Acute Modulation of Brain Connectivity in Parkinson Disease after Automatic Mechanical Peripheral Stimulation: A Pilot Study.

OBJECTIVE: The present study shows the results of a double-blind sham-controlled pilot trial to test whether measurable stimulus-specific functional connectivity changes exist after Automatic Mechanical Peripheral Stimulation (AMPS) in patients with idiopathic Parkinson Disease. METHODS: Eleven patients (6 women and 5 men) with idiopathic Parkinson Disease underwent brain fMRI immediately before and after sham or effective AMPS. Resting state Functional Connectivity (RSFC) was assessed using the seed-ROI based analysis. Seed ROIs were positioned on basal ganglia, on primary sensory-motor cortices, on the supplementary motor areas and on the cerebellum. Individual differences for pre- and post-effective AMPS and pre- and post-sham condition were obtained and first entered in respective one-sample t-test analyses, to evaluate the mean effect of condition. RESULTS: Effective AMPS, but not sham stimulation, induced increase of RSFC of the sensory motor cortex, nucleus striatum and cerebellum. Secondly, individual differences for both conditions were entered into paired group t-test analysis to rule out sub-threshold effects of sham stimulation, which showed stronger connectivity of the striatum nucleus with the right lateral occipital cortex and the cuneal cortex (max Z score 3.12) and with the right anterior temporal lobe (max Z score 3.42) and of the cerebellum with the right lateral occipital cortex and the right cerebellar cortex (max Z score 3.79). CONCLUSIONS: Our results suggest that effective AMPS acutely increases RSFC of brain regions involved in visuo-spatial and sensory-motor integration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that automatic mechanical peripheral stimulation is effective in modulating brain functional connectivity of patients with Parkinson Disease at rest. TRIAL REGISTRATION: Clinical Trials.gov NCT01815281.

Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients.

AIM: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients. METHODS: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson's disease (PD). Each patient underwent Unified Parkinson's Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores. RESULTS: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor. CONCLUSIONS: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients.

1-Hz repetitive transcranial magnetic stimulation increases cerebral vasomotor reactivity: a possible autonomic nervous system modulation.

BACKGROUND: Neuromodulation techniques, i.e. repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can modify cerebral hemodynamics. High frequency rTMS appeared to decrease cerebral vasomotor reactivity (VMR), while there is still poor evidence about the effect of low frequency (LF) rTMS on cerebral blood flow (CBF) and VMR. HYPOTHESIS: The present study aimed to test if LF rTMS decreases CBF and increases cerebral VMR. Monolateral or bilateral hemispheric involvement and duration of the effect were considered. A possible role of autonomic nervous system in CBF and VMR modulation was also investigated. METHODS: Twenty-four right-handed healthy subjects underwent randomly real (12) or sham (12) 20-min 1-Hz rTMS on left primary motor cortex. Mean flow velocity and VMR of middle cerebral arteries were evaluated by means of transcranial Doppler before (T0), after 10 min (T1) and after 2 (T2), 5 (T3) and 24 h (T4) from rTMS. Heart rate variability (HRV) was studied within the same timing interval, assessing low frequency/high frequency (LF/HF) ratio as index of autonomic balance. RESULTS: After real rTMS compared with sham stimulation, MFV decreased bilaterally at T1 (F = 3.240, P = .030) while VMR increased bilaterally (F = 5.116, P = .002) for at least 5 h (T3). LF/HF ratio decreased early after real rTMS (F = 2.881, P = .040). CONCLUSION: 1-Hz rTMS may induce a bilateral long-lasting increase of VMR, while its effect on MFV is short-lasting. Moreover, HRV changes induced by rTMS suggest a possible autonomic nervous system modulation.

Relationship among diffusion tensor imaging, EEG activity, and cognitive status in mild cognitive impairment and Alzheimer's disease patients.

