Empathy at school project: Effects of didactics of emotions® on emotional competence, cortisol secretion and inflammatory profile in primary school children. A controlled longitudinal psychobiological study.

Background: There is mounting evidence of the presence of chronic stress among children during primary school: girls and boys under the age of 15 years often experience anxiety, irritability and sleeping problems with negative consequences on scholastic climate and the spread of bullying and dropping out of school. The promotion of emotion regulation within school environment through innovative didactic methodologies represents a valuable tool for teachers and parents to reduce emotional distress and associated risk behaviours and to promote wellbeing. Aim: Our research aims to explore the psychological and biological consequences of teaching emotional training in an experimental group of Italian Primary School children. Methods: A sample of pupils (81 children aged between 6 and 8) was divided into an experimental group (33 subjects) and a control group (30 subjects). A further advanced group of 18 subjects, who have experienced the method in the previous school year, was also included. The experimental study lasted one school year (from October 2021 to May 2022). The following psychological tests were administered to all groups: TEC (Test of Emotion Comprehension) to measure the children's different emotional abilities and the Projective test (PT) 'A person in the rain', to identify the coping skills of children in a stressful condition. Morning salivary cortisol, IL-6 and TNF-alpha assays were conducted in all three groups. Psychological and biological tests were administered at the beginning of the study and at the end of the study. Results: The MR-Anova model for TEC score showed that there was not a significant group effect [Fgroup = 2.24, p = 0.114]. Pairwise comparisons showed that mean score significantly increased only in the Experimental group (pB < 0.001) and at the end of the project there was a significant difference between Experimental group and Control group (pB = 0.012). The mean score of PT test increased significantly from baseline to the end of the project for the Experimental group (pB < 0.001) and for the Advanced group (pB = 0.004). At the end of the project, there were significant differences between the Experimental group and the Control group (pB = 0.004) and between the Advanced group and the Control group (pB < 0.001). Salivary cortisol analysis revealed a significant effect between subjects [Fgroup = 9.66; p < 0.001] and significant effects within subjects with the main effect of the time [Ftime = 35.41; p < 0.001] and the significant interaction "time x group" [Ftimexgroup = 3.38; p = 0.040]. Pairwise comparisons showed that cortisol levels decreased significantly over time only in the Experimental group (pB < 0.001). Regarding to IL-6 levels, there was not a significant effect between subjects [Fgroups = 0.0481; p = 0.953]. The mean level decreased significantly for each group from baseline to post project (pB < 0.001). With respect to TNF-alpha levels, the mean levels decreased over time for all groups (pB = 0.006 for Experimental group; pB < 0.001 either for the Advanced or Control group). Conclusion: the results documented in the experimental groups who experienced didactics of emotion for at least one school year show a significant increase in children's ability to cope with reality, stress and anxiety, and an improvement of their emotional competence. Meanwhile, a significant reduction in the amount of salivary cortisol was observed in the experimental group at the end of the scholastic year; meantime a stable reduced amount of salivary cortisol in advanced group throughout the project was also observed. These findings show that an intervention through an emotional education program is able to regulate interpersonal skills and the stress axis response.

Hypomimia in Parkinson's disease: an axial sign responsive to levodopa.

BACKGROUND AND PURPOSE: Hypomimia is a prominent clinical feature in people with Parkinson's disease (PD), but it remains under-investigated. We aimed to examine the clinical correlates of hypomimia in PD and to determine whether this is a levodopa-responsive sign. METHODS: We included 89 people with PD. Hypomimia was assessed from digital video recordings by movement disorder specialists. Clinical evaluation included use of the Unified Parkinson's Disease Rating Scale part III (UPDRS-III), and assessment of motor and non-motor symptoms using standardized clinical scales. The relationships between hypomimia and other clinical data were analysed using Mann-Whitney U-tests and regression analysis. RESULTS: Hypomimia occurred in up to 70% of patients with PD. Patients with hypomimia had worse UPDRS-III 'off-medication' scores, mainly driven by bradykinesia and rigidity subscores. Patients with hypomimia also had worse apathy than patients without hypomimia. Finally, we found that hypomimia was levodopa-responsive and its improvement mirrored the change by levodopa in axial motor symptoms. CONCLUSION: Our study provides novel information regarding the clinical correlates of hypomimia in people with PD. A better understanding of hypomimia may be relevant for improving treatment and quality of life in PD.

