Connectivity of the Amygdala Predicts Risk Tolerance

What's the science?

Risk can be thought of as uncertainty — when there is some information about the possible outcome of a situation. Different individuals have different tolerance for risk when making decisions. We know that certain brain regions are generally involved in risk perception from studies looking at brain activation during risk (e.g. medial prefrontal cortex, anterior insula, anterior cingulate cortex, amygdala), however, we don’t know which brain regions and which inherent properties of these brain regions affect individual risk tolerance. This week in Neuron, Jung and colleagues use a data-driven approach to determine which brain regions and functional properties of these regions predict individual risk tolerance.

How did they do it?

Anatomical MRI, resting-state MRI (brain activity at rest) and Diffusion Tensor Imaging (structural connectivity) data from 108 healthy adults were acquired. Participants also performed a well-validated risk task to assess their risk tolerance. This task involves making binary decisions over several trials, choosing between a certain monetary reward and a larger uncertain (i.e. riskier) reward. They first analyzed the resting-state MRI data to compute individual functional connectivity throughout the brain (synchrony between brain regions at rest) to determine important regions that show a large amount of synchrony with other brain regions (i.e. highly central brain regions). In an exploratory, data-driven approach, they then assessed whether the strength of the functional connectivity in any these regions throughout the brain predicted individual risk tolerance.

What did they find?

The strength of functional connectivity in the amygdala showed the strongest correlation with risk tolerance of any brain region. Based on this finding, the authors focused on the amygdala for the remainder of their analyses. They tested which specific functional connections of the amygdala were important for risk tolerance. They used the amygdala as a seed region and found that the medial prefrontal cortex showed the strongest functional connections. There was a positive correlation between risk tolerance and functional connectivity between the amygdala and the medial prefrontal cortex; greater risk tolerance was associated with stronger functional connections. They then assessed whether the structural connectivity (white matter tracts) between the amygdala and the medial prefrontal cortex was associated with risk tolerance, and found that there was a negative correlation between structural connectivity and risk tolerance;  stronger white matter tract connectivity was associated with lower risk tolerance (significant for the right amygdala, and trending for the left amygdala). They also found that more gray matter volume in the amygdala was associated with a higher risk tolerance. In a regression analysis, they found that functional connectivity, gray matter volume and tract strength (only on the right) were all predictors of individual risk tolerance.

What's the impact?

This is the first study to show that the inherent properties of the amygdala and its’ connections are associated with individual risk tolerance. This study suggests that an individual’s brain structure and function, which can be thought of as their “brain signature” can be used to predict individual behavior. Localizing brain regions involved in risk tolerance is important for understanding why some individuals engage in risk-taking behavior.

W.H. Jung et al., Amygdala Functional and Structural Connectivity Predicts Individual Risk Tolerance. Neuron (2018). Access the original scientific publication here.

Antiepileptic Drugs Induce Mislocalization of Neurons in the Hippocampus

What's the science?

Valproic acid is an anti-epileptic drug prescribed to some pregnant women who have epilepsy. Use of the drug during pregnancy is associated with autism and Attention Deficit Hyperactivity Disorder in offspring, and these disorders are associated with a higher risk for seizures. High seizure risk has also been linked to mislocalized neural stem cells/progenitor cells in the hippocampus (which will become neurons in the hippocampus; a brain region involved in learning and memory). This week in PNAS, Sakai and colleagues explored whether exposure to valproic acid increased seizure susceptibility through hippocampal mechanisms in mice.

How did they do it?

To test whether exposure to valproic acid could cause seizures, they gave kainic acid (activates glutamate receptors and can promote seizure activity) to mice (at 12 weeks old) who had or had not been previously exposed to valproic acid prenatally. They used immunohistochemistry to locate progenitor cells in these mice. Next they used RNA-sequencing of neural stem cells/progenitor cells in the hippocampus at embryonic day 15, postnatal day 5, and 12 weeks old to identify differentially expressed genes whose expression levels varied due to prenatal valproic acid exposure at embryonic day 12, 13, and 14 (3 times). They then matched abnormal gene expression to known gene function (Gene Ontology analysis). Finally, they examined whether exercise (voluntary running) might mitigate the effects of valproic acid on seizure activity, due to its known role in neurogenesis (production of new neurons).

