Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Out with the Old and in with the New: the Contribution of Prefrontal and Cerebellar Areas to Backward Inhibition.

The inhibitory mechanism named backward inhibition (BI) counteracts interference of previous tasks supporting task switching. For instance, if task set A is inhibited when switching to task B, then it should take longer to immediately return to task set A (as occurring in an ABA sequence), as compared to a task set that has not been just inhibited (as occurring in a CBA sequence), because extra time will be needed to overcome the inhibition of task set A.The evidenced prefrontal and cerebellar role in inhibitory control suggests their involvement even in BI. Here, for the first time, we modulated the excitability of multiple brain sites (right presupplementary motor area (pre-SMA), left and right cerebellar hemispheres) through continuous theta burst stimulation (cTBS) in a valuable sham-controlled order-balanced within-subject experimental design in healthy individuals performing two domain-selective (verbal and spatial) task-switching paradigms. Verbal BI was abolished by prefrontal or cerebellar stimulations through opposite alterations of the basal pattern: cTBS on pre-SMA increased CBA reaction times, disclosing the current prefrontal inhibition of any interfering old task. Conversely, cerebellar cTBS decreased ABA reaction times, disclosing the current cerebellar recognition of sequences in which it is necessary to overcome previously inhibited events.

Learning by observation and learning by doing in Down and Williams syndromes.

New skills may be learned by active experience (experiential learning or learning by doing) or by observation of others' experience (learning by observation). In general, learning by observation reduces the time and the attempts needed to learn complex actions and behaviors. The present research aimed to compare learning by observation and learning by doing in two clinical populations with different etiology of intellectual disability (ID), as individuals with Down syndrome (DS) and individuals with Williams syndrome (WS), with the hypothesis that specific profiles of learning may be found in each syndrome. To this end, we used a mixture of new and existing data to compare the performances of 24 individuals with DS, 24 individuals with WS and 24 typically developing children on computerized tasks of learning by observation or learning by doing. The main result was that the two groups with ID exhibited distinct patterns of learning by observation. Thus, individuals with DS were impaired in reproducing the previously observed visuo-motor sequence, while they were as efficient as TD children in the experiential learning task. On the other hand, individuals with WS benefited from the observational training while they were severely impaired in detecting the visuo-motor sequence in the experiential learning task (when presented first). The present findings reinforce the syndrome-specific hypothesis and the view of ID as a variety of conditions in which some cognitive functions are more disrupted than others because of the differences in genetic profile and brain morphology and functionality. These findings have important implications for clinicians, who should take into account the genetic etiology of ID in developing learning programs for treatment and education.

Diagnostic accuracy of ultrasound in detecting the depth of invasion in women at risk of abnormally invasive placenta: A prospective longitudinal study.

INTRODUCTION: The aim of this study was to assess the diagnostic accuracy of ultrasound in detecting the depth of abnormally invasive placenta in women at risk. MATERIAL AND METHODS: Prospective longitudinal study including women with placenta previa and at least one prior cesarean delivery or uterine surgery. Depth of abnormally invasive placenta was defined as the degree of trophoblastic invasion through the myometrium and was assessed with histopathological analysis. The ultrasound signs explored were: loss of clear zone, placental lacunae, bladder wall interruption, uterovesical hypervascularity, and increased vascularity in the parametrial region. RESULTS: In all, 210 women were included in the analysis. When using at least one sign, ultrasound had an overall sensitivity of 100% (95% CI 96.5-100) and overall specificity of 61.9 (95% CI 51.9-71.2) for all types of abnormally invasive placenta. Using two ultrasound signs increased the diagnostic accuracy in terms of specificity (100%, 95% CI 96.5-100) but did not affect sensitivity. When stratifying the analysis according to the depth of placental invasion, using at least one sign had a sensitivity of 100% (95% CI 93.7-100) and 100% (95% CI 92.6-100) for placenta accreta/increta and percreta, respectively. Using three ultrasound signs improved the detection rate for placenta percreta with a sensitivity of 100% (95% CI 92.6-100) and a specificity of 77.2% (95% CI 69.9-83.4). CONCLUSION: Ultrasound has a high diagnostic accuracy in detecting the depth of placental invasion when applied to a population with specific risk factors for anomalies such as placenta previa and prior cesarean delivery or uterine surgery.

