Neural Changes Research Articles

Real-time fMRI neurofeedback modulates induced hallucinations and underlying brain mechanisms

Hallucinations can occur in the healthy population, are clinically relevant and frequent symptoms in many neuropsychiatric conditions, and have been shown to mark disease progression in patients with neurodegenerative disorders where antipsychotic treatment remains challenging. Here, we combine MR-robotics capable of inducing a clinically-relevant hallucination, with real-time fMRI neurofeedback (fMRI-NF) to train healthy individuals to up-regulate a fronto-parietal brain network associated with the robotically-induced hallucination. Over three days, participants learned to modulate occurrences of and transition probabilities to this network, leading to heightened sensitivity to induced hallucinations after training. Moreover, participants who became sensitive and succeeded in fMRI-NF training, showed sustained and specific neural changes after training, characterized by increased hallucination network occurrences during induction and decreased hallucination network occurrences during a matched control condition. These data demonstrate that fMRI-NF modulates specific hallucination network dynamics and highlights the potential of fMRI-NF as a novel antipsychotic treatment in neurodegenerative disorders and schizophrenia.

Characterization of neural networks involved in transdiagnostic emotion dysregulation from a pilot randomized controlled trial of a neurostimulation-enhanced behavioral intervention

BackgroundEmotional dysregulation is a serious and impairing mental health problem. We examined functional activity and connectivity of neural networks involved in emotional dysregulation at baseline and following a pilot neurostimulation-enhanced cognitive restructuring intervention in a transdiagnostic clinical adult sample. MethodsNeuroimaging data were analyzed from adults who scored 89 or higher on the Difficulties with Emotion Regulation (DERS) scale and had at least one DSM-5 diagnosis. These participants were part of a pilot randomized, double-blind, placebo-controlled trial combining a single therapeutic session of cognitive restructuring with active or sham transcranial magnetic stimulation over the dorsolateral prefrontal cortex. During the study, participants engaged in an emotional regulation task using personalized autobiographical stressors while undergoing functional magnetic resonance imaging (fMRI) before and after the pilot intervention. The fMRI task required participants to either experience the emotions associated with the memories or apply cognitive restructuring strategies to reduce their distress. ResultsWhole-brain fMRI results during regulation at baseline revealed increased activation in the dorsal frontoparietal network but decreased activation in the supplementary motor area, cingulate cortex, insula, and ventrolateral prefrontal cortex (vlPFC). Emotion dysregulation was associated with greater vmPFC and amygdala activation and functional connectivity between these regions. The strength of functional connectivity between the dlPFC and other frontal regions was also a marker of emotional dysregulation. Preliminary findings from a subset of participants who completed the follow-up fMRI scan showed that active neurostimulation improved behavioral indices of emotion regulation more than sham stimulation. A whole-brain generalized psychophysiological interaction analysis indicated that active neurostimulation selectively increased occipital cortex connectivity with both the insula and the dlPFC. Region-of-interest functional connectivity analyses showed that active neurostimulation selectively increased dlPFC connectivity with the insula and orbitofrontal cortex (OFC). ConclusionInsufficient neural specificity during the emotion regulation process and over-involvement of frontal regions may be a marker of emotional dysregulation across disorders. OFC, vlPFC, insula activity, and connectivity are associated with improved emotion regulation in transdiagnostic adults. In this pilot study, active neurostimulation led to neural changes in the emotion regulation network after a single session; however, the intervention findings are preliminary, given the small sample size. These functional network properties can inform future neuroscience-driven interventions and larger-scale studies.

Neural dynamics of pain modulation by emotional valence.

Definitions of human pain acknowledge at least two dimensions of pain, affective and sensory, described as separable and thus potentially differentially modifiable. Using electroencephalography, we investigated perceptual and neural changes of emotional pain modulation in healthy individuals. Painful electrical stimuli were applied after presentation of priming emotional pictures (negative, neutral, positive) and followed by pain intensity and unpleasantness ratings. We found that perceptual and neural event-related potential responses to painful stimulation were significantly modulated by emotional valence. Specifically, pain unpleasantness but not pain intensity ratings were increased when pain was preceded by negative compared to neutral or positive pictures. Amplitudes of N2 were higher when pain was preceded by neutral compared to negative and positive pictures, and P2 amplitudes were higher for negative compared to neutral and positive pictures. In addition, a hierarchical regression analysis revealed that P2 alone and not N2, predicted pain perception. Finally, source analysis showed the anterior cingulate cortex and the thalamus as main spatial clusters accounting for the neural changes in pain processing. These findings provide evidence for a separation of the sensory and affective dimensions of pain and open new perspectives for mechanisms of pain modulation.

