50 Years of Neuroscience: Progress and a Look Into the Future

Post by Stephanie Williams

What’s the science?

In honor of the 50th anniversary of the Society for Neuroscience, a group of scientists comment on the progress made in neuroscience over the previous 50 years. This week in The Journal of Neuroscience, Altimus, Marlin and colleagues review neuroscience research advancements and express a vision for the impact of future research.

What do we already know?

The authors review research in four major categories: 1) cellular and molecular neuroscience 2) developmental neuroscience 3) systems neuroscience and 4) disease. In the cellular section, the authors highlight technological innovation (patch-clamp electrophysiology, PCR, genomic sequencing), and progress made in the connectome project and in the creation of a cellular atlas of the mammalian brain. While acknowledging the reductive approach of some of these advancements, the authors argue that they will serve as a stepping stone to more detailed knowledge and will allow for novel cellular targeting strategies. In the development section, the authors highlight progress in understanding gene expression (i.e. the transcriptome) of neurons, whole-genome sequencing, the development of brain organoids and Brainbow, a fluorescent imaging approach in which individual neurons can be imaged using different colors. They review the debate over the existence of adult neurogenesis (production of new neurons) and cite recent evidence suggesting that adult hippocampal neurogenesis is indeed robust in healthy humans. In systems neuroscience, the authors focus on the potential of virally mediated gene-editing to study ensembles of neurons. They also point out the lack of precision in many behavioral measurements, which limits our ability to correlate behavior with neural activity. The authors list several brain-computer interface (BCI) advancements including BCI-mediated limb movement and visual imagery in the blind. In the disease section, the authors highlight the importance of collaborative research initiatives (eg. BRAIN, dementia research led by the United Kingdom), in accelerating research progress. They praise the progress made in psychiatric research, including the recent FDA approved treatments for major depressive disorder (esketamine), brexanolone (postpartum depression), siponimod (multiple sclerosis).

What’s next?

In cellular and molecular neuroscience, the authors predict that advancements in microscopy will allow us to visualize subcellular machinery at an unprecedented resolution. They predict that new tools will allow us to measure and manipulate epigenetic endpoints to better understand how the genome, transcriptome, and proteome relate to behavior. In the developmental neuroscience section, the authors call for the development of new technologies that can label neurons in vivo and be imaged non invasively, as well as tools that may be able to control neurogenesis across the lifespan. The authors predict that characterizing the transcriptome of neurons will lead to a new understanding of cell types. They also speculate that technological advances will resolve the difficulties that currently limit the establishment of brain organoids; brain organoids could one day act as a tool for screening potential therapies or replacing damaged brain tissue. In the systems neuroscience section, the authors predict that more precise behavioral measurements will allow for a better understanding of the corresponding neural activity. They suggest implementing new methods, such as computer vision, to automate and improve behavioral measurement and analysis. The authors predict that new imaging methods will be developed, such as cellular-resolution functional neuroimaging in humans, and hope that the imaging methods will be used to record from and interact with neural circuits in real-time. In the disease section, the authors predict we will enter an age of neurotherapeutics, characterized by an increase in the number of specific therapies for nervous system disorders. They foresee the use of technology—activity trackers and automated analysis tools—to improve diagnostics. They hope to see a shift towards preventative measures.

As a community, the authors call for scientists to prioritize addressing the lack of diversity in neuroscience, both in how research is conducted and the topics of research themselves. The authors criticize previous research for asymmetrically focusing on right-handed males, and previous clinical trials and genetic studies for asymmetrically focusing individuals of European descent. The authors also highlight the impact of neuroscience on education and recommend using neurodevelopmental and cognitive neuroscience to implement widespread changes in educational curricula so that students with disorders such as dyslexia or attention deficit hyperactivity disorder, can learn more effectively.  

Finally, the authors make several predictions about areas that will become more prominent in the next fifty years. They predict the rapid expansion of using neuroscience to explain criminal behavior, inform business practices, and advance wearable neurotechnology to customize marketing strategies.

What's the bottom line? 