Are young children able to learn exploratory strategies by observation?

New competencies may be learned through active experience (experiential learning or learning by doing) or observation of others' experiences (learning by observation). Observing another person performing a complex action facilitates the observer's acquisition of the same action. The present research is aimed at analyzing if the observation of specific explorative strategies adopted in a constrained environment, such as the Radial Arm Maze (RAM), could help young children to explore the maze and to build a cognitive spatial map of the explored environment. To this aim young children were randomly assigned to three groups: children who performed the RAM task following the observation of an actor solving the same maze by putting into action a highly structured exploratory strategy; children who performed the RAM task following the observation of the actor solving the same maze by putting into action a less structured exploratory strategy; children who directly performed the RAM task without any observation. The main result of the present research is that the children who observed the highly structured and correct exploratory strategy spent less time, made fewer errors, exhibited a longer spatial span, and thus they explored the maze more efficiently than the children who directly performed the RAM task without any observation. This finding indicates that when the observed explorative procedure is structured, sequential and repetitive the action understanding and information storage processes are more effective. Importantly, the observation of specific spatial strategies helped the children to build the cognitive spatial map of the explored environment and consequently to acquire/enrich the declarative knowledge of the environment.

Functional Role of Internal and External Visual Imagery: Preliminary Evidences from Pilates.

The present study investigates whether a functional difference between the visualization of a sequence of movements in the perspective of the first- (internal VMI-I) or third- (external VMI-E) person exists, which might be relevant to promote learning. By using a mental chronometry experimental paradigm, we have compared the time or execution, imagination in the VMI-I perspective, and imagination in the VMI-E perspective of two kinds of Pilates exercises. The analysis was carried out in individuals with different levels of competence (expert, novice, and no-practice individuals). Our results showed that in the Expert group, in the VMI-I perspective, the imagination time was similar to the execution time, while in the VMI-E perspective, the imagination time was significantly lower than the execution time. An opposite pattern was found in the Novice group, in which the time of imagination was similar to that of execution only in the VMI-E perspective, while in the VMI-I perspective, the time of imagination was significantly lower than the time of execution. In the control group, the times of both modalities of imagination were significantly lower than the execution time for each exercise. The present data suggest that, while the VMI-I serves to train an already internalised gesture, the VMI-E perspective could be useful to learn, and then improve, the recently acquired sequence of movements. Moreover, visual imagery is not useful for individuals that lack a specific motor experience. The present data offer new insights in the application of mental training techniques, especially in field of sports. However, further investigations are needed to better understand the functional role of internal and external visual imagery.

3D power Doppler in the evaluation of abnormally invasive placenta.

The anomalies in placental insertion and invasion, such as placenta previa and the various forms of abnormally invasive placenta, are today a rising obstetric pathology. Two-dimensional (2D) ultrasonography is the gold standard in the diagnosis of abnormally invasive placenta (AIP), but the important feto-maternal impact of this pathology suggests the opportunity to employ all the available diagnostic techniques, such as three-dimensional (3D) power Doppler. This technique allows acquiring multiplanar images on coronal, axial and sagittal planes and with a rotational technique, it permits visualizing the placenta-bladder interface more accurately. Consequently, it allows a better study of the degree of bladder invasion, which is information that has a great impact on the subsequent counseling and management. Thus, 3D power Doppler represents an important technique complementary to 2D ultrasound in the diagnosis of AIP. The aim of this paper is to illustrate the possible applications of this procedure, referring to the main literature data.

