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1.  Movement Preparation and Bilateral Modulation of Beta Activity in Aging and Parkinson’s Disease 
PLoS ONE  2015;10(1):e0114817.
In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson’s disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.
PMCID: PMC4312096  PMID: 25635777
2.  Sativex in the Management of Multiple Sclerosis-Related Spasticity: Role of the Corticospinal Modulation 
Neural Plasticity  2015;2015:656582.
Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, and Hmax/Mmax ratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability.
PMCID: PMC4325203
3.  Emerging Concepts in the Physiological Basis of Dystonia 
Work over the past two decades has led to substantial changes in our understanding of dystonia pathophysiology. Three general abnormalities appear to underlie the pathophysiological substrate. The first line is a loss of inhibition. This makes sense considering that it may be responsible for the excess of movement and for the overflow phenomena seen in dystonia. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Third, evidence from animal models of dystonia as well as from patients with primary dystonia has revealed significant alterations of synaptic plasticity characterised by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. We speculate that during motor learning this abnormal plasticity may lead to an abnormal sensorimotor integration leading to consolidation of abnormal motor engrams. If so, then removing this abnormal plasticity might have little immediate effect on dystonic movements because bad motor memories have already been “learned” and are difficult to erase. These considerations might explain the delayed clinical effects of DBS in patients with generalized dystonia. Current lines of research will be discussed from a network perspective.
PMCID: PMC4159671  PMID: 23893452
4.  Defective cerebellar control of cortical plasticity in writer’s cramp 
Brain  2013;136(7):2050-2062.
A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer’s cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients’ maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (−40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer’s cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer’s cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer’s cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing.
PMCID: PMC3692031  PMID: 23801734
cerebellum; dystonia; plasticity; transcranial magnetic stimulation; sensorimotor adaptation
5.  Sensory Abnormalities in Focal Hand Dystonia and Non-Invasive Brain Stimulation 
It has been proposed that synchronous and convergent afferent input arising from repetitive motor tasks may play an important role in driving the maladaptive cortical plasticity seen in focal hand dystonia (FHD). This hypothesis receives support from several sources. First, it has been reported that in subjects with FHD, paired associative stimulation produces an abnormal increase in corticospinal excitability, which was not confined to stimulated muscles. These findings provide support for the role of excessive plasticity in FHD. Second, the genetic contribution to the dystonias is increasingly recognized indicating that repetitive, stereotyped afferent inputs may lead to late-onset dystonia, such as FHD, more rapidly in genetically susceptible individuals. It can be postulated, according to the two factor hypothesis that dystonia is triggered and maintained by the concurrence of environmental factors such as repetitive training and subtle abnormal mechanisms of plasticity within somatosensory loop. In the present review, we examine the contribution of sensory-motor integration in the pathophysiology of primary dystonia. In addition, we will discuss the role of non-invasive brain stimulation as therapeutic approach in FHD.
PMCID: PMC4257013  PMID: 25538594
sensory-motor integration; transcranial magnetic stimulation; cortical plasticity; LTP; rehabilitation; focal dystonia
6.  Constrained spherical deconvolution analysis of the limbic network in human, with emphasis on a direct cerebello-limbic pathway 
The limbic system is part of an intricate network which is involved in several functions like memory and emotion. Traditionally the role of the cerebellum was considered mainly associated to motion control; however several evidences are raising about a role of the cerebellum in learning skills, emotions control, mnemonic and behavioral processes involving also connections with limbic system. In 15 normal subjects we studied limbic connections by probabilistic Constrained Spherical Deconvolution (CSD) tractography. The main result of our work was to prove for the first time in human brain the existence of a direct cerebello-limbic pathway which was previously hypothesized but never demonstrated. We also extended our analysis to the other limbic connections including cingulate fasciculus, inferior longitudinal fasciculus, uncinated fasciculus, anterior thalamic connections and fornix. Although these pathways have been already described in the tractographic literature we provided reconstruction, quantitative analysis and Fractional Anisotropy (FA) right-left symmetry comparison using probabilistic CSD tractography that is known to provide a potential improvement compared to previously used Diffusion Tensor Imaging (DTI) techniques. The demonstration of the existence of cerebello-limbic pathway could constitute an important step in the knowledge of the anatomic substrate of non-motor cerebellar functions. Finally the CSD statistical data about limbic connections in healthy subjects could be potentially useful in the diagnosis of pathological disorders damaging this system.
PMCID: PMC4259125  PMID: 25538606
CSD; probabilistic tractography; cerebello-limbic pathway; cerebellum; hippocampus; limbic system; quantitative analysis; MRI
7.  Neural Activations during Visual Sequence Learning Leave a Trace in Post-Training Spontaneous EEG 
PLoS ONE  2013;8(6):e65882.