Neural response to monetary incentives in acquired adolescent depression after mild traumatic brain injury: Stage 2 Registered Report.

Depression is a common consequence of traumatic brain injury. Separately, spontaneous depression-arising without brain injury-has been linked to abnormal responses in motivational neural circuitry to the anticipation or receipt of rewards. It is unknown if post-injury and spontaneously occurring depression share similar phenotypic profiles. This issue is compounded by the fact that nearly all examinations of these psychiatric sequelae are post hoc: there are rarely any prospective assessments of mood and neural functioning before and after a brain injury. In this Stage 2 Registered Report, we used the Adolescent Brain Cognitive Development Consortium dataset to examine if a disruption in functional neural responses to rewards is present in patients with depression after a mild traumatic brain injury. Notably, this study provides an unparalleled opportunity to examine the trajectory of neuropsychiatric symptoms longitudinally within-subjects. This allowed us to isolate mild traumatic brain injury-specific variance independent from pre-existing functioning. Here, we focus on a case-control comparison between 43 youth who experienced a mild traumatic brain injury between MRI visits, and 43 well-matched controls. Contrary to pre-registered predictions (https://osf.io/h5uba/), there was no statistically credible increase in depression in mild traumatic brain injury cases relative to controls. Mild traumatic brain injury was associated with subtle changes in motivational neural circuit recruitment during the anticipation of incentives on the Monetary Incentive Delay paradigm. Specifically, changes in neural recruitment appeared to reflect a failure to deactivate 'task-negative' brain regions (ventromedial prefrontal cortex), alongside blunted recruitment of 'task-positive' regions (anterior cingulate, anterior insula and caudate), during the anticipation of reward and loss in adolescents following mild brain injuries. Critically, these changes in brain activity were not correlated with depressive symptoms at either visit or depression change scores before and after the brain injury. Increased time since injury was associated with a recovery of cognitive functioning-driven primarily by processing speed differences-but depression did not scale with time since injury. These cognitive changes were also uncorrelated with neural changes after mild traumatic brain injury. This report provides evidence that acquired depression may not be observed as commonly after a mild traumatic brain injury in late childhood and early adolescence, relative to findings in adult cases. Several reasons for these differing findings are considered, including sampling enrichment in retrospective cohort studies, under-reporting of depressive symptoms in parent-report data, and neuroprotective factors in childhood and adolescence.

Mindfulness Training in High-Demand Cohorts Alters Resting-State Electroencephalography: An Exploratory Investigation of Individual Alpha Frequency, Aperiodic 1/f Activity, and Microstates

BackgroundMindfulness training (MT) programs have demonstrated utility as cognitive training tools, but there is little consensus on the neurophysiological processes that may underlie its benefits. It has been posited that intrinsic brain activity recorded at rest reflects the functional connectivity of large-scale brain networks and may provide insight into neuroplastic changes that support MT. In the current study, we indexed changes in several resting-state electroencephalography (EEG) parameters to investigate the neurophysiological underpinnings of MT. MethodsResting-state EEG data were collected from active-duty U.S. military personnel (N = 80) at 2 testing sessions: before (time [T] 1) and after (T2) engaging in an 8-week MT or active comparison intervention (positivity training). We examined longitudinal and/or groupwise differences in several EEG parameters through parameterization of power spectra (individual alpha frequency and 1/f activity) and microstate analysis. ResultsWhile no significant group × time differences were observed in individual alpha frequency, significant group × time effects were observed in several EEG parameters from T1 to T2. Compared with MT, positivity training was associated with a steepening of the 1/f slope and higher 1/f intercepts together with decreased duration and increased global field power of microstates. ConclusionsTaken together, these results suggest that the effects of interventions may be differentiated in resting-state brain activity in a sample of military personnel. Such findings provide insight into the neural underpinnings of MT-related brain changes, but more research is required to elucidate how these may relate to task-related neural and performance changes with MT and whether results generalize to other mindfulness interventions in alternative cohorts and contexts.

