Can Maternal Illness During Pregnancy Alter Neurodevelopment in Children?

Post by Lani Cupo

What is maternal immune activation (MIA)?

Since the 19th century, doctors and researchers have noticed a peculiar correlation—children born in the winter months have a slightly increased risk of developing psychotic disorders, such as schizophrenia, during adolescence and early adulthood. To investigate a potential factor contributing to this relationship, epidemiological studies known as birth-cohort studies (which follow participants from before birth as they age) looked for blood markers in pregnant women that indicated their immune systems were active. They found that the children of women who were sick during pregnancy had increased risks of developing Autism Spectrum Disorders (ASDs) during childhood, and schizophrenia in early adulthood. Interestingly, the associations were not limited to viral infections, even though they were initially found following influenza epidemics, such as the Spanish Flu. Increased rates of psychiatric disorders were also found following prenatal exposure to bacterial infection, such as pneumonia, or parasites, like Toxoplasma gondii. This implies that there is a connection between activation of the maternal immune system itself (Maternal Immune Activation or MIA) and an alteration in neurodevelopment.

The immune system is highly active during pregnancy in order to protect the mother and fetus from invading pathogens. When a pathogen, like the flu virus, enters the mother’s body, it can activate her immune system, causing a chain of reactions that ultimately lead to the release of “pro-inflammatory cytokines”, proteins that are secreted by cells of the immune system and travel throughout the body through the bloodstream. Examples of pro-inflammatory cytokines include interleukin (IL)-6, IL-17, and tumor necrosis factor (TNF) alpha. It is still unclear whether these cytokines can cross the placenta to the fetal compartment, or whether they cause changes to the placenta that impact the fetus.

What do we know?

While birth cohort studies in humans are extremely informative, they are difficult to conduct, as it takes decades to acquire data from before birth to early adulthood and participants often drop out before study completion. Furthermore, it is, of course, unethical to expose pregnant women to infections in order to conduct a controlled experiment manipulating an independent variable of interest. Because of these limitations, experiments that seek to investigate a risk factor over the lifespan often use nonhuman animals, many of which reach the equivalent of adulthood in a matter of months.

In such experiments using animal models, the maternal immune system can be activated with the introduction of compounds that mimic a viral or bacterial infection. This allows researchers to specifically assess the impact of MIA, rather than the effect of a particular pathogen. Studies in mice, rats, rabbits, and nonhuman primates provide robust evidence that MIA can contribute to altered trajectories of neurodevelopment, changing volume in brain regions of particular interest in the study of psychiatric disorders such as the hippocampus, anterior cingulate cortex, amygdala, and thalamus. These brain regions mainly comprise the limbic system, considered crucial to emotion processing and memory formation. There is also evidence for behavioral alterations consistent with psychiatric disorders, such as increased anxiety, decreased sociability, and memory impairment. Despite the considerable consensus that there is an impact of prenatal exposure to MIA on brain development and mental health in offspring, there are many factors to an experimental design that can influence results, including the timing of exposure, the severity of exposure, and timing of experimental outcomes (i.e. when researchers measure the impact in childhood, adolescence, or adulthood). This could in part contribute to the variability seen in many experimental results, with some studies failing to replicate the expected alterations.

The exact mechanisms of how MIA may contribute to changes to brain volume and behavior are unknown. Nevertheless, one hypothesis is that MIA leads to long-lasting alterations in certain immune molecules that help control neural connectivity and function in offspring. This could lead to changes in synapses (connections between neurons) that may last throughout the lifespan. There is some evidence that alterations in limbic regions may be associated with changes in inhibitory GABAergic neurons and overactive excitatory dopaminergic neurons, however, the data are preliminary, and require further investigation. Future research may focus on questions regarding the underlying mechanisms that explain the relationship between MIA and psychiatric symptoms in offspring.

Maternal immune activation and COVID-19

Given the long-term impact MIA can have on a global scale, the current COVID-19 pandemic may convey additional burdens on future generations, a hypothesis identified as a research and public health priority. While preliminary studies have already investigated whether pregnancy alters the severity of COVID-19 response in individuals exposed to the virus, there is, as of yet, no consensus. There is some evidence that COVID-19 may impact the risk for preterm birth, intrauterine growth restriction, and low birth weight, which can have health implications for children. These findings are still preliminary, however, and years of research lie between us and firmly established results.

What does this mean for me?

It is important to know, in humans most maternal infections do not lead to psychiatric disorders in children. If you or someone you love is pregnant and becomes ill, this does not mean that the child will develop a disorder. It is more likely that MIA works in concert with other risk factors, such as genetic predisposition, heavy adolescent drug exposure, or childhood trauma to contribute to the observed increase in risk. 

