Part 1 we talked about the importance of proper glucose oxidation. And to optimize glucose oxidation, we need proper thyroid function.
You’d be surprised how many mental conditions link back to suboptimal thyroid hormone levels.
Brain function and thyroid hormone levels
It has been well-known for at least 100 years that both hypo- and hyperthyroidism may cause almost any psychiatric symptom, depending on the severity of the illness (R).
Clinically, the association between thyroid hormone deficiency and cognition has been acknowledged since the realization that cretinism, a form of mental retardation, stems from congenital iodine and thyroid hormone deficiency.
Optimal thyroid hormone production is extremely important for brain function, glucose oxidation, neurosteroid synthesis, neurotransmitter synthesis and release, neuroprotection, neurogenesis, neuronal migration, neuronal and glial differentiation, myelination, and synaptogenesis, synaptic plasticity (Both short and long-term synaptic plasticity are impaired in adult-onset hypothyroidism, and experimental induction of hypothyroidism both impairs LTP (long term potentiation) and increases LTD (long term depression)), learning, etc.
- General intelligence
- Cognition, such as psychomotor speed, learning, paying attention and memory recall
- Visual attention and processing and visuospatial skills
- Motor skills
- Psychotic behavior, hallucinations and confusion
- Bipolar disorder
- Attention-deficit hyperactivity disorder (ADHD)
- Suicidal ideation
- Anxiety, etc
Other studies have suggested that cognitive impairment in hypothyroidism is likely to be related to abnormal brain development, decreased interneuronal connectivity and in particular, impairment of synaptic plasticity in the hippocampus (R).
The scary thing is that even mild thyroid hormone insufficiency during brain development (in rats) is associated with irreversible neurological defects (R). Hypothyroidism during pregnancy is linked to autism.
Since many of the psychiatric disorders are almost indistinguishable from hypothyroidism, it’s recommended to check for thyroid function first and normalize that first before other meds are given (R). Thyroid hormones are often given in conjunction with psychiatric drugs, which potentiates their effect and boosts their success many fold.
For example, a common symptom of hypothyroidism is psychosis, which is indistinguishable from schizo psychosis. One of the reasons is because dopamine receptors are increased during hypothyroidism in certain areas of the brain. Then doctors “treat” psychosis with a dopamine antagonist, but actually all you have to do is normalize T3 in the brain.
Thyroid and glucose oxidation
One of the many benefits of thyroid hormones is that they boost glucose oxidation. Brain glucose metabolism is regulated by thyroid hormones at multiple levels.
When there are insufficient thyroid hormones, or when their effects are inhibited by factors, such as stress, inflammation, insulin resistance, endotoxin absorption, etc., then many mental issues related to dysfunction glucose oxidation occurs.
Brain hypometabolism (meaning insufficient energy production from glucose) is commonly observed in thyroid disorders. Clinical data suggest that there is a significant and global decrease in brain glucose metabolism in severe hypothyroidism of short duration and that both neural activity and regional glucose metabolism are reduced in the brains of mild-moderate hypothyroid patients (specifically, in the hippocampus, bilateral amygdala, anterior, left subgenual, and right posterior cingulate cortex). And this can be restored to control levels following thyroid hormone replacement therapy.
For example, “reduction of the behavioral complaints during thyroid hormone therapy is associated with a restoration of metabolic activity in brain areas that are integral to the regulation of affect and cognition. The findings suggest that thyroid hormone modulates regional glucose metabolism and psychiatric symptoms in the mature brain” (R).
And brain hypo and hypermetabolism at the same time isn’t just seen in hypothyroidism, but also hyperthyroidism.
In patients with hyperthyroidism, lowered glucose metabolism is observed in limbic, frontal, and temporal lobes and the cerebral hypometabolism is corrected after antithyroid treatment.
Another important part of proper brain function is blood flow. Why are certain nootropics such as Ginkgo or Vinpocetine so popular? Because they enhance blood flow which allows for more oxygen and glucose to reach and fuel the brain.
However, back to the basics, thyroid hormones enhance blood flow to the brain (R). So no need for a supplement/nootropic if you can optimize your thyroid function.
“Marangell et al. (8) observed that peripheral TSH was inversely related to global and regional CBF (cerebral blood flow) and CMRGlc (cerebral glucose metabolism) in affectively ill patients.” (R) High TSH is indicative of hypothyroidism.
