Fractal Time Series: Background, Estimation Methods, and Performances.

Over the past 40 years, from its classical application in the characterization of geometrical objects, fractal analysis has been progressively applied to study time series in several different disciplines. In neuroscience, starting from identifying the fractal properties of neuronal and brain architecture, attention has shifted to evaluating brain signals in the time domain. Classical linear methods applied to analyzing neurophysiological signals can lead to classifying irregular components as noise, with a potential loss of information. Thus, characterizing fractal properties, namely, self-similarity, scale invariance, and fractal dimension (FD), can provide relevant information on these signals in physiological and pathological conditions. Several methods have been proposed to estimate the fractal properties of these neurophysiological signals. However, the effects of signal characteristics (e.g., its stationarity) and other signal parameters, such as sampling frequency, amplitude, and noise level, have partially been tested. In this chapter, we first outline the main properties of fractals in the domain of space (fractal geometry) and time (fractal time series). Then, after providing an overview of the available methods to estimate the FD, we test them on synthetic time series (STS) with different sampling frequencies, signal amplitudes, and noise levels. Finally, we describe and discuss the performances of each method and the effect of signal parameters on the accuracy of FD estimation.

Fractal Dimension as a discriminative feature for high accuracy classification in motor imagery EEG-based brain-computer interface.

BACKGROUND AND OBJECTIVE: The brain-computer interface (BCI) technology acquires human brain electrical signals, which can be effectively and successfully used to control external devices, potentially supporting subjects suffering from motor impairments in the interaction with the environment. To this aim, BCI systems must correctly decode and interpret neurophysiological signals reflecting the intention of the subjects to move. Therefore, the accurate classification of single events in motor tasks represents a fundamental challenge in ensuring efficient communication and control between users and BCIs. Movement-associated changes in electroencephalographic (EEG) sensorimotor rhythms, such as event-related desynchronization (ERD), are well-known features of discriminating motor tasks. Fractal dimension (FD) can be used to evaluate the complexity and self-similarity in brain signals, potentially providing complementary information to frequency-based signal features. METHODS: In the present work, we introduce FD as a novel feature for subject-independent event classification, and we test several machine learning (ML) models in behavioural tasks of motor imagery (MI) and motor execution (ME). RESULTS: Our results show that FD improves the classification accuracy of ML compared to ERD. Furthermore, unilateral hand movements have higher classification accuracy than bilateral movements in both MI and ME tasks. CONCLUSIONS: These results provide further insights into subject-independent event classification in BCI systems and demonstrate the potential of FD as a discriminative feature for EEG signals.

Band-Specific Altered Cortical Connectivity in Early Parkinson's Disease and its Clinical Correlates.

BACKGROUND: Functional connectivity (FC) has shown promising results in assessing the pathophysiology and identifying early biomarkers of neurodegenerative disorders, such as Parkinson's disease (PD). OBJECTIVES: In this study, we aimed to assess possible resting-state FC abnormalities in early-stage PD patients using high-density electroencephalography (EEG) and to detect their clinical relationship with motor and non-motor PD symptoms. METHODS: We enrolled 26 early-stage levodopa naïve PD patients and a group of 20 healthy controls (HC). Data were recorded with 64-channels EEG system and a source-reconstruction method was used to identify brain-region activity. FC was calculated using the weighted phase-lag index in θ, α, and ß bands. Additionally, we quantified the unbalancing between ß and lower frequencies through a novel index (ß-functional ratio [FR]). Statistical analysis was conducted using a network-based statistical approach. RESULTS: PD patients showed hypoconnected networks in θ and α band, involving prefrontal-limbic-temporal and frontoparietal areas, respectively, and a hyperconnected network in the ß frequency band, involving sensorimotor-frontal areas. The θ FC network was negatively related to Non-Motor Symptoms Scale scores and α FC to the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III gait subscore, whereas ß FC and ß-FR network were positively linked to the bradykinesia subscore. Changes in θ FC and ß-FR showed substantial reliability and high accuracy, precision, sensitivity, and specificity in discriminating PD and HC. CONCLUSIONS: Frequency-specific FC changes in PD likely reflect the dysfunction of distinct cortical networks, which occur from the early stage of the disease. These abnormalities are involved in the pathophysiology of specific motor and non-motor PD symptoms, including gait, bradykinesia, mood, and cognition. © 2023 International Parkinson and Movement Disorder Society.