Additionally, there is no evidence that vaccines administered during pregnancy or early in childhood contribute to the development of ASDs or schizophrenia. Risk-benefit analyses assessing influenza vaccines suggest the benefits of receiving the vaccination outweigh any risk. To date, no study reports adverse fetal or maternal outcomes following receipt of inactivated seasonal influenza vaccinations. If you are pregnant, receiving vaccinations as per physician recommendations can help protect you and your child.

References

Cavalcante et al. Maternal immune responses and obstetrical outcomes of pregnant women with COVID-19 and possible health risks of offspring. J Reprod Immunol. (2021). Access the original scientific publication here.

Estes & McAllister. Maternal immune activation: implications for neuropsychiatric disorders. Science. (2017). Access the original scientific publication here.

Guma et al. The role of maternal immune activation in altering the neurodevelopmental trajectories of offspring: A translational review of neuroimaging studies with implications for autism spectrum disorder and schizophrenia. Neurosci Biobehav Rev. (2019). Access the original scientific publication here.

Herberts et al. New adjuvanted vaccines in pregnancy: what is known about their safety? Expert Rev. Vaccines. (2010). Access the original scientific publication here.

Kepinska et al. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Frontiers in Psychiatry. (2020). Access the original scientific publication here.

McAlonan et al. Multidisciplinary research priorities for the COVID-19 pandemic. The Lancet Psychiatry. (2020). Access the original scientific publication here.

Nyffeler et al. Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: Implications for schizophrenia. Neuroscience. (2006). Access the original scientific publication here.

Racicot et al. Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol. (2014). Access the original scientific publication here.

Zuckerman et al. Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia. Neuropsychopharmacology. (2003). Access the original scientific publication here.

The Difference between an MRI Research Finding and a Psychiatric Diagnosis

Post by Anastasia Sares

“Why won’t my doctor…?”

Diagnosing a psychiatric illness is not always straightforward. Let’s take depression for example. The symptoms are not visible to the naked eye and can vary from patient to patient. On the other hand, there seems to be a wealth of brain imaging studies showing differences between people with and without depression. With all of these studies, it is tempting to think, “why won’t my doctor just give me an MRI scan to see if I have depression?”

To understand why, let’s take a simplified example: we have two groups of people, one group of males and another group of females (setting aside the complexities of gender identity for the moment). The only thing we know about these people is their height. Unless we have a very strange sample, we expect the groups to reflect the general population, with the female group having the smaller average height, and the male group having the larger average height. This, in our analogy, is similar to a research finding. Now, what if I pick a person at random and tell you that their height is 175 cm (5 feet 7 inches)? Could you reliably tell if they are from the male or female group? Not at all. This is similar to the challenge that arises when diagnosing a single person. To summarize, researchers can find subtle differences when they compare large groups of people with different psychological conditions, and this helps us to understand these conditions better. However, it can be difficult to classify any one person based on a brain scan.

Added to this is the expense of an MRI scan—these can cost hundreds to thousands of dollars an hour, and scheduling one will take time. Your doctor is constantly engaged in a cost-benefit analysis, trying to get you the most reliable diagnosis in the shortest time, and oftentimes an MRI may not be worth the cost. Why pay hundreds of dollars for a brain scan when a carefully validated questionnaire would also be effective?

So why are MRIs useful?

Firstly, there are several neurological conditions that can be diagnosed with an MRI, including strokes, tumors, and multiple sclerosis. The brain differences here are much easier to pick out, assuming sufficient training, and an MRI can help to determine definitively whether or not someone has the disease. In psychiatric conditions, MRI research has led to discovering much about the mechanisms behind different conditions. Let’s return to the previous example of depression. MRI has helped researchers to understand the involvement of certain brain regions in depression, like the frontal lobe and the amygdala, including how these regions differ in terms of their structure, function, and connectivity with other regions. This is also true for many other psychiatric conditions, such as obsessive-compulsive disorder, anxiety disorders or schizophrenia. In addition, MRI technology and analysis techniques are becoming more advanced every day. Researchers are now developing new MRI methods that may be able to visualize things at a higher resolution that we couldn’t see before. Techniques are also being developed that will help us to look at individual brain differences, and this can guide various personalized treatment approaches in psychiatry. Many also hope to employ artificial intelligence to identify more subtle abnormalities in scans and find people who might benefit from preventative treatments. If MRI costs were brought down somehow, the landscape of diagnosis might change dramatically as well.

What’s the bottom line?

What ultimately matters for a diagnosis is not always what your brain looks like, but rather what symptoms you’re having and how your daily functioning is affected. Although there are some diseases where MRI can be used to diagnose a patient, there are many cases where an MRI is complimentary or not necessarily needed. The usefulness of MRI in treatment will depend on whether looking at an MRI can help a clinician decide between various treatments (and whether it is worth the time and expense of a scan). MRI has provided immense value in understanding the causes and progression of many psychiatric diseases and this is crucial for the development of future treatments. As technology continues to advance, and if costs lower over time, MRI may become even more applicable to a wide variety of uses like diagnosis, guiding treatment, and monitoring recovery. 