Recent EEG studies have shown that implicit learning involving specific cortical circuits results in an enduring local trace manifested as local changes in spectral power. Here we used a well characterized visual sequence learning task and high density-(hd-)EEG recording to determine whether also declarative learning leaves a post-task, local change in the resting state oscillatory activity in the areas involved in the learning process. Thus, we recorded hd-EEG in normal subjects before, during and after the acquisition of the order of a fixed spatial target sequence (VSEQ) and during the presentation of targets in random order (VRAN). We first determined the temporal evolution of spectral changes during VSEQ and compared it to VRAN. We found significant differences in the alpha and theta bands in three main scalp regions, a right occipito-parietal (ROP), an anterior-frontal (AFr), and a right frontal (RFr) area. The changes in frontal theta power during VSEQ were positively correlated with the learning rate. Further, post-learning EEG recordings during resting state revealed a significant increase in alpha power in ROP relative to a pre-learning baseline. We conclude that declarative learning is associated with alpha and theta changes in frontal and posterior regions that occur during the task, and with an increase of alpha power in the occipito-parietal region after the task. These post-task changes may represent a trace of learning and a hallmark of use-dependent plasticity.
PMCID: PMC3683043  PMID: 23799058
8.  Framing the Use of Social Media Tools in Public Health 
Recent scholarship has focused on using social media (e.g., Twitter, Facebook) as a secondary data stream for disease event detection. However, reported implementations such as (4) underscore where the real value may lie in using social media for surveillance. We provide a framework to illuminate uses of social media beyond passive observation, and towards improving active responses to public health threats.
User-generated content enabled by social media tools provide a stream of data that augment surveillance data. Current use of social media data focuses on identification of disease events. However, once identification occurs, the leveraging of social media in monitoring disease events remains unclear (2, 3). To clarify this, we constructed a framework mapped to the surveillance cycle, to understand how social media can improve public health actions.
This framework builds on extant literature on surveillance and social media found in PubMed, Science Direct, and Web of Science, using keywords: “public health”, “surveillance”, “outbreak”, and “social media”. We excluded articles on online tools that were not interactive e.g., aggregated web-search results. Of 2,064 articles, 23 articles were specifically on the use of social media in surveillance work. Our review yielded five categories of social media use within the surveillance cycle (Table 1). This framing within surveillance illuminates a range of roles for social media tools beyond disease event detection. [Insert Image #1 here]
Finally, we used the 1918 Influenza Pandemic to illustrate an application of this framework (Fig 1), if it were part of the public health toolkit. In 1918, America was already becoming a “mass media” society. Yet a key difference in mass communications today is the enabling of public health to be more adaptive through the interactivity of social media.
We used this “pre-social media” disease event to underscore where the real value of social media may lie in the surveillance cycle. Thus for 1918, early detection of disease could have occurred with many, e.g., sailors aboard ships in New York City’s port sharing their “status updates” with the world. [Insert Image #2 here]
After detection, social media use could have shifted to help connect and inform. In 1918, this could include identifying and advising the infected on current hygiene practices and how to protect themselves. Social media would have enabled the rapid sharing of this information to friends and family, allowing public health officials to monitor the response. Then, to support multiple intervention efforts, public health officials could have rapidly messaged on local school closures; they could also have encouraged peer behavior by posting via Twitter or by “Pinning” handkerchiefs on Pinterest to encourage respiratory etiquette, and then monitored responses to these interventions, adjusting messaging accordingly.
The interactivity of social media moves us beyond using these tools solely as uni-directional, mass-broadcast channels. Beyond messaging about disease events, these tools can simultaneously help inform, connect, and intervene because of the user-generated feedback. These tools enable richer use beyond a noisy data stream for detection.
PMCID: PMC3692914
Surveillance; Public Health; Social Media
9.  Brain-Derived Neurotrophic Factor – A Major Player in Stimulation-Induced Homeostatic Metaplasticity of Human Motor Cortex? 
PLoS ONE  2013;8(2):e57957.
Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val66met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val66met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val66met (n = 12) and val66val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val66met carriers and val66val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val66met polymorphism, our results do not support the notion that the BDNF val66met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND.
PMCID: PMC3585283  PMID: 23469118
10.  rTMS enhances BDNF–TrkB signaling in both brain and lymphocyte 
Repetitive transcranial magnetic stimulation (rTMS) induces neuronal long-term potentiation or depression. Although brain-derived neurotrophic factor (BDNF) and its cognate tyrosine receptor kinase B (TrkB) contribute to the effects of rTMS, their precise role and underlying mechanism remain poorly understood. Here we show that daily 5 Hz-rTMS for 5 days improves BDNF-TrkB signaling in rats by increasing the affinity of BDNF for TrkB that results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC-γ1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF-TrkB signaling is accompanied by an increased association between the activated TrkB and N-methyl-D-aspartate receptor (NMDAR). In normal human subjects, 5-day rTMS to motor cortex decreased resting motor threshold that correlates with heightened BDNF-TrkB signaling and intensified TrkB-NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF-TrkB-NMDAR functioning in both cortex and lymphocytes.
