Induction of Hebbian associative plasticity through paired non-invasive brain stimulation of premotor-motor areas to elucidate the network's functional role

The ventral premotor cortex (PMv) is believed to play a pivotal role in a multitude of visuomotor behaviors, such as sensory-guided goal-directed visuomotor transformations, arbitrary visuomotor mapping, and hyper-learnt visuomotor associations underlying automatic imitative tendencies. All these functions are likely carried out through the copious projections connecting PMv to the primary motor cortex (M1). Yet, causal evidence investigating the functional relevance of the PMv-M1 network remains elusive and scarce. In the studies reported in this thesis we addressed this issue using a transcranial magnetic stimulation (TMS) protocol called cortico-cortical paired associative stimulation (ccPAS), which relies on multisite stimulation to induce Hebbian spike-timing dependent plasticity (STDP) by repeatedly stimulating the pathway connecting two target areas to manipulate their connectivity. Firstly, we show that ccPAS protocols informed by both short- and long-latency PMv-M1 interactions effectively modulate connectivity between the two nodes. Then, by pre-activating the network to apply ccPAS in a state-dependent manner, we were able to selectively target specific functional visuo-motor pathways, demonstrating the relevance of PMv-M1 connectivity to arbitrary visuomotor mapping. Subsequently, we addressed the PMv-to-M1 role in automatic imitation, and demonstrated that its connectivity manipulation has a corresponding impact on automatic imitative tendencies. Finally, by combining dual-coil TMS connectivity assessments and ccPAS in young and elderly individuals, we traced effective connectivity of premotor-motor networks and tested their plasticity and relevance to manual dexterity and force in healthy ageing. Our findings provide unprecedent causal evidence of the functional role of the PMv-to-M1 network in young and elderly individuals. The studies presented in this thesis suggest that ccPAS can effectively modulate the strength of connectivity between targeted areas, and coherently manipulate a networks’ behavioral output. Results open new research prospects into the causal role of cortico-cortical connectivity, and provide necessary information to the development of clinical interventions based on connectivity manipulation

Gradual enhancement of corticomotor excitability during cortico-cortical paired associative stimulation

Cortico-cortical paired associative stimulation (ccPAS) is an effective transcranial magnetic stimulation (TMS) method for inducing associative plasticity between interconnected brain areas in humans. Prior ccPAS studies have focused on protocol’s aftereffects. Here, we investigated physiological changes induced “online” during ccPAS administration. We tested 109 participants receiving ccPAS over left ventral premotor cortex (PMv) and primary motor cortex (M1) using a standard procedure (90 paired-pulses with 8-ms interstimulus interval, repeated at 0.1 Hz frequency). On each paired-pulse, we recorded a motor-evoked potential (MEP) to continuously trace the emergence of corticomotor changes. Participant receiving forward-ccPAS (on each pair, a first TMS pulse was administered over PMv, second over M1, i.e., PMv-to-M1) showed a gradual and linear increase in MEP size that did not reach a plateau at the end of the protocol and was greater in participants with low motor threshold. Participants receiving reverse-ccPAS (i.e., M1-to-PMv) showed a trend toward inhibition. Our study highlights the facilitatory and inhibitory modulations that occur during ccPAS administration and suggest that online MEP monitoring could provide insights into the malleability of the motor system and protocol’s effectiveness. Our findings open interesting prospects about ccPAS potential optimization in experimental and clinical settings

Driving Hebbian plasticity over ventral premotor-motor projections transiently enhances motor resonance

Background: Making sense of others' actions relies on the activation of an action observation network (AON), which maps visual information about observed actions onto the observer's motor system. This motor resonance process manifests in the primary motor cortex (M1) as increased corticospinal excitability finely tuned to the muscles engaged in the observed action. Motor resonance in M1 is facilitated by projections from higher-order AON regions. However, whether manipulating the strength of AON-to-M1 connectivity affects motor resonance remains unclear. Methods: We used transcranial magnetic stimulation (TMS) in 48 healthy humans. Cortico-cortical paired associative stimulation (ccPAS) was administered over M1 and the ventral premotor cortex (PMv), a key AON node, to induce spike-timing-dependent plasticity (STDP) in the pathway connecting them. Single-pulse TMS assessed motor resonance during action observation. Results: Before ccPAS, action observation increased corticospinal excitability in the muscles corresponding to the observed movements, reflecting motor resonance in M1. Notably, ccPAS aimed at strengthening projections from PMv to M1 (PMv→M1) induced short-term enhancement of motor resonance. The enhancement specifically occurred with the ccPAS configuration consistent with forward PMv→M1 projections and dissipated 20 min post-stimulation; ccPAS administered in the reverse order (M1→PMv) and sham stimulation did not affect motor resonance. Conclusions: These findings provide the first evidence that inducing STDP to strengthen PMv input to M1 neurons causally enhances muscle-specific motor resonance in M1. Our study sheds light on the plastic mechanisms that shape AON functionality and demonstrates that exogenous manipulation of AON connectivity can influence basic mirror mechanisms that underlie social perception

Cortico-cortical paired-associative stimulation to investigate the plasticity of cortico-cortical visual networks in humans

Cortico-cortical paired-associative stimulation (ccPAS) is an advanced dual-site transcranial magnetic stimulation technique that exploits the Hebbian principle to induce plastic changes in functional networks and modulate interactions between cortical brain regions. This review summarizes the growing body of ccPAS research on network dynamics underpinning visual perception. Studies revealed a functional dissociation within cortico-cortical connections in the visual system, where distinct hierarchically organized circuits shape diverse aspects of visual processing, including motion perception, emotion recognition, and metacognitive judgments. Prospective applications integrating ccPAS with neuroimaging techniques such as EEG/MEG hold promise for fine-tuning interventions and gaining deeper insights into visual system network dynamics and functional architecture, with potential clinical applications in neurological and psychiatric conditions

Children’s and adolescents’ rising animal-source food intakes in 1990–2018 were impacted by age, region, parental education and urbanicity

Animal-source foods (ASF) provide nutrition for children and adolescents’ physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the world’s child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 15–19 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes.publishedVersio

Incident type 2 diabetes attributable to suboptimal diet in 184 countries

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.8–14.4 million) incident T2D cases, representing 70.3% (68.8–71.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.0–27.1%)), excess refined rice and wheat intake (24.6% (22.3–27.2%)) and excess processed meat intake (20.3% (18.3–23.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.4–87.7%)) and Latin America and the Caribbean (81.8% (80.1–83.4%)); and lowest proportional burdens were in South Asia (55.4% (52.1–60.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally.publishedVersio

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Il popolamento castelnoviano dell’Emilia

L’articolo presenta una sintesi aggiornata dei dati disponibili sul popolamento dell’Emilia nel corso del Mesolitico recente, formulando alcune considerazioni sulle dinamiche insediative e la mobilità dei gruppi umani.This paper presents an updated synthesis on the peopling of Emilia in the Late Mesolithic and proposes some considerations on settlement dynamics and the mobility of human groups.L’article présente une synthèse des données disponibles sur le peuplement de l’Emilie au Mésolithique récent et propose quelques considérations sur les dynamiques d’occupation du territoire et la mobilité des groupes humains

Driving associative plasticity in premotor-motor connections through a novel paired associative stimulation based on long-latency cortico-cortical interactions

There is no evidence that ccPAS protocols based on long-latency interactions (i.e., ll-ccPAS) can induce associative plasticity in humans. Here we empirically address this question by testing the effect of 3 ll-ccPAS protocols on PMv-M1 interactions in healthy volunteers