Thyroid hormones can enhance glucose oxidation through a few mechanisms, such as enhanced glucose uptake in the brain, faster glucose entry into the Kreb cycle (enhances pyruvate dehydrogenase), better functioning of the electron transport chain and though interaction with glucocorticoid signaling.
It is well known that hypothyroidism causes a reduction in the brain blood flow, glucose uptake, insulin sensitivity and glucose oxidation (R). This alone contributes to many mental conditions associated with low glucose availability, brain hypometabolism and hyper and hypoactive areas of the brain.
Providing enough glucose is sometimes all that’s needed to restore proper glucose oxidation, but other times, adding thyroid and a few pro-metabolic substances in as well is needed.
Thyroid and brain activation
Here are just a couple of studies showing impaired metabolism in the brain when thyroid hormones are dysregulated.
“Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores.” (R)
“Relationships were assessed between regional brain activity and anxiety symptoms while controlling for depression severity. At baseline, Trait Anxiety Inventory measures covaried positively with relative brain activity bilaterally in the dorsal anterior cingulate, superior temporal gyri, parahippocampal gyri, amygdala, hippocampus, ventral striatum, and right insula; state anxiety showed a similar pattern. After treatment anxiety was improved significantly. Change in trait anxiety covaried positively with changes in relative activity in right amygdala and hippocampus. Change in state anxiety covaried positively with changes in relative activity in the hippocampus bilaterally and left thalamus, and negatively with changes in left middle frontal gyrus and right dorsal anterior cingulate. Results indicate that comorbid anxiety symptoms have specific regional cerebral metabolic correlates in bipolar depression and cannot only be explained exclusively by the depressive state of the patients” (R). Connecting it to hypothyroidism: “Hypothyroidism, either overt or more commonly subclinical, appears to the commonest abnormality found in bipolar disorder.” (R)
“Results: The hypothyroid patients were more anxious and depressed than the euthyroid participants. The multivariate covariance analysis showed increases in glucose metabolism primarily in the bilateral insula and surrounding areas and concomitant decreases in the parieto-occipital regions in the hypothyroid group. The level of thyrotropin was positively associated with the individual expression of the covariance pattern. The decreased 18F-FDG uptake in the right cuneus cluster from the univariate analysis was correlated with the increased thyrotropin level and greater depressive symptoms in the hypothyroid group.
Conclusions: These results suggest that temporary hypothyroidism, even for a short period, may induce impairment in glucose metabolism and related affective symptoms.” (R)
“Glucose metabolism was reduced in frontal cortex and increased at striatum in juvenile Parkinson’s disease.” (R)
“In the demented patients, cerebral glucose metabolism was diffusely decreased compared with that of the non-demented patients and the normal controls. The most significant decrease in glucose metabolism was observed in the angular gyrus (49.7% of the normal controls). The glucose metabolism in the cingulate, pre- and postcentral, occipital and subcortical regions was relatively spared (62.1 to 85.5% of the normal controls).” (R)
“Compared to MAA (methamphetamine abusers) participants, MAP (methamphetamine abusers with psychotic symptoms) participants had 1) decreased glucose metabolism in the left precentral gyrus and the left inferior frontal gyrus and 2) increased glucose metabolism in the putamen and pallidum. MAP participants also had increased cerebral perfusion in the right putamen and right pallidum compared to MAA.” (R) Psychotic symptoms correlate with glucose dysregulation.
Thyroid and neurotransmitter release
As mentioned above, thyroid hormones are involved in neurotransmitter release as well as modulating how your cells respond to them.
Thyroid and dopamine
Patients with hypothyroidism have a nearly two-fold higher risk for afiction with PD (R).
And this is because thyroid hormones promote the induction, differentiation of dopamine neurons from embryonic ventral midbrain (VM) neural precursor cells and maturation of dopamine neurons. They also effectively protect and restore dopamine neurons from neurotoxic insults (R).
Also “hypothyroidism often leads to the loss of dopamine neurons and neurodegenerative changes in the midbrains of Girk2 mutant mice.” (R)
Maternal hypothyroidism is shown to downregulate dopamine beta-hydroxylase and increase sensitivity to Parkinson’s disease-like movements in rat offsprings (R). Many other studies show that when the mother is hypothyroid during pregnancy, the child has a much higher risk of autism and cognitive dysfunction/brain degenerative conditions.
