Paying attention to null results: Examining the effects of Ritalin on the brain
Dr. Julio Martinez-Trujillo started his career in Cuba where he trained as a medical doctor. His career and passion for science has since brought him across the world. Now established in Canada, he commits 100% of his time to researching the brain in order to understand how we process complex cognitive tasks like attention and memory. From his experience as a physician, he noticed that we have little understanding of how many pharmaceutical drugs affect the brain which results in limited treatment options for conditions that impact the nervous system.
One such drug, methylphenidate, better known as Ritalin, is the most frequently prescribed drug for treating attention deficit/ hyperactivity disorder (ADHD). ADHD is one of the most common mental health conditions in children. In fact, it affects approximately 1 in 20 children in Ontario and chances are you probably know someone who has been diagnosed with ADHD. Clinically, ADHD is diagnosed based on symptoms like inattention, impulsivity, and hyperactivity. In day to day life, it may present as someone who can’t sit still or finish a story without veering off topic. Ultimately, you may notice that someone with ADHD has trouble paying attention and are easily distracted. In Ontario, a majority of kids with ADHD (around 70%) are given prescription medication like Ritalin1. However, despite its widespread use, we do not understand exactly how Ritalin alters the processing of attention in the brain.
Scientists define attention as the ability to focus on and process specific information in our environment. For example, while reading this article you are surrounded by distractions, be it the chatter of conversation across the room, a light flickering overhead or even an itchy tag on your shirt. All of these sounds, sights and sensations compete for your attention. Since our brains can’t process and attend to everything at once, they must decide what is important enough to focus on.
Previous research conducted using animal models and humans demonstrates that Ritalin enhances the brain’s ability to focus attention on important information. This has led researchers to suggest that Ritalin influences attention through the same mechanism across species, inferring that results from animal models would also apply to humans.
Previous experiments conducted in rodent animal models provide strong evidence that Ritalin acts on the prefrontal cortex, a region in the front part of the brain that is important in complex cognitive tasks like attention, decision making, and short-term memory. However, the prefrontal cortex is more recently evolved brain structure, with the human prefrontal cortex showing considerable expansions in size and complexity compared to other animals (see Figure 1). Therefore, whether Ritalin also acts on the prefrontal cortex in the human brain is still unclear.
After discussing this issue with psychiatrist Dr. Ridha Joober at the Research Centre of the Douglas Hospital in Montréal, Sébastien Tremblay and colleagues, under the supervision of Dr. Martinez-Trujillo, published a paper in 2019 that investigated how Ritalin influences the prefrontal cortex in an animal model with a more developed prefrontal cortex.
Figure 1. Differences in anatomy of the prefrontal cortex across species
The authors recorded brain activity in the prefrontal cortex during a complex attention task where subjects had to attend to an object while ignoring distractors. Before subjects performed this task, they were given either Ritalin or a placebo. A placebo is an ‘inactive’ pill that is not expected to change behavior or brain activity. For each subject, the authors determined optimal doses of Ritalin that led to improved task performance and resembled therapeutic doses used in clinics. They then examined many properties of neural activity and hypothesized that Ritalin would affect activity in the prefrontal cortex during performance of the attention task.
One of the important properties of neurons, the basic functional units of the brain, is how their activity can represent information about the objects around us or behaviours that we perform. Neurons in the brain transmit information through electrical signals, called ‘action potentials’, that are used to communicate with other neurons. The more action potentials an individual neuron elicits, the more information it can send to other neurons, resulting in increased neural activity. The authors looked for any differences in neural activity during performance of the attention task between Ritalin or placebo. Although the researchers predicted that Ritalin would increase neural activity when attention is focused on the target object, the results showed otherwise, and there was no difference between the effects of Ritalin and placebo.
Since their prediction was not supported, the authors reported ‘null’ results – meaning that they found an unexpected result that was not consistent with their prediction. Although null results are very common in scientific research, they often remain unpublished, tucked away on computer hard drives where no one can benefit from the potentially important information that they may provide.
This particular null result is important since it highlights the inconsistencies in our understanding about how Ritalin may affect the human brain. Authors suggest that this difference in brain activity between the current study and previous research may result from anatomical differences that should be considered when translating findings from animal models to humans. They suggest that new directions should be taken to explore the mechanism of Ritalin on the brain, which may include looking at the effects of Ritalin on other brain regions also known to be involved in attention.
Dr. Martinez plans to continue exploring the effect of pharmaceutical drugs on the brain as well as forming connections with those in the medical and scientific community to advance the translation of research findings from animal models to clinical applications so that safe and effective treatments can be developed for people with mental health conditions.
Original Research Article:
Sébastien Tremblay, Florian Pieper, Adam Sachs, Ridha Joober, Julio Martinez-Trujillo. The effects of methylphenidate (Ritalin) on the neurophysiology of the monkey caudal prefrontal cortex. eneuro, 2019; ENEURO.0371-18.2018 DOI:
10.1523/ENEURO.0371-18.2018 https://www.eneuro.org/content/6/1/ENEURO.0371-18.2018
References:
Hauck, T. S., Lau, C., Wing, L. L. F., Kurdyak, P., & Tu, K. (2017). ADHD Treatment in Primary Care: Demographic Factors, Medication Trends, and Treatment Predictors. Canadian Journal of Psychiatry, 62(6):393-402.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).