We developed a model of primary motor cortex (M1) microcircuits [1] with over 10,000 biophysically detailed neurons and 30 million synaptic connections. It simulates a cylindric cortical volume with a depth of 1350 μm and a diameter of 300 μm. Neuron densities, classes, morphology and biophysics, and connectivity at the long-range, local and dendritic scale were derived from experimental data published in over 30 studies. The model was developed using the NetPyNE tool, which facilitated the integration of this complex experimental data at multiple scales. Our model exhibited spontaneous neural activity patterns and oscillations consistent with M1 data.  Neural activity depended on cell class, cortical layer and sublaminar location. Different output dynamics were seen when the network was driven by brief activation of particular long-range inputs, or in the setting of different neuromodulatory conditions. Results yielded insights into circuit information pathways, oscillatory coding mechanisms and the role of HCN in modulating corticospinal output.  

LFP revealed physiological oscillations in delta (0.5-4 Hz) and high beta to low gamma (25-40 Hz) ranges across layers and populations. Oscillations occurred in the absence of rhythmic external inputs, emergent from neuronal biophysical properties and circuit connectivity. Filtering the LFP signal from the electrode located in  upper L5B revealed phase-amplitude coupling of fast oscillations on delta wave phase. LFP  spectrogram demonstrated that the fast oscillations occurred robustly during the time course of simulations. Strong LFP beta and gamma oscillations are characteristic of motor cortex activity, and have been found to enhance signal transmission in mouse neocortex. Phase-amplitude coupling may help integrate information across temporal scales and across networks.

Analysis of firing dynamics and information flow in our model confirmed and extended our understanding of information flow in cortical microcircuits. Consistent with existing models, sensory-related long-range inputs targeted superficial layers which in turn projected to deeper layers. Our simulations, however, provided further details: information flow was cell-class specific, going unidirectionally from IT to PT cells; sublaminar-specific, with superficial ITs targeting primarily the upper portion of L5B PT cells; and oscillation frequency-specific, with Granger causality peaks occurring at shifted beta/gamma range frequencies for different internal connections.

The VPOP (Virtual Populations for Obesity Prevention) project has involved developing various multi-scale computational simulation models to help decision makers address questions and issues related to obesity prevention and control.

As described in Nutrition Reviews and in Forbes, obesity is a multi-scale systems problem. The relevant scales are interconnected and include factors such as physiology, behavior, culture, social networks, environment, policy, and economics. Changing only parts of the system may have little effect—or, even worse, unintended consequences.

While the human brain can see single cause and single effect outcomes, unaided, it is difficult to understand the multi-scale factors and relationships with obesity. Multi-scale systems approaches, models, and tools that the VPOP project has developed designs and tests various obesity prevention measures, policies and interventions within the safety of a computer before trying them in real life, which can save considerable time, effort, and resources.

Here are some examples of questions that the VPOP project has used multi-scale modeling to answer and address: 

