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Tag: Cortex

  • Mapping the human dysfunctome with deep brain stimulation

    Mapping the human dysfunctome with deep brain stimulation

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    A new study led by investigators from Mass General Brigham demonstrated the use of deep brain stimulation (DBS) to map a ‘human dysfunctome’ -; a collection of dysfunctional brain circuits associated with different disorders. The team identified optimal networks to target in the frontal cortex that could be used for treating Parkinson’s disease, dystonia, obsessive compulsive disorder (OCD) and Tourette’s syndrome. Their results are published in Nature Neuroscience.

    “We were able to use brain stimulation to precisely identify and target circuits for the optimal treatment of four different disorders,” said co-corresponding author Andreas Horn, MD, PhD, of the Center for Brain Circuit Therapeutics in the Department of Neurology at Brigham and Women’s Hospital and the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital. “In simplified terms, when brain circuits become dysfunctional, they may act as brakes for the specific brain functions that the circuit usually carries out. Applying DBS may release the brake and may in part restore functionality.”

    Connections between the frontal cortex in the forebrain and basal ganglia, structures located deeper in the brain, are known to control cognitive and motor functions. If brain disorders occur, these circuits may become affected, and their communication may become overactive or malfunction. Previous studies have shown that electrically stimulating the subthalamic nucleus, a small region in the basal ganglia that receives inputs from the entire frontal cortex, can help alleviate symptoms of these disorders.

    To understand this relationship better, the authors analyzed data from 534 DBS electrodes in 261 patients from across the globe. Of this cohort, 70 patients were diagnosed with dystonia, 127 with Parkinson’s disease, 50 with OCD and 14 with Tourette’s syndrome. Using software developed by Horn’s team, the researchers mapped the precise location of each electrode and registered results to a common reference atlas to compare locations across patients. The researchers used computer simulations to map tracts that were activated in patients with optimal or suboptimal outcomes.

    Using these results, they were able to identify specific brain circuits that had become dysfunctional in each of the four disorders, such as those mapping to sensorimotor cortices in dystonia, the primary motor cortex in Tourette’s, the supplementary motor cortex in Parkinson’s disease and parts of the cingulate cortex in OCD. Notably, the identified circuits partially overlapped, implying that interconnected pathways are disrupted in these disorders.

    Further, the investigators were able to apply these findings to fine tune DBS treatments and demonstrate preliminary improved results in three cases, including one at Massachusetts General Hospital, a founding member of Mass General Brigham. This patient, a female in her early 20s, was diagnosed with severe, treatment-resistant OCD involving obsessions about food and water intake, along with compulsive skin picking. Following electrode implantation and targeted stimulation, the researchers were able to show a significant improvement in her symptoms one month after treatment.

    Except for the three patients that were tested prospectively, the study was a retrospective analysis of data aggregated from multiple centers. Further studies are needed to validate findings in prospective fashion.

    We can take this technique further and finely segregate dysfunctional circuits in order to have greater impact with treatment. For example, with OCD, we can look at isolating circuits for obsessions versus compulsions and so on.”


    Barbara Hollunder, MSc, lead author of the Movement Disorders and Neuromodulation Unit in the Department of Neurology, Charité – University Medicine Berlin

    Source:

    Journal reference:

    Hollunder, B., et al. (2024) Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation. Nature Neuroscience. doi.org/10.1038/s41593-024-01570-1.

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  • Delta opioid receptor agonist reduces anxiety-like behavior in mice

    Delta opioid receptor agonist reduces anxiety-like behavior in mice

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    Anxiety-related disorders can have a profound impact on the mental health and quality of life of affected individuals. Understanding the neural circuits and molecular mechanisms that trigger anxiety can aid in the development of effective targeted pharmacological treatments. Delta opioid receptors (DOP), which localize in the regions of the brain associated with emotional regulation, play a key role in the development of anxiety. Several studies have demonstrated the therapeutic effects of DOP agonists (synthetic compounds which selectively bind to DOPs and mimic the effect of the natural binding compound) in a wide range of behavioral disorders. One such selective DOP agonist-;KNT-127-;has been shown to exert ‘anxiolytic’ or anxiety-reducing effects in animal models, with minimal side effects. However, its mechanism of action is not clearly understood, thereby limiting its widespread clinical application.

