synthase-immunoreactive terminals making apposition with the target structures were observed to form synaptic membrane specializations within the plane of the randomly sampled sections. The most common targets of nitric oxide synthase-immunoreactive terminals were thin dendritic shafts (54% of the immunoreactive terminals in the cortex and 75.7% of the immunoreactive terminals in the striatum), while dendritic spines were a common secondary target (42% of the immunoreactive terminals in the cortex and 20.6% of the immunoreactive terminals in the striatum). The spines contacted by nitric oxide synthase-immunoreactive terminals typically also received an asymmetric synaptic contact from an unlabeled axon terminal. These findings suggest that: (i) nitric oxide synthase-immunoreactive neurons in the cortex and striatum preponderantly receive inhibitory input; (ii) nitric oxide synthase-containing terminals commonly make synaptic contact with target structures in the cortex and striatum; (iii) spines targeted by nitric oxide synthase-containing terminals in the cortex and striatum commonly receive an asymmetric contact as well, which may provide a basis for a synaptic interaction of nitric oxide with excitatory input to individual spines.

Neurological Involvement in Primary Sjögren Syndrome: A Focus on Central Nervous System

Objectives Sjögren syndrome is an autoimmune disease involving mainly salivary and lacrimal glands. Beyond widely described PNS involvement, high variable prevalence of CNS manifestations ranging from 2.5 and 60% of all pSS patients has been reported, without specific syndrome definition. The aim of this cohort study was to evaluate the prevalence of CNS signs and symptoms in pSS patients and to identify possible biomarkers of CNS damage. Methods 120 patients with pSS diagnosis according to the 2002 American-European Consensus Group criteria were enrolled after exclusion of secondary causes. All patients underwent to a wide neurological, neuropsychological, psychiatric, neuroradiological and ultrasonographic evaluation. Results Central and peripheral nervous system involvement was observed in 81 patients with a prevalence of 67.5%. The prevalence of CNS involvement was significantly higher than PNS disease (p 0.001). 68 patients (84%) shown non-focal CNS symptoms and 64 (79%) focal CNS deficits with headache as the most common feature (46.9%), followed by cognitive (44.4%) and mood disorders (38.3%). Particularly, we observed a high prevalence of migraine without aura, subcortical frontal executive functions and verbal memory impairment and apathy/alexythimia. MR spectroscopy revealed a reduction of NAA levels or NAA/Cr ratio decrease in subcortical frontal and basal ganglia white matter, while ultrasonography showed an impairment of microvasculature response. At multivariate analysis, headache, cognitive disorders and psychiatric symptoms was significantly associated to serological markers (anti-SSA), MRS and ultrasonographic features. Conclusions The higher prevalence of MWO-mimic headache, cognitive dys-esecutive syndrome and mood disorders observed in this series confirmed previous evidences of a higher diffused CNS compromission rather than focal involvement such as SM-like clinical course or NMO-like syndrome. The association with immunological biomarkers, metabolic cerebral dysfunction and microvascular damage suggests a possible endothelial dysfunction of the cerebral microcirculation or a potential inflammation-mediated shift of the neurovascular coupling.

The action of GABA on rat caudate neurones recorded intracellularly

Recent neurophysiologlcal investigations have shown that GABA can be a putative inhibitory neurotransmitter in some structures of cat central nervous system~,4,9,11. Considering the high labelling of nerve terminals by [aH]GABA in the rat caudate nucleus 8, we undertook to study the action of iontophoretically released GABA. The drug was applied extracellularly on rat caudate neurones whose activity was recorded intracellularly and extracellularly. The experiments were performed on male Wistar rats (250-300 g) anaesthetized with ether.!At the end of the prepara-

Cerebrovascular CO2 reactivity in migraine with aura and without aura. A transcranial doppler study

Inntroduction– We studied by means of Transcranial Doppler (TCD) recordings the CO2 cerebrovascular reactivity in migraine patients during the headache‐free period. Material & methods ‐ In three groups of subjects (15 controls, 15 suffering from migraine with aura and 15 from migraine without aura) the middle cerebral artery (MCA) mean flow velocity (MFV) was recorded under basal condition and hypocapnia induced by hyperventilation. Relative MFV, PI (Pulsatility Index) changes and Reactivity Index (RI) were calculated. Results ‐ Reactivity Index values were: 0.019 ± 0.007 (mean ± SD) in control subjects: 0.029 ± 0.008 in migraine with aura; 0.022 ± 0.008 in migraine without aura. Statistical analysis showed a significantly (P < 0.05) increased RI in migraine with aura group. Conclusion– Cerebrovascular CO2 reactivity is increased during the interictal period in migraine with aura patients.