Hypothyroidism increases endogenous tyrosine concentration in the hypothalamus and brown adipose tissue. Hyperthyroidism decreases endogenous tyrosine levels in the striatum, adrenals and heart. Tyrosine is needed for the synthesis of dopamine and noradrenaline, so an increase would mean decreased dopamine synthesis in hypothyroidism.
Hypothyroid rats have decreased dopamine concentration and utilization in the external layer of the median eminence (part of the hypothalamic tuberoinfundibular system) and it’s reversed by thyroid hormone replacement (R).
Mutation in thyroglobulin (the main precursor to thyroid hormones) in rats shows altered dopamine levels in the substantia nigra and striatum (R).
Articles related to increasing dopamine
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Dopamine and adrenergic receptors
T3 enhances beta-adrenoceptors in the striatum where changes in dopaminergic neuronal activity have previously been demonstrated, and also presynaptic alpha 2-adrenoceptor function (R).
This shows that there is an inverse relationship between thyroid and noradrenaline since a2-adrenoceptor activation lowers noradrenaline levels. So enhanced function would mean less noradrenaline release and also enhances beta-adrenoceptors sensitivity.
Same thing with dopamine. Low T3 leads to low dopamine and elevated dopamine receptors.
The effect of dopamine on thyroid
Dopamine blockers lead to increase in TSH level or to subclinical hypothyroidism (R).
On the other hand, certain anti-psychotic drugs have pro or anti-thyroid effects, by either enhancing type 2 deiodinase (which converts T4 into T3) (e.g. haloperidol; while clozapine decreases type 2 but increases type 3 deiodinase (which increases rT3) activity in several brain regions) or by competing with UDP-glucuronosyltransferase for detoxification, thus increasing thyroid hormones.
Thyroid and serotonin
5-HIAA (the breakdown metabolite of serotonin) is inversely correlated with T3, so euthyroidism reduces serotonin synthesis and/or turnover.
Hypothyroidism leads to elevated serotonin in certain areas of the brain (e.g. cortical) due to desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. This decrement of 5-HT1A receptor binding correlated with the severity of depression (R). Also, in hypothyroidism, there also appears to be an increase in cortical 5-HT2 receptor sensitivity and 5-HT2 receptors are the target for anti-depressants, anti-psychotics and many other mental drugs (R).
Interestingly, this study suggests that serotonergic dysfunction is caused by the destruction of dopaminergic neurons. “Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system.” (R)
One of the reasons we don’t want elevated serotonin is because serotonin promotes glycolysis away from oxidative phosphorylation, which is a very ineffective way of producing energy (R). For optimal brain function, we need proper oxidative phosphorylation; the production of H2O and CO2 from glucose and not lactate and serotonin is not helpful here at all.
- Serotonin, the fraudulent anti-depressant
- Anti-serotonin stack for more energy and well-being
- Asthma and Serotonin: how to address the cause
- The High Serotonin Personality
- The negative effects serotonin has on your physique: the “anti-depressant” molecule with depressing properties
- 60 Best ways to lower Serotonin (2020 update)
Thyroid and GABA
GABA is synthesized from glutamate through the enzyme GAD (Glutamate decarboxylase) and this enzyme activity is regulated by thyroid hormones (R). As you can recall, in part 1 of this series, low glucose intake or oxidation leads to elevated glutamate and lower GABA. So eating carbs and optimizing thyroid function helps to increase GABA levels.
“In hypothyroid patients, mean GABA+ was significantly lower in the mPFC region compared with controls (p = 0.031), and the mPFC GABA+ measurements were significantly correlated with depressive symptoms and memory function (r = -0.558, p = 0.016; r = 0.522, p = 0.026, respectively). After adequate L-T4 treatment, the mPFC GABA+ in hypothyroid patients increased to normal level, along with relieved neuropsychological impairments.” (R)
No wonder a little bit of thyroid hormones before bed can help a lot with sleep quality.
Thyroid and glutamate
Thyroid hormones not only lower excess glutamate by increasing its conversion to GABA, but also enhances glutamate uptake.