Magnetic resonance (MR) diffusion tensor imaging (DTI) can detect microstructural alterations by means of fractional anisotropy (FA) in patients with dementia, also in relation to cognitive status. The present study aimed at investigating the possible relation among white matter damage in DTI, quantitative electroencephalography (EEG) spectral power, and cognitive status in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients. Forty-seven subjects (8 moderate AD, 18 mild AD, 12 MCI, and 9 healthy controls) underwent brain MR, neuropsychological evaluation, and resting EEG recording. A progressive increase of EEG delta and theta spectral power was observed from controls to patients, mainly in more anterior areas, with a parallel widespread decrease of beta power. Moreover, a progressive decrease of FA from controls to patients in frontal areas and in the corpus callosum (genu) was observed. Correlation analyses indicated convergence among EEG rhythms changes, DTI values, and cognitive status mainly over anterior areas. The decrease of FA values and EEG spectral power changes might represent markers of neurodegenerative dysfunction, possibly preceding macrostructural atrophy.

The spontaneous fluctuation of the excitability of a single node modulates the internodes connectivity: a TMS-EEG study.

Brain effective connectivity can be tracked by cerebral recruitments evoked by transcranial magnetic stimulation (TMS), as measured by simultaneous electroencephalography (TMS-EEG). When TMS is targeting the primary motor area, motor evoked potentials (MEPs) can be collected from the "target" muscles. The aim of this study was to measure whether or not effective brain connectivity changes with the excitability level of the corticospinal motor pathway (CSMP) as parameterized by MEP amplitude. After averaging two subgroups of EEG-evoked responses corresponding to high and low MEP amplitudes, we calculated the individual differences between them and submitted the grand average to sLORETA algorithm obtaining localized regions of interest (RoIs). Statistical differences of RoI recruitment strength between low and high CSMP excitation was assessed in single subjects. Preceding the feedback arrival, neural recruitment for stronger CSMP activation were weaker at 6-10 ms of homotopic sensorimotor areas BA3/4/5 of the right nonstimulated hemisphere (trend), weaker at 18-25 ms of left parietal BA2/3/40, and stronger at 26-32 ms of bilateral frontal motor areas BA6/8. The proposed method enables the tracking of brain network connectivity during stimulation of one node by measuring the strength of the connected recruited node activations. Spontaneous increases of the excitation of the node originating the transmission within the hand control network gave rise to dynamic recruitment patterns with opposite behaviors, weaker in homotopic and parietal circuits, stronger in frontal ones. The effective connectivity within bilateral circuits orchestrating hand control appeared dynamically modulated in time even in resting state as probed by TMS.

Fe and Cu do not differ in Parkinson's disease: a replication study plus meta-analysis.

To evaluate whether iron and copper levels in serum, plasma, and cerebrospinal fluid are disarranged in Parkinson's disease (PD), we performed meta-analyses of 33 studies on the topic published from 1987 to 2011 and contextually carried out a replication study in serum by ourselves as well. We found no variation in metals between PD patients and healthy controls, according to our replication study. The metaregression for sex revealed that serum copper differences found in some studies could be referred to the different percentage of women in the PD sample. Transferrin and transferrin saturation levels found increased in PD subjects underline the concept to extend the iron study in PD to iron master proteins.

Mobile phone emission modulates inter-hemispheric functional coupling of EEG alpha rhythms in elderly compared to young subjects.

OBJECTIVE: It has been reported that GSM electromagnetic fields (GSM-EMFs) of mobile phones modulate--after a prolonged exposure--inter-hemispheric synchronization of temporal and frontal resting electroencephalographic (EEG) rhythms in normal young subjects [Vecchio et al., 2007]. Here we tested the hypothesis that this effect can vary on physiological aging as a sign of changes in the functional organization of cortical neural synchronization. METHODS: Eyes-closed resting EEG data were recorded in 16 healthy elderly subjects and 5 young subjects in the two conditions of the previous reference study. The GSM device was turned on (45 min) in one condition and was turned off (45 min) in the other condition. Spectral coherence evaluated the inter-hemispheric synchronization of EEG rhythms at the following bands: delta (about 2-4 Hz), theta (about 4-6 Hz), alpha 1 (about 6-8 Hz), alpha 2 (about 8-10 Hz), and alpha 3 (about 10-12 Hz). The aging effects were investigated comparing the inter-hemispheric EEG coherence in the elderly subjects vs. a young group formed by 15 young subjects (10 young subjects of the reference study; Vecchio et al., 2007). RESULTS: Compared with the young subjects, the elderly subjects showed a statistically significant (p<0.001) increment of the inter-hemispheric coherence of frontal and temporal alpha rhythms (about 8-12 Hz) during the GSM condition. CONCLUSIONS: These results suggest that GSM-EMFs of a mobile phone affect inter-hemispheric synchronization of the dominant (alpha) EEG rhythms as a function of the physiological aging. SIGNIFICANCE: This study provides further evidence that physiological aging is related to changes in the functional organization of cortical neural synchronization.