Neuroscience has come a long way in the past 50 years, and it’s an exciting time to pursue promising new avenues for research. In all pursuits, the authors call for caution and strict adherence to ethical principles as the field continues to accelerate, and emphasize the importance of international collaboration and the coordination of research internationally and across disciplines.

Altimus et al. The Next 50 Years of Neuroscience. The Journal of Neuroscience. (2019). Access the original scientific publication here.

Enjoying Sad Music: What’s Going On In the Brain?

Post by Anastasia Sares

What's the science?

There are many components to an emotional response, such as whether it is pleasant or unpleasant, the intensity of an emotion, and our aesthetic enjoyment of the experience. This can lead to situations where we experience a “negative” emotion (like in response to a sad piece of music) but enjoy it at the same time. In addition, emotions are dynamic, but many carefully controlled studies focus on short stimuli and static responses. This week in NeuroImage, Sachs and colleagues dynamically tracked the neural responses of people listening to a sad (but enjoyable) piece of music in order to separate out different aspects of emotional cognition.

How did they do it?

Thirty-six participants first listened to three musical pieces passively in an MRI scanner. The pieces were unfamiliar, wordless, and validated for emotional content by prior testing. After the MRI, they were asked to complete a rating task, using a sliding scale to continuously track their emotional states while listening to the same pieces again. They listened to each song twice, separately evaluating their enjoyment of the song and its emotional quality/intensity (how happy/sad it was). Participants also completed questionnaires about musicality, empathy, anxiety, and depression.

One sad piece, in particular, was chosen for the fMRI analysis: Discovery of the Camp by Michael Kamen. It clocks in at 11 minutes, which gave ample opportunity to examine emotions unfolding over time. The idea of the analysis was to find parts of the brain that acted in synchrony across individuals—meaning that they were probably responding to some aspect of the stimulus. The authors did this by recording the brain activity at many points in the brain (voxels) and calculating the correlation of the signals between participants at each voxel using a process called inter-subject correlation. They also looked for brain regions where inter-subject correlations were predicted by changes in the emotion and enjoyment ratings.

What did they find?

Signals from auditory brain regions and some motor brain regions were correlated across participants while listening to the music. Most of these were likely driven by the auditory signal itself. However, signals were also correlated in the insula, which is involved in processing the body’s own internal changes and the emotional states of other people. Both sadness and enjoyment involved synchronization in striatal regions. The intensity of sadness ratings was additionally related to dynamic synchronization in the limbic network, while enjoyment ratings were related to auditory, orbitofrontal, and default mode networks. This shows the separation between the emotion communicated by the piece (processed in the limbic system) and the participant’s enjoyment (aesthetic evaluation and reward, processed in other regions).

One subcategory of the empathy questionnaire, fantasy, measures how transported a person is by a story or narrative and has previously been associated with the enjoyment of sad music. The authors, therefore, divided the participants into a high-fantasy and low-fantasy group to see whether their brain synchronization differed as a function of empathy. The high-fantasy group demonstrated more correlated activity in the left auditory cortex, extending to the middle temporal gyrus, frontal areas, and some visual areas. The low-fantasy group had more correlated activity in posterior auditory and parietal areas as well as the insula and caudate. The authors interpret the group differences in the following manner: high-fantasy participants may focus on reflecting, understanding, and visualizing emotions during music listening, and thus may enjoy sad music, while low-fantasy participants may have a more intense emotional response.

What's the impact?

This study separates the emotions communicated by a piece of music from the enjoyment of that music, showing that different brain networks are involved in processing various aspects of our emotional experience. Individual differences in empathy also play a role in our reaction to emotional stimuli. This is a step forward, but we are still only scratching the surface of the rich and complex nature of human emotion.

Sachs et al. Dynamic intersubject neural synchronization reflects affective responses to sad music. NeuroImage (2019). Access the original scientific publication here.

The Relationship Between Vitamin D and Brain Morphology in Children

Post by Kasey Hemington

What's the science?

