Photoperiodism, testosterone and adult neurogenesis in canaries (Serinus canaria).

Domestic strains of canaries (Serinus canaria) variably respond to photoperiod changes and apparently stay in breeding state for extended periods. Fife Fancy canaries are supposed to be similar to the native species living at 27-39° north where photoperiod significantly changes across the year. Our birds showed reproductive cycles when exposed to light regimes mimicking the annual cycle of photoperiod. However after 6 months in short days (SD: 8L:16D), males developed large testes, as observed by X-ray tomography, and intense singing. Switching to long days (LD: 16L:8D) did not further increase song rate nor testes size but increased song duration, number of syllables per song, and trill occurrence frequency. No sign of regression was observed after 12 weeks in LD but return to SD produced a rapid decrease in testes size and singing activity below values in birds maintained throughout in SD. Fife Fancy thus does not seem to develop absolute but only relative refractoriness. The relatively high singing activity expressed by SD-photosensitive males does not seem to depend on high testosterone (T) concentrations. Singing did not correlate with plasma testosterone (T). Treatment with ATD + Flutamide only marginally decreased song rate and did not affect song quality nor song control nuclei volume. These birds are either supersensitive to low T levels or their reproductive physiology is activated by other mechanisms. Neurogenesis is increased by T and by LD but the function of new neurons incorporated in HVC is poorly understood. We developed a procedure based on X-ray focal irradiation to deplete neural progenitors adjacent to HVC and study the functional consequences. The decrease in neurogenesis increased the variability of T-induced songs in females and decreased their bandwidth. Neurogenesis in HVC thus plays a role in song production and X-ray focal irradiation represents an excellent tool to analyze adult neurogenesis.

Altered Corticospinal and Intracortical Excitability After Stroke: A Systematic Review With Meta-Analysis.

BACKGROUND: Intracortical inhibitory/faciliatory measures are affected after stroke; however, the evidence is conflicting. OBJECTIVE: This meta-analysis aimed to investigate the changes in motor threshold (MT), motor evoked potential (MEP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF), and identify sources of study variability using a machine learning approach. METHODS: We identified studies that objectively evaluated corticospinal excitability and intracortical inhibition/facilitation after stroke using transcranial magnetic stimulation. Pooled within- (ie, affected hemisphere [AH] vs unaffected hemisphere [UH]) and between-subjects (ie, AH and UH vs Control) standardized mean differences were computed. Decision trees determined which factors accurately predicted studies that showed alterations in corticospinal excitability and intracortical inhibition/facilitation. RESULTS: A total of 35 studies (625 stroke patients and 328 healthy controls) were included. MT was significantly increased and MEP was significantly decreased (ie, reduced excitability) in the AH when compared with the UH and Control (P < .01). SICI was increased (ie, reduced inhibition) for the AH when compared with the UH, and for the AH and UH when compared with Control (P < .001). ICF was significantly increased (ie, increased facilitation) in the AH when compared with UH (P = .016) and decreased in UH when compared with Control (P < 0.001). Decision trees indicated that demographic and methodological factors accurately predicted (73%-86%) studies that showed alterations in corticospinal and intracortical excitability measures. CONCLUSIONS: The findings indicate that stroke alters corticospinal and intracortical excitability measures. Alterations in SICI and ICF may reflect disinhibition of the motor cortex after stroke, which is contrary to the notion that stroke increases inhibition of the affected side.

Plastic reorganization of the topological asymmetry of hemispheric white matter networks induced by congenital visual experience deprivation.