Relating size and functionality in human social networks through complexity.

Extensive empirical evidence suggests that there is a maximal number of people with whom an individual can maintain stable social relationships (the Dunbar number). We argue that this arises as a consequence of a natural phase transition in the dynamic self-organization among N individuals within a social system. We present the calculated size dependence of the scaling properties of complex social network models to argue that this collective behavior is an enhanced form of collective intelligence. Direct calculation establishes that the complexity of social networks as measured by their scaling behavior is nonmonotonic, peaking around 150, thereby providing a theoretical basis for the value of the Dunbar number. Thus, we establish a theory-based bridge spanning the gap between sociology and psychology.

Is there evidence of bradykinesia in essential tremor?

BACKGROUND AND PURPOSE: Essential tremor (ET) is a movement disorder primarily characterized by upper limb postural and kinetic tremor. Although still under-investigated, bradykinesia may be part of the phenotypic spectrum of ET. The aim was to evaluate bradykinesia features in ET through clinical examination and kinematic analysis of repetitive finger movements. Data collected in ET patients were compared with those recorded in Parkinson's disease patients and healthy controls. METHODS: Overall, 258 subjects participated in the study (90 ET patients, 84 Parkinson's disease patients and 84 healthy controls). Repetitive finger tapping was kinematically recorded using a motion analysis system. Movement velocity, amplitude and decrement (sequence effect) were measured. The three groups were first compared by one-way analysis of variance. A cluster analysis was also performed to better address the data variability observed in ET patients. Possible relationships between kinematic and clinical data were assessed in ET patients. RESULTS: Essential tremor patients were slower than healthy controls. Movement slowness in ET did not correlate with postural or kinetic tremor severity. It was also found that movement slowness in ET was not associated with a sequence effect, which instead is a common feature in Parkinson's disease. Cluster analysis showed that a proportion of ET patients may have movement abnormalities similar to those observed in Parkinson's disease. CONCLUSIONS: Movement slowness without sequence effect is a common feature in ET patients. The present findings are relevant when interpreted in the context of the new tremor classification system and in the development of a more accurate bradykinesia definition.

Corticobasal syndrome: neuroimaging and neurophysiological advances.

Corticobasal degeneration (CBD) is a neurodegenerative condition characterized by 4R tau protein deposition in several brain regions that clinically manifests itself as a heterogeneous atypical parkinsonism typically expressed in adulthood. The prototypical clinical phenotype of CBD is corticobasal syndrome (CBS). Important insights into the pathophysiological mechanisms underlying motor and higher cortical symptoms in CBS have been gained by using advanced neuroimaging and neurophysiological techniques. Structural and functional neuroimaging studies often show asymmetric cortical and subcortical abnormalities, mainly involving perirolandic and parietal regions and basal ganglia structures. Neurophysiological investigations including electroencephalography and somatosensory evoked potentials provide useful information on the origin of myoclonus and on cortical sensory loss. Transcranial magnetic stimulation demonstrates heterogeneous and asymmetric changes in the excitability and plasticity of primary motor cortex and abnormal hemispheric connectivity. Neuroimaging and neurophysiological abnormalities in multiple brain areas reflect asymmetric neurodegeneration, leading to asymmetric motor and higher cortical symptoms in CBS.

Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy.