The Development of Human Navigation in Middle Childhood: A Narrative Review through Methods, Terminology, and Fundamental Stages.

Spatial orientation and navigation are fundamental abilities in daily life that develop gradually during childhood, although their development is still not clear. The main aim of the present narrative review was to trace the development of navigational skills in middle childhood (6 to 12 years old) by means of studies present in the literature. To this aim, this review took into account the terminology, methodologies, different paradigms, and apparatuses used to investigate egocentric self-centered and allocentric world-centered representations, besides the different types of spaces (reaching/small/large; physical/virtual). Furthermore, this review provided a brief description of the development of navigational strategies and competences in toddlers and preschool children (0-5 years). The main result of this review showed how middle childhood is a crucial period for the improvement and development of allocentric strategies, including metric information. In fact, during this developmental window, children learn to handle proximal and distal cues, to transpose paper and virtual information into real environments, up to performing similarly to adults. This narrative review could represent a starting point to better clarify the development of navigation and spatial orientation, finalized to trace a development curve useful to map normal development and to have a term of comparison to assess performance in atypical development.

Clinical application of mindfulness-oriented meditation in children with ADHD: a preliminary study on sleep and behavioral problems.

OBJECTIVE: High incidence of sleep problems in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD) has been described. Mindfulness meditation has emerged as a novel approach to sleep disturbances and insomnia remediation. This preliminary study tested the efficacy of Mindfulness-Oriented Meditation (MOM) training on sleep quality and behavioral problems in children with ADHD. DESIGN: Twenty-five children with ADHD aged 7-11 years underwent two programs three times per week for eight-weeks: the MOM training (15 children) and an Active Control Condition (10 children). MAIN OUTCOME MEASURES: Objective and subjective measures of sleep quality and behavioral measures were collected before and after the programs. RESULTS: Positive effects on sleep and behavioral measures were found only in the MOM group. CONCLUSION: Although they are preliminary, our results indicate that MOM training is a promising tool for ameliorating sleep quality and behavioral manifestations in ADHD.

Before or after does it matter? Different protocols of environmental enrichment differently influence motor, synaptic and structural deficits of cerebellar origin.

Cerebellar compensation is a reliable model of lesion-induced plasticity occurring through profound synaptic and neurochemical modifications in cortical and sub-cortical regions. As the recovery from cerebellar deficits progresses, the firstly enhanced glutamate striatal transmission is then normalized. The time course of cerebellar compensation and the concomitant striatal modifications might be influenced by protocols of environmental enrichment (EE) differently timed in respect to cerebellar lesion. In the present study, we analyzed the effects of different EE protocols on postural and locomotor behaviors (by means of a neurological rating scale), and on striatal synaptic activity (by means of recordings of spontaneous glutamate-mediated excitatory postsynaptic currents (sEPSCs)) and on morphological correlates (by means of density and dendritic length of Fast Spiking (FS) interneurons) following hemicerebellectomy (HCb) in rats. Cerebellar motor deficits were reduced faster in the enriched animals in comparison to standard housed HCbed rats. The beneficial influence of EE was higher in the animals enriched before the HCb than in rats enriched only after the lesion. In parallel, the HCb-induced increase in striatal sEPSCs was not observed in rats enriched before HCb and attenuated in rats enriched after HCb. Furthermore, the EE prevented the shrinkage of dendritic arborization of FS striatal interneurons. Also this effect was more marked in animals enriched before than after the HCb. The exposure to EE exerted either neuro-protective or therapeutic actions on the cerebellar deficits. The experience-dependent changes of the synaptic and neuronal connectivity observed in the striatal neurons may represent one of the mechanisms through which the enrichment facilitates functional compensation following the cerebellar damage.

Exposure to an enriched environment accelerates recovery from cerebellar lesion.

