Long term effect of high cognitive load
Discover how pushing through long periods of hard cognitive load might affect your brain and body.
An inflammatory environment
As we saw in the first text, glutamate is released when neurons are firring. During hours of intense cognitively demanding work without adequate breaks, glutamate can accumulate in the synaptic cleft, as the astrocytes, who is normally responsible for recycling the glutamate, cannot keep up.
While such buildup is usually reversible with rest, sustained or repeated periods of high cognitive load could, over time, contribute to stress on neural circuits, raising the possibility that, in some cases, glutamate imbalance might become more persistent.
A 2022 study found that a full day of highly demanding cognitive work increases glutamate levels in the lateral prefrontal cortex - the brain region primarily responsible for sustaining attention. The increase was greater in participants performing more cognitively demanding tasks compared to those engaged in less challenging work (Wiehler et al., 2022).
When glutamate is released to the synaptic cleft it normally binds to receptors on the receiving (postsynaptic) neuron. This binding opens channels that let calcium ions (Ca²⁺) flow into the neuron.
If astrocytes can’t efficiently clear glutamate from the synaptic cleft, the excess glutamate continues to stimulate these receptors, leading to a calcium overload inside the neuron.
Calcium overload can trigger oxidative stress, damage mitochondria - which are the cell’s “energy factories” that produce ATP - and disrupt normal enzyme activity.
Since ATP is the body’s primary energy currency and is essential for sustaining mental effort (as we discussed in the previous text), any damage to neurons mitochondria can directly impair our mental energy. On top of that, excessive glutamate outside the cell can over-activate NMDA receptors (NMDARs), which in some cases may lead to cell death (Verma et al., 2022) (Walters & Usachev, 2023).
When glutamate levels remain out of balance for a long time, it is hypothesized to lead to a pro-inflammatory environment in the brain. This results in an activation of immune cells called microglia, which then release inflammatory molecules like IL-1β and TNF-α.
These molecules disrupt communication between brain cells (synapses) and can therefore trigger even more glutamate release, making brain cells more vulnerable over time.
Over months or years, this ongoing process can lead to a noticeable loss of gray matter in areas like the prefrontal cortex and hippocampus.
These brain changes are linked to problems with working memory, slower thinking, and reduced emotional control.
Moreover, current evidence suggests that glutamate accumulation and its associated toxicity are directly linked to the progression of various neurodegenerative diseases (Almohmadi et al., 2025).
Although spikes in extracellular glutamate caused by acute stress can return to normal with rest, repeated cycles of glutamate overload and incomplete clearance at the synapse gradually push the brain toward a new “normal.” In this state, baseline glutamate levels and pro‐inflammatory cytokines (such as IL‐1β and TNF‐α) stay elevated.
This lowers the threshold for further glutamate‐related damage and keeps microglia—the brain’s immune cells—chronically active (Popoli et al., 2011). Over time, this altered chemical balance fosters a long‐lasting, trait‐like state of mental fatigue.
Consistent with these neurobiological alterations, individuals with a history of chronic cognitive strain exhibit slower information‐processing speed even outside of task contexts: reaction‐time studies demonstrate elevated baseline fatigue, delayed responses, and increased task‐switching costs relative to controls (DeLuca et al., 2004) (Lewerenz & Maher, 2015).
Moreover, as cognitively demanding work accumulates over weeks or months, individuals may become progressively more sensitive to fatigue.
Sleep‑deprivation studies show that prolonged elevations of extracellular adenosine lead to up‑regulation of A₁ adenosine receptors. This increases the likelihood of feeling fatigue.
The Dopamine System
An interesting observation that may explain why some individuals can continue to perform effectively despite sleep deprivation or prolonged cognitive load is that research shows surgeons often maintain their precision even when sleep-deprived. This suggests that the brain’s reward systems may preserve a “protective reserve” to safeguard critical actions the individual perceives as highly important. As discussed in the previous text, dopamine plays a key role in sustaining cognitive effort, which could help explain this phenomenon (Banfi et al., 2019) (Elmenhorst et al., 2007) (Kim et al., 2015).
However, it is also shown, that most likely, mental overuse can down-regulate certain dopamine receptors. This is seen both in sleep-deprivation models (Volkow et al., 2008) and in individuals with burnout (Morris et al., 2020) (Volkow et al., 2012).
Cross‐sectional data in physicians experiencing job‐related burnout show significantly lower cortical dopamine levels compared to less‐exhausted peers, suggesting that chronic mental overuse is associated with sustained reductions in dopaminergic tone (Yao et al., 2018).
This decline may be strengthened by the fact that chronic stress and burnout can lead to oxidative damage to dopaminergic neurons.
Evidence from animal studies indicates that elevated oxidative stress, which we have seen can appear as a result of prolonged cognitive load, can impair mitochondrial function and promote dopaminergic cell loss (Dias, Junn, & Mouradian, 2013).
Lastly, there’s evidence that chronic high cognitive load can produce trait‑like increases in off‑task thinking. In a three‑wave longitudinal survey of over 2,300 Swedish workers (2010, 2012, 2014), those with consistently high job demands reported progressively more work‑related rumination and poorer sleep quality at each follow‑up.
And, importantly, poorer sleep in turn predicted greater rumination at the next follow up, revealing a bidirectional, self‑reinforcing cycle (Van Laethem et al., 2017).Theoretically, this makes perfect sense: prolonged cognitive strain sets off a cascade of cellular and network‑level changes that bias the brain toward internally focused thought, or DMN activity.
In sum:
First, sustained glutamate buildup leads to increased Ca+ influx in the postsynaptic neuron. An elevated Ca+ influx then leads to oxidative stress, which damages the mitochondria in the neuron. Damaged mitochondria then produce less ATP, which is the “energy coin” that powers synaptic signaling.