To evaluate gray matter (GM) and white matter (WM) abnormalities and their clinical correlates in patients with progressive supranuclear palsy (PSP). Sixteen PSP patients and sixteen age-matched healthy subjects underwent a clinical evaluation and multimodal magnetic resonance imaging, including three-dimensional T1-weighted imaging and diffusion tensor imaging (DTI). Volumetric and DTI analyses were computed using SPM and FSL tools. PSP patients showed GM volume decrease, involving the frontal cortex, putamen, pallidum, thalamus and accumbens nucleus, cerebellum, and brainstem. Additionally, they had widespread changes in WM bundles, mainly affecting cerebellar peduncles, thalamic radiations, corticospinal tracts, corpus callosum, and longitudinal fasciculi. GM volumes did not correlate with WM abnormalities. DTI indices of WM damage, but not GM volumes, correlated with clinical scores of disease severity and cognitive impairment. The neurodegenerative changes that occur in PSP involve both GM and WM structures and develop concurrently though independently. WM damage in PSP correlates with clinical scores of disease severity and cognitive impairment, thus providing further insight into the pathophysiology of the disease.

Does the cerebellum intervene in the abnormal somatosensory temporal discrimination in Parkinson's disease?

INTRODUCTION: somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Altered STDT has been reported in Parkinson's disease (PD). The cerebellum seems to play a role in the pathophysiology of PD, and may consequently be involved in the pathophysiology of STDT abnormalities. METHODS: STDT was investigated in fifteen PD patients who underwent real and sham cerebellar continuous theta burst stimulation (cTBS) in the OFF condition. Eight patients underwent a further real cTBS session in ON condition. STDT was measured on both hands before, 5 and 25 min after real and sham cTBS delivered over the cerebellar hemisphere ipsilateral to the more affected side. We controlled the efficacy of our protocol by monitoring primary motor cortex (M1) excitability. Ten healthy subjects acted as control group. RESULTS: STDT values were increased in PD patients in the OFF condition compared with healthy subjects and PD patients in the ON condition. In PD patients OFF condition, real but not sham cerebellar cTBS, significantly reduced STDT values only in the hand ipsilateral to the stimulated cerebellar hemisphere. Cerebellar cTBS also decreased motor evoked potentials (MEP) size in the contralateral M1. When PD patients were tested in the ON condition, cerebellar cTBS failed to modify STDT values. CONCLUSION: cerebellar cTBS improved STDT values in PD patients exclusively in OFF condition. We hypothesize that cerebellar stimulation partially compensates for increased STDT values only when patients are OFF dopaminergic therapy. This suggests that the cerebellum may act as compensatory system in PD.

Critical slowing down in networks generating temporal complexity.

We study a nonlinear Langevin equation describing the dynamic variable X(t), the mean field (order parameter) of a finite size complex network at criticality. The conditions under which the autocorrelation function of X shows any direct connection with criticality are discussed. We find that if the network is prepared in a state far from equilibrium, X(0)=1, the autocorrelation function is characterized by evident signs of critical slowing down as well as by significant aging effects, while the preparation X(0)=0 does not generate evident signs of criticality on X(t), in spite of the fact that the same initial state makes the fluctuating variable η(t)≡sgn(X(t)) yield significant aging effects. These latter effects arise because the dynamics of η(t) are directly dependent on crucial events, namely the re-crossings of the origin, which undergo a significant aging process with the preparation X(0)=0. The time scale dominated by temporal complexity, aging, and ergodicity breakdown of η(t) is properly evaluated by adopting the method of stochastic linearization which is used to explain the exponential-like behavior of the equilibrium autocorrelation function of X(t).

