How Do Brain Cells Grow Differently in Children with ADHD?

What you need to know

• This study examined cell growth rates in induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) derived from children with ADHD compared to controls.
• No differences were found in the growth of iPSCs between ADHD and control groups.
• NSCs from the ADHD group showed significantly lower growth rates compared to controls.
• The findings suggest differences in neural development in ADHD may emerge at the NSC stage rather than earlier stem cell stages.

Understanding ADHD and brain development

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition affecting over 5% of children worldwide. Children with ADHD often struggle with attention, impulse control, and hyperactivity. While the exact causes are still unclear, both genetic and environmental factors are thought to play a role.

One intriguing observation from brain imaging studies is that children with ADHD show delays in brain maturation compared to their peers - on average about 3-5 years behind in some brain regions. However, the cellular and molecular mechanisms behind these developmental differences are not well understood.

To shed light on this, researchers are turning to stem cell models to study how brain cells develop in ADHD. This study used a technique called induced pluripotent stem cells (iPSCs) to examine cell growth at different stages of early neural development.

What are iPSCs and why are they useful for studying ADHD?

Induced pluripotent stem cells are a powerful tool for modeling human diseases. They are created by taking ordinary cells (like skin or blood cells) from a person and reprogramming them back into a stem cell state. These iPSCs can then be coaxed to develop into different types of cells in the lab, including brain cells.

The key advantage of iPSCs is that they retain the genetic makeup of the individual they came from. This allows researchers to create cellular models of ADHD that capture a person’s unique genetic risk factors for the condition.

In this study, the researchers created iPSCs from children diagnosed with ADHD as well as matched controls without ADHD. They then examined how these cells grew and developed at two key stages:

1. As iPSCs
2. As neural stem cells (NSCs) - an intermediate stage as iPSCs start to develop into brain cells

By comparing growth rates between the ADHD and control groups, they aimed to identify if and when differences in cellular development emerge.

Measuring cell growth rates

The researchers used two different methods to assess cell growth rates:

1. Real-time cell analysis (xCELLigence system): This technique uses electrical impedance to continuously monitor cell growth, attachment and proliferation in real-time over several days.

2. WST-1 assay: This is a colorimetric assay that measures the metabolic activity of cells, which correlates with the number of viable cells present. Measurements were taken at multiple time points over 4-5 days.

These complementary methods allowed the researchers to thoroughly characterize the growth patterns of both iPSCs and NSCs derived from children with and without ADHD.

Key findings: Differences emerge at the neural stem cell stage

When examining the iPSCs, no significant differences were found in growth rates between the ADHD and control groups. This was consistent across both measurement techniques.

However, when the iPSCs were differentiated into neural stem cells, clear differences emerged:

• NSCs from the ADHD group showed significantly lower growth rates compared to controls
• This reduced proliferation in ADHD NSCs was observed using both the xCELLigence system and WST-1 assays
• The differences became more pronounced at later time points (96-114 hours after plating the cells)

These findings suggest that altered cellular growth in ADHD may not be present at the earliest stages of development (represented by iPSCs), but emerge as cells begin to adopt a neural identity.

Implications for understanding ADHD

This study provides some of the first evidence for differences in neural cell growth rates in ADHD at a cellular level. The reduced proliferation of NSCs aligns with clinical observations of delayed brain maturation in children with ADHD.

Importantly, the fact that differences were only seen at the NSC stage, not in iPSCs, suggests there may be ADHD-associated changes in how cells transition from a pluripotent state to a neural identity. This could involve alterations in gene regulation or signaling pathways that govern neural development.

While preliminary, these findings open up new avenues for investigating the neurodevelopmental origins of ADHD. Understanding how and when cellular differences arise could potentially lead to new therapeutic strategies or earlier detection methods in the future.

Limitations and future directions

As a pilot study with a small sample size, these results will need to be replicated in larger cohorts. The researchers only examined male participants in this initial study, so future work should include females to identify any sex-specific effects.

It will also be important to follow these cells through later stages of neural development, including mature neurons, to see how early differences in NSC growth may impact the final cellular composition and function of brain circuits.

Additionally, the mechanisms driving the reduced NSC proliferation in ADHD remain to be elucidated. Examining gene expression patterns and specific signaling pathways involved in neural stem cell regulation could provide further insights.

Conclusions

• This study provides evidence for altered growth rates of neural stem cells, but not earlier-stage induced pluripotent stem cells, in cellular models of ADHD.
• The findings align with clinical observations of delayed brain maturation in ADHD and suggest these delays may originate early in neural development.
• While preliminary, this work establishes iPSC-based cellular models as a promising approach to study neurodevelopmental mechanisms in ADHD.
• Further research is needed to understand the molecular drivers of these cellular differences and their impact on brain circuit development in ADHD.