Vascular network-inspired diffusible scaffolds for engineering functional neural organoids.

Organoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present Vascular network-Inspired Diffusible (VID) scaffolds to fully recapture the benefits of physiological diffusion physics for generating functional organoids and phenotyping their drug response. In a proof-of-concept application, the VID scaffolds, 3D-printed meshed tubular channel networks, support the successful generation of engineered human midbrain organoids almost without necrosis and hypoxia in commonly used well-plates. Compared to conventional organoids, these engineered organoids develop with more physiologically relevant features and functions including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared to conventional organoids with significant diffusion limits. Combining these unique scaffolds and engineered organoids may provide insights for organoid development and therapeutic innovation.

Adaptive closed-loop modulation of cortical theta oscillations: Insights into the neural dynamics of navigational decision-making

Navigational decision-making tasks, such as spatial working memory (SWM), rely highly on information integration from several cortical and sub-cortical regions. Performance in SWM tasks is associated with theta rhythm, including low-frequency oscillations related to movement and memory. The interaction of the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC), reflected in theta synchrony, is essential in various steps of information processing during SWM. We used a closed-loop neurofeedback (CLNF) system to upregulate theta power in the mPFC and investigate its effects on circuit dynamics and behavior in animal models. Specifically, we hypothesized that enhancing the power of the theta rhythm in the mPFC might improve SWM performance. Animals were divided into three groups: closed-loop (CL), random-loop (RL), and OFF (without stimulation). We recorded local field potential (LFP) in the mPFC while electrical reward stimulation contingent on cortical theta activity was delivered to the lateral hypothalamus (LH), which is considered one of the central reward-associated regions. We also recorded LFP in the vHPC to evaluate the related subcortical neural changes. Results revealed a sustained increase in the theta power in both mPFC and vHPC for the CL group. Our analysis also revealed an increase in mPFC-vHPC synchronization in the theta range over the stimulation sessions in the CL group, as measured by coherence and cross-correlation in the theta frequency band. The reinforcement of this circuit improved spatial decision-making performance in the subsequent behavioral results. Our findings provide direct evidence of the relationship between specific theta upregulation and SWM performance and suggest that theta oscillations are integral to cognitive processes. Overall, this study highlights the potential of adaptive CLNF systems in investigating neural dynamics in various brain circuits.

Phase-Amplitude Coupling in Theta and Beta Bands: A Potential Electrophysiological Marker for Obstructive Sleep Apnea.

Phase-amplitude coupling (PAC) between the phase of low-frequency signals and the amplitude of high-frequency activities plays many physiological roles and is involved in the pathological processed of various neurological disorders. However, how low-frequency and high-frequency neural oscillations or information synchronization activities change under chronic central hypoxia in OSA patients and whether these changes are closely associated with OSA remains largely unexplored. This study arm to elucidate the long-term consequences of OSA-related oxygen deprivation on central nervous system function. : We screened 521 patients who were clinically suspected of having OSA at our neurology and sleep centers. Through polysomnography (PSG) and other clinical examinations, 103 patients were ultimately included in the study and classified into mild, moderate, and severe OSA groups based on the severity of hypoxia determined by PSG. We utilized the phase-amplitude coupling (PAC) method to analyze the modulation index (MI) trends between different frequency bands during NREM (N1/N2/N3), REM, and wakefulness stages in OSA patients with varying severity levels. We also examined the correlation between the MI index and OSA hypoxia indices. Apart from reduced N2 sleep duration and increased microarousal index, the sleep architecture remained largely unchanged among OSA patients with varying severity levels. Compared to the mild OSA group, patients with moderate and severe OSA exhibited higher MI values of PAC in the low-frequency theta phase and high-frequency beta amplitude in the frontal and occipital regions during N1 sleep and wakefulness. No significant differences in the MI of phase-amplitude coupling were observed during N2/3 and REM sleep. Moreover, the MI of phase-amplitude coupling in theta and beta bands positively correlated with hypoxia-related indices, including the apnea-hypopnea index (AHI) and oxygenation desaturation index (ODI), and the percentage of oxygen saturation below 90% (SaO2<90%). OSA patients demonstrated increased MI values of theta phase and beta amplitude in the frontal and occipital regions during N1 sleep and wakefulness. This suggests that cortical coupling is prevalent and exhibits sleep-stage-specific patterns in OSA. Theta-beta PAC during N1 and wakefulness was positively correlated with hypoxia-related indices, suggesting a potential relationship between these neural oscillations and OSA severity. The present study provides new insights into the relationship between neural oscillations and respiratory hypoxia in OSA patients.

