Energy Utilization: Lessons from "Brain Energy"

 

Hey team,

I recently read/listened to the book “Brain Energy” by Chris Palmer MD, who discusses energy utilization and metabolism in the brain as the common pathway for mental illness. I first heard about this theory and book last year while talking to a pharmacist working in psychiatry during a conversation about the biology of depression and mental illness. I have continued to read up on modern psychiatry and some of the biology behind it, which I have discussed a few times on this site. I decided to read this book as a healthy segue into learning more about symptom burden and treatment. Dr. Chris Palmer describes how all mental health conditions can be traced back to mitochondria, metabolism, and energy utilization. Initially, I thought this theory was overly reductionistic, comparable to the chemical imbalance theory, and therefore had only limited value. However, the more I read, the more comprehensive I found it to be. I realized that this theory is not reductionistic at all but is actually the common pathway, subject to all the contributing causes we know of. Let me expand.

If we understand that specific brain activation is related to specific states of subjective experience, such as the amygdala being active during heightened stress and anxiety, we can say that activation of those brain regions comes down to energy use. When the amygdala is active, it uses glucose as fuel to power its processes and send information elsewhere. Brain scans record metabolism, whether it’s glucose, water, blood, oxygen, etc., because active brain regions need more fuel. So, when a brain scan shows that the amygdala is lighting up while someone is having a panic attack, we know that the amygdala is hyperactive. I hope I explained that clearly enough. While amygdala activation is not inherently pathological—a healthy stress response has a helpful purpose—overactivation and hyper-excitation are pathological and come down to those brain regions being turned on too easily or not being able to turn off when they should. In the latter case, it comes down to parts of our prefrontal cortex (specifically the VMPFC), which serve to inhibit (or “turn off”) the amygdala/stress response being underactive. So, even if the amygdala is healthy and not necessarily easily turned on (hyper-excitable), if your cortex isn’t able to inhibit it as part of its standard duties, the amygdala will still be overactive and cause problems. It makes sense that our cortex would show poorer function relative to lower brain regions because it is one of the last parts of our brains to fully develop as we age.

This relationship between heightened activity and inhibitory underactivity extends beyond the example of the amygdala and anxiety. In the case of depression, we often see total low energy across the board (although each case of depression is unique). People with depression frequently feel like they have no energy, no motivation, no pleasure, and are burdened by constant feelings of guilt and hopelessness. While I can’t describe the exact neuronal pathways of those symptoms, I can show how they fit into the underactivity/hyperactivity model. The brain regions associated with guilt are overactive and can’t be properly tuned out by cortical inhibition. Regarding the feeling of energy, there is often underactivity in brain regions related to motivation, drive, and willpower (such as the VTA, motor cortex, insula, and ACC). Where exactly that stems from can be unclear, but on a cellular level, we can look at the mitochondria that produce energy in the form of ATP via oxidative phosphorylation. If hyperactivity or underactivity is seen at the macro level, and metabolism/energy utilization is the source of activity, we can examine mitochondria as the drivers of energy on a cellular level.

Mitochondria, as we all know, are the powerhouses of cells. They use glucose to make usable cellular energy in the form of ATP (adenosine triphosphate). Mitochondria do much more than this, but they are clearly the sources of most of our energy. They can be dysfunctional in many ways, such as being under abundant or present in normal abundance but in poor condition. Each cell can have tens of thousands of mitochondria, making them vitally important for maintaining cellular function.

Mitochondria do all this work and sometimes harm is done along the way. In their process of using sugar to make ATP, mitochondria produce reactive oxygen species (ROS), which causes oxidative stress. Those buzzwords, this means the oxygen used in the ATP process is no longer is in a stable form such as O2, CO2 or H2O. When unstable it can potentially damage the DNA inside the nucleus, the DNA in the mitochondria, and various proteins and organelles in the cell even leading to an immune response if bad enough). Fortunately, mitochondria also clean up ROS. This is one reason why each cell has so many mitochondria. It’s crucial to have functional mitochondria in the right places at the right time to produce energy and clean up the waste products of the process as needed. This is why foods containing antioxidants, such as coffee and blueberries, help protect against oxidative stress and have been shown to be neuroprotective—they help clean up the burden of ROS.

The development of energy imbalance as a common pathway of mental illness is no different from how I previously thought of it, except now I am more focused on the subcellular level. Chronic stress in vulnerable individuals can overwhelm the system, depriving it of the enhanced neuroplasticity and resilience needed to overcome challenges. These processes require a lot of energy, and without enough energy, the brain becomes "stuck" in frequent states of dysregulation. Not only does it take energy to grow, it takes energy to maintain and sustain. Biological processes are in place to help clear out “old” parts and build new, healthy ones. This again requires proper energy utilization, and mitochondria are central to this process. Not only do they need to help clear damaged organelles, but the mitochondria themselves need to clear themselves if dysfunctional. For mitochondria, this involves mitophagy (purposeful destruction of damaged mitochondria) and mitochondrial biogenesis (creation of new mitochondria). These processes are hugely important and likely what is happening when symptoms subside.

Reading “Brain Energy” by Chris Palmer MD has given me a new perspective on the biological underpinnings of mental illness. Understanding the role of mitochondria and energy metabolism provides a more comprehensive framework for considering treatment and symptom management. It reinforces the idea that mental health is deeply intertwined with physical health at the cellular level. This insight into how brain energy and plasticity are crucial for mental resilience highlights the importance of addressing metabolic health to improve mental health outcomes.