Disrupted resting-state functional connectivity in progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Studies on functional connectivity in progressive supranuclear palsy have been restricted to the thalamus and midbrain tegmentum. The present study aims to evaluate functional connectivity abnormalities of the subcortical structures in these patients. Functional connectivity will be correlated with motor and nonmotor symptoms of the disease. MATERIALS AND METHODS: Nineteen patients with progressive supranuclear palsy (mean age, 70.93 ± 5.19 years) and 12 age-matched healthy subjects (mean age, 69.17 ± 5.20 years) underwent multimodal MR imaging, including fMRI at rest, 3D T1-weighted imaging, and DTI. fMRI data were processed with fMRI of the Brain Software Library tools by using the dorsal midbrain tegmentum, thalamus, caudate nucleus, putamen, and pallidum as seed regions. RESULTS: Patients had lower functional connectivity than healthy subjects in all 5 resting-state networks, mainly involving the basal ganglia, thalamus, anterior cingulate, dorsolateral prefrontal and temporo-occipital cortices, supramarginal gyrus, supplementary motor area, and cerebellum. Compared with healthy subjects, patients also displayed subcortical atrophy and DTI abnormalities. Decreased thalamic functional connectivity correlated with clinical scores, as assessed by the Hoehn and Yahr Scale and by the bulbar and mentation subitems of the Progressive Supranuclear Palsy Rating Scale. Decreased pallidum functional connectivity correlated with lower Mini-Mental State Examination scores; decreased functional connectivity in the dorsal midbrain tegmentum network correlated with lower scores in the Frontal Assessment Battery. CONCLUSIONS: The present study demonstrates a widespread disruption of cortical-subcortical connectivity in progressive supranuclear palsy and provides further insight into the pathophysiologic mechanisms of motor and cognitive impairment in this condition.

Micronucleus test on Triturus carnifex as a tool for environmental biomonitoring.

The amphibian micronucleus test has been widely used during the last 30 years to test the genotoxic properties of several chemicals and as a tool for ecogenotoxic monitoring. The vast majority of these studies were performed on peripheral blood of urodelan larvae and anuran tadpoles and to a lesser extent adults were also used. In this study, we developed protocols for measuring micronuclei in adult shed skin cells and larval gill cells of the Italian crested newt (Triturus carnifex). Amphibians were collected from ponds in two protected areas in Italy that differed in their radon content. Twenty-three adult newts and 31 larvae were captured from the radon-rich pond, while 20 adults and 27 larvae were taken from the radon-free site. The animals were brought to the laboratory and the micronucleus test was performed on peripheral blood and shed skins taken from the adults and on larval gills. Samples from the radon-rich site showed micronucleus frequencies higher than those from the radon-free site and the difference was statistically significant in gill cells (P < 0.00001). Moreover, the larval gills seem to be more sensitive than the adult tissues. This method represents an easy (and noninvasive in the case of the shed skin) application of the micronucleus assay that can be useful for environmental studies in situ.

Cerebellum-dependent associative learning deficits in primary dystonia are normalized by rTMS and practice.

Eyeblink classical conditioning (EBCC) is a cerebellum-dependent paradigm of associative motor learning, and abnormal EBCC is a neurophysiological indicator of cerebellar dysfunction. We have previously demonstrated impaired EBCC in patients with primary dystonia, but it remains uncertain if this represents actual cerebellar pathology or reflects a functional cerebellar disruption. We examined this further by: (1) studying acquisition and retention of EBCC in a second session in eight patients with cervical dystonia (CD) who had a first session 7-10 days earlier; and (2) by investigating the potential of continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere to modify a first-ever EBCC session in 11 patients with CD. EBCC data of eight healthy controls previously studied were used for additional between-group comparisons. We observed an improvement of EBCC in a second session in patients with CD, which is in contrast to patients with proven cerebellar pathology who do not show further improvement of EBCC in additional sessions. We also found that cerebellar cTBS paradoxically normalized EBCC in patients with CD, while we previously showed that it disrupts EBCC in healthy volunteers. Combined, these two experiments are in keeping with a functional and reversible disruption of the cerebellum in dystonia, a phenomenon that is probably secondary to either cerebellar compensation or to cerebellar recruitment in the abnormal sensorimotor network.

Functional reorganization of sensorimotor cortex in early Parkinson disease.

OBJECTIVE: Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex. METHODS: Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves. RESULTS: The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants. CONCLUSIONS: Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD.

Pathophysiology of pain and fatigue in Parkinson's disease.