Congenital blindness offers a unique opportunity to investigate human brain plasticity. The influence of congenital visual loss on the asymmetry of the structural network remains poorly understood. To address this question, we recruited 21 participants with congenital blindness (CB) and 21 age-matched sighted controls (SCs). Employing diffusion and structural magnetic resonance imaging, we constructed hemispheric white matter (WM) networks using deterministic fiber tractography and applied graph theory methodologies to assess topological efficiency (i.e., network global efficiency, network local efficiency, and nodal local efficiency) within these networks. Statistical analyses revealed a consistent leftward asymmetry in global efficiency across both groups. However, a different pattern emerged in network local efficiency, with the CB group exhibiting a symmetric state, while the SC group showed a leftward asymmetry. Specifically, compared to the SC group, the CB group exhibited a decrease in local efficiency in the left hemisphere, which was caused by a reduction in the nodal properties of some key regions mainly distributed in the left occipital lobe. Furthermore, interhemispheric tracts connecting these key regions exhibited significant structural changes primarily in the splenium of the corpus callosum. This result confirms the initial observation that the reorganization in asymmetry of the WM network following congenital visual loss is associated with structural changes in the corpus callosum. These findings provide novel insights into the neuroplasticity and adaptability of the brain, particularly at the network level.

Brain plasticity following lumbar disc herniation treatment with spinal manipulation therapy based on resting-state functional magnetic resonance imaging.

As a prevalent spine disorder, Lumbar disc herniation (LDH) has been affecting more than 2 % of the worldwide population and is characterised by uncertain causes and recurring episodes. Studying the brain activity of patients could potentially provide insights into its pathogenesis and significantly enhance therapy. Therefore, we here examined brain function in patients under Spinal Manipulative Therapy (SMT). By analysing regional homogeneity (ReHo) at different frequency bands, we identified the discrepancies in brain activity between LDH patients and healthy people, highlighting the frequency dependence of spontaneous low-frequency oscillations among patients with LDH. Choosing seeds based on the peak ReHo differences helped to elucidate the functional connectivity alterations in the brain regions of LDH. Overall, this study showed that SMT significantly reduced pain, improved dysfunction, and partially rectified aberrant local consistency and functional connection in patients with LDH, not only offering insights into the pathophysiology of LDH from a neurological standpoint, but also providing inspiration for the development of new therapies based on neurobiology.

High fat diet affects the hippocampal expression of miRNAs targeting brain plasticity-related genes.

Metabolic disorders such as insulin resistance and type 2 diabetes are associated with brain dysfunction and cognitive deficits, although the underpinning molecular mechanisms remain elusive. Epigenetic factors, such as non-coding RNAs, have been reported to mediate the molecular effects of nutrient-related signals. Here, we investigated the changes of miRNA expression profile in the hippocampus of a well-established experimental model of metabolic disease induced by high fat diet (HFD). In comparison to the control group fed with standard diet, we observed 69 miRNAs exhibiting increased expression and 63 showing decreased expression in the HFD mice's hippocampus. Through bioinformatics analysis, we identified numerous potential targets of the dysregulated miRNAs, pinpointing a subset of genes regulating neuroplasticity that were targeted by multiple differentially modulated miRNAs. We also validated the expression of these synaptic and non-synaptic proteins, confirming the downregulation of Synaptotagmin 1 (SYT1), calcium/calmodulin dependent protein kinase I delta (CaMK1D), 2B subunit of N-methyl-D-aspartate glutamate receptor (GRIN2B), the DNA-binding protein Special AT-Rich Sequence-Binding Protein 2 (SATB2), and RNA-binding proteins Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) and Neuro-oncological ventral antigen 1 (NOVA1) in the hippocampus of HFD mice. In summary, our study offers a snapshot of the HFD-related miRNA landscape potentially involved in the alterations of brain functions associated with metabolic disorders. By shedding light on the specific miRNA-mRNA interactions, our research contributes to a deeper understanding of the molecular mechanisms underlying the effects of HFD on the synaptic function.

Short-term dietary changes are reflected in the cerebral content of adult ring-billed gulls.