    To bridge this gap, Professor Akiyoshi Saitoh, along with Ms. Ayako Kawaminami and team from the Tokyo University of Science, Japan, conducted a series of experiments and behavioral studies in mice. Explaining the rationale behind their work, Prof. Saitoh says, “There are currently no therapeutic drugs mediated by delta opioid receptors (DOPs). DOPs likely exert anti-depressant and anti-anxiety effects through a mechanism of action different from that of existing psychotropic drugs. DOP agonists may, therefore, be useful for treatment-resistant and intractable mental illnesses which do not respond to existing treatments.”  Their study was published on 29 December 2024, in Neuropsychopharmacology Reports,

    The neuronal network projecting from the ‘prelimbic cortex’ (PL) of the brain to the ‘basolateral nucleus of the amygdala’ (BLA) region, has been implicated in the development of depression and anxiety-like symptoms. The research team has previously shown that KNT-127 inhibits the release of glutamate (a key neurotransmitter) in the PL region. Based on this, they hypothesized that DOP activation by KNT-127 suppresses glutamatergic transmission and attenuates PL-BLA-mediated anxiety-like behavior. To test this hypothesis, they developed an ‘optogenetic’ mouse model wherein they implanted a light-responsive chip in the PL-BLA region of mice and activated the neural circuit using light stimulation. Further, they went on to assess the role of PL-BLA activation on innate and conditioned anxiety-like behavior.

    They used the elevated-plus maze (EPM) test, which consists of two open arms and two closed arms on opposite sides of a central open field, to assess behavioral anxiety in the mice. Notably, mice with PL-BLA activation spent lesser time in the central region and open arms of the maze, compared to controls, which was consistent with innate anxiety-like behavior. Next, the researchers assessed conditioned fear response of the animals by exposing them to foot shocks and placing them in the same shock chamber the following day without re-exposing them to current. They recorded the freezing response of the animals which reflects fear. Notably, animals with PL-BLA activation and controls exhibited similar behavior, suggesting that distinct neural pathways control innate anxiety-like behavior and conditioned fear response.

    Finally, they examined the effects or KNT-127 treatment on anxiety-like behavior of mice using the EPM test. Remarkably, animals treated with KNT-127 exhibited an increase in the percentage time spent in the open arms and central field of the maze, compared to controls. These findings suggest that KNT-27 reduces anxiety-like behavior induced by the specific activation of the PL-BLA pathway.

    Overall, the study reveals the role of the PL-BLA neuronal axis in the regulation of innate anxiety, and its potential function in DOP-mediated anxiolytic effects. Further studies are needed to understand the precise underlying molecular and neuronal mechanisms, for the development of novel therapies targeting DOP in the PL-BLA pathway.

    Highlighting the long-term clinical applications of their work, Prof. Saitoh remarks, “The brain neural circuits focused on in this study are conserved in humans, and research on human brain imaging has revealed that the PL-BLA region is overactive in patients with depression and anxiety disorders. We are optimistic that suppressing overactivity in this brain region using DOP-targeted therapies can exert significant anxiolytic effects in humans.”

    Source:

    Tokyo University of Science

    Journal reference:

    Saitoh, A., et al. (2018). The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice. Behavioural Brain Research. doi.org/10.1016/j.bbr.2017.08.041.

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  • Neural cell culture model sheds light on the intricate mechanisms underlying neurodegeneration

    Neural cell culture model sheds light on the intricate mechanisms underlying neurodegeneration

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    Scientists at the University of Zurich have developed an innovative neural cell culture model, shedding light on the intricate mechanisms underlying neurodegeneration. Their research pinpointed a misbehaving protein as a promising therapeutic target in the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

    Neurodegenerative diseases cause some of the neurons in our brains to die, resulting in different symptoms depending on the brain region affected. In amyotrophic lateral sclerosis (ALS), neurons in the motor cortex and spinal cord degenerate, leading to paralysis. In frontotemporal dementia (FTD), on the other hand, neurons located in the parts of the brain involved in cognition, language and personality are affected.

    Both ALS and FTD are relentlessly progressive diseases and effective treatments are still lacking. As the population ages, the prevalence of age-related neurodegenerative diseases such as ALS and FTD is expected to increase.

    Despite the identification of the aberrant accumulation of a protein called TDP-43 in neurons in the central nervous system as a common factor in the vast majority of ALS and about half of FTD patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown.

