The current views on brain function is too reductionist.
What makes you feel good? Dopamine!
But what about endocannabinoids, opioids, GABA, etc.
And about glucose oxidation (which is the primary fuel for proper brain function)?
Focusing on certain neurotransmitters does have an effect, but it’s too reductionist. Every neurotransmitter system is connected to others and targeting one will always have an effect on other as well.
I hear too often that if you have anhedonia for example, your dopamine is too low. Or your dopamine receptors are desensitized. So you just have to upregulate dopamine synthesis and dopamine receptor sensitivity, right? While this can work temporarily and to a degree, I’d like to pose this question.
Were you born with anhedonia?
If not, then something must have happened to your dopamine system (and brain and overall health in general) that cause that. So if you treat your dopamine system as if it is still the same as when you were born or in isolation, how can you expect results?
Meaning, something went wrong at a more elementary level that is messing with your dopamine levels or at least brain function in general.
And in this article, I’d like to put the focus on glucose oxidation. Part 2 will be about thyroid hormones and brain health and part 3 about solutions.
Brain function and glucose oxidation
The preferred fuel for the brain is glucose. Although the brain can also use ketones and lactate, they cannot fully compensate for the lack of glucose and are not optimal fuel sources by any means (ketones can also substitute for about 60% of the lack of glucose) (R).
“Inability of lactate and β-hydroxybutyrate to reverse effects of hypoglycemia was an important observation” (R).
The brain uses about 110-120g of glucose during rest and can go up substantially when “activated”. And it’s not just thinking, problem-solving, etc., that enhances glucose utilization, but any kind of input (e.g. visual, auditory, etc.) can enhance brain activation and glucose metabolism.
“Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components.” (R)
“The major energy demands of the brain are associated with neuronal signaling (resting potentials, action potentials, postsynaptic receptors, glutamate cycling, postsynaptic Ca2+) and account for ~70% of the calculated energy expense, with nonsignaling activities (protein, phospholipid, oligonucleotide turnover, axonal transport, mitochondrial proton leak, actin cytoskeleton remodeling, etc.) consuming an estimated 30%; excitatory neurons consume ~80–85% of calculated ATP use, whereas inhibitory neurons and glia account for 15–20% (708). Gray matter has regionally heterogeneous metabolic rates that are considerably higher than white matter (606) that has a higher fraction of nonsignaling energy demands than gray matter. Glucose is not only used for ATP generation, it is also the precursor for many compounds synthesized within the brain, including neurotransmitters and neuromodulators.” (R)
Cognition and glucose
Glucose is most well known for enhancing exercise performance, but few know that glucose has the same effect on the brain.
While accounting for only 2% of the body’s weight, the brain utilizes up to 20% of the body’s total energy. Not surprisingly, metabolic dysfunction and energy supply-and-demand mismatch have been implicated in a variety of neurological and psychiatric disorders (R).
- “Cognitive performance is dependent on adequate glucose supply to the brain” (R).
- “Cortical glucose metabolic rate correlates of abstract reasoning and attention.” (R)
- “Administration of either glucose or insulin causes markedly increased hippocampal glucose metabolism along with enhancement of memory performance.” (R)
- “The evidence suggests that glucose administration enhances neurocognitive markers of episodic memory and attentional processes underpinned by medial temporal and frontal activation, sometimes in the absence of measurable behavioural effects.” (R)
When glucose runs low, due to low calorie intake, low carb diets, insulin resistance, endotoxins, etc., cognitive processes decrease, and when providing glucose can then rescue brain function again (R).
Insulin and thyroid, which promote glucose uptake and oxidation, have cognitive-enhancing effects (R). Just a quick word on thyroid and carb intake, and more on thyroid in part 2.