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) are produced primarily in aquatic ecosystems and are considered essential nutrients for predators given their structural role in vertebrates' cerebral tissues. Alarmingly, with urbanization, many aquatic animals now rely on anthropogenic foods lacking n3-LCPUFAs. In this study undertaken in Newfoundland (Canada), we tested whether recent or longer term diet explains the cerebral fatty acid composition of ring-billed gulls (Larus delawarensis), a seabird that now thrives in cities. During the breeding season, cerebral levels of n3-LCPUFAs were significantly higher for gulls nesting in a natural habitat and foraging on marine food (mean ± s.d.: 32 ± 1% of total identified fatty acids) than for urban nesters exploiting rubbish (27 ± 1%). Stable isotope analysis of blood and feathers showed that urban and natural nesters shared similar diets in autumn and winter, suggesting that the difference in cerebral n3-LCPUFAs during the breeding season was owing to concomitant and transient differences in diet. We also experimentally manipulated gulls' diets throughout incubation by supplementing them with fish oil rich in n3-LCPUFAs, a caloric control lacking n3-LCPUFAs, or nothing, and found evidence that fish oil increased urban nesters' cerebral n3-LCPUFAs. These complementary analyses provide evidence that the brain of this seabird remains plastic during adulthood and responds to short-term dietary changes.

Effects and neural mechanisms of different physical activity on major depressive disorder based on cerebral multimodality monitoring: a narrative review.

Major depressive disorder (MDD) is currently the most common psychiatric disorder in the world. It characterized by a high incidence of disease with the symptoms like depressed mood, slowed thinking, and reduced cognitive function. Without timely intervention, there is a 20-30% risk of conversion to treatment-resistant depression (TRD) and a high burden for the patient, family and society. Numerous studies have shown that physical activity (PA) is a non-pharmacological treatment that can significantly improve the mental status of patients with MDD and has positive effects on cognitive function, sleep status, and brain plasticity. However, the physiological and psychological effects of different types of PA on individuals vary, and the dosage profile of PA in improving symptoms in patients with MDD has not been elucidated. In most current studies of MDD, PA can be categorized as continuous endurance training (ECT), explosive interval training (EIT), resistance strength training (RST), and mind-body training (MBT), and the effects on patients' depressive symptoms, cognitive function, and sleep varied. Therefore, the present study was based on a narrative review and included a large number of existing studies to investigate the characteristics and differences in the effects of different PA interventions on MDD. The study also investigated the characteristics and differences of different PA interventions in MDD, and explained the neural mechanisms through the results of multimodal brain function monitoring, including the intracranial environment and brain structure. It aims to provide exercise prescription and theoretical reference for future research in neuroscience and clinical intervention in MDD.

Macro and micro structural preservation of grey matter integrity after 24 weeks of rTMS in Alzheimer's disease patients: a pilot study.

Alzheimer's Disease (AD) is characterized by structural and functional dysfunction involving the Default Mode Network (DMN), for which the Precuneus (PC) is a key node. We proposed a randomized double-blind pilot study to determine neurobiological changes after 24 weeks of PC-rTMS in patients with mild-to-moderate AD. Sixteen patients were randomly assigned to SHAM or PC-rTMS, and received an intensive 2-weeks course with daily rTMS sessions, followed by a maintenance phase in which rTMS has been applied once a week. Before and after the treatment structural and functional MRIs were collected. Our results showed macro- and micro-structural preservation in PC-rTMS compared to SHAM-rTMS group after 24 weeks of treatment, correlated to an increase of functional connectivity (FC) within the PC in the PC-rTMS group. Even if preliminary, these results trigger the possibility of using PC-rTMS to arrest atrophy progression by manipulating distributed network connectivity patterns.

Effects of bottom-up versus top-down digital cognitive training in older adults: A randomized controlled trial.

INTRODUCTION: Impairments in bottom-up perceptual processing have been associated to the age-related cognitive decline. Digital cognitive training focusing on bottom-up and/or top-down processes have been studied as a tool to remediate age-related cognitive decline. However, the most effective training type and order of application remain unclear. METHODS: One hundred and fifteen older adults were randomly assigned to 40 h of bottom-up then top-down or top-down then bottom-up digital cognitive training or an active control group. We evaluated cognition at baseline, after 20 h and 40 h of training and at follow-up using a mixed-model analysis. RESULTS: Global cognition improved, for the top-down group, after 20 h of training (p = 0.04; d = 0.7) and for all three groups after 40 h. The improvement in global cognition remained five months after the bottom-up/ top-down training (p = 0.009; d = 4.0). There were also improvements in the recall cognitive domain, after 20 h of training, for the bottom-up group and, after 40 h, for all three groups. Gains were observed in verbal fluency after 40 h of training for both therapeutic groups. Processing speed was significantly slower, after 20 h of training, for the control and bottom-up groups and, after 40 h, only for the control group. Emotion recognition improved, after 20 h, for the control group as compared to the therapeutic groups. CONCLUSIONS: These results indicate that the bottom-up/top-down training has the most endurable effects, which reveals the importance of the order of application of the exercises for gains in cognition in older adults.