    Flexible, durable, reproducible: ideal cell culture model for ALS and FTD research

    In their study, first author Marian Hruska-Plochan and corresponding author Magdalini Polymenidou of the Department of Quantitative Biomedicine at the University of Zurich developed a novel neural cell culture model that replicates the aberrant behavior of TDP-43 in neurons. Using this model, they discovered a toxic increase in the protein NPTX2, suggesting it as a potential therapeutic target for ALS and FTD.

    To mimic neurodegeneration, Marian Hruska-Plochan developed a new cell culture model called “iNets,” derived from human induced pluripotent stem cells. These cells, originated from skin cells and reprogrammed to a very early, undifferentiated stage in the laboratory, serve as a source for developing many different, desired cell types. iNets are a network of interconnected neurons and their supporting cells growing in multiple layers in a dish.

    The cultures lasted exceptionally long – up to a year – and were easily reproduced. +

    The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise. And the flexibility of the model makes it suitable for a wide range of experimental methodologies.”


    Marian Hruska-Plochan, First Author

    As a case in point, the iNets cell cultures provided the ideal model to investigate the progression from TDP-43 dysfunction to neurodegeneration.

    How protein dysfunction leads to neurodegeneration

    Employing the iNets model, the researchers identified a toxic accumulation of NPTX2, a protein normally secreted by neurons through synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted ALS and FTD patient pathology.

    In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team engineered a setup in which they lowered the levels of NPTX2 while neurons were suffering from TDP-43 misbehavior. They found that keeping NPTX2 levels low counteracted neurodegeneration in the iNets neurons. Therefore, drugs that reduce the amount of the protein NPTX2 have potential as a therapeutic strategy to halt neurodegeneration in ALS and FTD patients.

    Magdalini Polymenidou sees great promise in this discovery: “We still have a long way to go before we can bring this to the patients, but the discovery of NPTX2 gives us a clear shot of developing a therapeutic that acts at the core of the disease,” she said. “In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents could emerge as a key component of combination therapies for ALS and FTD in the future,” she added.

    Source:

    Journal reference:

    Hruska-Plochan, M., et al. (2024). A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature. doi.org/10.1038/s41586-024-07042-7.

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  • Restoring brain pathways to fight opioid addiction

    Restoring brain pathways to fight opioid addiction

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    Medical University of South Carolina scientists report in Neuron that they have uncovered a way to restore an opioid-weakened brain pathway in a preclinical model.

    With funding from the National Institute on Drug Abuse, part of the National Institutes of Health, the MUSC research team, led by neuroscientist James Otis, Ph.D., used advanced neuroscience tools to return a pathway between the thalamus and basal ganglia to healthy functioning in mice. As a result, this restoration prevented mice that were opioid-dependent from seeking or self-administering heroin. Results also suggested that sustained opioid use was the cause of this weakened pathway, rather than being caused by it.

    Our study is the first showing that this pathway, associated with the capability of stopping behavior, can be ‘rescued’ after being weakened by opioid use.”


    James Otis, Ph.D., Neuroscientist 

    Otis was surprised that not only could this brain pathway be returned to healthy functioning, but that its recovery prevented relapse.

    “When we brought this brain circuit back to what we think of as a healthy state, we were excited to see that it could inhibit behaviors such as relapse,” said Otis.

    This pathway of neurons identified by Otis’ team is critical for controlling or stopping behavior – also referred to as behavioral control. Difficulty stopping is a hallmark feature of many neuropsychiatric disorders, including substance use disorders. The capacity to stop is a critical skill in recovering from drug dependence and avoiding relapse.

    Studies have shown that people with substance use disorders find it more difficult to stop behavior, he explained. In previous studies, they took longer to pause behavioral tasks than those without a history of substance use.

    Difficulty stopping is a key reason why people with substance use disorders may continue to use substances despite negative consequences or despite their desire to stop. Restoring behavioral control could improve their ability to stop such behaviors and remain drug abstinent.

    Researchers have identified pathways in the brain that influence our capacity to stop different behaviors. For example, our brains can stop motor movement when two regions of the brain – the prefrontal cortex and basal ganglia – talk to one another. The prefrontal cortex makes the decision to stop and sends this message to the basal ganglia. The basal ganglia then prevents the movement. The communication between these areas of the brain has been shown to be disrupted in people with substance use disorders, helping to explain the challenges they face with this skill.