Maternal vitamin D deficiencies during gestation have been associated with cognitive or neuropsychiatric disorders in offspring, such as autism, lower IQ, and schizophrenia. However, the neurobiological basis of these links (for example, between autism and low vitamin D) remain unclear. Further, our understanding of how gestational vitamin D affects brain morphology during development is limited. In animal studies lower gestational vitamin D has been associated with smaller brain volumes, however, there have been no investigations of the effects of vitamin D on brain morphology in human children. This week in NeuroImage, Zou and colleagues used different structural magnetic resonance imaging (MRI) techniques to examine the relationship between gestational vitamin D levels in human mothers and the brain morphology of their offspring.

How did they do it?

As part of the prospective cohort Generation R study (Rotterdam, the Netherlands), the authors included data from 2597 mother-child dyads, where gestational vitamin D concentration information and structural MRI brain scans of the children (aged between 9-11 years) were available. Vitamin D concentration information was obtained via maternal blood-samples at mid-pregnancy, and at birth from the umbilical cord. Some dyads only had vitamin D concentration data at one of the time points and 1536 dyads had data at both time points. In their statistical analysis of the relationship between vitamin D concentration and different measures of brain morphology, the authors also included data on factors that could potentially confound the relationship: maternal age, ethnicity, socioeconomic factors, alcohol and drug use, vitamin supplement use, and the season at which the vitamin D concentration was sampled. Vitamin D concentration was studied both as a continuous variable and as a categorical variable, where categories were defined as ‘deficient’ (<25 nmol/L) ‘insufficient’ (25-50 nmol/L) and ‘sufficient’ (>50 nmol/L).

The authors assessed 1) The relationship between gestational vitamin D concentrations at mid-pregnancy and the child’s total brain volume, cortical grey matter volume, cortical white matter volume and cerebellar volume using multiple linear regression, 2) Whether having sufficient vitamin D concentration at only one time point or both time points was associated with different brain volumes, 3) The relationship between gestational vitamin D concentration and the brain volume of subcortical structures and brain ventricles, and 4) The relationship between vitamin D concentration and surface-based brain metrics: cortical thickness, surface area, and gyrification (the curvature or folding of the brain’s cortical surface). For each regression analysis, the authors created one model (‘Model 1’) with age at MRI scan and the child’s sex as covariates, and a second model (‘Model 2’) which included the other potential confounders described above.

What did they find?

Vitamin D concentration at mid-pregnancy and at birth was positively associated with the children’s total brain volume, total grey matter, and total white matter in Model 1, but not when other potential confounders were included (Model 2). Vitamin D concentration was positively associated with cerebellar volume in both models 1 and 2, but this relationship did not survive when the authors corrected their statistical analysis for multiple statistical comparisons. There was no association between vitamin D concentration category (deficient, insufficient, sufficient) and any measures of brain volume in model 1 or 2. However, smaller cerebral grey matter volumes were found in children who were ‘consistently insufficient’ or ‘consistently deficient’ (not sufficient at either time point) versus children who were ‘consistently sufficient’ children after correction for multiple statistical comparisons. Smaller total brain cerebral white matter volumes were also seen in ‘consistently deficient’ children compared to the ‘consistently sufficient’ group. No relationships were found between subcortical or ventricle volume and vitamin D concentration. Finally, when the authors assessed cortical thickness, surface area, and gyrification in other groups compared to the ‘consistently sufficient’ group, they found smaller surface area of temporal region of the right hemisphere of the brain in children with ‘consistently insufficient’ vitamin D concentrations and smaller frontal and occipital surface area in the right hemisphere and less gyrification in the left hemisphere in those ‘consistently deficient’ in models 1 and 2.

What's the impact?

This study, which is the first longitudinal study to assess the relationship between brain morphology in children and gestational vitamin D levels, found that consistently low vitamin D levels were associated with smaller brain volumes and different brain surface area and gyrification in children. Studies such as this could help to provide insight on the link between vitamin D deficiencies and neurodevelopment or neuropsychiatric abnormalities. 

Zou et al. A prospective population-based study of gestational vitamin D status and brain morphology in preadolescents. NeuroImage (2020). Access the original scientific publication here.