References

Zhang, F. F., Peng, W., Sweeney, J. A., Jia, Z. Y., & Gong, Q. Y. (2018). Brain structure alterations in depression: Psychoradiological evidence. CNS neuroscience & therapeutics, 24(11), 994–1003. https://doi.org/10.1111/cns.12835

Lo, A., Chernoff, H., Zheng, T., & Lo, S. H. (2015). Why significant variables aren't automatically good predictors. Proceedings of the National Academy of Sciences of the United States of America, 112(45), 13892–13897. https://doi.org/10.1073/pnas.1518285112

Hunter SF. Overview and diagnosis of multiple sclerosis. Am J Manag Care. 2016 Jun;22(6 Suppl):s141-50. PMID: 27356023.

Foland-Ross, L. C., Sacchet, M. D., Prasad, G., Gilbert, B., Thompson, P. M., & Gotlib, I. H. (2015). Cortical thickness predicts the first onset of major depression in adolescence. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 46, 125–131. https://doi.org/10.1016/j.ijdevneu.2015.07.007

Jollans, L., Boyle, R., Artiges, E., Banaschewski, T., Desrivières, S., Grigis, A., Martinot, J. L., Paus, T., Smolka, M. N., Walter, H., Schumann, G., Garavan, H., & Whelan, R. (2019). Quantifying performance of machine learning methods for neuroimaging data. NeuroImage, 199, 351–365. https://doi.org/10.1016/j.neuroimage.2019.05.082

What Effect Does Music Have on the Brain?

Post by Amanda McFarlan

Music and the brain

Listening to music can be very visceral - it can evoke strong emotions, trigger memories and modulate physiological responses in the body. For example, songs with an upbeat tempo and major chords can evoke feelings of cheerfulness, while songs with a slower tempo using minor chords can evoke feelings of sadness. Learning to play music, especially from a young age, has been shown to have positive benefits that extend beyond enhanced musical abilities. Here, we will discuss how musical training as well as listening to music changes the brain.

What happens to our brain when we play music?

Playing a musical instrument is a complex task requiring coordinated use of multiple brain areas. Consider playing the guitar: The motor cortex and basal ganglia control the synchronized movements in the right and left hands for strumming and fingering. Meanwhile, feedback from the somatosensory cortex about hand, finger, and body positioning is relayed to brain areas like the cerebellum and prefrontal cortex for continuous modulation of movements. The auditory cortex analyzes the sounds being produced so play can be adjusted if necessary. If the musician is following a musical score, the visual system reads and interprets the musical symbols on the page. 

With such complex integration of nearly all sensory systems and higher-order cognitive processing in the brain, it is reasonable to think that playing a musical instrument might lead to changes in brain plasticity. Indeed, it has been shown that compared to non-musicians, musicians have larger brain volumes in areas involved in auditory and visuo-spatial processing, motor control and feedback integration. Studies have also demonstrated differences in how musicians vs. non-musicians process sounds — both for simple tones or complex melodies. For example, one study found that musicians had stronger cortical activation when they were presented with piano tones compared to pure tones, and that this activation was related to the age at which the individual began practicing their instrument. A different study found that auditory cortical representations in highly trained musicians are enhanced for musical timbres that are associated with their principal instrument, but not for musical timbres associated with other instruments. Musicians are also known to have enhanced abilities for musical imagery. In one study, participants were presented with the beginning of familiar melodies and were asked to imagine the melody. They were then presented with a tone and had to decide whether or not it was the next tone in the melody. Musicians were better at identifying whether the presented tone was correct compared to non-musicians. Thus, musical training may lead to a superior ability for musical imagery.

Considering the overlap between cortical networks for music and language, researchers have hypothesized that the two may be related. Research shows that musical training can have beneficial effects on language processing and in particular, in the discrimination of pitch. Musicians have a more robust neural representation of pitch contours compared to non-musicians. This increased ability was associated with the number of years of training, suggesting that years of experience may lead to better pitch discrimination.

What happens to our brain when we listen to music?

Not everyone plays a musical instrument, but nearly everyone listens to music. Just like playing an instrument, listening to music requires the activation of many brain areas, like the auditory cortex to discern and analyze pitches, timbres, rhythms, etc. in the music. Listening to music also recruits high-order brain areas involved in emotions, memory and attention. Indeed, listening to music can influence mood and arousal and evoke strong emotional responses including joy, sadness or tranquility. 