    Expanding on this research, Otis and his team identified a new pathway of neurons in mice involved with stopping behavior. In a previous study, his team found that this series of neurons, beginning in the thalamus, similarly communicated with the basal ganglia to control movement.

    This study reported in Neuron helps to resolve a long-standing chicken-or-egg debate about the relationship between difficulty stopping behavior and substance use disorder. Does an impaired capacity to stop increase the likelihood that someone will later develop a substance use disorder? Or does repeated drug use weaken the parts of the brain involved with this ability?

    “We wanted to know more about how opioid use influences these neurons, or if instead these neurons are already impaired in those who are vulnerable to future opioid addiction,” Otis explained.

    Findings from this research strongly suggest that the weakening of this pathway happens because of opioid use, rather than being a cause of opioid use. After two weeks of opioid use by the mice, Otis and his team observed that this pathway became half as strong as it was prior to drug use. 

    The next step is to see if these results can be repeated with substances such as alcohol, methamphetamine, amphetamine and cocaine.

    The experimental techniques used to restore this brain circuit in a preclinical model are not suitable for human studies. However, Otis can envision that future drug treatments could rehabilitate brain functioning associated with drug use.

    “The goal of addiction treatment should be to recover healthy brain circuitry, rather than just prevent relapse or prevent the symptoms of addiction,” said Otis.

    Source:

    Medical University of South Carolina

    Journal reference:

    Paniccia, J. E., et al. (2023). Restoration of a paraventricular thalamo-accumbal behavioral suppression circuit prevents reinstatement of heroin seeking. Neuron. doi.org/10.1016/j.neuron.2023.11.024.

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  • Study provides evidence that antidepressant use in pregnancy affects child’s brain development

    Study provides evidence that antidepressant use in pregnancy affects child’s brain development

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    The prefrontal cortex (PFC) is an important brain region with respect to behavioral regulation. Aberrations in serotonin (5-HT) during early development have been reported to be associated with behavioral dysregulations over the long term, but how this works is still unclear.

    Study: Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Image Credit: fizkes/Shutterstock.com
    Study: Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex. Image Credit: fizkes/Shutterstock.com

    A new study published in Nature Communications explored synapse maturation in the PFC of mice when exposed to 5-HT, shedding light on the link between the chemical and future behavioral changes.

    Researchers from the University of Colorado Anschutz Medical Campus demonstrated a direct link between antidepressant use during pregnancy, particularly fluoxetine found in medications like Prozac and Sarafem, and altered development of the prefrontal cortex in children, as well as subsequent mental health risks.

    Background

    The brain has over a billion neurons, with equal numbers of other cells linked in intricate and interwoven networks. These require exquisitely precise chemical regulation to develop correctly so as to provide the substrate for communication between themselves and the formation of neuronal pathways.

    5-HT is among the first neurochemicals to be detected, being found at peak levels two years after birth in humans. In mice, it peaks during the first week after birth. This period coincides with the time when excitatory synapses mature following experience-driven activity.

    Various causes of alteration in 5-HT are known, including maternal malnutrition, maternal abuse, varying levels of dietary tryptophan (the substrate for 5-HT formation), and the presence of chemicals that regulate the uptake or degradation of 5-HT.

    An example of the latter is the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). These can readily cross the placenta or enter breast milk, becoming available to the offspring during a critical period of brain development.

    Such imbalances in 5-HT levels at this period have been linked to a higher chance of neurodevelopmental disorders, including autism spectrum disorder (ASD), as well as permanent behavioral changes. The PFC is involved in cognitive processes that facilitate social interaction and is lavishly supplied with neurons that release 5-HT.

    Excitatory synapses are fundamental to the formation of neural circuits. They need to mature and stabilize for this to happen, with the primary sites of action of the neurotransmitter released at the synapse being the dendritic spines of the post-synaptic neuron. These bear multiple receptor types for 5-HT, with 5-HT2A and 5-HT7 being especially abundant in early infancy.

    When these are activated, excitatory cascades are activated via the coupled Gαq proteins. Higher levels of 5-HT signaling increase the dendritic spine plasticity. The current study looked at targeted 5-HT signaling at the level of neural circuits and individual excitatory synapses, seeking to identify the mode of regulation. 

    What did the study show?