“T3 is capable of regulating extracellular glutamate levels by modulating the astrocytic glutamate transporters and, consequently, by promoting neuronal development and neuroprotection.” (R)
“Several studies have shown that hypothyroidism leads to neuronal death in the hippocampus . The entire mechanism is not still well understood, but it involves the presence of oxidative stress  and the activation of the N-methyl-D-aspartate receptor- (NMDAR-) mediated glutamate excitotoxicity .” (R)
Thyroid and acetylcholine
Similar to low glucose intake, hypothyroidism or low thyroid hormones, lead to low/dysfunctional cholinergic function.
“a possible link between TH (thyroid hormone) and hippocampal cholinergic processes in modulation of memory (Smith et al. 2002; Carageorgiou et al. 2007; Alzoubi et al. 2009); hippocampal cholinergic function has often been implicated as a key mediator of glucose’s effects on cognition.” (R)
You can’t separate thyroid from glucose oxidation. The two goes together.
“Moreover, both short-term and long-term L-T4 treatment reduced the cognitive-impairing effects of scopolamine (a cholinergic antagonist). Improvements in performance were shown to occur alongside significantly increased cholinergic activity in frontal cortex and in the hippocampus of treated animals.” (R)
Anti-oxidant defense in the brain
Let’s change gears and focus on neuroprotection. One of the main reasons why cognitive defects occur is because of oxidative stress, inflammation and breakdown of proper energy metabolism that leads to neurodegeneration.
Many supplements focus specifically to lower oxidative stress to prevent lipid peroxidation, DNA damage, NAD wasting, etc. But what if I told you that perhaps all you need is proper thyroid hormones?
Both hypo and hyperthyroidism enhances the production of ROS that causes oxidative stress.
Hypothyroid and lipid peroxidation
PUFAs, especially omega 3, is thought to be much needed for proper brain function. And with that thought comes the idea that more is better. However, saturating your brain with omega 3 isn’t a good idea at all, especially if your thyroid hormones are too low.
“Hypothyroidism increases the levels of polyunsaturated n − 3 and n − 6 series (e.g., 22: 6n − 3 and 18: 2n − 6) and decreases the levels of monosaturated n − 7 and n − 9 fatty acids. In addition, the change in plasma membrane composition could, in turn, modify the activity of the Na+/K+-ATPase as well as other transmembrane ion exchangers. In fact, it has been described as the reduction of Na+/K+-ATPase activity in the hippocampus of hypothyroid rats.[104,105] The decrease in enzymatic activity might alter the sodium/potassium transmembranal gradient and diminish the uptake of the neurotransmitter glutamate or stimulate the reversed uptake of glutamate. This increase could, in turn, produce mitochondrial calcium overload, decline ATP production, and activate calcium-dependent phospholipases, proteases, and endonucleases. Those biochemical events may increase ROS production and as a result, the lipid peroxidation.” (R)
When thyroid hormones are low, PUFAs accumulate in the brain, reduces ATPase, increase glutamate and subsequent neurotoxicity and cell death. Glutamate enhances ROS production, mainly through nitric oxide, which damages the PUFAs in the brain cause neurodegeneration. And as a side note, these fats also interfere with proper thyroid hormone function. So excess PUFA intake can mimic a state of hypothyroidism in the brain, which then promotes this whole detrimental cascade.
On the other hand, giving thyroid hormones can reduce lipid peroxidation.
“MDA reduction when expressed as percentage showed reduction of 39.5% in patients of Group A (1.6 mcg/kg body weight). Similarly, Group B (1.6 mcg/kg body weight with 100 mcg twice a day selenium) patients showed a percentage reduction of 45.4%.” (R)
Thyroid hormones, ROS and nitric oxide
“In hypothyroid rats, lipid peroxidation, ROS and nNOS (neural nitric oxide synthase) increased in certain areas of the brain. Results show that hypothyroidism induces selective oxidative stress in both the hippocampus and amygdala, where the nitrergic system is involved.” (R)
Nitric oxide is mostly thought to be a good thing, but it’s actually dangerous, not only in large amounts but even in smaller amounts when you are hypothyroid.
