Metabolic Changes from TBI

From: Long-Lasting Mental Fatigue After Traumatic Brain Injury – A Major Problem Most Often Neglected Diagnostic Criteria, Assessment, Relation to Emotional and Cognitive Problems, Cellular Background, and Aspects on Treatment <a id="null" class="null" href="https://www.kultur.gu.se/digitalAssets/1473/1473556_46126.pdf">https://www.kultur.gu.se/digitalAssets/1473/1473556_46126.pdf</a>

Normally, the brain works in an energy-efficient manner and prominent energy reserves are present. This is due to well-functioning ion channel and amino acid transport systems and other effective physiological processes. After brain injury, some of these systems are downregulated, and when mental energy requirements are high the physiological processes do not function to their full capacity; these cease to function efficiently with a resultant energy loss. This may be an explanation as to why the mental fatigue appears.

Fatigue after traumatic brain injury (TBI) is common, but often overlooked. But for people fighting their fatigue after brain injury day after day, fatigue is a major problem. This postinjury mental fatigue is characterized by limited energy reserves to accomplish ordinary daily activities. Persons who have not experienced this extreme exhaustion which may appear suddenly, and without previous warning during mental activity, do not under‐ stand the problem. This is especially difficult to understand as the fatigue may appear even after seemingly trivial mental activities which, for uninjured persons, are regarded as relaxing and pleasant, as reading a book or having a conversation with friends. A nor‐ mal, well-functioning, brain performs mental activities simultaneously throughout the day, but after a brain injury, it takes greater energy levels to deal with cognitive and emotion‐ al situations.

In this chapter, we highlight mental fatigue after TBI. In the case of long-lasting mental fatigue, it could be the only factor that keeps people from returning to the full range of activities that they pursued prior to their injury with work, studies and social activities. We describe mental fatigue and suggest diagnostic criteria and we also give a theoretical explanation for this. At the end of the chapter, we discuss treatment strategies and give some examples of possible therapeutic alternatives which may alleviate the mental fatigue.

Theoretical explanation of mental fatigue
The cause of this extreme fatigue is not known. However, there are speculations that the symptom may be caused by dysfunction of the astrocytes, the most common supporting cells in the brain [17, 18]. As a consequence, nerve cell communications do not function properly.

Figure 2
Schematic drawing of a synapse with glutamate as the transmitter and an astrocyte with processes surrounding the synaptic terminal. After being released from the presynaptic terminal (pre-syn; this is shown in red in the figure), glutamate interacts with glutamate recognizing receptors on the postsynaptic membrane (post-syn; shown in green in the figure). After stimulation of the postsynaptic neuron, glutamate is taken up by glutamate transporting systems on the astrocyte processes. Glutamate is converted to glutamine in the astrocyte and transported back to the presynaptic terminal where glutamine is converted back to glutamate. During this process, and with decreasing ATP levels as the signal, glucose is taken up from the blood to supply neurons and astrocytes with energy.

<img src="/67ce3a19-3077-4e00-b925-5ccce43ed00b.png" />
Figure 3
Following TBI there is a neuroinflammation with down-regulation of astroglial glutamate transport systems. If this state is not restored completely, there will be an impaired extracellular glutamate clearing with slightly in‐ creased extracellular glutamate levels, slight astrocyte swelling and impaired glucose uptake. Neuronal activity, if long-lasting, may result in energy crisis.

On cellular mechanisms probably underlying mental fatigue
Following TBI there is a low-grade neuroinflammation with down-regulation of astrocyte glutamate transporters and Na+/K+ ATPase activity [19, 20]. If these physiological systems are not restored completely there will be a dysfunctional support of the glutamate transmission. Glutamate signaling is essential for information processing, including learning and memory formation. Low levels and fine-tuning of extracellular glutamate are necessary to maintain high precision in information processing, and thereby high efficiency in the information handling within the CNS. Our hypothesis implies that such dysfunction could underlie the mental fatigue at the cellular level.

From experimental data, the astroglial cells are considered the most important cells for clearing the extracellular space from glutamate during glutamate transmission. In addition, it is well-accepted from the experimental data that this clearing capacity is attenuated by substances or conditions associated with brain dysfunction or pathology (see [17]). If the capacities of these processes are not fully restored, neuronal function is impaired in at least two ways: 1) extracellular glutamate levels increase upon neuronal activity leading to unspecific signaling and 2) lack of energy. In the event of a high mental load with high neuronal activity, these factors may lead to a metabolic collapse of neuronal circuits – we have previously called this a “dead-lock” situation, which may take a long time to restore.

We consider this metabolic failure as one probable explanation for the prominent and abrupt exhaustion that the TBI victims with mental fatigue can experience. The long restoring time at a cellular level corresponds to the long time it takes for the TBI victims to restore mental activity. One way to restore this dysfunction is to stimulate Na+ /K+ -ATPase along the dopaminergic circuits which regulate attention and executive functions. Possible candidates are methylphe‐ nidate and the dopaminergic stabilizer OSU6162 (see below under the heading, ‘Treatment’).