    The scientists found that 5-HT is crucial for the normal development of excitatory synapses on the pyramidal neurons within layer 2/3 of the PFC during early development. With 5-HT inhibition, both spine density and maturation were reduced significantly within the PFC, though spine size remained intact. The converse was also true, with increased density, especially of large spines, but with normal size and morphology.

    Apart from these anatomical changes, 5-HT signaling causes structural long-term potentiation of dendritic spines on these neurons during this developmental window independent of excitatory stimulation. This effect, namely, the enlargement of small and medium spines, did not appear to depend on the activity of glutamate.

    Not only was it specific for the pattern of 5-HT stimulation, but also it was not observed at later stages or in pyramidal neurons. In addition, it occurred only in the presence of post-synaptic 5-HT2A and 5-HT7 signaling. This suggests that the underlying mechanism is 5-HT7 receptor-mediated influx of extracellular calcium ions, leading to 5-HT2A receptor-induced activation of PKC.

    Functional long-term potentiation of these receptors was also observed in response to 5-HT release, again via 5-HT2A and 5-HT7 receptor signaling. That is, stronger post-synaptic excitatory currents were measured following 5-HTergic stimulation.

    Individual dendritic spines newly formed on these neurons in the PFC were more likely to survive, indicating greater long-term stabilization following Gαs coupled 5-HT7 receptor signaling. This is important as it leads to increased spine density. Again, this effect, linked to long-term potentiation, is independent of glutamate release or structural potentiation and does not appear to occur with 5-HT2A receptor stimulation.

    Significantly, early research shows a risk of behavioral deficits and neurodevelopmental disorders with early fluoxetine exposure. In the present study, the use of fluoxetine, an SSRI that increases 5-HT levels in the synaptic cleft in younger but not older pups, led to increased spine density but not spine size. This was mediated by 5-HT2AR and 5-HT7R signaling in the PFC.

    What are the implications?

    The findings of this study indicate that 5-HT signaling plays a key role in excitatory synapse maturation during early development of the PFC circuits, regulating spine maturation and function. The effect is structural and functional potentiation of excitatory synapses of layer 2/3 pyramidal neurons in the PFC at a specific age and with a specific pattern of stimulation.

    The results also suggest a direct effect of 5-HT on maturation rather than via changes in excitability, but further work is required to rule out glutamatergic involvement in synaptic plasticity secondary to 5-HT signaling completely.

    The researchers propose that nascent spines are stabilized by 5-HT7 receptor activation via voltage-gated calcium channel opening, leading to the entry of calcium into the neuron. However, as they mature, both 5-HT7 and 5-HT2A receptors lead to synapse maturation via PKC activation, which further enhances extracellular calcium ion influx.

    Moreover, 5-HT receptor-mediated synaptic plasticity occurs in the first two weeks in mice. Further research will be required to demonstrate what receptor classes are involved at later stages. Again, increased excitatory post-synaptic current strength without spine size alterations needs to be explained.

    These findings may help treat patients who have been exposed to drugs like fluoxetine during early development, as this is a commonly prescribed drug during pregnancy. Moreover, it may be possible to treat individuals with aberrations in 5-HT receptor-mediated plasticity during this key period by selective inhibition of 5-HT receptors in certain brain regions or certain types of neurons.

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  • Study provides an important advancement of knowledge by showing neural compensation in healthy aging brains

    Study provides an important advancement of knowledge by showing neural compensation in healthy aging brains

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    In a recent study posted to the eLife preprint server, researchers performed complete-brain voxel-wise functional magnetic resonance imaging (fMRI) to identify brain areas with functional-type compensation. They also investigated neurophysiological changes that maintain cognitive function in older adults.

    Study: Neural Evidence of Functional Compensation for Fluid Intelligence in Healthy Ageing. Image Credit: LightField Studios/Shutterstock.com
    Study: Neural Evidence of Functional Compensation for Fluid Intelligence in Healthy Ageing. Image Credit: LightField Studios/Shutterstock.com

    *Important notice: Preprints publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

    Background

    Age-related functional compensatory mechanisms in the cognitive neurobiology of healthy aging are controversial, according to which older individuals increase brain activity to compensate for decreased cognitive ability. However, whether the additional brain activity helps cognitive performance is uncertain. Neuroimaging reveals that the human brain can adapt to tissue losses by increasing brain activities to sustain cognitive functioning. Age similarly influences fluid intelligence, a cognition skill.