The genome-wide relationships of the critically endangered Quadricorna sheep in the Mediterranean region.

Livestock European diffusion followed different human migration waves from the Fertile Crescent. In sheep, at least two diffusion waves have shaped the current breeds' biodiversity generating a complex genetic pattern composed by either primitive or fine-wool selected breeds. Nowadays most of the sheep European breeds derive from the second wave which is supposed to have largely replaced oldest genetic signatures, with the exception of several primitive breeds confined on the very edge of Northern Europe. Despite this, some populations also in the Mediterranean region are characterised by the presence of phenotypic traits considered ancestral such as the policeraty, large horns in the ram, short tail, and a moulting fleece. Italy is home of a large number of local breeds, albeit some are already extinct, others are listed as critically endangered, and among these there is the Quadricorna breed which is a four-horned sheep characterised by several traits considered as ancestral. In this context we genotyped 47 individuals belonging to the Quadricorna sheep breed, a relict and endangered breed, from Central and Southern Italy. In doing so we used the Illumina OvineSNP50K array in order to explore its genetic diversity and to compare it with other 41 breeds from the Mediterranean region and Middle-East, with the specific aim to reconstruct its origin. After retaining 32,862 SNPs following data filtering, the overall genomic architecture has been explored by using genetic diversity indices, Principal Component Analysis (PCA) and admixture analysis, while the genetic relationships and migration events have been inferred using a neighbor-joining tree based on Reynolds' distances and by the maximum likelihood tree as implemented in treemix. The Quadricorna breed exhibit genetic diversity indices comparable with those of most of the other analysed breeds, however, the two populations showed opposing patterns of genetic diversity suggesting different levels of genomic inbreeding and drift (FIS and FROH). In general, all the performed genome-wide analyses returned complementary results, indicating a westward longitudinal cline compatible with human migrations from the Middle-East and several additional genetic footprints which might mirror more recent historical events. Interestingly, among the Italian breeds, the original Quadricorna (QUAD_SA) first separated showing its own ancestral component. In addition, the admixture analysis does not suggest any signal of recent gene exchange with other Italian local breeds, highlighting a rather ancestral purity of this population. On the other hand, both the neighbor-joining tree and the treemix analysis seem to suggest a proximity of the Quadricorna populations to breeds of South-Eastern Mediterranean origin. Although our results do not support a robust link between the genetics of the first wave and the presence of primitive traits, the observed genetic uniqueness together with the inferred phylogeograpic reconstruction would suggest an ancient presence of the Quadricorna breed in the Italian Peninsula. Because of this singularity, urgent conservation actions are needed in order to keep the breed and all related cultural products alive.

Current and novel infusion therapies for patients with Parkinson's disease.

Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.

Objective measurement versus clinician-based assessment for Parkinson's disease.

INTRODUCTION: Although clinician-based assessment through standardized clinical rating scales is currently the gold standard for quantifying motor impairment in Parkinson's disease (PD), it is not without limitations, including intra- and inter-rater variability and a degree of approximation. There is increasing evidence supporting the use of objective motion analyses to complement clinician-based assessment. Objective measurement tools hold significant potential for improving the accuracy of clinical and research-based evaluations of patients. AREAS COVERED: The authors provide several examples from the literature demonstrating how different motion measurement tools, including optoelectronics, contactless and wearable systems allow for both the objective quantification and monitoring of key motor symptoms (such as bradykinesia, rigidity, tremor, and gait disturbances), and the identification of motor fluctuations in PD patients. Furthermore, they discuss how, from a clinician's perspective, objective measurements can help in various stages of PD management. EXPERT OPINION: In our opinion, sufficient evidence supports the assertion that objective monitoring systems enable accurate evaluation of motor symptoms and complications in PD. A range of devices can be utilized not only to support diagnosis but also to monitor motor symptom during the disease progression and can become relevant in the therapeutic decision-making process.