PMCID: PMC3161730  PMID: 21795553
Transcranial magnetic stimulation; plasticity; NMDA receptor; Signal transduction
Brain : a journal of neurology  2009;132(Pt 10):2871-2877.
Dystonia is characterised by two main pathophysiological abnormalities: reduced excitability of inhibitory systems at many levels of the sensorimotor system, and increased plasticity of neural connections in sensorimotor circuits at a brainstem and spinal level. A surprising finding in two recent papers has been the fact that abnormalities of inhibition similar to those in organic dystonia are also seen in patients who have psychogenic dystonia. To try to determine the critical feature that might separate organic and psychogenic conditions, we investigated cortical plasticity in a group of 10 patients with psychogenic dystonia and compared the results with those obtained in a matched group of 10 patients with organic dystonia and 10 healthy individuals. We confirmed the presence of abnormal motor cortical inhibition (short interval intracortical inhibition, SICI) in both organic and psychogenic groups. However, we found that plasticity (paired associative stimulation, PAS) was abnormally high only in the organic group, while there was no difference between the plasticity measured in psychogenic patients and healthy controls. We conclude that abnormal plasticity is a hallmark of organic dystonia; furthermore it is not a consequence of reduced inhibition since the latter is seen in psychogenic patients who have normal plasticity.
PMCID: PMC2997979  PMID: 19690095
associative plasticity; organic dystonia; psychogenic dystonia; paired associative stimulation; transcranial magnetic stimulation
12.  The Serial Reaction Time Task revisited: A study on motor sequence learning with an arm-reaching task 
With a series of novel arm-reaching tasks, we have shown that visuomotor sequence learning encompasses the acquisition of the order of sequence elements, and the ability to combine them in a single, skilled behavior. The first component, which is mostly declarative, is reflected by changes in movement onset time (OT); the second, which occurs without subject’s awareness, is measured by changes in kinematic variables, including movement time (MT). Key-press-based serial reaction time tasks (SRTT) have been used to investigate sequence learning and results interpreted as indicative of the implicit acquisition of the sequence order. One limitation to SRT studies, however, is that only one measure is used, the response time, the sum of OT and MT: this makes interpretation of which component is learnt difficult and disambiguation of implicit and explicit processes problematic. Here we used an arm-reaching version of SRTT to propose a novel interpretation of such results. The pattern of response time changes we obtained was similar to the key-press-based tasks. However, there were significant differences between OT and MT, suggesting that both partial learning of the sequence order and skill improvement took place. Further analyses indicated that the learning of the sequence order might not occur without subjects’ awareness.
PMCID: PMC2804101  PMID: 19104787
Incidental learning; Intentional learning; Implicit learning; Explicit learning; Motor strategy; Movement Time
13.  Lions and Prions and Deer Demise 
PLoS ONE  2008;3(12):e4019.
Contagious prion diseases – scrapie of sheep and chronic wasting disease of several species in the deer family – give rise to epidemics that seem capable of compromising host population viability. Despite this prospect, the ecological consequences of prion disease epidemics in natural populations have received little consideration.
Methodology/Principal Findings
Using a cohort study design, we found that prion infection dramatically lowered survival of free-ranging adult (>2-year-old) mule deer (Odocoileus hemionus): estimated average life expectancy was 5.2 additional years for uninfected deer but only 1.6 additional years for infected deer. Prion infection also increased nearly fourfold the rate of mountain lions (Puma concolor) preying on deer, suggesting that epidemics may alter predator–prey dynamics by facilitating hunting success. Despite selective predation, about one fourth of the adult deer we sampled were infected. High prevalence and low survival of infected deer provided a plausible explanation for the marked decline in this deer population since the 1980s.
Remarkably high infection rates sustained in the face of intense predation show that even seemingly complete ecosystems may offer little resistance to the spread and persistence of contagious prion diseases. Moreover, the depression of infected populations may lead to local imbalances in food webs and nutrient cycling in ecosystems in which deer are important herbivores.
PMCID: PMC2602978  PMID: 19107193
14.  Focal hand dystonia in a patient with thoracic outlet syndrome 
A patient affected by thoracic outlet syndrome, with an involvement of the left lower primary trunk due to a rudimentary cervical rib, developed a severe hand dystonia on the same side. The dystonic posture was characterised by a flexion of the wrist with the fingers curled into the palm. Polygraphic recordings performed on the left flexor digitorum superficialis (FDS4) and extensor digitorum superficialis (EDC4) muscles, during a repetitive tapping task of the fourth digit, showed a loss of well formed bursts without a clear silent period along with long duration bursts of cocontraction in antagonistic muscles. The study of reciprocal inhibition between forearm flexor and extensor muscles showed a reduced amount of inhibition in both the disynaptic and the later presynaptic phase of inhibition. The patient underwent an operation with resection of the cervical rib. Twelve hours after the operation the patient experienced a significant improvement of the hand dystonia; the distonia had disappeared completely by two months with a progressive normalisation of reciprocal inhibition.

PMCID: PMC2170179  PMID: 9703190

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