What did they find?

Mice exposed to valproic acid experienced increased susceptibility to seizures at 12 weeks of age, and increased mislocalization of newly generated neurons from stem cells/progenitor cells within the dentate gyrus (decreased in the granule cell layer, increased at the hilus). Several differentially expressed genes were present at different developmental stages in mice exposed to valproic acid, indicating that valproic acid affects gene expression in stem cells/progenitor cells the hippocampus. Using Gene Ontology, they identified several genes involved in cell and neuronal migration, including Cxcr4. When mice exposed to valproic acid voluntarily exercised (ran) for eight weeks, their susceptibility to seizures decreased and their Cxcr4 expression normalized, indicating that exercise may mitigate the effects of valproic acid on the hippocampus through Cxcr4.

What's the impact?

This is the first study to link valproic acid with mislocalization of hippocampal neurons and seizure susceptibility in the offspring of pregnant mice. We now have a better understanding of the mechanisms underlying the harmful effects of valproic acid. Exercise may be a particular avenue for focus, as it may mitigate the effects of improper hippocampal neuron placement on susceptibility to seizures.

A. Sakai et al., Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice. PNAS (2018). Access the original scientific publication here.

The Role of T Cell Populations in Multiple Sclerosis Disease Activity

What's the science?

In multiple sclerosis (MS), effector T cells (immune cells) can travel from the periphery to the central nervous system and mediate symptoms by causing inflammation and neurodegeneration. Some therapies use antibodies to target T cells, but different T cell populations function differently and may release different inflammatory factors, resulting in different effects in MS. This week in Brain, Langelaar and colleagues assessed blood and cerebral spinal fluid in patients with MS to characterize the function of different T cells in MS.

How did they do it?

Healthy controls and patients with MS participated. MS patients included those who had experienced the first presentation of MS (clinically isolated syndrome) who either went on to develop MS <1 year later or did not develop MS for 5 years, and those experiencing relapsing remitting MS who were on antibody treatment (natalizumab) or not. Blood draws and lumbar punctures were obtained. Flow cytometry was used to locate cells based on their antibodies. To confirm their findings, they also obtained blood and spinal fluid and brain tissue samples from 5 patients after death who had late-stage MS.

What did they find?

In patients with the clinically isolated syndrome (i.e. had experienced the first presentation of MS) who developed MS soon after (versus those who did not), a lower proportion of CD4+ cells in the blood were Th1-like Th17 (a type of T helper cell). A lower proportion of Th1-like Th17 cells in the blood was also found in treatment-naive relapsing remitting patients compared to healthy controls, indicating that this finding may be specific to MS. At the same time, the proportion of Th1-like Th17 cells was higher in the spinal fluid of MS patients (and co-produced high levels of inflammatory factors). Therefore, it appears that these cells are being activated and recruited (from the blood) to the central nervous system (lower in the blood, but higher in the cerebral spinal fluid). After death, there was a high proportion of Th1-like Th17 in brain tissues of MS patients but not in controls, providing further supporting evidence for recruitment of these cells to the central nervous system.  An adhesion molecule called VLA-4, which could help T cells migrate from the periphery to the central nervous system, was reduced following treatment with an MS drug, natalizumab (versus pre-treatment), indicating it was targeted by this antibody.

What's the impact?

This is the first study to demonstrate that a specific subset of T cells (Th1-like Th17 cells) is involved in disease activity in MS. This subset is the main population of inflammatory cells within the cerebral spinal fluid of the central nervous system. The findings suggest that migration of these cells from the periphery could underlie MS disease activity, and that an MS treatment (natalizumab) can target key inflammatory factors involved. This work could help to design more targeted therapies for MS, and demonstrates the usefulness of natalizumab early on in the disease.

J. van Langelaar et al., Characterizing the role of T cell populations in MS disease and treatment. Brain (2018). Access the original scientific publication here.