Combining Transcranial Magnetic Stimulation and Deep Brain Stimulation: Current Knowledge, Relevance and Future Perspectives.

Deep brain stimulation (DBS) has emerged as an invasive neuromodulation technique for the treatment of several neurological disorders, but the mechanisms underlying its effects remain partially elusive. In this context, the application of Transcranial Magnetic Stimulation (TMS) in patients treated with DBS represents an intriguing approach to investigate the neurophysiology of cortico-basal networks. Experimental studies combining TMS and DBS that have been performed so far have mainly aimed to evaluate the effects of DBS on the cerebral cortex and thus to provide insights into DBS's mechanisms of action. The modulation of cortical excitability and plasticity by DBS is emerging as a potential contributor to its therapeutic effects. Moreover, pairing DBS and TMS stimuli could represent a method to induce cortical synaptic plasticity, the therapeutic potential of which is still unexplored. Furthermore, the advent of new DBS technologies and novel treatment targets will present new research opportunities and prospects to investigate brain networks. However, the application of the combined TMS-DBS approach is currently limited by safety concerns. In this review, we sought to present an overview of studies performed by combining TMS and DBS in neurological disorders, as well as available evidence and recommendations on the safety of their combination. Additionally, we outline perspectives for future research by highlighting knowledge gaps and possible novel applications of this approach.

Assessing the interaction between L-dopa and γ-transcranial alternating current stimulation effects on primary motor cortex plasticity in Parkinson's disease.

L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients OFF dopaminergic medication, impaired M1 plasticity and defective GABA-A-ergic inhibition can be restored by boosting gamma (γ) oscillations via transcranial alternating current stimulation (tACS) during intermittent theta-burst stimulation (iTBS). However, it is unknown whether L-dopa modifies the beneficial effects of iTBS-γ-tACS on M1 in PD. In this study, a PD patients group underwent combined iTBS-γ-tACS and iTBS-sham-tACS, each performed both OFF and ON dopaminergic therapy (four sessions in total). Motor evoked potentials (MEPs) elicited by single TMS pulses and short-interval intracortical inhibition (SICI) were assessed before and after iTBS-tACS. We also evaluated possible SICI changes during γ-tACS delivered alone in OFF and ON conditions. The amplitude of MEP elicited by single TMS pulses and the degree of SICI inhibition significantly increased after iTBS-γ-tACS. The amount of change produced by iTBS-γ-tACS was similar in patients OFF and ON therapy. Finally, γ-tACS (delivered alone) modulated SICI during stimulation and this effect did not depend on the dopaminergic condition of patients. In conclusion, boosting cortical γ oscillatory activity via tACS during iTBS improved M1 plasticity and enhanced GABA-A-ergic transmission in PD patients to the same extent regardless of dopaminergic state. These results suggest a lack of interaction between L-dopa and γ-tACS effects at the M1 level. The possible neural substrate underlying iTBS-γ tACS effects, that is, γ-resonant GABA-A-ergic interneurons activity, may explain our findings.

The ancestral origin of the critically endangered Quadricorna sheep as revealed by genome-wide analysis.