Adaptive Strategies of Single-Sided Deaf Cochlear-Implant Users Revealed Through Resting State Activity: an Auditory PET Brain Imaging Study.

Brain plasticity refers to the brain's ability to reorganize its structure or function in response to experiences, learning, and environmental influences. This phenomenon is particularly significant in individuals with deafness, as the brain adapts to compensate for the lack of auditory stimulation. The aim of this study is to investigate whether cochlear implantation can restore a normal pattern of brain activation following auditory stimulation in cases of asymmetric hearing loss. We used a PET-scan technique to assess brain activity after cochlear implantation, specifically during an auditory voice/non-voice discrimination task. The results indicated a nearly normal pattern of brain activity during the auditory discrimination task, except for increased activation in areas related to attentional processes compared to controls. Additionally, brain activity at rest showed significant changes in implanted participants, including cross modal visuo-auditory processing. Therefore, cochlear implants can restore the brain's activation pattern through long-term adaptive adjustments in intrinsic brain activity.

Delta waves as a sign of cortical plasticity after full-face transplantation.

This study focused on detecting the reflections of healing and change in cortex activation in full-face transplantation and lesions patients on EEG activity. Face transplant patients have facial lesions before transplantation and, to identify pre-face transplant patients' brain activity in the absence of pre-transplant recordings, we used data obtained from pre-transplant facial lesion patients. Ten healthy, four facial lesion and three full-face transplant patients participated in this study. EEG data recorded for four different sensory stimuli (brush from the right face, right hand, left face, and left-hand regions) were analyzed using wavelet packet transform method. EEG waves were analyzed for standard bands. Our findings indicate significant change in the 2-4 Hz frequency range which may be a result of ongoing or previous cortical reorganization for face lesion and transplant patients. Alterations of the delta wave seen in patients with facial lesion and face transplant can also be explained by the intense central plasticity. Our findings show that the delta band differences might be used as a marker in the evaluation of post-transplant cortical plasticity in the future.

A single-center, assessor-blinded, randomized controlled clinical trial to test the safety and efficacy of a novel brain-computer interface controlled functional electrical stimulation (BCI-FES) intervention for gait rehabilitation in the chronic stroke population.

BACKGROUND: In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies. METHODS: This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally. DISCUSSION: BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial. TRIAL REGISTRATION: The trial was registered as "BCI-FES Therapy for Stroke Rehabilitation" on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.

Resting-state brain plasticity is associated with the severity in cervical spondylotic myelopathy.

OBJECTIVE: To investigate the brain mechanism of non-correspondence between imaging presentations and clinical symptoms in cervical spondylotic myelopathy (CSM) patients and to test the utility of brain imaging biomarkers for predicting prognosis of CSM. METHODS: Forty patients with CSM (22 mild-moderate CSM, 18 severe CSM) and 25 healthy controls (HCs) were recruited for rs-fMRI and cervical spinal cord diffusion tensor imaging (DTI) scans. DTI at the spinal cord (level C2/3) with fractional anisotropy (FA) and degree centrality (DC) were recorded. Then one-way analysis of covariance (ANCOVA) was conducted to detect the group differences in the DC and FA values across the three groups. Pearson correlation analysis was then separately performed between JOA with FA and DC. RESULTS: Among them, degree centrality value of left middle temporal gyrus exhibited a progressive increase in CSM groups compared with HCs, the DC value in severe CSM group was higher compared with mild-moderate CSM group. (P < 0.05), and the DC values of the right superior temporal gyrus and precuneus showed a decrease after increase. Among them, DC values in the area of precuneus in severe CSM group were significantly lower than those in mild-moderate CSM and HCs. (P < 0.05). The fractional anisotropy (FA) values of the level C2/3 showed a progressive decrease in different clinical stages, that severe CSM group was the lowest, significantly lower than those in mild-moderate CSM and HCs (P < 0.05). There was negative correlation between DC value of left middle temporal gyrus and JOA scores (P < 0.001), and the FA values of dorsal column in the level C2/3 positively correlated with the JOA scores (P < 0.001). CONCLUSION: Structural and functional changes have taken place in the cervical spinal cord and brain of CSM patients. The Brain reorganization plays an important role in maintaining the symptoms and signs of CSM, aberrant DC values in the left middle temporal gyrus may be the possible mechanism of inconsistency between imaging findings and clinical symptoms. Degree centrality is a potentially useful prognostic functional biomarker in cervical spondylotic myelopathy.

