Project 4

Project 4

Project Leaders: Ana Solodkin, PhD and Steven L. Small, MD, PhD

This project probes the effects of fragmented, unpredictable maternal signals on neuronal network structure and function using magnetic resonance brain imaging (MRI) of rats (with Project 1) and humans (with Project 2 and Project 3). This will enable defining a trajectory of structural and functional alterations and their correlation with fragmentation of maternal care and behavioral outcomes, resulting in potential biomarkers of vulnerability to overt cognitive and emotional pathology. We employ T1-weighted structural images, diffusion tensor imaging, and functional MRI at rest and during cognitive tasks.

In line with the overarching aims of the Center, we use targeted and focused analyses of MRI data to study the following questions:

Aim 1: To test if exposure to fragmented and unpredictable maternal signals alters the structure of specific and salient brain areas.

Significance and challenge: Fragmentation of early-life experience produces significant deficits in emotional and cognitive function in the rat. To date, structural changes were explored and found in synaptic connectivity in the hippocampus. However, it is not known if changes at the structural level occur in the human, and the distribution of such changes.

Approach: Building on preliminary data and in concert with assessments of pre-and postnatal fragmentation in Projects 2 and 3, we will use MRI to: (a) quantify volume and thickness of gray matter at the whole brain level; (b) quantify DTI derived measures at the whole brain level; (c) quantify gray matter and white matter kurtosis in the areas affected, providing a finer resolution for structural changes; (d) correlate these MRI measures with the measures of maternal fragmentation/unpredictability derived from Projects 2 and 3.

Aim 2: To test if exposure to fragmented maternal signals alters the function of salient brain networks.

Significance and challenge: Emotional and cognitive problems emerging after fragmentation in Projects 2 and 3, as well as the synaptic changes seen in the rat, suggest changes of functional brain networks. It is not known what networks are most affected in the human after fragmentation of early life maternal signals.

project4-aim2Approach: We will characterize the interactions of the hippocampus, defined by effective connectivity, with all other relevant structures in the brain. The hippocampus is at the center of a complex distributed network including neocortical areas and limbic regions. We will assess effective connectivity of the main hippocampal inputs and outputs based on fMRI during a modestly stressful cognitive task. We will test the hypothesis that the bias of the network will be towards neocortical-association areas in unaffected subjects (pink in figure), whereas in affected children the bias will be toward the limbic regions subserving emotional processing (blue in figure). Thus, whereas the key regions comprising the network might be similar for all cases, we anticipate a difference in the strength of the connections among regions. Lastly we will correlate these networks with the measures of fragmentation and unpredictability derived from Projects 2 and 3.

Aim 3: To test the hypothesis that imaging will provide a common platform across species that will reflect similarities in the mechanisms by which fragmented early-life maternal signals promote vulnerabilities to emotional and cognitive problems.

Significance and challenge: In the rodent, it is possible to probe molecular and cellular mechanisms by which early-life fragmented experience produces significant changes in synaptic physiology and connectivity in hippocampus, associated with spine and dendritic loss. If similar network changes take place in humans, then it is plausible that the underlying mechanisms are common and might provide molecular targets for intervention. It is unknown if impoverished dendritic trees and the functional connectivity changes in rodents can be visualized using imaging, and if similar defects are found in children exposed to fragmented early life experiences.

Approach: Working closely with Project 1, we will characterize across species: (a) hippocampal volume, and thickness of gray and white matter; (b) the morphological dynamics of the BOLD signal at rest in all hippocampal fields (overcoming issues of structural resolution);
(c) DTI changes in the integrity of hippocampal pathways representing subcortical-limbic interactions (fornix) and neocortical-cognitive functions (perforant path). Concordance of the imaging changes would support the idea that mechanisms established in Project 1 for rat might apply to the human.

Aim 4: To test if imaging outcome measures will provide predictive biomarkers for cognitive and emotional vulnerability in adolescence, and will contribute to the generation of predictive models.

Significance and challenge: Cognitive & emotional vulnerabilities after fragmented maternal signals are beginning to emerge in our human cohorts (Projects 2 and 3), and clearly occur in adolescent rats. It is unknown if MRI parameters may provide predictive biomarkers, in themselves, or in conjunction with behavioral measures during infancy and childhood. Importantly, MRI joins several independent and dependent measures assessed in Projects 1, 2 and 3. The complexity of the contributions of, and interactions, among specific measures poses a major analytic challenge.

Approach: Through the integral involvement of the computational / statistics core, we will assess the predictive value of structural and functional MRI measures to the emergence of vulnerability to mental disease during adolescence. In addition, the imaging data will be incorporated with the children’s emotional and cognitive behavioral evaluations obtained at ages 2 and 6 years (Projects 2 and 3) into comprehensive predictive models for adolescent behaviors that augur pathology.

Project Publications
  • Maras PM, Molet J, Chen Y, Rice C, Ji SG, Solodkin A, Baram TZ. Preferential loss of dorsal-hippocampus synapses underlies memory process impairment provoked by short, multi-modal stress. Mol Psychiatry. 2014; 19:811-22.
  • Baram TZ, Davis EP, Obenaus A, Sandman CA, Small SL, Solodkin A, Stern H. Fragmentation and Unpredictability of Early-Life Experience in Mental Disorders. Am J Psychiatry. 2012; 169:907-15.