“Sinha et al. demonstrated that THs are able to inhibit nNOS in rat embryonic neocortex. It is also suggested that hypothyroidism elevates nNOS activity and NO in amygdala and hippocampus. Hosseini et al. also demonstrated that hypothyroidism increases NO level in the hippocampus which is accompanied by the impairment of learning and memory.” (R)
Although certain nNOS inhibitors such as agmatine, magnesium, methylene blue, etc, can be helpful against neurodegeneration, they will not help long term if thyroid function is not fixed.
Thyroid hormones upregulates mitochondrial biogenesis (R), improves insulin sensitivity and glucose oxidation, enhances mitochondrial respiration as well as various anti-oxidant enzymes, such as uncoupling protein, superoxide dismutase (SOD), glutamate cysteine ligase (GCL; responsible for glutathione synthesis) (R, R)
The thyroid increases progesterone synthesis and release and progesterone, in turn, promotes thyroid function, thyroid hormone synthesis and release (R, R). Progesterone is also highly neuroprotective and is converted to allopregnanolone, which is low in depression and anxiety (R). Remember, depression and anxiety are common symptoms of low thyroid hormones, so low progesterone and allopregnanolone could be one of the major reasons for neuro-inflammation, neuro-toxicity and reduced cognitive functions.
Stress is one of the biggest plagues in modern life and is known to inhibit thyroid function, reduce T3, promote insulin resistance, cause neurodegeneration, cause cognitive defects, etc (R). Luckily progesterone is a potent glucocorticoid antagonist and will help to oppose and protect against excess cortisol. Stress also upregulates allopregnanolone synthesis in the short term, but with chronic stress and low thyroid hormones, both progesterone and thyroid hormones levels drop.
Additionally “Serum concentrations of DHEA, DHEA-S, and PREG-S were all significantly lower in patients with hypothyroidism (n = 24) than in age- and sex-matched healthy controls (n = 43). By contrast, in patients with hyperthyroidism.” (R)
DHEA, DHEA-S and preg-S are all highly neuroprotective. So with hypothyroidism, most, if not all, of the neuroprotective steroid drop.
PUFAs accumulate, ROS and RNS increase, protective steroids drop. Sounds like a recipe for disease. Now you can understand why hypothyroidism is linked to almost all mental conditions.
Body and brain temperature on brain function
Another benefit of optimizing thyroid function is the increase in body and brain temps. If your muscles are cold, they can’t move max velocity right away. Same thing with your brain. But you can’t do a warmup for your brain, you actually need to increase brain temps with thyroid or other compounds that increase heat production, such as salt, caffeine, aspirin, etc.
“A decreased level of body temperature due to hypothyroidism has been argued as a determining factor for the effects of hypothyroidism on the brain functions.” (R)
“A number of performance measures were better when body temperature was elevated, including working memory, subjective alertness, visual attention, and the slowest 10% of reaction times. These findings demonstrate that an increased body temperature, associated with and independent of internal biological time, is correlated with improved performance and alertness. These results support the hypothesis that body temperature modulates neurobehavioral function in humans.” (R)
“it has generally been reported that cognitive function is improved by increasing body temperature slightly above the normal temperature of ∼37°C and that cognitive function is reduced by decreasing body temperature below normal (3, 23-26,46, 48).” (R)
Also, very interestingly, animals living in colder areas have smaller brains than animals living in warmer areas.
“Our framework predicts that ectothermic animals living in tropical climates should have brain sizes that are several times larger than those of ectothermic animals living in cold climates. This prediction was confirmed by data from experiments in fish brains. Our framework also suggests that a rapid increase in the number of less energy-demanding glial cells may be another important factor contributing to the ten-fold increase in the brain sizes of endotherms compared with ectotherms.” (R)
So basically, low temps, reduced glucose oxidation and lower thyroid hormones all lead to smaller brain size and reduce intellect and since intellect correlates with longevity, it makes no sense to say that being hypometabolic promotes longevity.
Being hypometabolic reduces brain size, lowers glucose oxidation, increases PUFAs in the brain and as a result reduces intellect and predisposes someone to cognitive degeneration. Awful stuff.
All in all, if you want optimal brain function, eat enough glucose, optimize thyroid function and prevent prolonged drops (for a few hours or more) in body temps.
Next week I’m going to discuss solutions for how to optimize cellular function to maximize glucose oxidation and help improve cognitive function.
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