Livestock European diffusion followed different human migration waves from the Fertile Crescent. In sheep, at least two diffusion waves have shaped the current breeds' biodiversity generating a complex genetic pattern composed by either primitive or fine-wool selected breeds. Among primitive breeds, aside from sharing common ancestral genomic components, they also show several traits such as the policeraty, large horns in the ram, short tail, and a moulting fleece, considered as ancestral. Although most of the primitive breeds characterized by these traits are confined on the very edge of Northern Europe, several residual populations are also scattered in the Mediterranean region. In fact, although in Italy a large number of local breeds are already extinct, others are listed as critically endangered, and among these there is the Quadricorna breed which is a four-horned sheep characterized by several ancestral traits. In this context we genotyped 47 individuals belonging to the Quadricorna sheep breed, a relict and endangered breed, from Central and Southern Italy. In doing so we used the Illumina OvineSNP50K array in order to explore its genetic diversity and to compare it with other 33 primitive traits-related, Mediterranean and Middle-East breeds, with the specific aim to reconstruct its origin. After retaining 35,680 SNPs following data filtering, the overall genomic architecture has been explored by using genetic diversity indices, Principal Component Analysis (PCA) and admixture analysis, while the genetic relationships and migration events have been inferred using a neighbor-joining tree based on Reynolds' distances and by the maximum likelihood tree as implemented in treemix. Multiple convergent evidence from all our population genetics analyses, indicated that the two Quadricorna populations differ from all the other Italian breeds, while they resulted to be very close to the Middle Eastern and primitive European breeds. In addition, the genetic diversity indices highlighted values comparable with those of most of the other analyzed breeds, despite the two populations exhibit slightly different genetic indices suggesting different levels of genomic inbreeding and drift (FIS and FROH). The admixture analysis does not suggest any signal of recent gene exchange with other Italian local breeds, highlighting a rather ancestral purity of the two populations, while on the other hand the treemix analysis seems to suggest an ancient admixture with other primitive European breeds. Finally, all these evidences seem to trace back the residual Quadricorna sheep to an early Neolithic spread, probably following a Mediterranean route and that urgent conservation actions are needed in order to keep the breed and all related cultural products alive.

Handwriting Declines With Human Aging: A Machine Learning Study.

Background: Handwriting is an acquired complex cognitive and motor skill resulting from the activation of a widespread brain network. Handwriting therefore may provide biologically relevant information on health status. Also, handwriting can be collected easily in an ecological scenario, through safe, cheap, and largely available tools. Hence, objective handwriting analysis through artificial intelligence would represent an innovative strategy for telemedicine purposes in healthy subjects and people affected by neurological disorders. Materials and Methods: One-hundred and fifty-six healthy subjects (61 males; 49.6 ± 20.4 years) were enrolled and divided according to age into three subgroups: Younger adults (YA), middle-aged adults (MA), and older adults (OA). Participants performed an ecological handwriting task that was digitalized through smartphones. Data underwent the DBNet algorithm for measuring and comparing the average stroke sizes in the three groups. A convolutional neural network (CNN) was also used to classify handwriting samples. Lastly, receiver operating characteristic (ROC) curves and sensitivity, specificity, positive, negative predictive values (PPV, NPV), accuracy and area under the curve (AUC) were calculated to report the performance of the algorithm. Results: Stroke sizes were significantly smaller in OA than in MA and YA. The CNN classifier objectively discriminated YA vs. OA (sensitivity = 82%, specificity = 80%, PPV = 78%, NPV = 79%, accuracy = 77%, and AUC = 0.84), MA vs. OA (sensitivity = 84%, specificity = 56%, PPV = 78%, NPV = 73%, accuracy = 74%, and AUC = 0.7), and YA vs. MA (sensitivity = 75%, specificity = 82%, PPV = 79%, NPV = 83%, accuracy = 79%, and AUC = 0.83). Discussion: Handwriting progressively declines with human aging. The effect of physiological aging on handwriting abilities can be detected remotely and objectively by using machine learning algorithms.

