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.

Pairing Vagus Nerve and Tactile Stimulation Improves Somatosensory Function Following Nerve Injury

Post by Elisa Guma

What's the science?

Sensory dysfunction is a common consequence of injury to the nervous system due to nerve damage or stroke. Sensory training using tactile stimulation in affected areas is the most common form of rehabilitation for these patients, but most are left with sensory loss. Promising clinical data has identified a potential novel therapy involving pairing stimulation of the vagus nerve with tactile rehabilitation; this is thought to enhance synaptic plasticity and facilitate recovery of sensory function. This week in Annals of Neurology, Darrow and colleagues rigorously test this hypothesis in a rodent model of nerve damage.

How did they do it?

To create a model of chronic sensory loss in rodents, rats underwent transection followed by repair of the median and ulnar nerves in the forelimb, which produces lasting deficits in somatosensation in spite of reinnervation. This injury results in a denervation of mechanoreceptors on the ventral (but not dorsal) surface of the forepaw. Typically, reinnervation does occur over time, however animals still experience long lasting impairments in somatosensation and have disruptions in nerve morphology. The rats were also implanted with stimulating cuff electrode on the left cervical vagus nerve.

Sixteen weeks after the injury, animals were randomized to receive either 1) a tactile rehabilitation paradigm consisting of the presentation of various mechanical stimuli to the surface of the paw, or 2) a tactile rehabilitation paradigm with 0.5 s bursts of vagus nerve stimulation paired with the presentation of each tactile stimulus, daily for 6 weeks. The tactile stimuli included a paintbrush, a 10g filament, a copper rod, and a puff of air to the affected ventral forepaw. Mechanosensory thresholds were measured at baseline, weekly throughout the therapy, and every two weeks for 8 weeks after the cessation of therapy to see if benefits were long-lasting. Given that sensory and motor function are highly related, additional measures of forelimb sensorimotor function were recorded including the spontaneous use of the injured forelimb during exploration, grip strength, placement of the forelimb in a horizontal ladder rung task, and toe spread analysis.

What did they find?

The authors found that pairing tactile rehabilitation with vagus nerve stimulation improved recovery of somatosensation in the forelimbs of animals with chronic sensory deficits compared to tactile rehabilitation alone. Improvements were already detectable in the first week of therapy and were maintained up to 2 months after the cessation of therapy. Furthermore, the animals that received paired vagus nerve and tactile stimulation therapy also had improved motor function in the injured forelimb, observable in exploratory behaviour, as well as reducing the length of toe spread during normal walking, and decreased missed placements and slips in the horizontal ladder task. The only motor behaviour that the paired therapy did not improve was for grip strength, where no difference between treatment groups were observed. 

What's the impact?

This study, motivated by recent clinical findings, provides compelling evidence for the efficacy of pairing tactile stimulation with vagus nerve stimulation for restoring somatosensation and motor function in a rodent model of sensory loss. This paired therapy could be a promising new approach for recovery from neurological injury. Future studies are needed to validate this strategy in other clinical populations, as well as to uncover the precise mechanisms supporting recovery.

Michael J Darrow et al. Restoration of somatosensory function by pairing nerve stimulation with tactile rehabilitation. Annals of Neurology (2019). Access the original scientific publication here.

Dopamine Projection Neurons in the VTA Have Distinct Roles in Reward Association and Motivation

Post by Amanda McFarlan 

What's the science?

The ventral tegmental area (VTA) is a midbrain structure with a large population of dopaminergic neurons that innervate the two major regions of the nucleus accumbens (NAc): the core and the shell. It is well known that dopamine projection neurons from the VTA to the NAc facilitate reward association and motivation. However, how dopamine release in the two regions of the NAc acts to facilitate these distinct functions remains unclear. This week in Neuron, Heymann and colleagues investigated the role of dopamine release in the NAc core versus the NAc shell in reward association and motivation.

How did they do it?

The authors used patterns of expression of different neuropeptide-associated genes in the VTA to identify distinct populations of dopamine neurons in the VTA that project to either the core or the shell of the NAc. Then, to understand the importance of these VTA to NAc connections during reward learning, they optogenetically inhibited projection neurons from the VTA to either the NAc shell or core in mice that were being trained in a Pavlovian conditioning paradigm. In this paradigm, mice were conditioned to expect a reward following the presentation of a lever, and had to press the lever and enter their head into an area with food to receive a reward. Next, the authors determined whether optogenetic activation of dopamine projection neurons from the VTA to the NAc would be sufficient to promote intracranial optical self-stimulation (i.e. a rewarding stimulation) in mice. To do this, they targeted the expression of Channelrhodopsin-2 (an excitatory light-gated ion channel) to VTA neurons that project to either the NAc shell or core and allowed mice to lever press for optical stimulation of these neurons. Additionally, the authors investigated the role of VTA projection neurons in reward-seeking behaviour: they trained calorie-restricted mice on a fixed-ratio schedule of food reinforcement (where food is delivered after a set number of responses) for 5 days and then switched the mice to 5 days of intracranial optical self-stimulation. Finally, the authors assessed the effect of simultaneous activation of VTA projection neurons to the NAc core and shell on reward seeking behaviours. 

What did they find?

The authors found that the dopamine neurons in the VTA expressing corticotropin-releasing hormone receptor 1, preferentially innervated neurons in the NAc core, while dopamine neurons in the VTA expressing cholecystokinin, preferentially innervated neurons in the NAc shell. Then, they revealed that inhibiting VTA projection neurons that target the NAc core, but not the shell, during the Pavlovian conditioning paradigm significantly reduced the number of head entries in response to the conditioned stimulus. Similarly, they determined that optogenetic activation of VTA neurons innervating the NAc core, but not the shell, was sufficient to promote intracranial optical self-stimulation in mice, suggesting that VTA to NAc core connections are important for reward association. 

Next, the authors showed that the switch from food reinforcement to intracranial optical self-stimulation in calorie-restricted mice resulted in an acute increase in lever pressing for optogenetic activation of VTA neurons innervating the NAc core on day 1 that decreased over time. However, there was an increase in lever pressing for optogenetic activation of VTA neurons innervating the NAc shell that persisted all 5 days, suggesting that the VTA to NAc shell connections may be important for the motivation involved in maintaining reward-seeking behavior. Finally, the authors revealed that simultaneous activation of the VTA neurons that innervate the NAc core and shell resulted in robust self-stimulation in mice, suggesting that robust behavioural responses emerge from coincident activation of pathways involved in reward association and motivation.

What’s the impact?

This is the first study to show that dopamine neurons in the VTA that preferentially innervate either the NAc core or shell can be isolated using neuropeptide-associated genes. The authors revealed that dopamine neurons in the VTA that project to the NAc core are important for reward association, while dopamine neurons in the VTA that project to the NAc shell are involved in motivation. Altogether, these findings highlight how the coincident activation of both VTA to NAc pathways leads to robust behavioural changes in response to a reward. 

Heymann et al. Synergy of Distinct Dopamine Projection Populations in Behavioral Reinforcement. Neuron (2019). Access the original scientific publication here.