Neural activation changes following attention bias modification treatment or a selective serotonin reuptake inhibitor for social anxiety disorder.

Delineation of changes in neural function associated with novel and established treatments for social anxiety disorder (SAD) can advance treatment development. We examined such changes following selective serotonin reuptake inhibitor (SSRI) and attention bias modification (ABM) variant - gaze-contingent music reward therapy (GC-MRT), a first-line and an emerging treatments for SAD. Eighty-one patients with SAD were allocated to 12-week treatments of either SSRI or GC-MRT, or waitlist (ns = 22, 29, and 30, respectively). Baseline and post-treatment functional magnetic resonance imaging (fMRI) data were collected during a social-threat processing task, in which attention was directed toward and away from threat/neutral faces. Patients who received GC-MRT or SSRI showed greater clinical improvement relative to patients in waitlist. Compared to waitlist patients, treated patients showed greater activation increase in the right inferior frontal gyrus and anterior cingulate cortex when instructed to attend toward social threats and away from neutral stimuli. An additional anterior cingulate cortex cluster differentiated between the two active groups. Activation in this region increased in ABM and decreased in SSRI. In the ABM group, symptom change was positively correlated with neural activation change in the dorsolateral prefrontal cortex. Brain function measures show both shared and treatment-specific changes following ABM and SSRI treatments for SAD, highlighting the multiple pathways through which the two treatments might work. Treatment-specific neural responses suggest that patients with SAD who do not fully benefit from SSRI or ABM may potentially benefit from the alternative treatment, or from a combination of the two. ClinicalTrials.gov, Identifier: NCT03346239. https://clinicaltrials.gov/ct2/show/NCT03346239.

Age-related neural changes underlying long-term recognition of musical sequences

Aging is often associated with decline in brain processing power and neural predictive capabilities. To challenge this notion, we used magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to record the whole-brain activity of 39 older adults (over 60 years old) and 37 young adults (aged 18–25 years) during recognition of previously memorised and varied musical sequences. Results reveal that when recognising memorised sequences, the brain of older compared to young adults reshapes its functional organisation. In fact, it shows increased early activity in sensory regions such as the left auditory cortex (100 ms and 250 ms after each note), and only moderate decreased activity (350 ms) in medial temporal lobe and prefrontal regions. When processing the varied sequences, older adults show a marked reduction of the fast-scale functionality (250 ms after each note) of higher-order brain regions including hippocampus, ventromedial prefrontal and inferior temporal cortices, while no differences are observed in the auditory cortex. Accordingly, young outperform older adults in the recognition of novel sequences, while no behavioural differences are observed with regards to memorised ones. Our findings show age-related neural changes in predictive and memory processes, integrating existing theories on compensatory neural mechanisms in non-pathological aging.

Motor versus Psychomotor? Deciphering the Neural Source of Psychomotor Retardation in Depression.