“In general, high carbohydrate diets are associated with higher serum T3 concentrations compared to diet
low in carbohydrate content. KD, similar to fasting, significantly reduces the levels of serum T3 levels along with a concomitant increase in reverse-T3, and these changes are correlated to the presence of ketone bodies.” (R)
“Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism.” (R)
Another word on insulin:
“Insulin decreases expression of orexigenic AgRP and NPY, leading to decreased food intake . Additionally, insulin increases expression of POMC, resulting in increased levels of α-melanocyte stimulating hormone (α-MSH), which promotes anorexia and increases energy expenditure , presumably via melanocortin-4-receptors (MC4R) expressing neurons…. In normal weight men, intranasal insulin (40 IU) increased brain ATP and phosphocreatine, and changes in brain energy content were inversely proportional to subsequent caloric intake, suggesting that intranasal insulin may play a role in meal termination.” (R)
“Brain insulin resistance is implicated in memory impairment and cognitive dysfunction” (R).
Glucose dysregulation in mental dysfunction
Glucose oxidation can be dysregulated in many mental conditions, ranging from “less serious” conditions, such as ADHD, OCD (R), brain fog, etc., all the way to more serious conditions, such as Alzheimer’s disease (R), Parkinson’s disease (R), amyotrophic lateral sclerosis (R), Hunting disease (R), Wilsons disease (R), traumatic brain injury (R), Down syndrome (R), depression (R), bipolar (glutamate is elevated) (R), suicidal ideation (R), benign hereditary chorea (R), etc.
Providing glucose or boosting insulin can often improve cognitive function and elevate mood in most of these conditions (R).
There are many hiccups where glucose oxidation can become dysfunctional, such as:
- GLUT1 and 3 downregulation, thus reducing glucose uptake in the brain
- Low pyruvate dehydrogenase (PDH) activity, thus less pyruvate is able to enter the Kreb cycle and is rather wasted to lactate.
- Breakdown of the electron transport chain, which lowers ATP and CO2 production and enhances ROS production
- Inhibition of various enzymes in the Kreb cycle
We’ll go into strategies how to fix proper glucose oxidation in part 3 of this series.
Hypoglycemia and brain function
Hypoglycemia is defined as low blood sugar. The reason why this is a problem is because the tissue doesn’t get enough glucose and can’t produce enough energy. This is similar to dysfunctional glucose oxidation, where glucose isn’t converted all the way to CO2 and H2O through complete oxidative phosphorylation.
So whether it be hypoglycemia or a hiccup in the system preventing complete glucose oxidation, the effects are more or less the same.
The body is generally very good at preventing hypoglycemia, but repeated bouts of hypoglycemia desensitizes the body to it, thus allowing low blood sugar to persist for longer than it should. And this can contribute to cognitive decrements in performance. This is actually very common amongst type I diabetics.
Continued hypoglycemia for a period of just one week decreases cerebral glucose utilization (R). Thyroid hormone conversion is also dependent on glucose levels, and you’ll find out how important thyroid is for the brain in part 2 of this series.
Hypoglycemia alone can trigger the production of oxidative stress and cellular dysfunction.
“it has been demonstrated that nutrient deprivation (mainly oxygen and glucose) is one of the most potent ERE (endoplasmic reticulum stress) triggers , since it impairs N-linked protein glycosylation and diminishes the ATP obtaining. The processes mentioned before lead to a decrease in the amount of energy available to maintain the oxidizing environment needed to the correct formation of disulfide bonds and the proper folding of proteins in the endoplasmic reticulum (ER).” (R)
Glucose deprivation, through undereating, hypoglycemia, stress or anything that interferes with proper glucose oxidation can cause neuroinflammation and even brain shrinkage.
“In the eating disorder anorexia nervosa (AN), patients suffer from undernutrition and develop volume reductions of the cerebral cortex, associated with reduced astrocyte proliferation and cell count. Long-term glucose starvation increased the expression of a subset of pro-inflammatory genes and shifted the primary astrocyte population to the pro-inflammatory A1-like phenotype. Moreover, genes encoding for proteins involved in the unfolded protein response were elevated. The two primary roles of astrocytes are to buffer (protect) against stress and supply glucose to the brain. Its ability to provide glucose is mainly how it protects against stress. In another in vitro study of diabetes, recurrent hypoglycemic phases lead to a shift from glucose metabolism to fatty acid oxidation in human primary astrocytes (Weightman Potter et al. 2019). The same effect was shown after prolonged inflammation induced by LPS stimulation in astrocytes in vitro. In the blood of patients with obesity, high levels of free fatty acids provoke ER stress which induces low but chronic inflammation” (R)
And you don’t even have to be hypoglycemic to suffer from cellular glucose starvation as chronic stress can do this as well. Glucocorticoids (such as cortisol) suppress glucose uptake and oxidation in certain regions of brain, such as the hypothalamus and hippocampus (R).