    About the study

    In the present study, researchers used fMRI data from a fluid intelligence test to identify brain areas involved in functional compensation and understand brain responses to tissue loss. They also explored the relationship between age-related changes in brain activation and cognitive performance, specifically in fluid intelligence tasks.

    The team analyzed data from 223 adult participants of the Cambridge Centre for Ageing Neuroscience (Cam-CAN) study to examine the relationship between age, cognitive performance, and brain activation patterns. Participants were aged 19 to 87 years, fluent in English, and mentally and physically fit, excluding those with MRI contraindications, poor mini-mental state examination (MMSE) scores, and psychiatric, medical, visual, or hearing impairments.

    The team performed functional and structural neuroimaging to study the relationship between age, cognitive performance, and brain activation patterns. They performed a problem-solving task based on the modified Cattell Culture Fair Intelligence test during fMRI. They scanned participants during the Cattell fluid intelligence task, completing puzzles from two difficulty levels, to determine whether the candidate compensation regions exhibited multivariate evidence of compensation.

    The dependent variables were the differences in functional MRI activation for hard vs. easy task blocks. The team used multivariate Bayesian decoding (MVB) to explore the role of multivoxel patterning in providing additional data related to task difficulty. They predicted that regions associated with functional compensation would have more data related to tasks with age. MVB was used to identify areas with additional multivariate data and support functional-type compensation, which involves the brain increasing activity to support cognitive functions in response to tissue loss.

    To identify patterns of brain activation, the team overlaid maps testing for positive influences of age and performance on brain function, assessed using the hard vs. easy contrast. They used multiple regressions for analysis, with activation maps reflecting the unique effects of each. The team repeated multiple regression after scaling the influence of Cattell activation by estimating the resting state fluctuation amplitude (RSFA) for each region of interest (ROI) from an independent resting-state scan for each participant.

    The team analyzed participant data using boxcar functions and statistical parametric mapping (SPM) hemodynamic response functions, fitting a model to each voxel. They defined functional compensation ROIs, the cuneal and frontal cortex by the empirical Bayes approach. They standardized and treated age and behavioral performance variables as linear predictors.

    Results

    Bilateral cuneal cortical activity increased with performance and age for hard vs. easy problems, even after adjusting for age-associated disparities in cerebrovascular reactivation. The cuneus region showed multivariate data supporting functional compensation, and age enhanced the likelihood of activation patterns, providing non-redundant data beyond the MDN work usually activated in the task.

    The modified Cattell task showed a decrease in behavioral performance with age during fMRI scans. A strong correlation was found between fMRI and standard Cattell task performance measures when performed one to three years prior. Bilateral activation in multiple demand network (MDN) regions, including the intraparietal sulcus, middle/inferior frontal gyri, anterior cingulate cortical region, anterior insula, and lateral and ventral occipital temporal cortical region, was observed, probable due to the visual type of tasks like problem-solving and fluid intelligence.

    Age-association increase in activity in the middle area of the frontal gyrus, precuneus, and motor supplementary areas was positively associated with performance in regions with higher activity for hard vs. easy tasks.

    Two brain regions, the bilateral cuneal and frontal cortical regions, exhibited spatially overlapping positive influences of performance and age, indicating age-associated compensatory responses. However, the frontal area demonstrated additive influences of both study variables, while the cuneus area exhibited signs of interaction. The study found that age significantly influences performance as older individuals engage in compensatory patterns.

    Conclusion

    Overall, the study findings showed that healthy older individuals compensate for fluid intelligence during visual problem-solving tasks by increasing the recruitment of the bilateral cuneal cortex. The compensation allows the brain to react to the loss of tissue by increasing cognitive functions, known as functional compensation. Fluid intelligence, which involves solving abstract problems, declines with age. The MDN involvement in fluid-intelligence tasks tends to decrease with age. The cuneus region may play a role in functional compensation, and its activation increases with age.

    *Important notice: Preprints publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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  • Maternal happiness during pregnancy linked to child’s brain development

    Maternal happiness during pregnancy linked to child’s brain development

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    In a recent study published in the journal Nature Mental Health, researchers explored the relationship between maternal mental health and children’s brain development. Their results contribute to the medical understanding of the importance of the intrauterine environment and suggest that in addition to positive outcomes for the mother, emotional well-being during pregnancy can be an important protective factor for brain development in children.