Major depressive disorder (MDD) is characterized by psychomotor retardation whose underlying neural source remains unclear. Psychomotor retardation may either be related to a motor source like the motor cortex or, alternatively, to a psychomotor source with neural changes outside motor regions, like input regions such as visual cortex. These two alternative hypotheses in main (n = 41) and replication (n = 18) MDD samples using 7 Tesla MRI are investigated. Analyzing both global and local connectivity in primary motor cortex (BA4), motor network and middle temporal visual cortex complex (MT+), the main findings in MDD are: 1) Reduced local and global synchronization and increased local-to-global output in motor regions, which do not correlate with psychomotor retardation, though. 2) Reduced local-to-local BA4 - MT+ functional connectivity (FC) which correlates with psychomotor retardation. 3) Reduced global synchronization and increased local-to-global output in MT+ which relate to psychomotor retardation. 4) Reduced variability in the psychophysical measures of MT+ based motion perception which relates to psychomotor retardation. Together, it is shown that visual cortex MT+ and its relation to motor cortex play a key role in mediating psychomotor retardation. This supports psychomotor over motor hypothesis about the neural source of psychomotor retardation in MDD.

Resting-state neural dynamics changes in older adults with post-COVID syndrome and the modulatory effect of cognitive training and sex.

Post-COVID syndrome manifests with numerous neurological and cognitive symptoms, the precise origins of which are still not fully understood. As females and older adults are more susceptible to developing this condition, our study aimed to investigate how post-COVID syndrome alters intrinsic brain dynamics in older adults and whether biological sex and cognitive training might modulate these effects, with a specific focus on older females. The participants, aged between 60 and 75years, were divided into three experimental groups: healthy old female, post-COVID old female and post-COVID old male. They underwent an adaptive task-switching training protocol. We analysed multiscale entropy and spectral power density of resting-state EEG data collected before and after the training to assess neural signal complexity and oscillatory power, respectively. We found no difference between post-COVID females and males before training, indicating that post-COVID similarly affected both sexes. However, cognitive training was effective only in post-COVID females and not in males, by modulating local neural processing capacity. This improvement was further evidenced by comparing healthy and post-COVID females, wherein the latter group showed increased finer timescale entropy (1-30ms) and higher frequency band power (11-40Hz) before training, but these differences disappeared following cognitive training. Our results suggest that in older adults with post-COVID syndrome, there is a pronounced shift from more global to local neural processing, potentially contributing to accelerated neural aging in this condition. However, cognitive training seems to offer a promising intervention method for modulating these changes in brain dynamics, especially among females.

Bed nucleus of the stria terminalis network responses to unpredictable threat in early alcohol abstinence.

Anxiety during early alcohol abstinence, likely resulting from neural changes caused by chronic alcohol use, contributes to high relapse rates. Studies in rodents show heightened activation during early abstinence in the bed nucleus of the stria terminalis (BNST)-a neural hub for anxiety-and its extended anxiety-related corticolimbic network. Despite the clinical importance of early abstinence, few studies investigate the underlying neural mechanisms. To address this gap, we investigated brain function in early alcohol abstinence (EA = 20, 9 women) relative to controls (HC = 20, 11 women) using an unpredictable threat task shown to engage the BNST and corticolimbic brain regions involved in anxiety and alcohol use disorder (AUD). Group, anxiety, and sex were predictors used to determine whole-brain activation and BNST functional connectivity. We found widespread interactions of group × anxiety and group × anxiety × sex for both activation and BNST connectivity during unpredictable threat. In the EA group, higher anxiety was correlated with activation in the BNST, rostral anterior cingulate cortex (ACC), insula (men only), and dorsal ACC (men only). In the HC group, higher anxiety was negatively correlated with activation in the BNST, nucleus accumbens, thalamus, and insula (men only). For connectivity, anxiety was positively correlated in EA and negatively correlated in HC, between the BNST and the amygdala, ventromedial prefrontal cortex (PFC), and dorsomedial PFC; EA men showed stronger BNST-vmPFC connectivity than HC men. These novel findings provide preliminary evidence for alterations in the BNST and anxiety-related corticolimbic brain regions in early alcohol abstinence, adding to growing literature in humans supporting the BNST's role in anxiety and sex-dependent effects of chronic alcohol use.

