Metabolic Energy and Motivation – How Neurotransmitters Regulate Mental Focus and Fatigue

When the brain is active, neurons (nerve cells) send messages using a combination of both electrical and chemical signals. 

When a message is passed from one neuron to the next, an electrical impulse triggers the release of chemicals into the gap between two neurons. This space is called the synaptic cleft.

One of the main chemicals released to help the message continue over the synaptic cleft is called glutamate. 

Glutamate is an excitatory neurotransmitter, meaning that it promotes activity in the receiving neuron. In contrast, inhibitory neurotransmitters suppress activity. If there are more excitatory than inhibitory signals present, the message continues across the synaptic cleft.

During mentally demanding tasks, many of these messages are sent rapidly and repeatedly. 

This causes large amounts of glutamate to be released. Over time, this can lead to glutamate buildup in the synaptic cleft.

Normally, astrocytes, which are specialized support cells, remove glutamate and recycle it. But during prolonged, demanding work, astrocytes cannot clear it fast enough. And as a result, glutamate accumulates in the synaptic cleft. (Pellerin & Magistretti, 1994; Falkowska et al., 2015).

The Role of Astrocytes in Clearing Glutamate

In order for astrocytes to clear glutamate from the synaptic cleft, they must take up glutamate molecules from the extracellular space (outside the cells). 

They do this by co-transporting glutamate together with sodium ions (Na⁺) across their cell membrane.

This process takes advantage of the fact that Na⁺ naturally flows into cells due to its electrochemical gradient.

By opening specific membrane transporters, the cell harnesses the inward flow of Na⁺ to drive the co-uptake of substances like glutamate.

However, as astrocytes take in glutamate along with Na⁺,  Na⁺ begins to accumulate inside the cell. To maintain ionic balance, the astrocyte activates the Na⁺/K⁺ pump, which uses ATP to actively transport Na⁺ out of the cell in exchange for K⁺.

ATP is the energetic coin of the body, and the Na⁺/K⁺ pump pumping process is therefore energy-demanding. To meet the increased energy need, astrocytes break down their internal glycogen stores into glucose, which can be utilized to create ATP and lactate.

The ATP powers the Na⁺/K⁺ pump, while the lactate is exported to nearby neurons, where it can be used as a valuable energy source.

(Falkowska, A, et al 2015)

ATP, Adenosine, and Mental Fatigue

ATP, which is short for adenosine triphosphate, is made up of three phosphate-bound adenosine units. 

When one of these bonds is broken, energy is released, and it’s this energy that powers many of the cell’s functions. And as a result, an adenosine molecule will be free – no longer bound in the ATP-structure.

Both astrocytes and neurons use ATP during brain activity. Sustained effort burns ATP faster than it can be replenished, which causes adenosine to accumulate alongside glutamate.

Adenosine binds to something called A1 receptors on neurons, which slows down communication between nerve cells by blocking other signal-carrying molecules from passing messages across the synaptic cleft.

This makes it harder to focus, stay alert, and process information efficiently.

This is also how caffeine works: it binds to the same receptors as adenosine but without causing drowsiness. By blocking adenosine, caffeine keeps you alert (Reichert et al., 2022; Kok, 2022).

The Anterior Cingulate Cortex (ACC) – A Regulator of Mental Energy, and the involvement of dopamine, motivation, and cognitive effort.

Viewed together, these processes act as a natural brake, slowing the brain's processes down and protecting against overactivation.

The Anterior Cingulate Cortex (ACC) is a key region involved in mechanisms related to mental energy regulation, particularly in evaluating cognitive effort and task difficulty.

It serves as a central hub for monitoring performance and attention, and for assessing internal energy availability. The ACC estimates how metabolically demanding a task is by integrating input from astrocytes and monitoring neuromodulators such as adenosine, glutamate, and dopamine.

In general, if the ACC detects low energy availability – for example via high levels of adenosine - it may prompt restorative behaviors like taking a break or initiating sleep.

It constantly balances the energy required for a task against current capacity and the perceived outcome.

As adenosine builds up and binds to A1 receptors, it becomes harder for signals to pass across the synaptic cleft. This increases the energy cost of communication between neurons, making tasks feel more cognitively demanding.

Maybe because mentally draining tasks such as focusing and concentrating mainly involve an activation of the frontal part of the brain, when the energy cost outweighs the expected reward, the ACC may reduce top-down control from the frontal regions of the brain. 

This reduction in executive activation can lead to lower motivation and reduced focus. 

The ACC acts as a switch between the Central Executive Network (CEN), which supports attention and goal-directed tasks, and the Default Mode Network (DMN), which is engaged during internally oriented activities such as self-reflection, autobiographical memory, future planning, and mind-wandering.