“a diet rich in fat ad libitum decreased hippocampal neurogenesis in male, but not female, rats. There was no obesity, but male rats fed a diet rich in fat exhibited elevated serum corticosterone levels compared with those fed standard rat chow. These data indicate that high dietary fat intake can disrupt hippocampal neurogenesis, probably through an increase in serum corticosterone levels.” (R)
And a little more on stress hormones:
“the effects of stress on hippocampal metabolism are bi-directional: within minutes, NE (norepinephrine) promotes glucose metabolism, while hours into the stress response GCs (glucocorticoids) act to suppress metabolism. These bi-directional effects of NE and GCs on glucose metabolism may occur at least in part through direct modulation of glucose transporter-4. In contrast, chronic stress and prolonged elevation of hippocampal GCs cause chronically suppressed glucose metabolism, excitotoxicity and subsequent memory deficits.” (R)
Hypoglycemia, or low glucose availability and oxidation in the brain, impairs cognition and is associated with dementia in diabetic subjects. Hypoglycemia-associated cognitive impairment is associated with vascular changes in the brain. Oxidative stress is concomitant with hypoglycemia-associated cognitive deficit (R).
Furthermore, hypoglycemia can also contribute to insufficient neurotransmitter release in certain areas of the brain.
Glucose intake and neurotransmitter release
“In rats that developed hypoglycemic stupor and were then treated with glucose, the animals recovered apparently normal behavior, and the concentrations of acetylcholine and the incorporation of [1-2H2, 2-2H2]-choline into acetylcholine returned to control values in the striatum but not in the cerebral cortex. Thus, impaired acetylcholine metabolism in selected regions of the brain may contribute to the early symptoms of neurological dysfunction in hypoglycemia.” (R)
“Hypoglycemia induced changes in ChAT and AchE gene expression is suggested to cause impaired acetylcholine metabolism in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment.” (R).
“glucose increases hippocampal extracellular ACh levels when the ACh system is inhibited, an effect that likely contributes to the effects of glucose on memory.” (R)
Aspartate is an excitatory neurotransmitter that, similar to glutamate, can cause neurotoxicity.
“Exposure of synaptosomes to hypoglycemia led to lower levels of ATP and increased levels of ADP, and subsequent depletion in synaptosomal membrane potential with increased release of aspartate . This depleted energy status may be responsible for increased cytosolic free Ca2+ levels, which in turn, may contribute to brain damage during severe hypoglycemia” (R)
ATP is needed for the uptake of glutamate and when astrocyte glucose uptake and oxidation is impaired, astrocytes lack the energy to sufficiently clear glutamate from the synapse. This leads to excitatory neurotoxicity, defined in part by increased ROS and mitochondrial dysfunction, and neuronal death. A high carb diet yields a better ATP:ADP ratio compared to a low carb diet and is more neuroprotective. In a low-energy state, there is more glutamate in the synapsis that can cause excitatory neurotoxicity (R, R).
GABA is synthesized from glutamate, via the enzyme glutamate decarboxylase, which uses vitamin B6 as a cofactor.
A low-carb diet increases glutamate and reduces GABA. A high carb diet increases GABA metabolism and decreased glutamate metabolism in both the hypothalamus and hippocampus with the increase of age (R).
High carb intake has been shown to boost dopamine synthesis and release (R). Insulin promotes one of the enzymes that’s involved in the synthesis of dopamine (tyrosine hydroxylase) and also inhibits dopamine breakdown (inhibit MAO-B) (R).
Fructose consumption is able to increase the activity as well as orexin A and dopamine levels in the hypothalamus and brainstem (R).
Also, one of the rate-limit enzymes in glucose oxidation, hexokinase II, protects against dopaminergic neurodegeneration (R).
On the other hand, insulin resistance and hyperglycemia suppress the firing of midbrain dopaminergic neurons (R).
Carbs, specifically insulin (hyperinsulinemia), is thought to increase serotonin.