Wearable Electrochemical Sensors in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with widespread aggregation of α-synuclein and dopaminergic neuronal loss in the substantia nigra pars compacta. As a result, striatal dopaminergic denervation leads to functional changes in the cortico-basal-ganglia-thalamo-cortical loop, which in turn cause most of the parkinsonian signs and symptoms. Despite tremendous advances in the field in the last two decades, the overall management (i.e., diagnosis and follow-up) of patients with PD remains largely based on clinical procedures. Accordingly, a relevant advance in the field would require the development of innovative biomarkers for PD. Recently, the development of miniaturized electrochemical sensors has opened new opportunities in the clinical management of PD thanks to wearable devices able to detect specific biological molecules from various body fluids. We here first summarize the main wearable electrochemical technologies currently available and their possible use as medical devices. Then, we critically discuss the possible strengths and weaknesses of wearable electrochemical devices in the management of chronic diseases including PD. Finally, we speculate about possible future applications of wearable electrochemical sensors in PD, such as the attractive opportunity for personalized closed-loop therapeutic approaches.

Long-term changes in short-interval intracortical facilitation modulate motor cortex plasticity and L-dopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: Abnormal glutamatergic neurotransmission in the primary motor cortex (M1) contributes to Parkinson's disease (PD) pathophysiology and is related to l-dopa-induced dyskinesia (LID). We previously showed that short-term treatment with safinamide, a monoamine oxidase type-B inhibitor with anti-glutamatergic properties, improves abnormally enhanced short-interval intracortical facilitation (SICF) in PD patients. OBJECTIVE: To examine whether a long-term SICF modulation has beneficial effects on clinical measures, including LID severity, and whether these changes parallel improvement in cortical plasticity mechanisms in PD. METHODS: We tested SICF in patients with and without LID before (S0) and after short- (14 days - S1) and long-term (12 months - S2) treatment with safinamide 100 mg/day. Possible changes in M1 plasticity were assessed using intermittent theta-burst stimulation (iTBS). Finally, we correlated safinamide-related neurophysiological changes with modifications in clinical scores. RESULTS: SICF was enhanced at S0, and prominently in patients with LID. Safinamide normalized SICF at S1, and this effect persisted at S2. Impaired iTBS-induced plasticity was present at S0 and safinamide restored this alteration at S2. There was a significant correlation between the degree of SICF and the amount of iTBS-induced plasticity at S0 and S2. In patients with LID, the degree of SICF at S0 and S2 correlated with long-term changes in LID severity. CONCLUSIONS: Altered SICF contributes to M1 plasticity impairment in PD. Both SICF and M1 plasticity improve after long-term treatment with safinamide. The abnormality in SICF-related glutamatergic circuits plays a role in LID pathophysiology, and its long-term modulation may prevent LID worsening over time.

The effect of gamma oscillations in boosting primary motor cortex plasticity is greater in young than older adults.

OBJECTIVE: In healthy subjects, the long-term potentiation (LTP)-like plasticity of the primary motor cortex (M1) induced by intermittent theta-burst stimulation (iTBS) can be boosted by modulating gamma (γ) oscillations through transcranial alternating current stimulation (tACS). γ-tACS also reduces short-interval intracortical inhibition (SICI). We tested whether the effects of γ-tACS differ between young (YA) and older adults (OA). METHODS: Twenty YA (27.2 ± 2.7 years) and twenty OA (65.3 ± 9.5 years) underwent iTBS-γ tACS and iTBS-sham tACS in randomized sessions. In a separate session, we delivered γ-tACS alone and recorded SICI during stimulation. RESULTS: iTBS-sham tACS produced comparable motor evoked potential (MEP) facilitation between groups. While iTBS-γ tACS boosted MEP facilitation in both the YA and OA groups, the magnitude of its effect was significantly lower in OA. Similarly, γ-tACS-induced modulation of GABA-A-ergic neurotransmission, as tested by SICI, was reduced in OA. The effect of iTBS-γ tACS negatively correlated with the age of OA subjects. CONCLUSIONS: Mechanisms underlying the effects of γ oscillations on LTP-like plasticity become less efficient in older adults. This could reflect age-related changes in neural elements of M1 resonant to γ oscillations, including GABA-A-ergic interneurons. SIGNIFICANCE: The beneficial effect of γ-tACS on iTBS-induced plasticity is reduced in older adults.