Changes in brain functional connectivity and muscle strength independent of elbow flexor atrophy following upper limb immobilization in young females.

Muscle disuse induces a decline in muscle strength that exceeds the rate and magnitude of muscle atrophy, suggesting that factors beyond the muscle contribute to strength loss. The purpose of this study was to characterize changes in the brain and neuromuscular system in addition to muscle size following upper limb immobilization in young females. Using a within-participant, unilateral design, 12 females (age: 20.6 ± 2.1 years) underwent 14 days of upper arm immobilization using an elbow brace and sling. Bilateral measures of muscle strength (isometric and isokinetic dynamometry), muscle size (magnetic resonance imaging), voluntary muscle activation capacity, corticospinal excitability, cortical thickness and resting-state functional connectivity were collected before and after immobilization. Immobilization induced a significant decline in isometric elbow flexion (-21.3 ± 19.2%, interaction: P = 0.0440) and extension (-19.9 ± 15.7%, interaction: P = 0.0317) strength in the immobilized arm only. There was no significant effect of immobilization on elbow flexor cross-sectional area (CSA) (-1.2 ± 2.4%, interaction: P = 0.466), whereas elbow extensor CSA decreased (-2.9 ± 2.9%, interaction: P = 0.0177) in the immobilized arm. Immobilization did not differentially alter voluntary activation capacity, corticospinal excitability, or cortical thickness (P > 0.05); however, there were significant changes in the functional connectivity of brain regions related to movement planning and error detection (P < 0.05). This study reveals that elbow flexor strength loss can occur in the absence of significant elbow flexor muscle atrophy, and that the brain represents a site of functional adaptation in response to upper limb immobilization in young females.

Randomized controlled trials of non-pharmacological interventions for healthy seniors: Effects on cognitive decline, brain plasticity and activities of daily living-A 23-year scoping review.

Little is known about the simultaneous effects of non-pharmacological interventions (NPI) on healthy older adults' behavior and brain plasticity, as measured by psychometric instruments and magnetic resonance imaging (MRI). The purpose of this scoping review was to compile an extensive list of randomized controlled trials published from January 1, 2000, to August 31, 2023, of NPI for mitigating and countervailing age-related physical and cognitive decline and associated cerebral degeneration in healthy elderly populations with a mean age of 55 and over. After inventorying the NPI that met our criteria, we divided them into six classes: single-domain cognitive, multi-domain cognitive, physical aerobic, physical non-aerobic, combined cognitive and physical aerobic, and combined cognitive and physical non-aerobic. The ultimate purpose of these NPI was to enhance individual autonomy and well-being by bolstering functional capacity that might transfer to activities of daily living. The insights from this study can be a starting point for new research and inform social, public health, and economic policies. The PRISMA extension for scoping reviews (PRISMA-ScR) checklist served as the framework for this scoping review, which includes 70 studies. Results indicate that medium- and long-term interventions combining non-aerobic physical exercise and multi-domain cognitive interventions best stimulate neuroplasticity and protect against age-related decline and that outcomes may transfer to activities of daily living.

Sports promote brain evolution: a resting-state fMRI study of volleyball athlete.