The restraint stress-induced antinociceptive effects decreased by antagonism of both orexin receptors within the CA1 region of the hippocampus

Studies have indicated that stress-related symptoms can lead to hormonal and neural changes, affecting the pain threshold and nociceptive behaviors. The precise role of orexin receptors (OX1r and OX2r) in stress-induced analgesia (SIA) remains an inquiry yet to be comprehensively elucidated. The current investigation aimed to assess the impact of acute immobilization restraint stress on pain-related behavioral responses after administering antagonists targeting OX1r and OX2r in a rat model using the tail-flick test. After a period of five to seven days post-stereotaxic surgery in CA1, the baseline tail-flick latency (TFL) was recorded for each animal. Subsequently, rats were unilaterally administered varying doses of the OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), the OX2r antagonist (TCS OX2 29; 1, 3, 10, and 30 nmol), or a vehicle (0.5 μl solution containing 12% DMSO) through an implanted cannula. Following a 5-min interval, the animals were subjected to a restraint stress (RS) lasting for 3 h. The tail-flick test was conducted after the stress exposure, and the TFLs were assessed at 60-min intervals. The findings of this study revealed that RS elicits antinociceptive responses in the tail-flick test. Microinjection of OX1r and OX2r antagonists into the CA1 attenuated RS-induced analgesia during the tail-flick test. Furthermore, the results underscored the preeminent role of OX2 receptors in modulating SIA. In conclusion, the orexin system localized within the hippocampal CA1 region may, in part, contribute to the manifestation of SIA in the context of acute pain.

Initial learning in the brain: From rules to action

Abstract We used fMRI to investigate the neural changes and representational dynamics associated with different learning modes during initial learning and subsequent implementation of previously acquired stimulus-response (S-R) associations. We compared instruction-based learning (INS) and trial-and-error learning (TE) via a third observation-based learning (OBS) condition. This was yoked to the TE condition and shared features with both, the INS and TE conditions. During learning, neural changes were observed in the Frontoparietal and Default Mode Networks across learning modes, consistent with a general decrease in cognitive control demand as learning progresses. INS and TE exhibited condition-specific signal changes, which we interpreted in the context of covert motor preparation during INS, and intentional action and increased cognitive control demand during early TE trials, respectively. Multivariate pattern analysis revealed individual rule information in bilateral prefrontal, premotor, and parietal cortices across learning modes. Most regions revealed consistent representations of individual S-R rules between the learning stage and subsequent implementation stage, regardless of the learning mode. This suggests that initially formed S-R rule representations guide task performance during S-R rule implementation, irrespective of how they are acquired. Finally, within the primary motor and sensory cortices, individual S-R rules were decodable during the learning stage not only when motor responses were overtly executed, as in TE, but also in the absence of overt motor execution, as in INS. This finding substantiates previous claims of covert motor preparatory mechanisms during INS.

Significance of Neurotransmitters in Cerebral Ischemia: Understanding the Role of Serotonin, Dopamine, Glutamate, and GABA in Stroke Recovery and Treatment.

Brain ischemia occurs following heart failure, thromboembolism, and atherosclerosis, and it is characterized by the disturbance of blood flow resulting from the blockage of blood vessels. After a series of studies, it is deduced that various changes occur following stroke, including neural death and changes in plasticity. Studies have reported that neurotransmitters tend to change following a stroke. These changes that occur surrounding the infarct area following a stroke can be considered new therapeutic targets for stroke rehabilitation. Although various studies have reported that different neurotransmitters have a promising role in either the progression or the rehabilitation following stroke, they have not found any pharmacological interventions to help the previous rehabilitation therapeutics. Phytocompounds also offer potential therapeutic benefits in stroke management due to their antioxidative and anti-inflammatory properties. This article aimed to compile recent advancements in neurotransmitter research related to ischemia and explore the potential use of neurotransmitter agonists/antagonists in ischemic conditions to identify potential drug candidates for treating the severe and prolonged stages of stroke in the future.

A single-cell transcriptomic landscape of cadmium-hindered brain development in mice

The effects of neurotoxicant cadmium (Cd) exposure on brain development have not been well elucidated. To investigate this, we have herein subjected pregnant mice to low-dose Cd throughout gestation. Using single-cell RNA sequencing (scRNA-seq), we explored the cellular responses in the embryonic brain to Cd exposure, and identified 18 distinct cell subpopulations that exhibited varied responses to Cd. Typically, Cd exposure impeded the development and maturation of cells in the brain, especially progenitor cells such as neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). It also caused significant cell subpopulation shifts in almost all the types of cells in the brain. Additionally, Cd exposure reduced the dendritic sophistication of cortical neurons in the offspring. Importantly, these changes led to aberrant Ca2+ activity in the cortex and neural behavior changes in mature offspring. These data contribute to our understanding of the effects and mechanisms of Cd exposure on brain development and highlight the importance of controlling environmental neurotoxicant exposure at the population level.