    Study: Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Image Credit: Prostock-studio / ShutterstockStudy: Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Image Credit: Prostock-studio / Shutterstock

    Background

    Research suggests that depression, anxiety, and stress during pregnancy can have enduring adverse effects on the child’s brain development. Maternal anxiety and depression have been found to affect gray matter density in the medial temporal and prefrontal cortex as well as hippocampal growth.

    Maternal health factors can also modify the cortico-limbic system, which helps regulate stress responses and emotional states. These widespread effects have been observed to be more prominent in female children between birth and early childhood. These findings highlight the need to address prenatal mental health to promote brain development in children.

    However, emotional well-being is not merely the absence of mental illness but also includes the experience of positive emotions and mental affect. While the effect of positive maternal emotions on parenting behavior, mother-infant bonding, long-term mental health, and child development has been studied, its impacts on brain development have not been explored.

    About the study

    The study followed a longitudinal prospective birth cohort design to investigate the relationship between maternal well-being and brain development in 7.5-year-old children using magnetic resonance imaging (MRI). This age was chosen because it is a key neurodevelopmental period when significant cognitive processes and brain changes occur.

    Participants in the study included pregnant Asian (Malay, Indian, or Chinese) women in their first trimester who were recruited while they antenatal care at an ultrasound scan clinic in Singapore. For the MRI, children were included if they had a gestational age of more than 30 weeks and a birth weight of more than 2 kg to avoid the confounding effects of birth complications.

    The authors hypothesized that positive emotions during pregnancy would be associated with significant differences in brain structures, such as the amygdala and hippocampus as well as functional networks, such as the default mode and visual networks. The mental health of the mothers was assessed using the Beck Depression Inventory, the Edinburgh Postnatal Depression Scale, and the State-Trait Anxiety Inventory.

    Additionally, the survey included questions on socioeconomic status, relationships with friends and family, life stress, and other topics related to prenatal health and well-being. This information was used to construct an overall socio-environmental adversity factor and scores for four risk domains – personal, interpersonal, socioeconomic, and life stress.

    Findings

    The sample of participants who underwent the structural MRI included 381 children, of whom 369 also underwent the functional MRI procedure. After controlling for the overall socio-environmental adversity factor and the child’s age during the MRI, researchers found that more positive maternal emotions during the prenatal period were associated with a larger bilateral hippocampal volume in female children but not males. However, maternal positive emotions were not seen to be associated with cortical thickness or volumes of the thalamus, amygdala, lateral ventricles, or basal ganglia.

    In terms of functional networks, more maternal positive emotions were associated with higher functional connectivity between the right frontoparietal and visual association networks, salience and thalamo-hippocampal networks, and posterior default mode and attention networks. Notably, these results were significant after controlling for child sex and age as well as postnatal parenting stress and other risk factors. These outcomes were not, however, associated with anxiety or depressive symptoms during pregnancy.

    Conclusions

    These findings indicate that there may be a neural basis through which positive emotions during pregnancy are transmitted from the mother to her offspring during the early development of the brain. Of the significantly associated outcomes, only the change in the bilateral hippocampi differed between male and female children. This research implies that ensuring mothers’ mental health could lead to sustained benefits for offspring in terms of neural development.

    While the study has several strengths and offers novel insights, the authors acknowledged some limitations. While brain development was assessed through neuroimaging, data on maternal mood and well-being were collected through subjective reports and may, therefore, be subject to biases related to recall and social desirability. Self-reports of positive emotions may not be an adequate proxy for psychological well-being, a complex and multifaceted issue. The study participants were all Asian, leading to a lack of generalizability to other populations.

    Future studies can build on these findings by including individuals of other races and factoring in positive emotions during other stages (such as during the postnatal period). This work adds to a growing body of literature showing the transgenerational nature of mental health outcomes and the importance of ensuring that mothers and children are not just healthy but happy, too.

    Journal reference:

    • Maternal positive mental health during pregnancy impacts the hippocampus and functional brain networks in children. Qui, A., Shen, C., López-Vicente, M., Szekely, E., Chong, Y., White, T., Wazana, A. Nature Mental Health (2024). DOI: 10.1038/s44220-024-00202-8, https://www.nature.com/articles/s44220-024-00202-8

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