As the prefrontal cortex (PFC) likely carries the heaviest metabolic burden during sustained attention and working‑memory tasks, its neurons are packed with mitochondria and fire at especially high rates; this could make them disproportionately vulnerable to Ca²⁺‑driven oxidative damage (Walters & Usachev, 2023).
When PFC mitochondria begin to fail, ATP supply get impaired, which weakens the PFC’s top‑down suppression of the Default Mode Network (DMN). Neuroimaging and EEG studies show that reduced frontal control co‑occurs with unchecked DMN activation (Scheeringa et al., 2009).
Second, elevated extracellular glutamate and metabolic stress promote neuroinflammation, which over time contributes to gray‑matter loss in PFC regions critical for executive control.
Meanwhile accumulated adenosine from rapid ATP breakdown binds to up‑regulated A₁ receptors, heightening fatigue sensitivity so that even moderate effort feels exhausting.
Fourth, chronic overuse and oxidative damage weakens dopaminergic signaling, reducing the motivational drive needed to sustain focus.
Finally, the anterior cingulate cortex continuously weights energy availability against task demands. It detects this unfavorable balance and scales back executive activation, allowing the DMN (the brain area related to self‑referential and wandering thought) to intrude more often.
Together, these changes can make one feel more tired faster and suggests that prolonged periods of high cognitive load may lead to a persistent inability to suppress DMN activity, allowing self-referential thinking to intrude more consistently (DeLuca et al., 2004).
Mood
Chronic cognitive strain can also impact mood.
As noted, long-term strain may cause mitochondrial dysfunction in the prefrontal cortex (PFC), which a region that is also essential for emotion regulation.
Genome-wide transcriptomic studies in chronically stressed mice as well as analyses of human Major Depressive Disorder (MDD) postmortem PFC, show disrupted expression of mitochondria-related genes, particularly oxidative phosphorylation subunits.
In mice, this is accompanied by reduced mitochondrial respiration in PFC, which indicates impaired ATP-generating capacity (Weger et al., 2020).
Further more, a study on mice showed that mitochondrial deficits are closely linked to anhedonia—the reduced ability to experience pleasure or joy—where stressed mice with impaired ATP synthesis in the hippocampus (and disrupted mitochondrial pathways in PFC) exhibit diminished reward sensitivity (Strekalova et al., 2023).
These types of mitochondrial dysfunctions are frequently coupled to elevated oxidative stress and inflammatory signaling, which are both well-documented features of depression (Liu et al., 2025).
When mitochondrial energy supply drops, the PFC’s ability to maintain top-down control weakens. This shift allows the Default Mode Network (DMN) to dominate.
Neuroimaging meta-analyses consistently show DMN hyperconnectivity in MDD, particularly between medial PFC and posterior cingulate hubs, a pattern closely tied to rumination (Hamilton et al., 2015).
Experimental induction of rumination even produces immediate mood declines, underscoring its causal role (Chou et al., 2023).
Inflammation adds another layer of vulnerability: mitochondrial dysfunction increases reactive oxygen species, activating inflammasome signaling and cytokines (e.g., IL-1β). These cascades further disrupt mood-regulating circuits, reinforcing depressive symptoms (Liu et al., 2025).
Taken together, the picture seems to be:
Chronic cognitive stress → mitochondrial failure in PFC → reduced ATP + oxidative/inflammatory stress →weakened executive control → DMN dominance and rumination → acute mood decline → a self-perpetuating spiral into low mood.
Meditation
Meditation practices that train sustained, non-reactive attention (mindfulness, focused attention, slow breathing), can interrupt the overload cascade at several neurobiological levels.
Regular practice strengthens fronto-parietal control networks and reduces Default Mode Network (DMN) intrusions, lowering the metabolic “tax” on the lateral PFC during tasks (Brewer et al., 2011).
Even brief interventions can boost ACC/PFC efficiency and improve white matter integrity, suggesting that less glutamate-heavy signaling is needed to achieve the same level of control (Tang et al., 2015).
Yoga and meditation studies also show increased cortical GABA—an inhibitory counterweight to glutamate—which helps ease astrocytic clearance demands (Streeter et al., 2010).
Practices that enhance vagal tone, such as slow breathing and compassion-based mindfulness, reduce sympathetic arousal and lower inflammatory markers like IL-6 and TNF-α.
This dampens microglial activation and interrupts the pro-inflammatory loop that sensitizes neurons to excitotoxicity (Creswell et al., 2016).
PET imaging further suggests that meditation can boost or preserve striatal dopamine tone, buffering against the receptor down-regulation seen in chronic overload (Kjaer et al., 2002).
By repeatedly engaging the anterior cingulate in a low-threat monitoring context, meditation may also recalibrate the brain’s effort–cost calculations, which would then raise the threshold at which adenosine-mediated fatigue shuts down executive control (Tang et al., 2015).
In sum, consistent meditation appears to:
1. reduce baseline excitatory load,
2. enhance inhibitory buffering,
3. Eases inflammation,
4. stabilize dopamine signaling, and
5. improve network efficiency—training the brain to resist slipping into self-perpetuating overload.
Long-term studies of meditation on the two anticorrelated networks - the DMN and the Dorsal Attention Network (DAN) - show that experienced meditators don’t necessarily focus better because of stronger DAN regulation. Instead, the main benefit comes from reducing DMN overactivation.
In other words, meditation works less by boosting attention directly and more by quieting the brain’s “noisy background”, which is an extremely importnt feature when talking about mental energy (Devaney et al., 2021).
References:
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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.