Plasma and Red Blood Cell PUFAs in Home Parenteral Nutrition Paediatric Patients-Effects of Lipid Emulsions.

Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9-21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth.

Gamma-transcranial alternating current stimulation and theta-burst stimulation: inter-subject variability and the role of BDNF.

OBJECTIVE: The main limitation of neuromodulation techniques is inter-subject variability. Combining theta-burst stimulation (TBS) with gamma-transcranial alternating current stimulation (γ-tACS) allows to shape cortical plasticity. However, it is unknown whether γ-tACS modifies TBS-induced response variability. In this study, we measured the inter-subject variability of TBS-γ tACS and controlled the effect of the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism. METHODS: Intermittent TBS (iTBS)-sham tACS, iTBS-γ tACS, continuous TBS (cTBS)-sham tACS, and cTBS-γ tACS were applied in randomised sessions. Inter-subject variability was measured using grand average and clustering methods. TBS-γ tACS effects on motor evoked potentials (MEP) were compared between Val/Val and Met carriers. RESULTS: We found that γ-tACS boosted iTBS-induced MEP facilitation and cancelled cTBS-induced MEP depression. Grand average analysis showed that γ-tACS prominently increased the percentage of iTBS responders and cTBS non-responders. The clustering method demonstrated that TBS-γ tACS response varied between subjects, a phenomenon unrelated to the BDNF genotype. CONCLUSIONS: Enhancing γ oscillations through tACS boosts iTBS-induced LTP-like plasticity and suppresses cTBS-induced LTD-like plasticity of the primary motor cortex in a reliable manner. The BDNF Val66Met polymorphism does not influence these effects. SIGNIFICANCE: Since γ-tACS significantly increases the number of iTBS responders, it may be used in clinical settings.

Enhancing Gamma Oscillations Restores Primary Motor Cortex Plasticity in Parkinson's Disease.

In humans, γ oscillations in cortical motor areas reflect asynchronous synaptic activity and contribute to plasticity processes. In Parkinson's disease (PD), γ oscillatory activity in the basal ganglia-thalamo-cortical network is altered and the LTP-like plasticity elicited by intermittent theta burst stimulation (iTBS) is reduced in the primary motor cortex (M1). In this study, we tested whether transcranial alternating current stimulation (tACS) delivered at γ frequency promotes iTBS-induced LTP-like plasticity in M1 in PD patients. Sixteen patients (OFF condition) and 16 healthy subjects (HSs) underwent iTBS during γ-tACS (iTBS-γ tACS) and during sham-tACS (iTBS-sham tACS) in two sessions. Motor-evoked potentials (MEPs) evoked by single-pulse transcranial magnetic stimulation and short-interval intracortical inhibition (SICI) were recorded before and after the costimulation. A subgroup of patients also underwent iTBS during ß tACS. iTBS-sham tACS facilitated single-pulse MEPs in HSs, but not in patients. iTBS-γ tACS induced a larger MEP facilitation than iTBS-sham tACS in both groups, with similar values in patients and HSs. In patients, SICI improved after iTBS-γ tACS. The effect produced by iTBS-γ tACS on single-pulse MEPs correlated with disease duration, while changes in SICI correlated with Unified Parkinson's Disease Rating Scale Part III scores. The effect of iTBS-ß tACS on both single-pulse MEPs and SICI was similar to that obtained in the iTBS-sham tACS session. Our data suggest that γ oscillations have a role in the pathophysiology of the abnormal LTP-like plasticity in PD. Entraining M1 neurons at the γ rhythm through tACS may be an effective method to restore impaired plasticity.SIGNIFICANCE STATEMENT In Parkinson's disease, the LTP-like plasticity of the primary motor cortex is impaired, and γ oscillations are altered in the basal ganglia-thalamo-cortical network. Using a combined transcranial magnetic stimulation-transcranial alternating current stimulation approach (iTBS-γ tACS costimulation), we demonstrate that driving γ oscillations restores the LTP-like plasticity in patients with Parkinson's disease. The effects correlate with clinical characteristics of patients, being more evident in less affected patients and weaker in patients with longer disease duration. These findings suggest that cortical γ oscillations play a beneficial role in modulating the LTP-like plasticity of M1 in Parkinson's disease. The iTBS-γ tACS approach may be potentially useful in rehabilitative settings in patients.