These two networks are anticorrelated: when one is active, the other is suppressed. The ACC orchestrates this switching through dopaminergic pathways, integrating effort, reward, and task demands to efficiently allocate cognitive resources.

During demanding tasks, dopamine supports the stability of working memory, especially in the prefrontal cortex, by enhancing the likelihood of these messages continuing over the synaptic cleft from one nerve cell to another.

But when energy is low or the predicted reward is not sufficient, dopamine release decreases. This weakens the signaling strength and makes it harder to stay focused.

The involvement of dopamine, therefore, links motivation to the equation of mental energy.

One must assume that if one is strongly intrinsically motivated by a given task, more dopamine would be available, strengthening the brain's ability to send these messages.

Frontal Midline Theta (FMθ) activity, which is a brain rhythm associated with cognitive control, typically increases during focused work as it, amongst else, plays a role in suppressing DMN activity. 

But as the task continues and the brain has less and less energy, FMθ plateaus or drops, allowing DMN activity to rise and focus to decline. (Kok, A 2022), (Westbrook, A.. & Beaver, T. S, 2016), (Wascher, et al, 2013), (Scheeringa, R. 2008)

Why Mental Fatigue Feels Like Hitting the Brakes and how we should react to this feeling

So, from this, we can see that when you are feeling mentally tired, in most cases, it’s actually your brain hitting the brakes because energy levels are running low.

Your brain shifts into Default Mode Network activity, which is linked to self-focused, repetitive thoughts. When executive control is low, due to mental fatigue, these thoughts can become intrusive or harder to regulate.

When you focus for long periods, your brain uses real fuel. Signals between brain cells slow down, and a chemical called adenosine builds up, making it harder to think clearly. 

Sleep pressure naturally builds throughout the day, and demanding mental work, makes this biological drive for rest more powerful.

At the same time, the ACC is always ”weighing” the reward vs the price: Is this worth the effort? If energy is low or the reward isn’t considered big enough, frontal executive control will lessen. Focus fades, and distractions get more tempting.

And I believe we should use these insights.

Although motivation plays a part here, it’s rarely meaningful to power through extreme periods of mentally demanding work. Because by then it’s not as much a question of your willpower as you probably think. It’s a question of having enough energy, similar to when fatigue is building up by the end of a marathon.

We should start managing our mental energy, just as one would manage physical energy. After a tough run, one would feel tired and relax on the couch for an extended period of time before doing squats in the gym.

This does not mean pulling up the phone. Use small breaks, naps, and meditations strategically to optimize your mental energy.

Author: Nicolas Lassen, OptiMindInsights

References:

• Pellerin, L., & Magistretti, P. J. (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proceedings of the National Academy of Sciences, 91(22), 10625–10629. https://doi.org/10.1073/pnas.91.22.10625
• Falkowska, A., Gutowska, I., Goschorska, M., Nowacki, P., Chlubek, D., & Baranowska-Bosiacka, I. (2015). Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism. International Journal of Molecular Sciences, 16(11), 25959–25981. https://doi.org/10.3390/ijms161125939
• Reichert, C. F., et al. (2022). Sleep pressure and mental fatigue: A neurocognitive perspective. Journal of Sleep Research, 31(3), e13597. https://doi.org/10.1111/jsr.13597
• Kok, A. (2022). Cognitive control, motivation and fatigue: A cognitive neuroscience perspective. Brain and Cognition, 160, 105880. https://doi.org/10.1016/j.bandc.2022.105880
• Westbrook, A., & Braver, T. S. (2016). Dopamine does double duty in motivating cognitive effort. Neuron, 89(4), 695–710. https://doi.org/10.1016/j.neuron.2015.12.029
• Wascher, E., Getzmann, S., & Falkenstein, M. (2013). Frontal theta activity reflects distinct aspects of mental fatigue. Biological Psychology, 96(1), 57–65. https://doi.org/10.1016/j.biopsycho.2013.01.001
• Scheeringa, R., Petersson, K. M., Oostenveld, R., Norris, D. G., Hagoort, P., & Bastiaansen, M. C. M. (2008). Frontal theta EEG activity correlates negatively with the default mode network in resting state. International Journal of Psychophysiology, 67(3), 242–251. https://doi.org/10.1016/j.ijpsycho.2007.05.017

Disclaimer:
This summary is based on the scientific references listed directly in the text and is intended to provide a simplified overview of complex brain processes. While care has been taken to reflect the core ideas from the original research, some explanations have been adapted or rephrased to improve clarity and accessibility.
OptiMindInsights and any contributors cannot take responsibility for how this information is interpreted or applied. The content is not medical advice and should not replace professional consultation. If you're curious or want to dive deeper, we encourage you to explore the original sources.