The exposure to enriched environments allows the maintenance of normal cognitive functioning even in the presence of brain pathology. Up until now, clinical and experimental studies have investigated environmental effects mainly on the symptoms linked to the presence of neuro-degenerative diseases, and no study has yet analyzed whether prolonged exposure to complex environments allows modifying the clinical expression and compensation of deficits of cerebellar origin. In animals previously exposed to complex stimulations, the effects of cerebellar lesions have been analyzed to verify whether a prolonged and intense exposure to complex stimulations affected the compensation of motor and cognitive functions following a cerebellar lesion. Hemicerebellectomized or intact animals housed in enriched or standard conditions were administered spatial tests. Postural asymmetries and motor behavior were also assessed. Exposure to the enriched environment almost completely compensated the effects of the hemicerebellectomy. In fact, the motor and cognitive performances of the enriched hemicerebellectomized animals were similar to those of the intact animals. The plastic changes induced by enhanced mental and physical activity seem to provide the development of compensatory responses against the disrupting motor and cognitive consequences of the cerebellar damage.

Spatial competences in Prader-Willi syndrome: a radial arm maze study.

The present study was aimed at investigating the spatial abilities in Prader-Willi syndrome (PWS) by using the Radial Arm Maze (RAM) task. We trained PWS individuals with the deletion subtype in two different RAM paradigms that tapped different aspects of spatial memory. To evaluate the extent of spatial deficit in PWS individuals, it seemed interesting to compare their performances with those of individuals with Williams syndrome (WS) in which deficits in spatial abilities have been well described. The two syndromic groups were compared to typically developing (TD) individuals mental-age and gender matched. The findings evidenced the impairment of PWS individuals in solving the RAM task with variable severity depending on the paradigm requests. Since the RAM is a task that allows the acquisition of spatial competences through the movement, we advance that the spatial deficits observed in PWS individuals may be related to the malfunctioning of spatial and motor integrative processing.

Cerebellar damage loosens the strategic use of the spatial structure of the search space.

The influence of a hemicerebellar lesion on the exploration of environments with different spatial distributions of multiple rewards was analyzed. Hemicerebellectomized (HCbed) and intact rats were submitted to a search task in which they had to explore nine food trays in an open field, avoiding repeated visits. Trays were spatially arranged in four configurations: cross, 3 x 3 matrix, circle, and three clusters of three trays each. Lesioned and intact rats' performances improved in all configurations used. However, the explorative activity of the HCbed animals differed from that of intact rats. Lesioned animals spent more time, made more errors, displayed lower search efficiency, exhibited shorter final spans, and traveled longer distances. They tended to perseverate and to neglect some trays. The cerebellar damage differentially influenced performances as a specific effect of the susceptibility of the configurations to being explored in a principled way. In the cross configuration that had strong spatial constraints, both groups made their lowest number of errors. In the circle configuration, the altered explorative strategies of lesioned animals made extremely demanding the acquisition of the task of searching multiple rewards, in spite of the attempt of favoring their altered procedures through an appropriate spatial arrangement. Since the procedural impairment elicited by cerebellar damage affected the central exploration, the matrix configuration was the most difficult configuration to be explored by the HCbed rats. The poor performances in the cluster configuration indicated that chunking was a strategy of relative strength in rats in general and in HCbed rats in particular.

Peripersonal Visuospatial Abilities in Williams Syndrome Analyzed by a Table Radial Arm Maze Task.

Williams syndrome (WS) is a genetic deletion syndrome characterized by severe visuospatial deficits affecting spatial exploration and navigation abilities in extra-personal space.To date, little is known about spatial elaboration and reaching abilities in the peripersonal space in individuals with WS. The present study is aimed at evaluating the visuospatial abilities in individuals with WS and comparing their performances with those of mental age-matched typically developing (TD) children by using a highly sensitive ecological version of the Radial Arm Maze (table RAM). We evaluated 15 individuals with WS and 15 TD children in two different table RAM paradigms: the free-choice paradigm, mainly to analyze the aspects linked to procedural and memory components, and the forced-choice paradigm, to disentangle the components linked to spatial working memory from the procedural ones.Data show that individuals with WS made significantly more working memory errors as compared with TD children, thus evidencing a marked deficit in resolving the task when the mnesic load increased. Our findings provide new insights on the cognitive profile of WS.