Effects of a Synbiotic Formula on Functional Bowel Disorders and Gut Microbiota Profile during Long-Term Home Enteral Nutrition (LTHEN): A Pilot Study.

Long-term enteral nutrition (LTEN) can induce gut microbiota (GM) dysbiosis and gastrointestinal related symptoms, such as constipation or diarrhoea. To date, the treatment of constipation is based on the use of laxatives and prebiotics. Only recently have probiotics and synbiotics been considered, the latter modulating the GM and regulating intestinal functions. This randomized open-label intervention study evaluated the effects of synbiotic treatment on the GM profile, its functional activity and on intestinal functions in long-term home EN (LTHEN) patients. Twenty LTHEN patients were recruited to take enteral formula plus one sachet/day of synbiotic (intervention group, IG) or enteral formula (control group, CG) for four months and evaluated for constipation, stool consistency, and GM and metabolite profiles. In IG patients, statistically significant reduction of constipation and increase of stool consistency were observed after four months (T1), compared to CG subjects. GM ecology analyses revealed a decrease in the microbial diversity of both IC and CG groups. Biodiversity increased at T1 for 5/11 IG patients and Methanobrevibacter was identified as the biomarker correlated to the richness increase. Moreover, the increase of short chain fatty acids and the reduction of harmful molecules have been correlated to synbiotic administration. Synbiotics improve constipation symptoms and influences Methanobrevibacter growth in LTHEN patients.

LTD-like plasticity of the human primary motor cortex can be reversed by γ-tACS.

BACKGROUND: Cortical oscillatory activities play a role in regulating several brain functions in humans. However, whether motor resonant oscillations (i.e. ß and γ) modulate long-term depression (LTD)-like plasticity of the primary motor cortex (M1) is still unclear. OBJECTIVE: To address this issue, we combined transcranial alternating current stimulation (tACS), a technique able to entrain cortical oscillations, with continuous theta burst stimulation (cTBS), a transcranial magnetic stimulation (TMS) protocol commonly used to induce LTD-like plasticity in M1. METHODS: Motor evoked potentials (MEPs) elicited by single-pulse TMS, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated before and 5, 15 and 30 min after cTBS alone or cTBS delivered during ß-tACS (cTBS-ß) or γ-tACS (cTBS-γ). Moreover, we tested the effects of ß-tACS (alone) on short-latency afferent inhibition (SAI) and γ-tACS on SICI in order to verify whether tACS-related interneuronal modulation contributes to the effects of tACS-cTBS co-stimulation. RESULTS: cTBS-γ turned the expected after-effects of cTBS from inhibition to facilitation. By contrast, responses to cTBS-ß were similar to those induced by cTBS alone. ß- and γ-tACS did not change MEPs evoked by single-pulse TMS. ß-tACS reduced SAI and γ-tACS reduced SICI. However, the degree of γ-tACS-induced modulation of SICI did not correlate with the effects of cTBS-γ. CONCLUSION: γ-tACS reverses cTBS-induced plasticity of the human M1. γ-oscillations may therefore regulate LTD-like plasticity mechanisms.