• Can sugar-sweetened beverage (SSB) warning labels impact obesity prevalence? The VPOP project built virtual representations of Baltimore, Philadelphia, and San Francisco to help city officials determine the potential impact of introducing SSB warning labels. The results from the VPOP’s multi-scale simulation model show when SSB warning labels appeared in all store locations in the three cities and reduced the chances of someone purchasing a sugary drink by 8%, obesity prevalence went down overtime by 1.69% in Baltimore, 4.08% in San Francisco, and 2.17% in Philadelphia while overweight prevalence dropped by 1.39% in Baltimore, 3.1% in San Francisco, and 0.36% in Philadelphia. Full paper published in AJPM.
• Can following the current formula-feeding and solid food recommendations result in infants who are overweight or have obesity? Since most of the available formula-feeding and solid food guidelines for infants vary significantly, the VPOP project was utilized to evaluate how this can affect infant weight gain. The National Institutes of Health (NIH) and media outlets covered the results, which call for more consistent guidelines across the board. Specifically, the findings indicate that following each of the formula-feeding guidelines in the study led to infants becoming overweight/with obesity by 6 months old. Findings also suggested that following each of the solid food guidelines in the study for just a few months would drive the average body mass index (BMI) for the infants into the overweight category. Full papers published in Pediatric Research and AJPM.
• What is the impact of youth physical inactivity in the U.S. and what is the value of increasing physical activity among children to different degrees? VPOP has developed a multi-scale, national model to estimate the cost of youth physical inactivity. Results from the model showed even modest increases in youth’s physical activity levels could avert billions in healthcare and other costs. For example, if half of the youth in the U.S. aged 8-11 years old were physically active, VPOP’s multi-scale model results showed this would avert $8.1 billion in direct medical costs and $13.8 billion in productivity losses. Increasing to 75% would avert $16.6 billion and $23.6 billion, respectively. The findings sparked heavy media coverage in outlets including New York Times, USA Today, and Yahoo News. Leaders in the field continue to bring the VPOP project’s generated results to the table to show decision makers the substantial savings attributed to getting and keeping youth physically active. Full paper published in Health Affairs.
• What is the value of programs to increase youth sports participation in different locations? The Aspen Institute’s Sports & Society Program worked with the VPOP project for its ProjectPlay State of Play Report. The VPOP’s multi-scale computational simulation models were utilized at local levels to generate numbers for East Harlem, New York and Southeast Michigan in order to better understand the impact of increasing youth sport participation. The projections are used to show stakeholders the benefits of more youth meeting the CDC’s physical activity guidelines. Results from the VPOP project showed if 50% of youth in East Harlem get and stay active into adulthood, $36.1 million in direct medical costs and $38.5 million in productivity losses would be averted. If 50% of youth in Southeast Michigan get and stay active into adulthood, the VPOP project’s results show this will avert $1.8 billion in direct medical costs and $1.9 billion in productivity losses.
• What is the value of increasing physical activity in a pre-existing program? Girl Scouts of Central Maryland (GSCM) worked with the VPOP projectto better understand the impact of its original Fierce & Fit program and how changes to the sessions could result in even greater benefits. Based on the results from the VPOP project, GSCM decided to change its Fierce & Fit program sessions six-fold. Results showed that this updated version of the program could save $84,828 in lifetime direct medical costs and $81,365 in lifetime productivity losses. By doubling the length, frequency and increasing the amount of physical activity during its sessions six-fold, the program is expected to deliver cost savings nearly 2.5 times greater than the cost of implementing the program. Full paper published in Obesity.
• Can crime have an impact on physical activity levels and obesity? The National Heart, Lung, and Blood Institute (NHLBI) wanted to better understand the impact crime has on African American women’s physical activity levels and obesity prevalence in Washington D.C. Results from the VPOP project showed that reducing crime so that more physical activity locations were safely accessible could help decrease the annual rise in obesity prevalence. For example, results from VPOP’s multi-scale computational model suggest that reducing crime in Washington D.C. so more physical activity locations were accessible (increasing from 10% to 50%) decreased the annual rise in obesity prevalence in African American women by 2.69%. Full paper published in Obesity.
• What is the value of reducing an adult’s weight at different ages? The VPOP project built a multi-scale computational simulation model to represent the U.S. adult population to show the lifetime costs and health effects for an individual with obesity, overweight, and healthy weight statuses at ages 20 through 80. The results from the VPOP project show that a 20-year-old adult who goes from having obesity to being overweight would save an average of $17,655 in direct medical costs and productivity losses over their lifetime. If the same person were to go from having obesity to a healthy weight, the average savings would be $28,020. The expected average savings are even higher—$18,262 and $31,447, respectively—for a 40-year-old. Full paper published in Obesity.

For more information on VPOP multi-scale computer simulation models, email Bruce Y. Lee, MD, MBA at BruceLeeMDMBA@gmail.com.