The Transition from Childhood to Adolescence: Between Health and Vulnerability.

Transitioning from childhood into adolescence is an extraordinary time of life, associated with major physical, emotional, cognitive, and social changes and characterized by dynamic development in which interaction with the environment modulates the individual resources responsible for well-being and health. This sensitive period is the time when, in addition to hormonal, metabolic, and neural changes, certain behavioral strategies begin to take shape that will shortly go on to define the emotional, social, and cultural identity of the individual. This narrative review aimed to uncover the crucial processes underlying the transition by identifying processes that are responsible for cognitive, psychosocial, and emotional development, in the absence of disease. For this aim, we highlight (1) the physical, psychological, and social determinants during the transition from childhood to adolescence; (2) the role of health-related variables in resilience or vulnerability mechanisms; and (3) recent school-based strategies to promote health and well-being. Recognizing that health and well-being are the result of the interaction of many biological, psychological, social, cultural, and physical factors will lead to comprehensive health promotion involving all actors joining the growth process, from health professionals and the educational community to parents and community. Furthermore, it is important that psychosocial dimensions are strengthened already during childhood to prevent the onset of frailty and illness in adolescence.

Neural-Targeted Rehabilitation Strategies to Restore Typical Activation after Joint Injury.

In patients with musculoskeletal injury, changes have been observed within the central nervous system that contribute to altered movement planning. This maladaptive neuroplasticity potentially explains the clinical disconnect where residual neuromuscular dysfunction and high rates of reinjury that are often observed even after individuals clear return-to-activity functional testing. An improved understanding of these neural changes could therefore serve as a guide for facilitating a more complete recovery and minimizing risk of re-injury. Therefore, we propose a paradigm of neural-targeted rehabilitation to augment commonly used therapeutic techniques targeting sensorimotor function in order to better address maladaptive plasticity. While most treatments have the capability to modify neural function, optimizing these treatments and combining them with integrative therapies (e.g. implementation of motor learning strategies, transcranial direct current stimulation) may enhance neural efficiency and facilitate return-to activity in patients with musculoskeletal injury. To complete this model, consideration of affective aspects of movement and associated interventions must also be considered to improve the durability of these changes.

Measuring neuroplasticity in human development: the potential to inform the type and timing of mental health interventions.

Neuroplasticity during sensitive periods, the molecular and cellular process of enduring neural change in response to external stimuli during windows of high environmental sensitivity, is crucial for adaptation to expected environments and has implications for psychiatry. Animal research has characterized the developmental sequence and neurobiological mechanisms that govern neuroplasticity, yet gaps in our ability to measure neuroplasticity in humans limit the clinical translation of these principles. Here, we present a roadmap for the development and validation of neuroimaging and electrophysiology measures that index neuroplasticity to begin to address these gaps. We argue that validation of measures to track neuroplasticity in humans will elucidate the etiology of mental illness and inform the type and timing of mental health interventions to optimize effectiveness. We outline criteria for evaluating putative neuroimaging measures of plasticity in humans including links to neurobiological mechanisms shown to govern plasticity in animal models, developmental change that reflects heightened early life plasticity, and prediction of neural and/or behavior change. These criteria are applied to three putative measures of neuroplasticity using electroencephalography (gamma oscillations, aperiodic exponent of power/frequency) or functional magnetic resonance imaging (amplitude of low frequency fluctuations). We discuss the use of these markers in psychiatry, envision future uses for clinical and developmental translation, and suggest steps to address the limitations of the current putative neuroimaging measures of plasticity. With additional work, we expect these markers will significantly impact mental health and be used to characterize mechanisms, devise new interventions, and optimize developmental trajectories to reduce psychopathology risk.