In Parkinson's disease (PD), nigral degeneration determines an altered neuronal ouput from the subthalamic nucleus and globus pallidus, and as a consequence functional changes in the motor circuits linking basal ganglia to the motor cortical areas. Movement slowness, rigidity and tremor are among the principal motor symptoms of PD. Studies of movement execution have shown that PD patients have difficulty in performing simultaneous and sequential movements. In executing sequential movements the abnormalities of PD patients worsen as the sequence progresses. This phenomenon, called sequential effect, may be one of the mechanisms underlying the fatigue of PD patients. Cortical deafferentation is thought to be responsible for the motor disturbances of PD and studies using transcranial magnetic stimulation showed that in PD patients there are abnormalities in cortical plasticity and in cortical connectivity. Sensorimotor integration refers to the processes that link sensory input to motor output to produce appropriate voluntary movements. Sensory information is important for motor preparation and execution in parkinsonian patients, and PD patients have greater difficulty in performing movements when no external cues are provided. Investigating the role of sensory information, several studies provided evidence that PD patients have numerous somatosensory deficits, including tactile temporal discrimination threshold. Neurophysiological testing in PD has also found altered central somatosensory processing. Finally PD patients may experience painful sensations after the onset of the disease and various evidence suggests an abnormal nociceptive input processing in the central nervous system that might predispose PD patients to developing pain.

Cancer multitarget pharmacology in prostate tumors: tyrosine kinase inhibitors and beyond.

Tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs, essentially because many kinases and regulators are molecules related to frequently mutated oncogenes and tumor suppressors. Many experiments and clinical data in different tumors show that better cancer therapy can be obtained by blocking several tumor cell biochemical pathways at once, accurately selecting critical targets and adjusting drug dosages for the best results. Through our direct experience in experimental models of prostate cancer (PCa), we discuss in this review the issues of tyrosine kinase inhibition in neoplastic cells and illustrate the opportunities to extend cancer proliferation control to other key biological targets of clinical interest, aiming at the realization of better polypharmacology applications in cancer chemotherapy. Briefly, in this review the main experimental evidences on the efficacy of tyrosine kinase inhibitors (TKIs) on PCa are described, together with a reasoned analysis of biological data which may be useful for a general extension to other clinical areas of cancer multitargeted and possibly individualized polychemotherapy.

Correlation between cortical plasticity, motor learning and BDNF genotype in healthy subjects.

There is good evidence that synaptic plasticity in human motor cortex is involved in behavioural motor learning; in addition, it is now possible to probe mechanisms of synaptic plasticity using a variety of transcranial brain-stimulation protocols. Interactions between these protocols suggest that they both utilise common mechanisms. The aim of the present experiments was to test how well responsiveness to brain-stimulation protocols and behavioural motor learning correlate with each other in a sample of 21 healthy volunteers. We also examined whether any of these measures were influenced by the presence of a Val66Met polymorphism in the BDNF gene since this is another factor that has been suggested to be able to predict response to tests of synaptic plasticity. In 3 different experimental sessions, volunteers underwent 5-Hz rTMS, intermittent theta-burst stimulation (iTBS) and a motor learning task. Blood samples were collected from each subject for BDNF genotyping. As expected, both 5-Hz rTMS and iTBS significantly facilitated MEPs. Similarly, as expected, kinematic variables of finger movement significantly improved during the motor learning task. Although there was a significant correlation between the effect of iTBS and 5-Hz rTMS, there was no relationship in each subject between the amount of TMS-induced plasticity and the increase in kinematic variables during motor learning. Val66Val and Val66Met carriers did not differ in their response to any of the protocols. The present results emphasise that although some TMS measures of cortical plasticity may correlate with each other, they may not always relate directly to measures of behavioural learning. Similarly, presence of the Val66Met BDNF polymorphism also does not reliably predict responsiveness in small groups of individuals. Individual success in behavioural learning is unlikely to be closely related to any single measure of synaptic plasticity.