Background: Long-term skill learning can lead to structure and function changes in the brain. Different sports can trigger neuroplasticity in distinct brain regions. Volleyball, as one of the most popular team sports, heavily relies on individual abilities such as perception and prediction for high-level athletes to excel. However, the specific brain mechanisms that contribute to the superior performance of volleyball athletes compared to non-athletes remain unclear. Method: We conducted a study involving the recruitment of ten female volleyball athletes and ten regular female college students, forming the athlete and novice groups, respectively. Comprehensive behavioral assessments, including Functional Movement Screen and audio-visual reaction time tests, were administered to both groups. Additionally, resting-state magnetic resonance imaging (MRI) data were acquired for both groups. Subsequently, we conducted in-depth analyses, focusing on the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) in the brain for both the athlete and novice groups. Results: No significant differences were observed in the behavioral data between the two groups. However, the athlete group exhibited noteworthy enhancements in both the ALFF and ReHo within the visual cortex compared to the novice group. Moreover, the functional connectivity between the visual cortex and key brain regions, including the left primary sensory cortex, left supplementary motor cortex, right insula, left superior temporal gyrus, and left inferior parietal lobule, was notably stronger in the athlete group than in the novice group. Conclusion: This study has unveiled the remarkable impact of volleyball athletes on various brain functions related to vision, movement, and cognition. It indicates that volleyball, as a team-based competitive activity, fosters the advancement of visual, cognitive, and motor skills. These findings lend additional support to the early cultivation of sports talents and the comprehensive development of adolescents. Furthermore, they offer fresh perspectives on preventing and treating movement-related disorders. Trial registration: Registration number: ChiCTR2400079602. Date of Registration: January 8, 2024.

"Love looks not with the eyes": supranormal processing of emotional speech in individuals with late-blindness versus preserved processing in individuals with congenital-blindness.

Processing of emotional speech in the absence of visual information relies on two auditory channels: semantics and prosody. No study to date has investigated how blindness impacts this process. Two theories, Perceptual Deficit, and Sensory Compensation, yiled different expectations about the role of visual experience (or its lack thereof) in processing emotional speech. To test the effect of vision and early visual experience on processing of emotional speech, we compared individuals with congenital blindness (CB, n = 17), individuals with late blindness (LB, n = 15), and sighted controls (SC, n = 21) on identification and selective-attention of semantic and prosodic spoken-emotions. Results showed that individuals with blindness performed at least as well as SC, supporting Sensory Compensation and the role of cortical reorganisation. Individuals with LB outperformed individuals with CB, in accordance with Perceptual Deficit, supporting the role of early visual experience. The LB advantage was moderated by executive functions (working-memory). Namely, the advantage was erased for individuals with CB who showed higher levels of executive functions. Results suggest that vision is not necessary for processing of emotional speech, but early visual experience could improve it. The findings support a combination of the two aforementioned theories and reject a dichotomous view of deficiencies/enhancements of blindness.

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence.

Perineuronal nets (PNN) are a special highly structured type of extracellular matrix encapsulating synapses on large populations of CNS neurons. PNN undergo structural changes in schizophrenia, epilepsy, Alzheimer's disease, stroke, post-traumatic conditions, and some other brain disorders. The functional role of the PNN microstructure in brain pathologies has remained largely unstudied until recently. Here, we review recent research implicating PNN microstructural changes in schizophrenia and other disorders. We further concentrate on high-resolution studies of the PNN mesh units surrounding synaptic boutons to elucidate fine structural details behind the mutual functional regulation between the ECM and the synaptic terminal. We also review some updates regarding PNN as a potential pharmacological target. Artificial intelligence (AI)-based methods are now arriving as a new tool that may have the potential to grasp the brain's complexity through a wide range of organization levels-from synaptic molecular events to large scale tissue rearrangements and the whole-brain connectome function. This scope matches exactly the complex role of PNN in brain physiology and pathology processes, and the first AI-assisted PNN microscopy studies have been reported. To that end, we report here on a machine learning-assisted tool for PNN mesh contour tracing.