Unlike other rewarding stimuli like food or drugs of abuse, music does not have an obvious benefit for survival, nor addictive properties. However, music has been reported to produce very strong feelings of euphoria for the listener in some cases, commonly described as ‘chills down the spine’. Brain imaging studies have shown that listening to ‘chills down the spine’ music compared to neutral music results in increased cerebral blood flow to reward-related brain areas (e.g. the ventral striatum). The nucleus accumbens (also implicated in reward) was also found to be activated while listening to unfamiliar joyful music compared to silence and singing compared to speech. In line with these findings, positron emission tomography (PET) imaging studies have shown that dopamine release in the nucleus accumbens occurs during passages of music that induce ‘chills down the spine’.

In addition to having a rewarding effect and regulating mood, listening to music can affect arousal. Studies have shown that listening to relaxing music (slow tempo, low pitch and no lyrics) can reduce stress and anxiety brought on by an invasive medical procedure. Furthermore, music therapy that uses relaxation techniques and classical music was shown to reduce stress-related hormones and the activity of the hypothalamic-pituitary-adrenal (HPA) axis, responsible for the body’s stress response. The brainstem is thought to play an important role in changes in arousal while listening to music. One hypothesis to explain how music regulates stress and arousal is via the initiation of reflexive responses in the brainstem, which mediates heart rate, pulse, blood pressure, and body temperature. Listening to fast, upbeat music can cause an increase in these vital signs, while slow, relaxing music can decrease them.  

How does music affect the developing brain?

A large body of research demonstrates the benefits of exposing children to music at a young age. As discussed in the previous sections, playing music involves the recruitment of many different areas of the brain. One study showed that school-age children who received 15 months of musical training had increased grey matter density compared to age-matched children who did not receive musical training. Similarly, an MRI study revealed differences in macro and microscopic brain structure, including the maturation of cortical thickness in the temporal lobe, in students in a music program, but not those in a sports program. Research has shown that musical training in young children benefits speech. For example, rhythmic training can have a positive effect on both phonological processing and reading. One study in 9-month old babies revealed that babies who participated in a 12-session music program were better able to identify violations in music and speech versus a control group. Another study in young children found that those who received music (versus painting) instruction demonstrated stronger reading and pitch discrimination. Finally, musical training can also impact math skills. Students with low mathematics achievement improve in number production (reading, writing and counting numbers) after participating in non-instrumental musical training classes. All together, these findings suggest that musical training in young children can have beneficial effects that extend beyond enhanced musical abilities.

How can music help heal us?

The effects of music on mood and arousal make it a useful tool to improve well-being. Music therapy is a type of treatment whereby trained professionals administer music-based interventions, modulating attention, emotion, cognition, behaviour and communication. For example, listening to or playing music can be a useful distraction from negative sensations such as pain, anxiety, or sadness. Music-based interventions have been shown to decrease anxiety, perceived pain and depression symptoms in cancer patients. Therapeutic approaches using music can be helpful for the treatment of disorders such as depression, anxiety, and post-traumatic stress disorder, which are known to be associated with limbic system abnormalities. Further, music therapy can also have therapeutic effects in neurological disorders like stroke and Alzheimer’s disease. Music is a natural way to improve mood and well-being and is a promising tool for a wide variety of diseases or conditions. A greater understanding of the neurochemical effects of music is developing, however, more research is needed to understand the full potential of music therapy.

References

Chanda, M. L., & Levitin, D. J. (2013). The neurochemistry of music. Trends in cognitive sciences, 17(4), 179–193. https://doi.org/10.1016/j.tics.2013.02.007

Fernandez S. (2018). Music and Brain Development. Pediatric annals, 47(8), e306–e308. https://doi.org/10.3928/19382359-20180710-01

González-Martín-Moreno, M., Garrido-Ardila, E. M., Jiménez-Palomares, M., Gonzalez-Medina, G., Oliva-Ruiz, P., & Rodríguez-Mansilla, J. (2021). Music-Based Interventions in Paediatric and Adolescents Oncology Patients: A Systematic Review. Children (Basel, Switzerland), 8(2), 73. https://doi.org/10.3390/children8020073

Koelsch S. (2009). A neuroscientific perspective on music therapy. Annals of the New York Academy of Sciences, 1169, 374–384. https://doi.org/10.1111/j.1749-6632.2009.04592.x

Pantev, C., & Herholz, S. C. (2011). Plasticity of the human auditory cortex related to musical training. Neuroscience and biobehavioral reviews, 35(10), 2140–2154. https://doi.org/10.1016/j.neubiorev.2011.06.010

Särkämö, T., & Soto, D. (2012). Music listening after stroke: beneficial effects and potential neural mechanisms. Annals of the New York Academy of Sciences, 1252, 266–281. https://doi.org/10.1111/j.1749-6632.2011.06405.x

Wang, S., & Agius, M. (2018). The neuroscience of music; a review and summary. Psychiatria Danubina, 30(Suppl 7), 588–594.