Study finds altered glutamate concentrations in specific brain areas of adolescents with ADHD

A neuroimaging study of adolescents with ADHD found age-related increases in glutamate levels in the medial prefrontal cortex region of the brain in these individuals. In contrast, individuals who experienced a remission of ADHD symptoms and participants who never suffered from ADHD had an age-related decrease in glutamate levels in this area of the brain. The paper was published in Translational Psychiatry.

ADHD, or attention-deficit/hyperactivity disorder, is a neurodevelopmental condition whose main symptoms are inattention, hyperactivity, and impulsivity. It usually begins in childhood. However, it is most often diagnosed when a child starts school and the symptoms of ADHD come into conflict with school rules—typically, with the expectation that children pay attention and sit quietly in their assigned seats. As a result of this conflict, the academic performance of many individuals with ADHD suffers.

People with ADHD tend to have difficulty organizing tasks, managing time, following instructions, or sustaining concentration. They may also interrupt others, act without considering consequences, or feel unusually restless. Symptoms vary widely, and some people mainly have attention difficulties without obvious hyperactivity. The development of ADHD is strongly influenced by genetic and neurological factors, although environmental factors may affect how severe the symptoms become. While some people experience a remission of ADHD symptoms as they grow up, the symptoms can persist into adulthood for others.

Study author Marine Bouyssi-Kobar and her colleagues note that the dysregulation of specific systems in the brain seems to be associated with ADHD. Previous studies have already implicated the dysregulation of systems based on the neurotransmitters dopamine and noradrenaline in this disorder. Novel findings indicate that the primary excitatory neurotransmitter of the brain—glutamate—might also play a role.

They conducted a neuroimaging study in which they focused on glutamate levels in the medial prefrontal cortex region of the brains of youth with ADHD. The authors noted that the medial prefrontal cortex mediates cognitive processes implicated in ADHD, including the allocation of attention, decision-making, and emotional regulation. The neural circuitry that uses glutamate in the prefrontal cortex also interacts with the catecholaminergic systems (based on dopamine and noradrenaline) that are known to play a role in the formation of ADHD symptoms.

For their analysis, the study authors selected participants from an existing longitudinal cohort study (the Neurobehavioral Clinical Research study) for whom glutamate concentration data—obtained using proton magnetic resonance spectroscopy of their brains—were available.

Overall, the participants were 161 adolescents. Sixty-nine of them had persistent ADHD, 20 had remitting ADHD, and 72 participants never had ADHD. Participants with remitting ADHD were individuals who showed ADHD symptoms at the start of the study but not at a later assessment. The participants’ average age was 14 to 15 years. Most of them were boys: 80% of the persistent ADHD group, 75% of the remitting ADHD group, and 64% of the group without ADHD.

Study participants completed proton magnetic resonance spectroscopy and magnetic resonance imaging of their brains. Nearly half of the participants also completed follow-up scans, typically about two years later.

Results showed that participants with persistent ADHD and those without ADHD or with remitting ADHD displayed different developmental trajectories regarding glutamate levels in the medial prefrontal cortex. Participants with persistent ADHD experienced an age-related increase in glutamate concentrations in this region of the brain. On the other hand, participants with remitting ADHD and those who never had ADHD showed an age-related decrease in glutamate levels in the same region. The researchers suspect this means that persistent ADHD is linked to a delayed or altered neurodevelopmental process, whereas remitting ADHD mirrors the typical, healthy maturation of the brain as it enters adolescence.

Additionally, these altered prefrontal glutamate concentrations in the persistent ADHD group were associated with changes in intrinsic connectivity between the default mode network (the network of brain cells that is active while we are at rest, which includes the medial prefrontal cortex) and subcortical regions of the brain. Intrinsic connectivity is the degree to which spontaneous activity patterns of two neural networks or brain regions are synchronized or correlated when a person is not performing a specific task.

“These findings may indicate altered maturation of glutamate in the medial prefrontal cortex in youth with persistent ADHD,” the study authors concluded.

The study contributes to the scientific knowledge about ADHD. However, it should be noted that the cross-sectional and longitudinal design of this study does not allow any definitive causal inferences to be derived from the results. Furthermore, the study was limited to a single predefined brain region due to the specific scanning sequence used, and it did not account for the hormonal fluctuations of puberty, which can also influence brain maturation.

The paper, “Developmental trajectories of glutamate and the variable clinical course of ADHD in youth,” was authored by Marine Bouyssi-Kobar, Yan Zhang, Luke Norman, Saadia Choudhury, Wendy Sharp, Gustavo Sudre, Tonya White, and Philip Shaw.