Muscles in "concert": study of primary motor cortex upper limb functional topography.

BACKGROUND: Previous studies with Transcranial Magnetic Stimulation (TMS) have focused on the cortical representation of limited group of muscles. No attempts have been carried out so far to get simultaneous recordings from hand, forearm and arm with TMS in order to disentangle a 'functional' map providing information on the rules orchestrating muscle coupling and overlap. The aim of the present study is to disentangle functional associations between 12 upper limb muscles using two measures: cortical overlapping and cortical covariation of each pair of muscles. Interhemispheric differences and the influence of posture were evaluated as well. METHODOLOGY/PRINCIPAL FINDINGS: TMS mapping studies of 12 muscles belonging to hand, forearm and arm were performed. Findings demonstrate significant differences between the 66 pairs of muscles in terms of cortical overlapping: extremely high for hand-forearm muscles and very low for arm vs hand/forearm muscles. When right and left hemispheres were compared, overlapping between all possible pairs of muscles in the left hemisphere (62.5%) was significantly higher than in the right one (53.5% ). The arm/hand posture influenced both measures of cortical association, the effect of Position being significant [p = .021] on overlapping, resulting in 59.5% with prone vs 53.2% with supine hand, but only for pairs of muscles belonging to hand and forearm, while no changes occurred in the overlapping of proximal muscles with those of more distal districts. CONCLUSIONS/SIGNIFICANCE: Larger overlapping in the left hemisphere could be related to its lifetime higher training of all twelve muscles studied with respect to the right hemisphere, resulting in larger intra-cortical connectivity within primary motor cortex. Altogether, findings with prone hand might be ascribed to mechanisms facilitating coupling of muscles for object grasping and lifting -with more proximal involvement for joint stabilization- compared to supine hand facilitating actions like catching. TMS multiple-muscle mapping studies permit a better understanding of motor control and 'plastic' reorganization of motor system.

Phosphatidylinositol 3-kinase, protein kinase C, and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites.

The dopamine transporter (DAT) modulates dopamine neurotransmission and is a primary target for psychostimulant influences on locomotion and reward. Selective DAT expression by dopaminergic neurons has led to use of cocaine analog DAT radioligands to assess rates of progression of dopamine neuronal degeneration in Parkinson's disease. We have documented that DAT is a phosphoprotein that is regulated by phosphorylation through pathways that include protein kinase C cascades. We now extend this work using drugs selective for phosphatidylinositol 3-kinase (PI3K), protein kinase C, MEK1/2, p38 kinase, and Ca2+/calmodulin kinase II. We compare the drug effects on wild type DAT to the effects on 20 DAT mutants and a DAT deletion. PI3K and MEK1/2 modulators exert strong effects on DAT expression patterns and dopamine uptake Vmax. PKC principally modulates Vmax. Neither p38 nor Ca2+/calmodulin kinase II agents exert significant influences on wild type DAT. Several mutants and a DAT with an N-terminal deletion display alterations that interact with the effects of kinase modulators, especially S7A for PKC effects; T62A, S581A, and T612A for PI3K effects; and S12A and T595A mutants for MEK1/2 effects. 32P-Labeling studies confirm several of these effects of kinase pathway modulators on DAT phosphorylation. DAT expression and activities can be regulated by kinase cascades that require phosphoacceptor sites most concentrated in its N terminus. These results have a number of implications for DAT regulation and mandate caution in using DAT radioligand binding to infer changes in dopaminergic neuronal integrity after treatments that alter activities of these kinase pathways.