Craniocervical dystonia: clinical and pathophysiological features.

Blepharospasm, oromandibular, lingual, laryngeal and cervical dystonia are common forms of adult-onset dystonia. Each condition may appear in isolation or manifest along with other forms of craniocervical dystonia. Although the various craniocervical dystonias typically present with involuntary muscle spasms causing abnormal postures, they differ for some clinical features. Neurophysiologic and neuroimaging studies have shown a number of motor and sensory abnormalities at cortical and subcortical levels, probably reflecting a dysfunction in the basal ganglia-thalamo-cortical circuits. The best treatment for craniocervical dystonia is botulinum toxin injected into the overactive muscles.

suPAR, a soluble form of urokinase plasminogen activator receptor, inhibits human prostate cancer cell growth and invasion.

Urokinase-type plasminogen activator (uPA) and its specific membrane receptor (uPAR) control extracellular matrix proteolysis, cell migration, invasion and cell growth in several cancers. The uPAR released from human cancers is detected in blood as soluble uPAR (suPAR). No information is available on the mechanism(s) of action of suPAR on prostate cancer (PCa) cell growth and invasion. In order to clarify this issue, we tested the effect of a treatment with the human recombinant suPAR (comprising amino acids l-303) on the proliferation, migration and invasion of DU145 cells, a PCa cell line expressing a potent autocrine uPA-uPAR signalling system. The results indicate that suPAR significantly inhibits cell growth, promotes apoptosis and decreases both migration and Matrigel invasion of DU145 cells. The mechanism of action of suPAR seems to be linked to a decrease of ERK and FAK activation. Cleavage of suPAR by chymotripsin reverses these effects. When added to the uPA-negative LNCaP cells, suPAR was ineffective; on the contrary, when LNCaP cells were cultured on fibronectin-coated plates in order to stimulate uPA expression, suPAR significantly decreased cell proliferation. In conclusion, our data suggest that suPAR can function as a potent molecule scavenger for uPA in human PCa cells characterized by high levels of uPA/uPAR as in DU145 cells, while it is ineffective in uPA-deficient LNCaP cells. The molecular mechanism(s) through which suPAR participates in the control of PCa progression may bear relevance for the long-term goal to identify new therapeutic targets aimed at silencing tumours in vivo.

Fast voluntary neck movements in patients with cervical dystonia: a kinematic study before and after therapy with botulinum toxin type A.

OBJECTIVE: To study fast voluntary neck movements in patients with cervical dystonia (CD) before and after therapy with botulinum toxin type-A (BTX-A). METHODS: A selected sample of 15 patients with CD (with prevalent torticollis) and 13 age-matched control subjects performed both right and left rotational, and flexion and extension neck movements as fast as possible. Movements were recorded with a motion analysis system (SMART, BTS). Movement time, angular amplitude, and peak angular velocity were analyzed. In patients, rotational neck movements were pooled as "pro-dystonic" (toward the dystonic side) and "anti-dystonic" (toward the non-dystonic side). Results obtained in patients before BTX-A treatment were compared with those of control subjects. The effect of BTX-A treatment was evaluated by comparing movement performance before and after treatment. RESULTS: Before receiving BTX-A, patients performed pro- and anti-dystonic movements with lower peak angular velocity than control subjects. Pro-dystonic movements had a reduced angular amplitude. Anti-dystonic movements showed an abnormally long movement time. Flexion and extension movements required longer movement times, but the other kinematic variables were normal. After BTX-A injections, pro-dystonic movement amplitude and anti-dystonic movement peak angular velocity increased, whereas flexion and extension movements remained unchanged. CONCLUSIONS: Before BTX-A injection patients with CD perform fast voluntary neck movements abnormally and BTX-A injections improved their peak velocity and amplitude. SIGNIFICANCE: Kinematic studies can detect specific neck movement disturbance in patients with CD, and can quantify both the severity of clinical picture and the effect of BTX-A injections in these patients.