Severe congenital myasthenic syndrome associated with novel biallelic mutation of the CHRND gene.

Congenital myasthenic syndromes (CMS) are a group of inherited disorders caused by mutations in genes encoding proteins essential for neuromuscular transmission. CMS is characterized by fatigable muscle weakness with onset at birth or in early childhood; rarely, symptoms may present later. The most frequently involved proteins are choline acetyltransferase, the endplate species of acetylcholinesterase and the acetylcholine receptor subunits. Defects in the cholinergic receptor nicotinic delta subunit (CHRND) are a rare cause for CMS but they should be considered in patients with a severe, early onset disease, with respiratory distress. We describe two sisters, clinically and genetically diagnosed with CMS, carrying two heteroallelic variants in the CHRND gene: c.730C>T; p.(Arg244Cys) and c.1304T>C; p.(Leu435Pro). The first variant has already been described yet no clinical relevance has been proved; the second one, is a novel variant documented here for the first time. These two cases expand the clinical spectrum of CMS linked to CHRND mutations.

Effects of chronic donepezil treatment and cholinergic deafferentation on parietal pyramidal neuron morphology.

Although clinical and experimental research has demonstrated that acetylcholinesterase inhibitors, such as donepezil, are able to enhance cognitive functioning in intact subjects as well as in patients affected by different degrees of dementia, no morphological study has ever analyzed whether donepezil treatment is able to modify neocortical neuronal morphology in the intact brain and in response to cholinergic depletion. Spines (number, density, distribution) and branching (length, intersections, nodes) of apical and basal dendrites of III-layer parietal pyramidal neurons were evaluated following chronic donepezil treatment in intact animals and in animals in which the cholinergic lesion was produced by intracerebroventricular injections of immunotoxin 192 IgG-saporin. In intact animals, the drug treatment provoked a proximal shift of spines towards the cell soma in basal dendrites. In lesioned animals, donepezil treatment reduced the upregulation of the spines induced by the cholinergic lesion in both apical and basal dendrites. Thus, while in the intact brain chronic donepezil treatment induced plastic changes in the dendritic morphology of pyramidal neurons of parietal cortex, in the presence of cholinergic depletion, it prevented the compensatory response of parietal pyramidal neurons to the loss of cholinergic inputs from basal forebrain.

Cognitive performances of cholinergically depleted rats following chronic donepezil administration.

Since acute and chronic administration of the acetylcholinesterase inhibitors, namely donepezil, improves cognitive functions in patients afflicted by mild to moderate dementia and reverses memory deficits in experimental models of learning and memory, it seemed interesting to assess the effects of chronic donepezil treatment on cognitive functions in adult rats with forebrain cholinergic depletion. Lesions were performed by means of intracerebroventricular injections of the immunotoxin 192 IgG-saporin. The cognitive functions of lesioned animals treated or not treated with donepezil were compared with those of intact animals. Cholinergic depletion affected working memory functions, weakened procedural competencies, affected the acquisition of localizing knowledge, and evoked remarkable compulsive and perseverative behaviors. In lesioned animals, chronic donepezil treatment ameliorated localizatory capabilities, performances linked to cognitive flexibility and procedural abilities. Furthermore, it attenuated compulsive deficits. The present data indicate positive effects of chronic donepezil treatment on specific cognitive performances, suggesting that an aimed use of acetylcholinesterase inhibitors, targeting some symptoms more than others, may be beneficial in the case of cholinergic hypofunction. The animal model used in the present research may provide an efficient method for analyzing cognition-enhancing drugs before clinical trials.

Increased concentrations of nerve growth factor and brain-derived neurotrophic factor in the rat cerebellum after exposure to environmental enrichment.