Insulin increases the binding of tryptophan to the albumin in the blood, thereby reducing the level of the free tryptophan in the circulation by about a half, which would decrease the influx of tryptophan into the brain. But then insulin simultaneously reduces the levels in the blood of six or more of the amino acids which compete with tryptophan for transport carriers into the brain, which would increase the influx of tryptophan. So, the net result of these two opposing effects is that insulin causes only a slight increase in the influx of tryptophan into the brain (R).
An excess of serotonin can cause sluggishness, but most people report feeling more energized after eating a carbohydrate-rich meal.
Insulin also boosts tryptophan hydroxylase (which stimulates serotonin synthesis) and inhibits MAO-A, which inhibits serotonin breakdown (R).
But it’s not necessarily the boost in serotonin that’s bad, but rather the ratio between dopamine and serotonin. Hyperinsulinemia can cause excess serotonin synthesis and suppressed dopamine release. And this gives people tired, unmotivated behavior, which makes them prone to addition to snap them out of the anhedonic state.
Starches are the most insulinogenic foods there are, whereas fruits, honey and other foods with fructose and much less insulinogenic.
High carb diet and cognitive benefits
As mentioned earlier, glucose intake improves cognitive function, unless glucose can’t be properly converted to energy.
And if you want to live a natural life, meaning eat natural foods, drink natural things, etc., you’ll end up with fruits, veggies, dairy, meat, etc.
So when it comes to high carb intake, that glucose or other sugars are coming from fruits, milk, honey, etc.
And if you look at the studies, all of them show that fruit intake is associated with improved cognitive function. And fruit is superior to veggies. Both fruit and veggies have polyphenols, etc., but fruits have fructose, which veggies don’t have. Certain veggies are also rich in many anti-nutrients that aren’t found in fruit.
Let’s look at studies:
“After adjusting for covariates, no significant association was observed between the consumption of sweets and mathematics scores (coefficient: 0.15; 95% confidence interval (CI): -0.02-0.32), while a higher consumption of sweets was significantly associated with higher scores in the Mongolian language.” (R)
“Participants in the highest compared with lowest tertile of fruit consumption had reduced odds of prevalent depressive symptoms.” (R)
“Dietary GI, but not GL, was inversely associated with depressive symptoms” (R)
Higher carb intake is associated with lower levels of depression and higher energy (R)
“a result of greater improvements in these psychological mood states for the LF (low fat) diet compared with the LC diet after 1 year” (R)
Fruits, honey, maple syrup, etc, are very rich in polyphenols which has cognitive enhancing effects (R).
“The data suggest that chronic consumption of fruits, vegetables, and juices is beneficial for cognition in healthy older adults. The limited data from acute interventions indicate that consumption of fruit juices can have immediate benefits for memory function in adults with mild cognitive impairment.” (R)
“These data demonstrate that consumption of FR orange juice can acutely enhance objective and subjective cognition over the course of 6 h in healthy middle-aged adults.” (R)
“Fruit and vegetable consumption predicted an increased cognitive performance in older adults including improved verbal recall, improved delayed verbal recall, improved digit span test performance and improved verbal fluency; the effect of fruit consumption was much stronger than the effect of vegetable consumption. Regarding mental health, fruit consumption was significantly associated with better subjective quality of life and less depressive symptoms; vegetable consumption, however, did not significantly relate to mental health.” (R)
“Purple grape juice significantly improved reaction time on a composite attention measure (p = 0.047) and increased calm ratings (p = 0.046) when compared to placebo.” (R)
“observational studies showing that diets low in carbohydrate and high in fat and protein are associated with higher levels of anxiety and depression.” (R)
“The results of the study indicate as predicted, that, when a person restricts carbohydrates from the diet, he will experience more fatigue, more negative affect, and less positive affect in response to exercise than those individuals who are not restricting carbohydrates.” (R)
“In the present study, LCHO (low carb) in conjunction with training and exercise adversely affected the mood state of trained female cyclists as compared with MCHO (moderate carb) and HCHO (high carb) diets.” (R)
This study shows that low protein high carb diets are a great strategy for delaying brain aging, similar to calorie restriction (R).
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