The molecular mechanism of environmental enrichment (EE) on brain function and anatomy has been partially attributed to the up-regulation of proteins involved in neuronal survival and activity-dependent plasticity, such as the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in the cerebral cortex and hippocampus of animal models. Nevertheless, at present, little indication is available on the influence of EE on neurotrophin levels in the cerebellum. Thus, in this study, we exposed male Wistar rats to EE from weaning to 5 months of age and evaluated the production of NGF and BDNF in the cerebellum and compared the neurotrophin changes in this region with those obtained in other brain structures where neurotrophins are produced or transported. We found that in rats exposed to EE from 21st until 140th postnatal day, a significant increase of both BDNF and NGF concentrations was observed in the cerebellum, as compared to rats reared in standard conditions. In addition, cerebellum was the brain region where NGF and BDNF levels were more influenced by EE as compared to the changes observed in other regions. EE also caused a concomitant increase in NGF levels in the striatum while in the same brain region, BDNF levels were reduced. In summary, this study shows that a prolonged exposure to EE is associated with an increase in cerebellar NGF and BDNF production, thus suggesting that the beneficial effects of EE on the cerebellum of adult animals could be mediated, at least in part, by neurotrophins.

The Development of Spatial Memory Analyzed by Means of Ecological Walking Task.

The present study is aimed at investigating the development of spatial memory in pre-school children aged 4-6 years using an ecological walking task with multiple rewards. The participants were to explore an open space in order to find nine rewards placed in buckets arranged in three spatial configurations: a Cross, a 3 × 3 Matrix, and a Cluster composed of three groups of three buckets each. Clear age-related improvements were evident in all the parameters analyzed. In fact, there was a general trend for younger children to display worse performance than the older ones. Moreover, males performed better than females in both the search efficiency and visiting all buckets. Additionally, the search efficiency proved to be a function of the difficulty of the configuration to be explored: the Matrix and Cluster configurations were easier to explore than the Cross configuration. Taken altogether, the present findings suggest that there is a general improvement in the spatial memory abilities in preschoolers and that solving an open space task could be influenced by gender. Moreover, it can be proposed that both the procedural competences and the memory load requested to explore a specific environment are determined by its specific features.

Effects of pre-reproductive maternal enrichment on maternal care, offspring's play behavior and oxytocinergic neurons.

Potentiating social, cognitive, and sensorimotor stimulations the Environmental Enrichment (EE) increases levels of novelty and complexity experienced by individuals. Growing evidence demonstrates that parental EE experience, even occurring in the pre-reproductive phase, affects behavioral and neural developmental trajectories of the offspring. To discover how the accumulation of early maternal complex experiences may inform and shape the social behavior of the following generation, we examined the effects of pre-reproductive enrichment of dams (post-natal days 21-72) on the play performances of their male and female adolescent offspring. Furthermore, we examined the effects of pre-reproductive enrichment on maternal behavior (during post-partum days 1-10) and male intruder aggression (on post-partum day 11). Since oxytocin modulates maternal care, social bonding, and agonistic behavior, the number of oxytocinergic neurons of the paraventricular (PVN) and supraoptic (SON) nuclei was examined in both dams and offspring. Results revealed that enriched females exhibited higher levels of pup-oriented behaviors, especially Crouching, and initiated pup-retrieval more quickly than standard females after the maternal aggression test. Such behavioral peculiarities were accompanied by increased levels of oxytocinergic neurons in PVN and SON. Moreover, pre-reproductive maternal EE cross-generationally influenced the offspring according to sex. Indeed, male pups born to enriched females exhibited a reduced play fighting associated with a higher number of oxytocinergic neurons in SON in comparison to male pups born to standard-housed females. In conclusion, pre-reproductive EE to the mothers affects their maternal care and has a cross-generational impact on the social behavior of their offspring that do not directly experiences EE. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".